HK1230079A1 - Compositions and methods for improving prognosis of a human with subarachnoid hemorrhage - Google Patents

Description

Compositions and methods for improving prognosis in a person with subarachnoid hemorrhage

The present application is a divisional application of the following applications: application date: 2 month 13 of 2012; application No.: 201280013759.2, respectively; the invention name is as follows: as above.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional application No.61/441,695 filed on 11/2/2011 and is a partial continuation of U.S. application No.12/137,320 filed on 11/6/2008, which claims priority to U.S. provisional application No.60/976,902 filed on 29/10/2007 and U.S. provisional application No.60/943,124 filed on 11/6/2007. Each of these applications is incorporated by reference herein in its entirety.

Technical Field

The present invention relates to compositions, systems, and methods for treating adverse consequences of subarachnoid hemorrhage.

Background

The human brain represents only about 2% of the total body weight, but it receives about 15% of cardiac output and its oxygen consumption is about 20% of the total systemic oxygen consumption. These values indicate that high metabolic rates and oxygen demand of the brain are compensated by correspondingly high blood flow rates per unit brain weight. Cerebral blood circulation is supplied by the internal carotid and vertebral arteries. The total blood flow to the brain is approximately 750-; with about 350 ml of flow through each internal carotid artery and about 100 and 200 ml of flow through the vertebrobasilar system. Venous outflow is discharged through the internal jugular vein and the vertebral vein.

The term "stroke" or "cerebrovascular accident" as used herein refers to the usually focal and acute neurological symptoms and signs resulting from diseases involving blood vessels. Stroke can be occlusive (due to vessel occlusion) or hemorrhagic (due to vessel bleeding). The term "ischemia" as used herein refers to a lack of blood supply and oxygen that occurs when the autoregulatory dilation of a resistant vessel does not compensate for the distally reduced perfusion pressure of an abnormally constricted (constricted) vessel. When ischemia is severe and persists for long periods of time, neurons and other cellular molecules die; this condition is known as "infarction". Bleeding may occur at the surface of the brain (extraparenchymal), for example, as a result of rupture of the congenital aneurysm at the Willis's annulus resulting in subarachnoid hemorrhage (SAH). Bleeding may also be intraparenchymal, e.g., by rupture of blood vessels damaged by long-standing hypertension, which may lead to blood clots in the brain hemispheres, brain stems, or cerebellum (intracerebral hematomas). Bleeding may be accompanied by ischemia or infarction. The mass effect of intracerebral hematomas can compromise the blood supply to adjacent brain tissue; or subarachnoid hemorrhage may result in reactive vasospasm of the blood vessels on the brain surface, causing further ischemic brain injury. The infarcted tissue may also become secondary bleeding. Aneurysms can sometimes rupture into the brain causing intracerebral hematomas, and rupture into the ventricles causing intracerebral hemorrhage.

While most occlusive strokes are caused by atherosclerosis and thrombosis, and most hemorrhagic strokes are associated with hypertension or aneurysms, either type of stroke can occur at any age for a variety of reasons, including heart disease, trauma, infection, tumor, blood cachexia, vascular malformations, immune disorders, and foreign toxins.

Cerebral artery

Fig. 1 and 5 show schematic views of cerebral blood vessels. Each hemisphere is supplied by an internal carotid artery, which originates in the common carotid artery below the jaw angle, enters the cranium through the carotid ostia, passes through the cavernous sinus (branches off the ophthalmic artery), enters the dura mater and bifurcates into the anterior and middle cerebral arteries. The large superficial branches of the anterior cerebral artery feed the cortex and white matter of the lower frontal lobe, the medial surface of the frontal and parietal lobes, and the anterior corpus callosum. The smaller penetrating branches feed deeper brain and diencephalon, including limbic structures, caudate head, and the inner capsular forelimb. The large superficial branches of the arteries in the brain supply most of the cortex and white matter of the convex surface of the hemisphere, including the frontal, parietal, temporal, occipital and cerebral islands. The smaller penetrating branch supplies the deep white matter and mesencephalic structures such as the inner capsular hind limb, nucleus, lateral globus pallidus and caudate body. After the internal carotid artery emerges from the cavernous sinus, it also branches off the anterior choroidal artery, which feeds the anterior hippocampus and the posterior leg of the inner capsule at the caudal level. Each vertebral artery originates from the subclavian artery, enters the skull through the macropore of the occipital bone, and is divided into the anterior spinal artery and the posterior lower cerebellar artery. The vertebral arteries join at the junction of the pons and medulla oblongata to form the basilar artery, which branches at the level of the pons into the lower anterior cerebellar artery and the internal ear artery and at the midbrain into the upper cerebellar artery. The basilar artery then bifurcates into two posterior cerebral arteries. The large superficial branches of the posterior cerebral artery supply the inferior temporal and medial occipital lobes and the posterior corpus callosum; the smaller penetrating branches of these arteries feed the diencephalon structures including the thalamus and subthalamic nucleus as well as part of the midbrain (see Principles of Neural Sciences, second edition, ericr. kandel and James h.schwartz, Elsevier Science Publishing co., inc., new york, pages 854-56 (1985)).

When part of the blood supply is impaired, the interconnection (anastomosis) between the blood vessels provides protection to the brain. Anastomosis is the protection of interconnections between blood vessels of the brain when part of the blood supply is impaired. At the circle of Willis, two anterior cerebral arteries are connected by an anterior communicating artery, and a posterior cerebral artery is connected to an internal carotid artery by a posterior communicating artery. Other important anastomoses include the orbital junction between the branches of the ocular and external carotid arteries, and the junction between the branches of the middle, anterior and posterior arteries of the brain at the surface of the brain (Principles of Neural Sciences, second edition, Eric r.kandel and James h.schwartz, Elsevier Science Publishing co., inc., new york, thPage (1985)).

When referring to animals, there is typically a head and mouth at one end and an anus and tail at the opposite end, the end where the head is located being referred to as the cranial end and the tail end being referred to as the caudal end. Within the head itself, the rostral portion indicates the direction towards the end of the nose, while the caudal portion is used to indicate the direction of the tail. The surface or side of the animal's body that faces generally upward, away from gravitational pull, is the dorsal side; the opposite side, which is usually closest to the ground when walking, swimming or flying with all legs, is the ventral side. On a limb or other appendage, the point closer to the subject is "proximal"; the points of remoteness are "distal". Three base reference planes were used in the animal anatomy. The "sagittal" plane divides the body into left and right parts. The "midsagittal" plane is in the midline, i.e., it will pass through a midline structure such as the spine, and all other sagittal planes are parallel thereto. The "coronal" plane divides the body into the back and the abdomen. The "transverse" plane divides the body into cranium and cauda. When talking about humans, the body and its parts are always described by assuming the body is standing upright. The body parts closer to the head end are "upper" (corresponding to the cranium in the animal) and those further away are "lower" (corresponding to the tail in the animal). The subject near the front of the body is called "anterior" (corresponding to the abdomen in an animal); those near the back of the body are called "back" (corresponding to the back in the animal). The transverse, axial or horizontal plane is the X-Y plane, parallel to the ground, which separates the upper/head from the lower/foot. The coronal or frontal plane is the Y-Z plane, perpendicular to the ground, which separates the anterior portion from the posterior portion. The sagittal plane is the X-Z plane, perpendicular to the ground and coronal planes, which separates the left and right portions. The median sagittal plane is the particular sagittal plane located just in the middle of the body.

Structures near the midline are called mesial, and structures near the sides of the animal are called lateral. Thus, structures in the mesial are closer to the median sagittal plane, and structures in the lateral are farther from the median sagittal plane. Structures within the midline of the body are central. For example, the top of the nose of a human subject is in the midline.

Ipsilateral means on the same side, contralateral means on the opposite side, bilateral means on both sides. Structures closer to the center of the body are proximal or central, while structures further away are distal or peripheral. For example, the hand is at the distal end of the arm and the shoulder is at the proximal end.

The ventricles are the chambers in the brain containing cerebrospinal fluid, including two lateral ventricles, a third ventricle, and a fourth ventricle. The lateral ventricle is in the hemisphere. They pass through the portal opening into the third ventricle, which is located between the two diencephalon structures of the brain. The third ventricle leads to the fourth ventricle via the west ear weies' aqueduct. The fourth ventricle is in the posterior fossa between the brain stem and cerebellum. Cerebrospinal fluid flows out of the fourth ventricle through the Luschka hole and the Madendi hole to the basal pool. The cerebrospinal fluid then penetrates into the subarachnoid cistern and flows out into the venous system via the arachnoid villi.

Vasoconstriction and vasodilation

The term "vasoconstriction" as used herein refers to the narrowing of a blood vessel caused by the contraction of the muscle wall of the blood vessel. When the blood vessels constrict, the flow of blood is restricted or slowed. The term "vasodilation" as opposed to vasoconstriction as used herein refers to widening of blood vessels. The term "vasoconstrictor", "vasopressor" or "pressor" as used herein refers to a factor that causes vasoconstriction. Vasoconstriction usually results in elevated blood pressure and can be mild or severe. Vasoconstriction may be caused by disease, medication, or psychological conditions. Vasoconstrictors causing drugs include, but are not limited to, catecholamines, antihistamines, decongestants, methylphenidate, cough and cold compositions, pseudoephedrine, and caffeine.

Vasodilators are drugs or chemicals that relax smooth muscle in blood vessels to cause it to relax. The relaxation of arterial vessels (primarily arterioles) results in a decrease in blood pressure. Relaxation of smooth muscle is dependent on removal of stimuli for contraction, which is dependent primarily on intracellular calcium ion concentration and phosphorylation of Myosin Light Chain (MLC). Vasodilation is therefore achieved mainly by: 1) reducing the intracellular calcium ion concentration; or 2) dephosphorylation of MLC, which involves stimulation of myosin light chain phosphatase and induction of calcium symporters and antiporters (which pump calcium ions out of intracellular compartments). Re-uptake of ions into the sarcoplasmic reticulum of smooth muscle by the exchanger and expulsion of ions through the plasma membrane also contribute to achieving vasodilation. The specific mechanisms by which different vasodilators achieve these effects differ and can be classified as endogenous and exogenous. The term "endogenous" as used herein refers to a compound derived from an internal or internal origin; or by conditions within the organism rather than externally. The term "exogenous" as used herein refers to originating from outside, or originating from outside, and not arising from a condition within the organism.

Vasodilation directly affects the relationship between mean arterial pressure and cardiac output and Total Peripheral Resistance (TPR). Cardiac output can be calculated by multiplying the heart rate (beats/minute) by the stroke volume (volume of blood ejected during systole). TPR depends on several factors including, but not limited to, the length of the blood vessel, the viscosity of the blood (as measured by a hematocrit), and the diameter of the blood vessel. Vessel diameter is the most important variable in determining resistance. An increase in cardiac output or TPR causes an increase in mean arterial pressure. Vasodilators act to lower TPR and blood pressure through relaxation of smooth muscle cells in the media layers of the aorta and the smaller arterioles.

Vasodilation occurs in superficial blood vessels of warm-blooded animals when their surroundings are hot; this process diverts the hot blood flow to the skin of the animal where the heat can be more easily released into the air. Vasoconstriction is the opposite physiological process. Vasodilation and vasoconstriction are naturally regulated by local paracrine substances produced by endothelial cells (e.g., bradykinin, adenosine), as well as by the autonomic nervous system and adrenal glands of organisms that secrete catecholamines such as norepinephrine and epinephrine, respectively.

Vasodilators are used to treat the following conditions: such as hypertension where the patient has abnormally high blood pressure) as well as angina and congestive heart failure, where lower blood pressure is maintained to reduce the risk of the patient developing other heart problems.

Ventricle

Fig. 6 is a schematic diagram of the ventricular system of the brain. The system is a series of cavities within the brain (ventricles) and is connected to the subarachnoid space and the spinal central canal. There are 4 ventricles: the right and left ventricles, and the midline third and fourth ventricles. The two lateral ventricles are located inside the brain and are each connected to the third ventricle via the portal interventricular foramen. The third ventricle is located in the diencephalon and is connected to the fourth ventricle through the west ear weiershi aqueduct. The fourth ventricle is located in the hindbrain and is at least embryologically connected to the spinal central canal. Three holes connect the fourth ventricle to the subarachnoid space: a median or maxdie hole, and left and right ruffian holes.

CSF flow in brain

Fig. 7 shows a schematic representation of CSF flow from the ventricle to the subarachnoid space. Cerebrospinal fluid (CSF) is a clear body fluid that occupies the ventricular system, the subarachnoid space of the brain, and the central canal of the spinal cord. CSF is produced by modified ependymal cells of the choroid plexus present throughout the ventricular system. In addition, cerebrospinal fluid is also formed around blood vessels and ventricular walls, presumably from the extracellular space of the brain. CSF flows from the lateral ventricle into the third ventricle through the interventricular foramen. The CSF then flows into the fourth ventricle through the cerebral aqueduct. CSF flows out to the subarachnoid space through the median, left and right foramen. Finally, CSF is reabsorbed into the dural venous sinus by arachnoid granules and arachnoid villi. Arachnoid granules consist of a collection of villi. These villi are visible protrusions of the arachnoid membrane that pass through the dura mater and into the superior sagittal sinus and other venous structures. Granulation appears to act as a valve that allows one-way flow of CSF from the subarachnoid space to venous blood. The entire components of CSF exit with the fluid, including small molecules, proteins, microorganisms, and red blood cells.

CSF is produced at a rate of about 0.3-0.37 ml/min or 20 ml/h or 500 ml/day. The volume of the CSF compartment is about 150 ml and CSF circulates 3.7 times per day.

The choroid plexus maintains the chemical stability of CSF using capillary filtration and epithelial secretion mechanisms. Although the capillaries that cross the choroid plexus are free to permeate plasma solutes, there is a barrier at the level of the epithelial cells that make up the choroid plexus, which is responsible for the active transport mediated by the carrier. Under normal physiological conditions, the CSF and extracellular fluids of the brain are in a steady state, and the plasma and CSF are in osmotic equilibrium.

Blood brain barrier

The blood-brain barrier prevents blood-borne substances from entering the brain and effectively acts on neurons to maintain a stable environment. It results from the specialization of brain microvascular endothelial cells, the main anatomical sites of the blood brain barrier, their intercellular junctions and the relative lack of vesicular transport, which distinguishes such cells from those of the general capillaries. Blood brain barrier endothelial cells of blood vessels are also not porous; instead, they are interconnected by a complex array of tight junctions that block diffusion across the vessel wall.

Subarachnoid hemorrhage

The brain is surrounded by 3 membranes or meninges: the pia, arachnoid and dura mater. The subarachnoid space is the region between the arachnoid and pia mater that surrounds the brain. The term "subarachnoid hemorrhage" (also referred to as "SAH") refers to the flow of blood into the subarachnoid space. SAH may occur spontaneously, usually caused by a cerebral aneurysm, or as a result of trauma. Symptoms include rapid onset severe headache (sometimes called "thunderbolt headache"), vomiting, and altered levels of consciousness. Computed Tomography (CT) scanning, or sometimes lumbar puncture diagnosis, is commonly employed. Treatment was performed by close observation, drug therapy, and early neurosurgical studies and treatments to prevent relapse and complications.

SAH is a medical emergency and, even if identified and treated at an early stage, can lead to death or severe disability. Half of all SAH cases are fatal, with 10-15% of patients dying before reaching the hospital. SAH is considered a form of stroke and accounts for 1% -7% of all strokes. In the case caused by rupture of intracranial aneurysms, bleeding can be seen in the subarachnoid space, less frequently in the ventricles and intracerebral pause. SAH-induced hemorrhage may lead to brain damage, brain displacement, decreased brain perfusion, and hydrocephalus. It is estimated that the incidence of SAH caused by rupture of intracranial aneurysms in the united states is 1 case per 10,000, resulting in about 27,000 and 30,000 new cases per year. These ruptured aneurysms have a 30-day mortality rate of 45%. In addition, it is estimated that 30% of survivors will have moderate to severe disability.

Several studies have shown an annual incidence of SAH of 9.1 cases per 100,000 persons on average. Studies in japan and finland have shown that these countries have higher rates (22.7 per 100,000 persons and 19.7 per 100,000 persons, respectively) for reasons that are not fully understood. In contrast, south and central america have a ratio of 4.2 cases per 100,000 people on average. The risk population for SAH is younger than the population normally affected by stroke, but the risk still increases with age. The risk of SAH in young people is much lower than in middle aged people (0.1 or 10% risk). The risk increases with age, and very elderly people (over 85 years) have a 60% higher risk of disease than those between the ages of 45 and 55. SAH is at a risk of about 25% in women over the age of 55, and may reflect hormonal changes caused by menopause.

Patients who survive SAH are also at risk for secondary complications. Of these complications, aneurysm re-bleeding, angiographic cerebral vasospasm and late cerebral ischemia (DCI) are most notable.

DCI is the occurrence of focal nerve damage (e.g., hemiparesis, aphasia, apraxia, hemianopsia, or neglect), or a decrease in glasgow coma scale score (either on the total score or in each of its parts [ eye, motion on each side, language ]). This may or may not last for at least 1 hour, is not immediately apparent after occlusion of the aneurysm, and cannot be attributed to other reasons via clinical assessment, brain CT or Magnetic Resonance Imaging (MRI) scans, and appropriate laboratory studies. Cerebral infarction may be the result of DCI, and is defined as a cerebral CT or MRI scan within 6 weeks after SAH, or the latest CT or MRI scan made within 6 weeks before death, or evidence of cerebral infarction at autopsy, absent on CT or MRI scans between 24 and 48 hours after early aneurysm occlusion, and not attributable to other causes such as surgical clipping or intravascular treatment. Low density on CT imaging caused by a ventricular catheter or intraparenchymal hematoma is not generally considered a DCI-induced cerebral infarction. Angiographic cerebral vasospasm is a description of radiological studies (CT angiography [ CTA ], MR angiography [ MRA ] MRA or catheter angiography [ CA ]), and may be the cause of DCI. The term "angiographic cerebral vasospasm" refers to the narrowing of the large volume arteries at the base of the brain (i.e., cerebral arteries) after bleeding into the subarachnoid space, and resulting in reduced perfusion of the distal brain region. Angiographic vasospasm is the result of SAH, but may also occur following any pathology of blood deposition in the subarachnoid space.

Symptoms and signs

The typical symptom of SAH is thunderbolt headache (described as the "worst" headache or "kicking head" that develops within seconds to minutes), although this is the symptom of only about one third of SAH patients. About 10% of patients with this symptom seeking medical care have potential SAH. Patients may also develop vomiting and seizures occur in 1 of 14 cases. Stiffness of the neck and other symptoms of pseudomeningitis may occur, such as confusion, decreased levels of consciousness or coma. Intraocular hemorrhage may occur in response to elevated pressure around the brain. Subretinal vitreous (vitreous membrane covering the vitreous of the eye) and vitreous hemorrhage can be seen in the fundus examination. This is considered to be Terson syndrome (occurring in 3-13% of cases) and is more common in more severe SAH. In patients with thunderbolt headaches, while seizures are more common if the bleeding is the result of rupture of an aneurysm rather than other causes, none of the above signs are useful in determining or eliminating bleeding. Dysoculomotor (downward and outward affected eye movement, inability to lift the ipsilateral eyelid, but normal pupillary reflex) may indicate aneurysm bleeding occurring near the posterior communicating artery. Dilation of the pupil alone may also reflect a cerebral hernia caused by an increase in intracranial pressure.

Bleeding causes the body to release large amounts of adrenaline and similar hormones, which results in a dramatic increase in blood pressure. Following a bleeding episode, the heart develops substantial damage and may develop rapidly, neuropulmonary edema, myocardial stunning, cardiac arrhythmia, electrocardiographic changes (with occasional large reverse "brain" T-waves) and cardiac arrest (3%).

SAH may also occur in people who have suffered a head injury. Symptoms may include headache, a decreased level of consciousness, or hemiparesis. SAH is considered to be a serious complication of head injury, especially if it is associated with lower glasgow coma scale levels.

Diagnosis of

The initial step in evaluating a patient with suspected SAH is the step of obtaining a medical record and performing a physical examination. Since only 10-25% of hospitalized patients with thunderbolt headaches suffer from SAH, other possible causes such as meningitis, migraine headaches and cerebral venous sinus thrombosis are generally considered together. Sometimes twice as often as SAH is misdiagnosed as SAH.

SAH cannot be clinically diagnosed alone. Typically, medical imaging of the brain [ typically a high sensitivity (particularly on the first day after bleeding episodes, with over 95% correct identification) computed tomography (CT scan) ] is required to determine or rule out bleeding. After several days of onset, magnetic resonance imaging (MRI scan) may be more sensitive than CT scan. In persons with normal CT or MRI scans, lumbar puncture with a needle to remove cerebrospinal fluid (CSF) from the lumbar capsule indicated that 3% of the groups found normal at CT had bleeding; therefore, lumbar puncture is considered necessary if the imaging is negative. CSF samples were tested for yellowing (yellow appearance of centrifuged fluid) or for bilirubin (decomposition product of hemoglobin in CSF) using spectrophotometry.

After confirmation of SAH, its origin needs to be determined. Usually the first step is CT angiography (visual inspection of the vessel on a CT scan with a radioactive contrast agent) to identify the aneurysm, although the more invasive catheter angiography (pushing the radioactive contrast agent through the catheter towards the cerebral arteries) is a gold standard test, but has a higher risk of complications. The latter is beneficial if the intention is to eliminate bleeding sources such as aneurysms at the same time.

Reason for

Spontaneous SAH is most commonly due to rupture of a cerebral aneurysm (85%). A cerebral aneurysm is a weak point in the wall of an enlarged cerebral artery. They tend to be located in the Willis loop and its branches. Although the majority of SAH cases are due to small aneurysm bleeding, larger (less common) aneurysms are more likely to rupture. Aneurysms are undetectable in 15-20% of cases of spontaneous SAH from first angiograms. Non-aneurysmal mesencephalic bleeding (where blood is confined to the midbrain region) leads to another 10% of SAH cases. In these cases, no aneurysm is usually found. The remaining 5% of cases are due to vascular inflammatory injury of the arteries, other conditions affecting the blood vessels, conditions of the spinal vessels, and bleeding in various tumors. Most traumatic SAH occurs near the site of a skull fracture or contusion within the brain.

Grading

A variety of graded scales are available for SAH. These scales were obtained by retrospectively matching the patient's characteristics to their results. In addition to the widely used Glasgow Coma Scale (GCS), three other specialized scores were used. In all scores, a larger number correlates to a worse result. The strict first scale was described by Hunt and Hess in 1968 ("Hunt and Hess scale") and classified the clinical condition of patients. The Fisher rating classifies the appearance of SAH on CT scans. The Fisher scale was modified by classen and coworkers ("classen scale") to reflect the additional risk from SAH scale and the accompanying intracerebroventricular hemorrhage. The world association of neurosurgeons classifies the use of GCS and focal neurological deficits to assess the severity of symptoms. Ogilvy and Carter proposed a comprehensive grading protocol to predict outcome and evaluate treatment. The Ogilvy system has 5 ratings, 1 point assigned for the presence or absence of each of the following 5 factors: the age is greater than 50 years; hunt and Hess grades 4 or 5; fischer scale 3 or 4; the aneurysm size is greater than 10 mm; and a posterior circulatory aneurysm 25mm or greater.

Treatment of

Management of SAH includes general measures to stabilize patients, special measures to prevent re-bleeding by eliminating the source of bleeding, prevention of vasospasm, and prevention and treatment of complications.

General measurement

The first focus is to stabilize the patient. Those patients with reduced levels of consciousness may require intubation and mechanical ventilation. Blood pressure, pulse, respiratory rate and glasgow coma scales are monitored frequently. Once diagnosed, it may be preferable to enter an intensive care unit, especially considering that 15% of such patients have further episodes (re-bleeding) within the first few hours after hospitalization. Nutrition was an early focus, with oral or nasal tube feeding being preferred over parenteral routes. Analgesia (pain control) is generally limited to non-sedatives such as codeine, as sedation can affect mental states and thus interfere with the ability to monitor levels of consciousness. Deep vein thrombosis is prevented by the elastic socks, intermittent inflation and pressurization of the calf, or both.

Preventing re-bleeding

Patients with large hematomas with reduced levels of consciousness or focal neuropathy may be candidates for emergency surgery to remove blood and seal the bleeding aneurysm. A catheter or tube may be inserted into the ventricle to treat hydrocephalus. The remaining patients were more fully stabilized and then transfemoral catheter angiography or CT angiography was performed. After the first 24 hours, there is also a risk of re-bleeding of about 40% within the following 4 weeks, indicating that intervention should be aimed at reducing this risk.

Rebleeding is difficult to predict, but can occur at any time and lead to a dire prognosis. Interventions to prevent re-bleeding, mainly clipping or coil embolization ruptured aneurysms, are therefore performed as early as possible. If a cerebral aneurysm is identified on an angiogram, two measures can be taken to reduce the risk of further bleeding from the same aneurysm: neurosurgical clipping or endovascular coil embolization. Clipping requires craniotomy (opening of the skull) to locate the aneurysm, followed by placement of a clip across the neck of the aneurysm. Coil embolization through large vessels: a catheter is inserted into the femoral artery in the groin and pushed through the aorta to the arteries supplying the brain (two carotid arteries and two spinal arteries). When the aneurysm is located, the metal coil is deployed to guide to the blood clot formed in the aneurysm and to remove it. Decisions such as what treatment to take are typically made by a multidisciplinary team comprising a neurosurgeon and a neuroradiologist.

Aneurysms of the middle cerebral artery and its associated vessels are difficult to access with angiography, tending to be treated with clipping, while those of the basilar and posterior cerebral arteries are difficult to access surgically and are often more suitable for endovascular treatment. The main drawback of coil embolization is the possibility of reoccurrence of the aneurysm; this risk is very small during surgical treatment. Patients who have undergone coil embolization surgery often use angiography or other measures to ensure early identification of aneurysm recurrence over the next years.

Prognosis

Early morbidity and mortality

The mortality rate for SAH is between 40% and 50%. At least 25% of those patients who survive initial hospitalization, treatment and complications have significant limitations in lifestyle, with less than 20% of patients without any residual symptoms. A delay in diagnosis (or mistaking sudden headache as migraine) in a small percentage of SAH patients who do not have coma symptoms causes adverse results. Risk factors for poor outcome include higher age, poorer neurological grade, more blood and larger aneurysm on the initial CT scan, aneurysm localization in the posterior circulation, systolic hypertension, and previously diagnosed heart failure, hypertension, liver disease or previous SAH. During the hospitalization period, the prognosis is also worsened by the occurrence of late ischemia due to vasospasm, the occurrence of intracerebral hematoma or intracerebroventricular hemorrhage (hemorrhage into the ventricles), and the occurrence of fever on the eighth day of hospitalization.

SAH in which no aneurysm is found by comprehensive catheter angiography can be referred to as "angiographic negative SAH". This leads to a better prognosis than SAH caused by aneurysms; however, it is still associated with the risk of ischemia, re-bleeding and hydrocephalus. However, the mesencephalic SAH (hemorrhage around the midbrain portion of the brain) has a low rate of rebleeding or late cerebral ischemia, and the prognosis of this subtype is excellent.

Long term results

Neuro-cognitive symptoms such as fatigue, mood disorders, and other related symptoms are common among people who have suffered SAH. Even in those with good neurological recovery, anxiety, depression, post-traumatic stress disorder, and cognitive impairment are common. More than 60% of frequent headaches are reported. Aneurysm SAH may cause damage to the hypothalamus and pituitary glands, both areas of the brain that play a central role in hormone regulation and production. Studies have shown that at least 25% of people who have previously suffered SAH are likely to develop a deficiency in one or more hypothalamic-pituitary hormones, such as growth hormone, prolactin or thyroid stimulating hormone.

Vasospasm of blood vessel

Angiographic cerebral vasospasm is the most common cause of post-SAH ischemic episodes. As it causes up to 23% of SAH-related disability and death, the outcome of patients with SAH is adversely affected. In all types of ischemic stroke, vasospasm is unique in that it is predictable, preventable, and treatable to some extent (see Macdonald, r.l. and Weir, b.in cereral vasospace, academic Press, Burlington, ma, 2001).

Vasospasm leads to decreased cerebral blood flow and increased cerebral vascular resistance. Without being limited by theory, it is generally believed that vasospasm is caused by local damage to blood vessels such as that caused by atherosclerosis and other structural damage including traumatic head injury, aneurysmal subarachnoid hemorrhage, and other causes of subarachnoid hemorrhage. Cerebral vasospasm is a naturally occurring vasoconstriction that can also be triggered by the presence of blood in the CSF, usually after rupture of an aneurysm or traumatic head injury. Due to the interruption of blood supply, cerebral vasospasm can eventually lead to brain cell damage in the form of cerebral ischemia and infarction.

Angiographic vasospasm is one process that leads to DCI. Other processes that may lead to DCI are cortical spreading ischemia and microthrombus emboli (fig. 4). DCI is a multifactorial process attributed to at least these processes as well as early brain injury. Cortical spreading ischemia is described as a new mechanism leading to DCI in animal models of SAH. It has been detected in people with SAH and angiographic vasospasm. Another process that may lead to DCI is the formation of microthrombus emboli.

About 1 out of 10,000 people per year develop aneurysm rupture. Mortality and morbidity increase with bleeding volume and reflect the age and health of the patient, and the likelihood of developing an aneurysm steadily increases with age. Rebleeding is particularly disadvantageous due to the increased amount of SAH and the increased likelihood of spreading into the brain and ventricles. Most deaths from ruptured aneurysms occur outside of the hospital or shortly after admission, due to the effects of initial bleeding or early rebleeding. Possible manifestations of symptoms caused by vasospasm only occur in patients who survive the first few days.

The incidence of vasospasm is lower than that of SAH (since only some SAH patients develop vasospasm). The incidence of vasospasm will depend on the type of patient received at a particular hospital and the method used to diagnose the vasospasm.

The non-limiting term "vasospasm" is generally used to refer to a stenosis of an artery as defined above as determined by angiography. Clinical vasospasm is most often used synonymously with late-onset cerebral ischemia (DCI). This should be elaborated upon when used in another way, for example, for vasospasm upon an increase in the intracranial doppler velocity of the middle cerebral artery.

Some degree of angiographic stenosis will occur in patients who are angiographic between 4 and 12 days after a SAH of at least 2/3. The number of patients with neurological deterioration due to such DCI varies with the level of detail of patient monitoring and the effectiveness of the prophylaxis, but is estimated to be about one third. 5-10% of SAH patients who are hospitalized die from vasospasm. Since they have a small amount of SAH, patients with a very good state after SAH are less likely to develop vasospasm when compared to moderately scored patients after SAH, while patients with a poor state after SAH are more likely to die prematurely from the initial episode. The presence of a widely distributed thick subarachnoid blood clot can be seen on Computed Tomography (CT) scans performed in close proximity to the site of bleeding episodes, a key prognostic factor. The absence of blood on the initial CT scan indicates that vasospasm is highly unlikely to occur without further bleeding. The likelihood of vasospasm and subsequent DCI is reduced by factors that reduce the time of exposure to blood clots. Conversely, by using anti-fibrinolytic drugs that prolong arterial exposure to blood clots and possibly lead to ischemia by other mechanisms, the incidence of vasospasm and DCI increases. Poor admission clinical scores were associated with DCI, presumably because both indicated a greater amount of SAH. No clear relationship has been established between age, hypertension, or gender and DCI. Smokers may be more prone to vasospasm and DCI. Factors unrelated to the occurrence of vasospasm include season, geographical environment, contrast agents, and diabetes.

Patients with vasospasm are more severe than those without. If surgery or aneurysm coil embolization is performed earlier (on about day 1), the results are often better than in the case of delayed treatment. When the surgery is preferably performed during the peak period of vasospasm, the results are generally worse. Vasospasm was not caused by early surgery or coil embolization; early surgery or coil embolization allows for more aggressive treatment if vasospasm occurs. If a thick blood clot is present, careful removal may be attempted. The amount of blood clot remaining after surgery is a prognostic factor for DCI. Open surgery exposes the patient to retractor pressure, venous loss, transient pinch ischemia, brain removal, and arterial trauma. Studies have shown a decrease in post-operative cerebral blood flow, local cerebral oxygen metabolism rate, and oxygen uptake rate.

Independent variables such as admission neurological score, age increase, and massive intracranial or intracerebroventricular hemorrhage were more closely linked to outcome than vasospasm. Since vasospasm is a hierarchical process, it is expected that in the absence of systemic hypertension, cardiac dysfunction, hypoxia, and intracranial hypertension, only extreme cases will lead to infarction. Preexisting hypertension and an increase in age also strongly affect the vulnerability of the brain to ischemia. The etiological relationship between vasospasm and infarction in fatal cases is not controversial.

There is evidence that removal of blood clots by surgical or pharmaceutical means can reduce vasospasm. There is also data showing that DCI can be alleviated by hypertension and hypervolemia as well as calcium antagonists. Vasospasm can be eliminated mechanically or transiently by drug angioplasty.

Incidence of vasospasm

The incidence of angiographic vasospasm depends on the time interval after SAH. The peak incidence occurs 6-8 days (range 3-12 days) after SAH. In addition to time after SAH, other major factors affecting vasospasm development are the amount and distribution of subarachnoid blood.

Prognostic factor for vasospasm

Prognostic factors for vasospasm include: blood on a CT scan; hypertension; anatomical and systemic factors; clinical scoring; whether the patient received an antifibrinolytic agent; age and sex; smoking; a physiological parameter; and hydrocephalus.

Diagnosis of

The diagnosis of vasospasm is primarily clinical. Vasospasm may be asymptomatic; however, when cerebral blood flow is below the ischemic threshold, symptoms become manifest. Symptoms often develop subacute and may fluctuate. Symptoms may include excessive drowsiness, burnout, stupor, hemiparesis or hemiplegia, anhedonia, language dysfunction, visual field impairment, gaze dysfunction, and cranial nerve paralysis. While some symptoms are local, they are not diagnostic of any particular pathological process; therefore, other diagnoses such as re-bleeding, hydrocephalus and seizures should be quickly ruled out by using radiology, clinical and laboratory assessments. Cerebrovascular angiography is the gold standard for observing and studying cerebral arteries; transcranial doppler ultrasonography was also used.

The pathophysiology of vasospasm may involve structural and biochemical changes in the vascular endothelium and smooth muscle cells. The presence of blood within the subarachnoid space may trigger these changes. In addition, hypovolemia and impaired brain autoregulation may co-interfere with brain perfusion. The cumulative effects of these processes may result in a decrease in cerebral blood flow that is so severe as to cause cerebral ischemia resulting in an infarction. Furthermore, a severe constriction phase may lead to morphological changes in the cerebral artery wall, which may keep it stenotic without the continued presence of vasoactive substances. The brain region supplied by the affected artery may experience ischemia (i.e., blood supply limitation).

Other complications

Hydrocephalus, a condition characterized by excessive accumulation of CSF leading to ventricular dilatation and increased intracranial pressure, may be associated with SAH both short and long term and may be detected on CT scans. Surgical removal of excess fluid (e.g., by ventricular drainage or shunting) is sometimes necessary if the level of consciousness is reduced.

Blood pressure fluctuations and electrolyte disturbances, as well as pneumonia and cardiac decompensation, occur in about 50% of hospitalized patients with SAH and may worsen the prognosis. The symptomatic treatment of these disorders.

Seizures occur in about 1/3 of all cases.

Treatment of

Nimodipine, an oral calcium channel blocker, has been shown in clinical trials to reduce the chance of adverse outcomes, but it may not significantly reduce the number of vasospasm detected on angiography. Other calcium channel blockers and magnesium sulfate have been studied but are not currently recommended. There is no evidence of the benefit of intravenous nimodipine administration. In traumatic SAH, the efficacy of oral nimodipine remains uncertain.

The hemodynamic procedure previously referred to as "3H" therapy is often used as a means of treating vasospasm. This requires the use of intravenous fluids to achieve conditions of hypertension (high blood pressure), hypervolemia (excess fluid in the circulation) and hemodilution (moderate dilution of the blood). Although the basis for using this method has not been determined and a sufficiently large number of randomized controlled trials have not been performed to demonstrate its benefits, induced hypertension is considered to be the most important component of this therapy.

If symptomatic vasospasm is resistant to medical treatment, angiography can be attempted to identify the location of the vasospasm and to administer vasodilators (drugs that relax the vessel wall) directly into the artery (drug angioplasty), and mechanical angioplasty (opening the constriction region with a balloon) can be performed.

Voltage-gated ion channels

Voltage-gated ion channels are a class of integral membrane proteins that allow the passage of selected inorganic ions across the cell membrane by opening and closing in response to changes in voltage across the membrane. (Sands, Z. et al, "Voltage-gated channels," Current Biology,15(2): R44-R47 (2005)). These types of ion channels are particularly critical in nerve cells, but are common in many types of cells. They play an important role in excitatory nerve cells and muscle tissue, since they rapidly and synergistically depolarize in response to changes in trigger voltage. Distributed along axons and over synapses, voltage-gated ion channels propagate electrical signals directly.

Structure of the product

Voltage-gated potassium, sodium and calcium ion channels are believed to have similar overall configurations. (Sands, Z et al, "Voltage-gated channels," Current Biology,15(2): R44-R47 (2005)). Voltage-gated ion channels are typically composed of several subunits arranged: there is a central aperture through which ions can move along the electrochemical gradient. This channel tends to be highly ion specific, although to some extent similarly sized and charged ions can also pass through them.

Mechanism for controlling a motor

Assuming that this structure remains intact in the corresponding plasma membrane, crystallographic structural studies of potassium channels have shown that when a potential difference is introduced across the membrane, the associated electromagnetic field causes a conformational change in the potassium channels. The conformational change deforms the shape of the channel protein sufficiently that the channel or cavity is open to allow ions to flow in or out across the membrane along its electrochemical gradient. This then generates a current sufficient to depolarize the cell membrane.

Voltage-gated sodium and calcium channels consist of a single polypeptide with 4 homeodomains. Each domain includes 6 transmembrane α helices. The voltage-induced helix S4 has multiple positive charges, such that the high positive charge outside the cell repels the helix and causes a conformational change such that ions can flow through the channel. Potassium channels function in a similar manner, except that they are composed of 4 independent polypeptide chains (each chain comprising 1 domain). The voltage sensitive protein domains of these channels ("voltage sensors") generally include a region consisting of the S3b and S4 helices (called "paddles" due to their shape), which appear to be a conserved sequence.

Voltage-dependent calcium channels

Voltage-dependent calcium channels (VDCCs) are a group of voltage-gated ion channels that control calcium entry into cells in response to changes in membrane potential. (Van Petegem F. et al, Biochemical Society Transactions,34(5):887-893 (2006)). Voltage-dependent calcium channels are present in excitable cells(e.g., muscle cells, glial cells, nerve cells, etc.). At physiological or resting membrane potentials, VDCCs are normally off. They are activated (i.e., turned on) at a depolarizing membrane potential. Activation of specific VDCCs allows Ca²⁺Entering a cell; muscle contraction, nerve cell stimulation, up-regulation of gene expression, or release of hormones or neurotransmitters, depending on the cell type. (Catterall W.A. et al, "International Union of Pharmacology.XLVI. nomenclature and structure-function relationships of voltage-gated capacitors," Pharmacol.Rev.,57(4): 411-25 (2005); Yamakage M. et al, "Calcium channels- -basic assays of the structure, function and production;" evaluation of the reaction of the channels- -a review, "Can.J.Anaesth, 49(2): 151-64 (2002)).

The voltage-dependent calcium channel is formed in a complex from several different subunits α _l、α₂、β_1-4And gamma. α subunits form ion conduction pathways, while related subunits have multiple functions including gating regulation (Dolphin A.C. "assisted tissue of voltage-gated calcium channels," Br. J. Pharmacol.,147 (supplement 1): S56-62 (2006))

α₁Subunit (II)

α₁The subunit pore (molecular weight of about 190kDa) is the major subunit necessary for the functioning of the channel in VDCCs and consists of characteristically 4 homologous I-IV domains each comprising 6 helices spanning membrane α. α subunit forms Ca²⁺10 α subunits have been identified in humans (Dolphin A.C. "Ashort history of voltage-gated calcium channels," Br.J.Pharmacol.,147 (supplement 1): S56-62 (2006))

α₂Subunit (II)

α₂The gene encodes two subunits, α₂And they are interconnected by disulfide bonds and have a combined molecular weight of 170kDa α₂Is mostly α ₁Extracellular glycosylation of subunit interactionsThe subunit has a single transmembrane region with a short intracellular portion that serves to anchor the protein in the plasma membrane, there are four α₂Genes CACNA2D1(CACNA2D1), (CACNA2D2), (CACNA2D3) and (CACNA2D 4). α₂Co-expression of (A) can increase α₁Expression levels of subunits and resulting in increased current amplitudes, faster activation and inactivation kinetics, and hyperpolarization shifts in voltage-dependent inactivation some of these effects are observed in the absence of β subunit, but in other cases, co-expression of β subunit is required α₂-1 and α₂The-2 subunit is a binding site for at least two anticonvulsant drugs, gabapentin and pregabalin, which are also useful in the treatment of chronic neuropathic pain. (Dolphin A.C. "A short history of voltage-gated calcium channels," Br.J. Pharmacol.,147 (supplement 1): S56-62 (2006))

Beta subunit

The intracellular β subunit (55kDa) is an intracellular membrane-associated guanylate kinase (MAGUK) class protein containing a Guanylate Kinase (GK) domain and an SH3(src homology 3) domain the guanylate kinase domain of the β subunit adheres to α₁4 isoforms of β subunits are known to exist, CACNB1, CACNB2, CACNB3 and CACNB4 (Dolphin A.C. "A short history of voltage-gated capacitors", Br.J.Pharmacol.,147 (suppl. 1): S56-62 (2006))

Without being limited by theory, it is believed that the intracytoplasmic β subunit stabilizes the final α₁Subunit conformation and passage of its pairs α₁The I-II loop of the α subunit contains an endoplasmic retention brake, which is masked when binding the β subunit, thus, the function of the β subunit is initially to regulate current density by controlling the number of α subunits expressed on the cell membrane.

In addition to this potential transport role, the β subunit has more important functions in regulating activation and inactivation kinetics, as well as hyperpolarizationThe voltage dependence of the subunits used to activate the α subunit pore, and thus more current, passes for less depolarization. β subunit functions as an important regulator of channel electrophysiological properties. β subunit exerts a regulatory role that depends on α between the I and II domains₁Subunit intracellular linker (α interaction domain, AIDBP) and β subunit GK domain a region (α interaction domain binding pocket) between a highly conserved 18 amino acid region and the β subunit SH3 domain also exerts more regulatory effects on channel function, suggesting that β subunit and α ₁The subunit pore may have multiple regulatory interactions the α interaction domain sequence does not appear to include an endoplasmic reticulum retention signal and it may be located in I-II α₁Other regions of the subunit linker.

Gamma subunit

The γ 1 subunit is known to be associated with the skeletal muscle VGCC complex, but has not been elucidated with respect to other subtypes of calcium channels. The gamma 1 subunit glycoprotein (33kDa) consists of 4 transmembrane helices. The γ 1 subunit does not affect transport and is for the most part not required for the regulation of the channel complex. However, γ 2, γ 3, γ 4 and γ 8 are also associated with α -amino-3-hydroxy-S-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors (glutamate non-NMDA-ionotropic transmembrane receptors that mediate rapid synaptic transmission in the CNS). NMDA-type receptors are receptors that specifically bind to NMDA (N-methyl-D-aspartate). There are 8 genes for the gamma subunit, gamma 1(CACNG1), gamma 2(CACNG2), gamma 3(CACNG3), gamma 4(CACNG4), (CACNG5), (CACNG6), (CACNG7), and (CACNG 8). (Chu P.J. et al, "Calcium channel gamma. Subunitsprovide instruments into the evolution of this Gene family," Gene,280 (1-2): 37-48 (2002)).

The voltage-dependent calcium channels differ greatly in structure and morphology according to their pharmacological and electrophysiological properties, the calcium channels are divided into L-, N-, P/Q, T-and R-types, these channel subtypes have distinct physiological functions₁Subunit sequence α₁The subunits have activity inducing activity in separate channelsHas special function. However, selective blockers against these channel subtypes are necessary to define the specific channels involved in each activity. The nerve N-type channel is blocked by omega-conotoxin GVIA; r-type channels are resistant to other blockers and toxins, are blocked by SNX-482, and may be involved in brain processes; the closely related P/Q-type channels are blocked by omega-spider toxins. Dihydropyridine-sensitive L-type channels are responsible for the stimulus-contraction coupling of skeletal, smooth and cardiac muscle and hormone secretion in endocrine cells, and are also antagonized by phenylalkylamines and benzothiazepines.

Types of Voltage-gated calcium channels

L-type calcium channels

When smooth muscle cells depolarize, L-type voltage-gated calcium channels open. This depolarization may be caused by cell stretching, its G-protein coupled receptor (GPCR) binding agonists, or stimulation of the autonomic nervous system. Opening of L-type calcium channels leads to extracellular Ca ²⁺Which then binds to calmodulin. The activated calmodulin molecule activates Myosin Light Chain Kinase (MLCK), which phosphorylates myosin in crude silk. Phosphorylated myosin is capable of forming cross-bridges with actin filaments, and smooth muscle fibers (i.e., cells) are contracted by the slick-silk mechanism. (Yamakage M. et al, "Calcium channels- -basic assays of the structures, functions and gene encoding; anestic actions on the channels- -a review," Can. J. Anaesth.,49(2): 151-64 (2002))

L-type calcium channels are also abundant in t-tubes of striated muscle cells such as skeletal muscle fibers and cardiac muscle fibers. As in smooth muscle, L-type calcium channels open when these cells depolarize. In skeletal muscle, the opening of L-type calcium channels causes the opening of RYR, since the L-type calcium channels and calcium release channels (srilankanine (ryanodine) receptors or RYRs) are mechanically gated to each other, the latter being located in the Sarcoplasmic Reticulum (SR). In the myocardium, the opening of L-type calcium channels allows calcium ions to flow into the cells. Calcium ions bind to calcium release channels (RYR) in sarcoplasmic reticulum, opening the calcium release channels (called "Calcium-induced calcium release "or" CICR "). Ca whatever the RYR opening (by mechanical gating or CICR) ²⁺Released from the sarcoplasmic reticulum and able to bind to troponin C on actin filaments. The muscle then contracts via a slick-silk mechanism, causing the sarcomere to shorten and the muscle to contract.

R-type voltage-dependent calcium channels

R-type voltage-dependent calcium channels (VDCCs) are involved in the regulation of calcium ion flow. R-type VDCCs play an important role in the reduction of cerebral blood flow observed after SAH. Without being limited by theory, R-type voltage-dependent calcium channels, which may be located in small-diameter cerebral arteries, can regulate total and local cerebral blood flow, since the concentration of intracellular free calcium ions determines the contractile state of vascular smooth muscle. Yamakage M. et al, "Calcium channels- -basic observations of the structure, function and gene encoding; anesthetic action on the channels-a review, "Can.J. Anaesth.,49(2): 151-64 (2002).

The R-type voltage-dependent calcium channel inhibitor is a blocking drug for calcium ion entry, and the main pharmacological action of the R-type voltage-dependent calcium channel inhibitor is to prevent or slow down calcium ion entry into cells through R-type voltage-gated calcium channels. Gene Ca_v2.3 major pore-forming units encoding R-type voltage-dependent calcium channels expressed in neural cells.

N-type calcium channels

N-type ('N' means "neuro-type") calcium channels are predominantly present at presynaptic terminals and are involved in neurotransmitter release. The strong depolarization by the action potential causes these channels to open and Ca to form ²⁺Influx, which initiates vesicle fusion and release of stored neurotransmitters. The N-type channel is blocked by omega-conotoxin. Yamakage M. et al, "Calcium channels- -basic observations of the structure, function and gene encoding; anesthetic action on the channels-a review, "Can.J. Anaesth.,49(2): 151-64 (2002).

P/Q-type calcium channels

P-type ('P' denotes cerebellar Purkinje (Purkinje) cells) calcium channels play a similar role as N-type calcium channels in neurotransmitter release at presynaptic terminals and in neuronal cell integration in multiple types of neurons. They are also present in purkinje fibers in the cardiac electrical conduction system (Winds, r. et al, j. physiol. (Lond.)305:171-95 (1980); lllinds, r. et al, proc.natl.acad.sci.u.s.a.86(5):1689-93 (1989)). Q-type calcium channel blockers appear to be present in cerebellar granulocytes. They have a high threshold of activation and relatively slow kinetics. Yamakage M. et al, "Calcium channels- -basic observations of the structure, function and genencoding; anesthetic action on the channels-a review, "Can.J. Anaesth.,49(2): 151-64 (2002).

T-type calcium channels

T-type ('T' denotes transient) calcium channel blockers are low voltage activated. They are usually present in neurons and cells with pacing activity as well as in bone cells. Midapridil (mibefradil) shows some selectivity for T-type calcium channels relative to other types of VDCCs. Yamakage M. et al, "Calcium channels- -basic aspects of the Soft Structure, function and gene encoding; anestmatic action on the channels-a review, "Can.J. Anaesth.,49(2): 151-64 (2002).

Blockers and inhibitors of calcium channels

Calcium channel blockers are a class of drugs or natural substances that act on many of the body's excitatory cells (e.g., cardiac muscle, vascular smooth muscle, or nerve cells). The primary effect of calcium channel blockers is to lower blood pressure.

Most calcium channel blockers reduce the contractile force of the myocardium. This is known as the "negative inotropic effect" of calcium channel blockers. Because of their negative muscle action, most calcium channel blockers are not the preferred choice for treatment of individuals with cardiomyopathy.

Many calcium channel blockers slow down the conduction of electrical activity in the heart by blocking calcium channels during the cardiac action potential plateau. This "negative conduction effect" causes a decrease in heart rate and may lead to a block of cardiac conduction (this is known as the "negative frequency effect" of calcium channel blockers). The negative frequency effects of calcium channel blockers make them a common type of drug for heart rate control in individuals with atrial fibrillation or flutter.

Calcium channel blockers act on voltage-gated calcium channels (VGCC) in myocytes of the heart and blood vessels. By blocking calcium channels, they prevent a substantial increase in intracellular calcium levels upon stimulation, which subsequently leads to less muscle contraction. In the heart, the reduction in available calcium per beat results in a reduction in cardiac contractility. In blood vessels, a decrease in calcium leads to less constriction of vascular smooth muscle and a resulting increase in vessel diameter. The resulting vasodilatation reduces the total peripheral resistance, while the reduction in cardiac contractility reduces cardiac output. Since blood pressure is determined in part by cardiac output and peripheral resistance, blood pressure drops.

Calcium channel blockers do not reduce the heart's response to inputs from the sympathetic nervous system. Since blood pressure regulation is accomplished by the sympathetic nervous system (via the pressure-sensitive reflex), calcium channel blockers maintain blood pressure more effectively than β -blockers. However, as calcium channel blockers cause blood pressure to drop, the baroreflex often initiates reflex enhancement in sympathetic nerve activity that causes an increase in heart rate and contractility. A decrease in blood pressure may also reflect a direct effect of VDCC antagonism in vascular smooth muscle leading to vasodilation. Beta-blockers can be used in combination with calcium channel blockers to minimize these effects.

Blockers against L-, N-, and P/Q-type calcium channels are used in differentiating channel subtypes. Omega-spider toxin IIIA exhibits blocking activity for the R-type calcium channel subtype, although its selectivity is very low. This peptide binds to all high voltage activated channels including L, N and the P/Q subtype (j. biol. chem.,275,21309 (2000)). A putative R-type (or. alpha.1E class) selective blocker SNX-482, a toxin from the Bactrocera championii gibba (hysterorates gigas), is a 41 amino acid residue peptide with 3 disulfide bonds (1-4, 2-5 and 3-6 arrangements) (Biochemistry,37,15353(1998), Peptides 1998,748 (1999)). This peptide blocks class E calcium channels (IC50 ═ 15nM to 30nM) and blocks R-type calcium flow in the neurohypophyseal nerve terminals at 40nM concentrations. The R-type (E-type) calcium channel blocking activity is highly selective; no effect was observed on potassium and sodium ion streams and L, P/Q and T-type calcium streams. N-type calcium flux was only weakly blocked (30-50%) at 300nM to 500 nM. Over the area, a different sensitivity of R-type flow to SNX-482 was observed; no significant effect on R-type flow occurred in the preparation of nerve cells, retinal ganglion cells and hippocampal pyramidal cells. Using SNX-482, 3 α E-calcium subunits with distinct pharmacological properties were identified in cerebellar R-type calcium channels (j. neurosci, 20, 171 (2000)). Likewise, oxytocin, but not vasopressin, secretion has been shown to be regulated by R-type calcium flow at the end of the neurohypophysis (j. neurosci, 19,9235 (1999)).

Because vasodilation and hypotension may cause reflex tachycardia, dihydropyridine calcium channel blockers are often used to reduce systemic vascular and arterial resistance, but not to treat angina (except amlodipine, which is used to indicate treatment of chronic stable angina and vasospastic angina). Such calcium channel blockers are readily identifiable by the suffix "flat".

The phenylalkylamine calcium channel blockers are relatively selective for the myocardium. They reduce the oxygen demand of the myocardium and reverse coronary vasospasm. They have minimal vasodilatory effect compared to dihydropyridines. Their action is intracellular.

Benzothiazepine calcium channel blockers are an intermediate class between phenylalkylamines and dihydropyridines in terms of their selectivity for vascular calcium channels. Benzothiazepines, due to their sedative and vasodilatory effects, lower arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines.

L-type VDCC inhibitors are calcium entry blockers with a primary pharmacological effect of preventing or slowing the passage of calcium through the L-formVoltage-gated calcium channels enter cells. Examples of L-type calcium channel inhibitors include, but are not limited to: dihydropyridine L-type blockers, such aS nisoldipine, nicardipine and nifedipine, AHFs (such aS (4aR,9aS) - (+) -4 a-amino-1, 2,3,4,4a,9 a-hexahydro-4 a 14-fluorene, HCl), isradipine (such aS 4- (4-benzofurazanyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl 1-methylethyl ester), calviper (such aS isolated from Dendroaspinospora fasciata), H-Arg-Ile-Cys-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Lys-Ala-Thr-Cys-Val-Glu-Asn-Thr-Cys-Tyr-Lys-Met) -Phe-Ile-Arg-Thr-Gln-Arg-Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met-Trp-Pro-Tyr-Gln-Thr-Glu-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH, calcein (Calcicludine) species (as isolated from Dongfennese African Bolbilus viridis et al), H-Trp-Gln-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys-Lys-Gln-Phe-Ser-Phe-Tyr-Lys-Trp-Thr-Ala-Ser-Ser-Ser-Gln-Ser-Thr-Gln-Ser-Gln-Ser- -Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-Gly-Cys-Gly-Gly-Asn-Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Cys-Leu-Gly-Lys-OH, cilnidipine (e.g. also known as FRP-8653, an inhibitor of the dihydropyridine type), dilantin (dilantinezem) classes (e.g. (2S,3S) - (+) cis-3-acetoxy-5- (2-dimethylaminoethyl) -2, 3-dihydro-2- (4-methoxyphenyl) -1, 5-benzothiazepin-4 (5H) -one hydrochloride, Diltiazem (e.g. benzothiazepine-4 (5H) -one, 3- (acetoxy) -5- [2- (dimethylamino) ethyl) ]2, 3-dihydro-2- (4-methoxyphenyl) -, (+) -cis-, monohydrochloride), felodipine (e.g. ethyl methyl 4- (2, 3-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinecarboxylate), FS-2 (e.g. isolate from black snake venom), FTX-3.3 (e.g. isolate from spider funnel-web (Agelenopsis aperta), neomycin sulfate (e.g. C)₂₃H₄₆N₆O₁₃·3H₂SO₄) Nicardipine (e.g. 1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) methyl-2- [ methyl (phenylmethyl) amino)]-ethyl 3, 5-pyridinedicarboxylate hydrochloride, also known as YC-93), nifedipine (e.g. dimethyl 1, 4-dihydro-2, 6-dimethyl-4- (2-nitrophenyl) -3, 5-pyridinedicarboxylate), nimodipine (e.g. 4-dihydro-2, 6-dimethyl-4- (3-nitro-2, 3-pyridinedicarboxylate)Phenyl) -3, 5-pyridinedicarboxylic acid 2-methoxyethyl-1-methylethyl ester or (2-methoxyethyl 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid isopropyl ester), nitrendipine (e.g., 1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) -3, 5-pyridinedicarboxylic acid ethylmethyl ester), S-Petasin (Petasin) compounds (e.g., 3S,4aR,5R,6R) - [2,3,4,4a,5,6,7, 8-octahydro-3- (2-propenyl) -4a, 5-dimethyl-2-oxo-6-naphthyl.]Z-3 ' -methylthio-1 ' -acrylate), phloretins (Phloretin) such as 2 ', 4 ', 6 ' -trihydroxy-3- (4-hydroxyphenyl) propiophenone, and 3- (4-hydroxyphenyl) -1- (2,4, 6-trihydroxy-phenyl) -1-propanone, and b- (4-hydroxyphenyl) -2,4, 6-trihydroxy propiophenone, and protoporphyrins such as C ₂₀H_I9NO₅C1) SKF-96365 (e.g. 1- [ b- [3- (4-methoxyphenyl) propoxy)]-4-methoxybenzyl ethyl]-1H-imidazole, HCl), tetrandrines (e.g. 6,6 ', 7, 12-tetramethoxy-2, 2' -dimethyltetrandrine), (+ -) methoxy verapamil or (+) -verapamil (e.g. 54N- (3, 4-dimethoxyphenylethyl) methylamino]-2- (3, 4-dimethoxyphenyl) -2-isopropylvaleronitrile hydrochloride), and (R) - (+) -Bay K8644 species (e.g. R- (+) -1, 4-dihydro-2, 6-dimethyl-5-nitro-442- (trifluoromethyl) phenyl]-3-pyridinecarboxylic acid methyl ester). The foregoing examples may be specific for L-type voltage-gated calcium channels or may inhibit a broader range of voltage-gated calcium channels, such as N, P/Q, R and T-type.

Endothelin

Endothelin is a vasoconstricting peptide produced primarily in endothelial cells that increases blood pressure and vascular tone. Peptides of this family include endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3). These small peptides (21 amino acids) play an important role in vascular homeostasis. ET-1 is secreted primarily by vascular endothelial cells. The major ET-1 isoform is expressed in the vascular system and is the most potent vasoconstrictor. ET-1 also has inotropic, chemotactic and mitogenic properties. It stimulates the sympathetic nervous system and affects salt and water homeostasis through its effects on the renin-angiotensin-aldosterone system (RAAS), vasopressin and atrial natriuretic peptide (atrial natriuretic peptide). Endothelin is among the strongest known vasoconstrictors and is involved in vascular disease in a variety of organ systems, including the heart, systemic circulation, and brain.

There are two key types of endothelin receptors, ETA and ETB. ETA and ETB have different pharmacological profiles. The ETA receptor has much higher affinity for ET-1 than for ET-3. ETA receptors are located in vascular smooth muscle cells, but not in endothelial cells. Binding of endothelin to ETA enhances vasoconstriction and sodium retention, resulting in elevated blood pressure. ETB receptors are predominantly located on endothelial cells distributed within blood vessels. Endothelin binds to ETB receptors to lower blood pressure by increasing natriuresis and diuresis, as well as releasing nitric oxide. ET-1 and ET-3 equally activate ETB receptors, which subsequently cause vasodilation through the production of NO and prostaglandins. Endothelin-1 (ET-1) has also been shown to cause vascular smooth muscle contraction through ETA receptor stimulation and to promote the production of NO in endothelial cells through ETB receptors. Some ETB receptors are located in vascular smooth muscle where they may mediate vasoconstriction. Many endothelin receptors are regulated by a variety of factors. Angiotensin II and phorbol esters down-regulate endothelin receptors, while ischemia and cyclosporine increase the number of endothelin receptors.

A large number of peptidic and non-peptidic ET antagonists have been studied. ETA receptor antagonists may include, but are not limited to, A-127722 (non-peptide), ABT-627 (non-peptide), BMS 182874 (non-peptide), BQ-123 (peptide), BQ-153 (peptide), BQ-162 (peptide), BQ-485 (peptide), BQ-518 (peptide), BQ-610 (peptide), EMD-122946 (non-peptide), FR 139317 (peptide), IPI-725 (peptide), L-744453 (non-peptide), LU 127043 (non-peptide), LU 135252 (non-peptide), PABSA (non-peptide), PD 147953 (peptide), PD151242 (peptide), PD 155080 (non-peptide), PD 156707 (non-peptide), RO 611790 (non-peptide), SB-247083 (non-peptide), Clatansentan (clazosentan) (non-peptide), atrasentan (non-peptide), sitaxsentan sodium (non-peptide), TA-0201 (non-peptide), TTA-1125 1 (non-peptide), TTA-1125-7338 (peptide), WS) peptide (non-B-7338 (peptide), atrasentan, ZD-1611 (non-peptide), and aspirin (non-peptide). ETA/B receptor antagonists may include, but are not limited to, A-182086 (non-peptide), CGS 27830 (non-peptide), CP 170687 (non-peptide), J-104132 (non-peptide), L-751281 (non-peptide), L-754142 (non-peptide), LU 224332 (non-peptide), LU 302872 (non-peptide), PD142893 (peptide), PD 145065 (peptide), PD 160672 (non-peptide), RO-470203 (bosentan, non-peptide), RO 462005 (non-peptide), RO 470203 (non-peptide), SB 209670 (non-peptide), SB 217242 (non-peptide), and TAK-044 (peptide). ETB receptor antagonists may include, but are not limited to: a-192621 (non-peptide), A-308165 (non-peptide), BQ-788 (peptide), BQ-017 (peptide), IRL1038 (peptide), IRL 2500 (peptide), PD-161721 (non-peptide), RES 701-1 (peptide) and RO 468443 (peptide).

ET-1 is initially translated as a 212 amino acid peptide (pre-proendothelin-1). Further conversion to proendothelin-1 occurs after removal of the secretory sequence. The subsequent cleavage of proendothelin-1 by furin produces the biologically inactive precursor macroendothelin-1. Mature ET-1 is formed upon cleavage of macroendothelin-1 by one of several Endothelin Converting Enzymes (ECE). ECE-1 has two splice forms; ECE-1a and ECE-1b, respectively. Each with a different functional and organizational distribution. ECE-1a expresses and cleaves large endothelin-1 in the Golgi network of endothelin producing cells to form ET-1. ECE-1b is located at the plasma membrane and cleaves extracellular macrophysin-1. Both ECE-1a and ECE-1b are inhibited by the metalloprotease inhibitor phosphoramidon. ECE is also distributed on alpha actin filaments in smooth muscle cells. Inhibition of ECE by phosphoramidon completely blocked vasoconstriction by large endothelin-1. ECE inhibitors may include, but are not limited to, B-90063 (non-peptide), CGS 26393 (non-peptide), CGS 26303 (non-peptide), CGS35066 (non-peptide), phosphoramidon (peptide), PP-36 (peptide), SM-19712 (non-peptide), and TMC-66 (non-peptide).

In healthy individuals, a delicate balance between vasoconstriction and vasodilation is maintained, on the one hand by endothelin and other vasoconstrictors, and on the other hand by nitric oxide, prostacyclin and other vasodilators. Endothelin antagonists can act in the treatment of cardiac, vascular and renal diseases associated with local or systemic vasoconstriction and cell proliferation, such as essential hypertension, pulmonary hypertension, chronic heart failure and chronic renal failure.

Transient receptor potential channels

The Transient Receptor Potential (TRP) channel family is a member of the calcium channel group. These channels include transient receptor potential proteins and homologs thereof, capsaicin receptor subtype I, stretch suppressible non-selective cation channels, olfactory, mechanosensitive channels, insulin-like growth factor I regulated calcium channels, and vitamin D responsive apical epithelial calcium channels (ECaC). Each molecule is at least 700 amino acids in length and has certain conserved structural features. The predominant of these structural features is the 6 transmembrane domain, with an additional hydrophobic loop included between the 5 th and 6 th transmembrane domains. This ring is believed to be necessary for activity in forming the channel pores upon membrane insertion. TRP channel proteins also include one or more ankyrin domains and often have a proline-rich region at the N-terminus.

Transient Receptor Potential (TRP) cation channels are present in vascular smooth muscle and are involved in the depolarizing response of smooth muscle to stimuli such as membrane stretching. Uridine Triphosphate (UTP) causes membrane depolarization and contraction of vascular smooth muscle by activating the cation flux, which appears to be rectifying inward, UTP does not desensitize rapidly and can be sensitized by Gd ³⁺And (4) blocking. The classical Transient Receptor Potential (TRPC) protein forms Ca in various mammalian tissues²⁺TRPC6, a member of this channel family, has been reported to inhibit the flow of cations that prevent α adrenergic receptor activation in cultured rabbit portal muscle cells, however, inhibition of TRPC6 channels in cerebrovascular smooth muscle does not attenuate UTP-induced membrane depolarization and vasoconstriction, in contrast, TRPC3 has been found to mediate agonist-induced depolarization, unlike TRPC6, as observed in rat cerebral arteries after the P2Y receptor is activated by UTP, thus TRPC3 channels in vascular smooth muscle mediate agonist-induced depolarization, which contributes to vasoconstriction in resistant cerebral arteries.

The TRP1 channel family includes a large number of channels that mediate a range of signal and sensory transduction pathways. Proteins of the mammalian TRPC subfamily are products of at least 7 genes encoding cation channels that appear to be activated in response to phospholipase c (plc) coupled receptors. The putative ion channel subunits TRPC3, TRPC6 and TRPC7 comprise a structurally related subfamily of the mammalian TRPC channel family. Ion channels formed by these proteins may be activated downstream of phospholipase c (plc). It has been shown that PLC-dependent activation of TRPC6 and TRPC7 involves diacylglycerol and is independent of the G-protein or inositol 1,4, 5-triphosphate (IP 3).

TRPC channel is widely expressed in various cell types and is likely to be in receptor-mediated Ca²⁺Plays an important role in signal transduction. The TRPC3 channel is known to be Ca activated in response to a PLC-coupled receptor²⁺A conductive channel. It has been shown that TRPC3 channels interact directly with intracellular inositol 1,4, 5-triphosphate receptors (instp 3Rs), i.e. activation of the channel is mediated by coupling to instp 3 Rs.

The agent for increasing arterial blood flow, inhibiting vasoconstriction or inducing vasodilation is an agent that inhibits TRP channels. These inhibitors include compounds that are TRP channel antagonists. Such inhibitors are referred to as activity inhibitors or TRP channel activity inhibitors. The term "activity inhibitor" as used herein refers to an agent that interferes with or prevents TRP channel activity. Active inhibitors may interfere with the ability of the TRP channel to bind to agonists such as UTP. An active inhibitor may be an agent that competes with a naturally occurring activator of a TRP channel for interaction with an activating binding site on the TRP channel. Alternatively, the active inhibitor may bind to the TRP channel at a site different from the activation binding site, but such binding may for example cause a conformational change in the TRP channel which is conducted to the activation binding site, thereby precluding binding of the native activator. In addition, an activity inhibitor may interfere with a component upstream or downstream of the TRP channel, but the component affects the activity of the TRP channel. The latter type of activity inhibitor is called a functional antagonist. Non-limiting examples of TRP channel inhibitors as activity inhibitors are gadolinium chloride, lanthanum chloride, SKF 96365 and LOE-908.

Current therapeutic approaches to prevent or reduce cerebral vasospasm include prevention or minimization of secondary brain injury, use of calcium channel blockers, hemodynamic management, and intravascular therapy. Treatment is often initiated prophylactically in a patient and may include: hemodynamic stabilization including maintenance of normovolemic blood volume, control of blood pressure, and oral administration of L-type voltage-gated calcium channel antagonists (in phase 1); and (in stage 2) further hemodynamic control or infusion of vasodilator drugs into or expansion with balloons of the artery where vasospasm occurs. However, the above-described treatment methods are expensive, time-consuming, and only partially effective.

For over 35 years, physicians have been working on preventing or reducing the incidence of the adverse consequences of SAH, including vasospasm, with only limited efficacy due to the side effects or lack of effectiveness of the currently used drugs. There is currently no FDA approved drug for preventing vasospasm or reducing delayed ischemic neurological deficits, also known as Delayed Cerebral Ischemia (DCI). Current methods of preventing vasospasm have not been successful due to lack of efficacy or safety issues (mainly hypotension and cerebral edema). Currently, the only available drug approved by the FDA is nimodipine, which, although it improves outcomes in SAH patients, does not reduce vasospasm.

Voltage-gated calcium channel antagonists may be effective in preventing and reversing vasospasm to some extent, however, the prior art treatments are administered at too low a dose to exert the greatest pharmacological effect. Endothelin receptor antagonists may also be effective in preventing and reversing vasospasm to some extent, but this reversal or prevention of vasospasm does not translate into a significant improvement in the outcome expected by reducing vasospasm. Without being limited by theory, it is believed that systemic delivery of voltage-gated calcium channel blockers may result in counteracting side effects that produce beneficial effects on vasospasm, such as systemic hypotension and pulmonary vasodilation with pulmonary edema, which prevents the use of higher systemic doses. Dilation of blood vessels in the lungs may also cause pulmonary edema and lung injury.

Although conventional therapies have focused on treating cerebral vasospasm after subarachnoid hemorrhage, the accumulated evidence suggests that there are additional complications from subarachnoid hemorrhage that need to be targeted for interventional therapy to improve the prognosis after treatment of subarachnoid hemorrhage. The present invention provides such a solution.

Disclosure of Invention

According to one aspect, the present invention provides a method for treating a delayed complication associated with a brain injury in a mammal in need thereof, wherein the brain injury comprises an interruption of at least one cerebral artery, the method comprising: (a) providing a pharmaceutical composition comprising (i) a microparticulate formulation of a voltage-gated calcium channel blocker; and optionally (ii) a pharmaceutically acceptable carrier; and (b) administering a therapeutic amount of the pharmaceutical composition to the site of administration by a device for administering the therapeutic amount of the pharmaceutical composition, wherein the therapeutic amount is effective to reduce signs or symptoms of at least one delayed complication associated with brain injury, and wherein the at least one delayed complication is at least one of Delayed Cerebral Ischemia (DCI), a plurality of microthromboemboli, Cortical Spreading Ischemia (CSI), and angiographic vasospasm.

According to one embodiment of the method, in step (b), the means for administering is a surgical injection device and the site of administration is in close proximity to at least one cerebral artery affected by the brain injury. According to another embodiment, in step (b), the means for administering is a surgical injection device and the site of administration is the ventricle. According to another embodiment, the surgical injection apparatus is a needle, a cannula, a catheter, or a combination thereof. According to another embodiment, the microparticle formulation is carried by cerebrospinal fluid to contact cerebral arteries affected by brain injury. According to another embodiment, the therapeutic amount is effective to increase the inner diameter of a cerebral artery affected by the brain injury as compared to a control. According to another embodiment, the brain injury is the result of an aneurysm, a traumatic head injury, subarachnoid hemorrhage (SAH), or a combination thereof. According to another embodiment, the brain injury is the result of subarachnoid hemorrhage. According to another embodiment, the at least one delayed complication associated with brain injury further comprises at least one of an intracerebral hematoma, intracerebroventricular hemorrhage, fever, behavioral deficits, neurological deficit, cerebral infarction, and neuronal cell death. According to another embodiment, the behavioral deficit is ameliorated such that the improved behavioral deficit comprises increased appetite. According to another embodiment, improving the neurological deficit such that the improved neurological deficit comprises improvement in ataxia or paresis. According to another embodiment, the pharmaceutical composition exerts advantageously a localized pharmacological effect in the treatment of said at least one delayed complication associated with brain damage. According to another embodiment, the pharmaceutical composition exerts a diffuse pharmacological effect throughout the brain in the treatment of the at least one delayed complication associated with brain injury. According to another embodiment, the microparticle formulation comprises a plurality of microparticles, wherein the microparticles are in a uniform size distribution, and wherein each microparticle comprises a matrix. According to another embodiment, the microparticle formulation further comprises a plurality of microparticles impregnated with the voltage-gated calcium channel blocker. According to another embodiment, the microparticle formulation comprises a suspension of microparticles. According to another embodiment, the ventricle is a lateral ventricle, a third ventricle, a fourth ventricle, or a combination thereof. According to another embodiment, the microparticulate formulation of a voltage-gated calcium channel blocker includes a slow-release compound. According to another embodiment, the sustained release compound is a polymer. According to another embodiment, the voltage-gated calcium channel blocker is disposed in or on a sustained release polymer. According to another embodiment, the microparticulate formulation of a voltage-gated calcium channel blocker comprises poly (D, L-lactide-co-glycolide). According to another embodiment, the microparticulate formulation of a voltage-gated calcium channel blocker comprises a poly (orthoester). According to another embodiment, the microparticle formulation of the voltage-gated calcium channel blocker comprises a polyanhydride. According to another embodiment, the voltage-gated calcium channel blocker is selected from the group consisting of an L-type voltage-gated calcium channel blocker, an N-type voltage-gated calcium channel blocker, a P/Q-type voltage-gated calcium channel blocker, or a combination thereof. According to another embodiment, the voltage-gated calcium channel blocker is a dihydropyridine calcium channel blocker. According to another embodiment, the dihydropyridine calcium channel blocker is nimodipine. According to another embodiment, the pharmaceutically acceptable carrier comprises a gel compound. According to another embodiment, the gel compound is a biodegradable hydrogel. According to another embodiment, the pharmaceutical composition does not comprise a pharmaceutically acceptable carrier. According to another embodiment, the pharmaceutically acceptable carrier does not include hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid in a range between 0% and 5%. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.3% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 5% hyaluronic acid.

According to another aspect, the present invention provides a semi-solid multiparticulate delivery system for treating delayed complications associated with brain injury in a mammal in need thereof, wherein the brain injury comprises an interruption of at least one cerebral artery, the system comprising: (a) a pharmaceutical composition comprising (i) a microparticulate formulation of a voltage-gated calcium channel blocker; and optionally (ii) a pharmaceutically acceptable carrier; and (b) a device for administering a therapeutic amount of the pharmaceutical composition to an administration site, wherein the therapeutic amount is effective to reduce the signs or symptoms of at least one delayed complication associated with brain injury.

According to one embodiment, the at least one delayed complication is at least one of Delayed Cerebral Ischemia (DCI), a plurality of microthromboemboli, Cortical Spreading Ischemia (CSI), and angiographic vasospasm. The system of claim 31, wherein the means for administering is a surgical injection device and the site of administration is in close proximity to at least one cerebral artery affected by the brain injury. According to another embodiment, the means for administering is a surgical injection device and the site of administration is the ventricle. According to another embodiment, the surgical injection apparatus is a needle, a cannula, a catheter, or a combination thereof. According to another embodiment, the microparticle formulation is carried by cerebrospinal fluid to contact cerebral arteries affected by brain injury. According to another embodiment, the therapeutic amount is effective to increase the inner diameter of a cerebral artery affected by the brain injury as compared to a control. According to another embodiment, the brain injury is the result of an aneurysm, a traumatic head injury, subarachnoid hemorrhage (SAH), or a combination thereof. According to another embodiment, the brain injury is the result of subarachnoid hemorrhage. According to another embodiment, the at least one delayed complication associated with brain injury further comprises at least one of an intracerebral hematoma, intracerebroventricular hemorrhage, fever, behavioral deficits, neurological deficit, cerebral infarction, and neuronal cell death. According to another embodiment, the behavioral deficit is ameliorated such that the improved behavioral deficit comprises increased appetite. According to another embodiment, improving the neurological deficit such that the improved neurological deficit comprises improvement in ataxia or paresis. According to another embodiment, wherein the pharmaceutical composition exerts a localized pharmacological effect with advantage in the treatment of said at least one delayed complication associated with brain damage. According to another embodiment, the pharmaceutical composition exerts a diffuse pharmacological effect throughout the brain in the treatment of the at least one delayed complication associated with brain injury. According to another embodiment, the microparticle formulation comprises a plurality of microparticles, wherein the microparticles are in a uniform size distribution, and wherein each microparticle comprises a matrix. According to another embodiment, the microparticle formulation further comprises a plurality of microparticles impregnated with the voltage-gated calcium channel blocker. According to another embodiment, the microparticle formulation comprises a suspension of microparticles. According to another embodiment, the ventricle is a lateral ventricle, a third ventricle, a fourth ventricle, or a combination thereof. According to another embodiment, the microparticulate formulation of a voltage-gated calcium channel blocker includes a slow-release compound. According to another embodiment, the sustained release compound is a polymer. According to another embodiment, the voltage-gated calcium channel blocker is disposed in or on a sustained release polymer. According to another embodiment, the microparticulate formulation of a voltage-gated calcium channel blocker comprises poly (D, L-lactide-co-glycolide). According to another embodiment, the microparticulate formulation of a voltage-gated calcium channel blocker comprises a poly (orthoester). According to another embodiment, the microparticle formulation of the voltage-gated calcium channel blocker comprises a polyanhydride. According to another embodiment, the voltage-gated calcium channel blocker is selected from the group consisting of an L-type voltage-gated calcium channel blocker, an N-type voltage-gated calcium channel blocker, a P/Q-type voltage-gated calcium channel blocker, or a combination thereof. According to another embodiment, the voltage-gated calcium channel blocker is a dihydropyridine calcium channel blocker. According to another embodiment, the dihydropyridine calcium channel blocker is nimodipine. According to another embodiment, the pharmaceutically acceptable carrier comprises a gel compound. According to another embodiment, the gel compound is a biodegradable hydrogel. According to another embodiment, the pharmaceutical composition does not comprise a pharmaceutically acceptable carrier. According to another embodiment, the pharmaceutically acceptable carrier does not include hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier is hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid in a range between 0% and 5%. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.3% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 5% hyaluronic acid.

Drawings

Fig. 1 shows a schematic diagram of a cerebral artery.

Figure 2A shows a schematic representation of administration of a calcium channel blocker, endothelin receptor antagonist, or putative transient receptor potential protein blocker gel, sustained release solid or semi-solid compound to an anterior communicating artery according to one embodiment of the present invention.

Figure 2B shows a diagram of an embodiment of administering a calcium channel blocker, an endothelin receptor antagonist, or a putative transient receptor potential protein blocker gel, a sustained release solid or semi-solid compound to an artery in the brain.

Figure 2C shows a schematic of an embodiment of administering a calcium channel blocker, an endothelin receptor antagonist, or a putative transient receptor potential protein blocker gel, a slow release solid or semi-solid compound to the internal carotid artery.

Fig. 3 shows a time trend plot of subarachnoid hemorrhage outcome in 7 population-based studies of subarachnoid hemorrhage (SAH), indicating a 50% reduction in mortality over 20 years.

Fig. 4A shows a simple flow chart for prognosis of subarachnoid hemorrhage.

Fig. 4B shows a flow diagram of the proposed pathway involved in late complications after subarachnoid hemorrhage.

Fig. 5 shows a schematic diagram of a cerebral artery. (from Netter FH. the CIBA Collection of medical Illustrations: volume 1, Nervous System. Vol.1. part I. CIBA: USA.1986. p.256).

FIG. 6 shows a schematic representation of the ventricles (page 192, Ross LM, Lamberti ED, Taub E (EDs.), Schuenke M, Schulte E, Schumacher U.S. Thieme Atlas of Anatomy.Georg Thieme Verlag: Stuttgart.2006, page 541).

FIG. 7 shows a schematic representation of CSF flowing from the ventricles to the subarachnoid space (page 194, Ross LM, Lamberti ED, Taub E (EDs.), Schuenke M, Schulte E, Schumacher U.S. Thieme Atlas of Anatomy. Georg Thieme Verlag: Stuttgart.2006, page 541).

Figure 8 shows a schematic of the administration of a suspension of microparticles of a calcium channel blocker, an endothelin receptor antagonist or a putative TRP protein blocker to the ventricles of the brain via an intraventricular catheter. (the figure is from Mccomb JG: Techniques of CSFdivision. in: Scott RM (eds.). Hydrocephalus. Vol.3.Williams & Wilkins: Baltimore. 1990. 48, page 128).

FIG. 9 shows a schematic depicting The administration of a composition comprising at least one of a calcium channel blocker, an endothelin receptor antagonist, or a putative TRP protein blocker in or on microparticles carried by CSF flow to each subarachnoid artery (Pollay M: Cerebrospinal fluid. in: Tindall GT, Cooper PR, Barrow DL (eds.). The Practice of neurosurger. Vol.1.Williams & Wilkins: Baltimore.1996. pp.36, 1381).

Figure 10 shows a bar graph showing the change in percent (%) of mean basal artery diameter from baseline following topical treatment in study 1 by intracisternal administration of a low dose (10mg) of particulate nimodipine formulation plus saline vehicle ("low dose"), a high dose (30mg) of particulate nimodipine formulation plus saline vehicle ("high dose"), and a particulate placebo formulation plus saline vehicle ("placebo").

Figure 11 shows a plot of the performance score over time (days) in study 1 obtained with dogs suffering from subarachnoid hemorrhage treated with either a particulate placebo formulation plus saline vehicle ("placebo"), a low dose (10mg) particulate nimodipine formulation plus saline vehicle, or a high dose (30mg) particulate nimodipine formulation plus saline vehicle.

Figure 12 shows a plot of blood concentration (ng/mL) versus time (day) in dogs suffering from subarachnoid hemorrhage treated with either a particulate placebo formulation plus saline vehicle ("placebo"), a low dose (10mg) particulate nimodipine formulation plus saline vehicle ("low dose"), or a high dose (30mg) particulate nimodipine formulation plus saline vehicle ("high dose") in study 1. Values are mean +/-standard deviation (n 2 for each group).

Figure 13 shows histopathological pictures of dogs suffering from subarachnoid hemorrhage treated with either the microparticulate placebo formulation plus saline vehicle (a) or the microparticulate nimodipine formulation at a low dose (10mg) plus saline vehicle (B). The subarachnoid space of dogs treated with placebo microparticles showed mild granulomatous inflammation (a). Microthrombus emboli were observed in small blood vessels of subarachnoid bleeding dogs treated with placebo, low or high dose nimodipine microparticles. There were qualitatively more microthrombotic plugs in the brain of placebo-treated dogs. Figure (B) shows an example of microthromboemboli in small blood vessels of dogs treated with low dose nimodipine microparticles.

Figure 14 shows a cross-sectional view used in a dog model experiment.

Figure 15 is a bar graph showing the effect of intracisternal administration of a dose 1(40mg) of microparticle nimodipine formulation plus Hyaluronic Acid (HA) vehicle ("formulation 1") in study 2; microparticle nimodipine formulation plus Hyaluronic Acid (HA) vehicle ("formulation 1") at dose 2(100mg) administered intracisternally; microparticle nimodipine formulation without Hyaluronic Acid (HA) by intracerebroventricular administration of dose 2(100mg) ("formulation 2"); and the percent (%) change in mean basal artery diameter from baseline after treatment with control (by intracisternal administration of the particulate placebo formulation plus Hyaluronic Acid (HA) vehicle, followed by oral nimodipine).

Figure 16 shows a plot of blood concentration (ng/mL) over time (days) in study 2 in a dog suffering from subarachnoid hemorrhage administered intracisternally a dose of 1(40mg) of the microparticle nimodipine formulation plus a Hyaluronic Acid (HA) vehicle ("formulation 1"); microparticle nimodipine formulation plus Hyaluronic Acid (HA) vehicle ("formulation 1") at dose 2(100mg) administered intracisternally; microparticle nimodipine formulation without Hyaluronic Acid (HA) by intracerebroventricular administration of dose 2(100mg) ("formulation 2"); and treatment with control (by intracisternal administration of a particulate placebo formulation plus Hyaluronic Acid (HA) vehicle, followed by oral nimodipine).

Figure 17 shows a plot of spinal fluid (CSF) nimodipine concentration (ng/mL) over time (day) in a dog suffering from subarachnoid hemorrhage administered intracisternally at a dose of 1(40mg) of a microparticle nimodipine formulation plus Hyaluronic Acid (HA) vehicle ("formulation 1") in study 2; microparticle nimodipine formulation plus Hyaluronic Acid (HA) vehicle ("formulation 1") at dose 2(100mg) administered intracisternally; microparticle nimodipine formulation without Hyaluronic Acid (HA) by intracerebroventricular administration of dose 2(100mg) ("formulation 2"); and treatment with controls (by intracisternal administration of a particulate placebo formulation plus Hyaluronic Acid (HA) vehicle, followed by oral nimodipine).

Detailed Description

Term(s) for

The term "active" as used herein refers to an ingredient, component or constituent of a composition of the present invention that contributes to the intended therapeutic effect.

The term "antagonist" as used herein refers to a substance that counteracts the action of another substance.

The term "administration" as used herein includes in vivo administration as well as direct administration to ex vivo (ex vivo) tissue. In general, the compositions may be administered systemically by oral means, buccal means, parenteral means, topical means, inhalation or insufflation (i.e., through the mouth or through the nose), or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired, or topically by methods such as, but not limited to, injection, implantation, transplantation, topical administration or parenteral means.

The term "agonist" as used herein refers to a chemical substance capable of activating a receptor to induce a full or partial pharmacological response. Receptors can be activated or inactivated by endogenous or exogenous agonists and antagonists, resulting in stimulation or inhibition of biological responses. Physiological agonists are substances that produce the same bodily response, but do not bind to the same receptor. Endogenous agonists of a particular receptor are compounds naturally produced by the body that bind to and activate the receptor. Superagonists are compounds that are capable of producing a greater maximal response than endogenous agonists for the target receptor and thus produce greater than 100% efficacy. This does not necessarily mean that the compound is more potent than the endogenous agonist, but rather a comparison of the maximum possible responses that can be produced in the cell following receptor binding. Full agonists bind to and activate the receptor and exhibit full efficacy at this receptor. Partial agonists also bind to and activate a given receptor, but have only partial efficacy at that receptor relative to full agonists. Inverse agonists are substances that bind to the same receptor binding site as agonists of the receptor and reverse the constitutive activity of the receptor. Inverse agonists produce the opposite receptor agonist pharmacological effect. An agonist that binds to a receptor in a manner that permanently binds to the receptor such that the receptor is permanently activated. It differs from a generic agonist in that the binding of a generic agonist to a receptor is reversible, whereas the binding of an irreversible agonist to a receptor is considered irreversible. This allows the compound to produce a transient burst of agonist activity followed by receptor desensitization and internalization, which in the case of long-term treatment produces a more antagonist-like effect. Selective agonists are specific for a particular type of receptor.

As used herein, the terms "anastomosis" and "anastomosis" refer interchangeably to the interconnection between blood vessels. These interconnections provide protection to the brain when the blood supply to parts of the blood vessels is impaired. At the location of the circle Willis, the two anterior cerebral arteries are connected by an anterior communicating artery, and the posterior cerebral artery is connected to the internal carotid artery by a posterior communicating artery. Other important anastomoses include the orbital junction between the branches of the ocular and external carotid arteries, and the junction between the branches of the middle, anterior and posterior arteries of the brain at the surface of the brain (Principles of Neural Sciences,2d Ed., Eric R.Kandel and James H.Schwartz, Elsevier Science Publishing Co., Inc., New York, N.C.)Page (1985)).

The term "angiographic vasospasm" as used herein refers to a decrease in blood vessel size that can be detected upon angiographic examination, occurring in approximately 50% of patients after subarachnoid hemorrhage. In another aspect, the term "clinical vasospasm" as used herein refers to a syndrome of confusion and a reduced level of consciousness associated with reduced blood flow to the brain parenchyma, occurring in about 50% of patients.

The term "antagonist" as used herein refers to a substance that counteracts the action of another substance.

The term "ataxia" as used herein refers to the inability to regulate muscle activity during intentional exercise.

The term "biocompatible" as used herein means not causing clinically relevant tissue irritation, injury, toxic reactions or immune reactions against living tissue.

The term "biodegradable" as used herein refers to a material that actively or passively decomposes over time by simple chemical processes, by the action of bodily enzymes, or by other similar bioactive mechanisms.

The term "blocking agent" as used herein refers to a substance that inhibits the physiological effect of another substance.

The term "carrier" as used herein describes a substance that does not cause significant irritation to an organism and does not impair the biological activity and performance of the active compounds in the compositions of the present invention. The carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the mammal being treated. The carrier may be inert, or it may have a pharmaceutical benefit, a cosmetic benefit, or both. The terms "excipient," "carrier," or "vehicle" are used interchangeably to refer to a carrier substance suitable for formulation and administration of the pharmaceutically acceptable compositions described herein. Carriers and vehicles useful herein include any such materials known in the art to be non-toxic and non-interactive with other components.

As shown in fig. 1, the term "cerebral artery" refers to at least one of anterior communicating artery, middle cerebral artery, internal carotid artery, anterior cerebral artery, ocular artery, anterior choroidal artery, posterior communicating artery, and arteries such as basilar artery and vertebral artery.

The term "cerebral vasospasm" as used herein refers to delayed onset of massive arterial stenosis in the base of the brain following subarachnoid hemorrhage, which is often associated with decreased perfusion in the distal region of the affected blood vessel. Cerebral vasospasm can occur at any time after the aneurysm ruptures, but the most common peak occurs 7 days after bleeding and often resolves within 14 days, when the blood has been absorbed by the body.

The phrase "immediately adjacent" as used herein means less than 10mm, less than 9.9mm, less than 9.8mm, less than 9.7mm, less than 9.6mm, less than 9.5mm, less than 9.4mm, less than 9.3mm, less than 9.2mm, less than 9.1mm, less than 9.0mm, less than 8.9mm, less than 8.8mm, less than 8.7mm, less than 8.6mm, less than 8.5mm, less than 8.4mm, less than 8.3mm, less than 8.2mm, less than 8.1mm, less than 8.0mm, less than 7.9mm, less than 7.8mm, less than 7.7mm, less than 7.6mm, less than 7.5mm, less than 7.4mm, less than 7.3mm, less than 7.2mm, less than 7.1mm, less than 7.0mm, less than 6.9mm, less than 6.8mm, less than 6.5mm, less than 6.4mm, less than 7.3mm, less than 5.6mm, less than 6mm, less than 5.5mm, less than 6mm, less than 6.5mm, less than 6mm, less than 5.2mm, less than 5.4mm, less than 5.3mm, less than 5.2mm, less than 5.1mm, less than 5.0mm, less than 4.9mm, less than 4.8mm, less than 4.7mm, less than 4.6mm, less than 4.5mm, less than 4.4mm, less than 4.3mm, less than 4.2mm, less than 4.1mm, less than 4.0mm, less than 3.9mm, less than 3.8mm, less than 3.7mm, less than 3.6mm, less than 3.5mm, less than 3.4mm, less than 3.3mm, less than 3.2mm, less than 3.1mm, less than 3.0mm, less than 2.9mm, less than 2.8mm, less than 2.7mm, less than 2.6mm, less than 2.5mm, less than 2.4mm, less than 2.3mm, less than 2.2mm, less than 2.1mm, less than 2.0, less than 1.9mm, less than 1.7mm, less than 1.0mm, less, less than 0.2mm, less than 0.1mm, less than 0.09mm, less than 0.08mm, less than 0.07mm, less than 0.06mm, less than 0.05mm, less than 0.04mm, less than 0.03mm, less than 0.02mm, less than 0.01mm, less than 0.009mm, less than 0.008mm, less than 0.007mm, less than 0.006mm, less than 0.005mm, less than 0.004mm, less than 0.003mm, less than 0.002mm, less than 0.001mm or into the blood vessels immediately adjacent to the brain injury site.

The term "complication" as used herein refers to a pathological process or event that occurs during the treatment of a pre-existing condition. Complications associated with subarachnoid hemorrhage include, but are not limited to, angiographic vasospasm, microthrombotic emboli, and cortical spreading ischemia.

The term "condition" as used herein refers to various health states and is intended to include disorders or diseases caused by any underlying mechanism or disorder, injury, and promotion of healthy tissues and organs.

As used herein, the term "contacting" and its various grammatical forms refer to a state or condition of contact or close or local proximity.

The term "controlled release" means any drug-containing formulation from which the drug is released in a controlled manner and morphology. This refers to immediate as well as non-immediate release formulations, including but not limited to sustained release and delayed release formulations.

The term "cortical diffusive depolarization" or "CSD" as used herein refers to the wave of near-complete nerve cell depolarization and nerve cell swelling in the brain that forms when passive cation influx across the cell membrane exceeds ATP-dependent sodium and calcium pump activity. The cation influx was followed by water influx and about 70% extracellular space contraction. If normal ion homeostasis is not restored by additional recruitment of sodium and calcium pump activity, cell swelling is maintained-a process thus termed "cytotoxic edema" as it potentially leads to cell death through prolonged intracellular calcium oscillations and mitochondrial depolarization. CSD causes dilation of resistant vessels in healthy tissue; thus, local cerebral blood flow increases during the depolarization phase of the nerve cells. (Dreier, J.P. et al Brain 132:1866-81 (2009)).

The term "cortical spreading ischemia" or "CSI" or "reversal of the hemodynamic response" refers to severe microvascular spasm associated with the depolarization phase of nerve cells. The resulting diffuse hypoperfusion prolongs nerve cell depolarization [ as reflected by prolonged negative extracellular Direct Current (DC) potential shift ] and intracellular sodium and calcium fluctuations. The hypoperfusion is significant enough to create a mismatch between the energy demand and supply of the nerve cells. (Id.).

The term "late onset cerebral ischemia" or "DCI" as used herein indicates a present focal neurological deficit (e.g., hemiparesis, aphasia, apraxia, hemianopsia, or neglect), or one of the decreases in the glasgow coma scale score (either in total score or in individual portions thereof [ eye, motion on each side, language ]). This may or may not last for at least 1 hour, is not immediately apparent after occlusion of the aneurysm, and cannot be attributed to other reasons with clinical assessment, brain CT or Magnetic Resonance Imaging (MRI) scans, and appropriate laboratory studies. Angiographic cerebral vasospasm is a description of radiological studies (CT angiography [ CTA ], MR angiography [ MRA ] MRA or catheter angiography [ CA ]), and may be the cause of DCI.

The term "delayed release" is used herein in its conventional sense to refer to a pharmaceutical formulation wherein there is a time delay between administration of the formulation and release of the drug therefrom. "delayed release" may or may not include gradual release of the drug over an extended period of time, and thus may or may not be "sustained release".

The term "diffusible pharmacological effect" as used herein refers to a pharmacological effect that spreads, disperses or spreads widely across gaps or surfaces.

The term "disease" or "disorder" as used herein refers to a condition of impaired or abnormal function of health.

The term "disposed" as used herein refers to being disposed, arranged, or distributed in a particular manner.

The term "drug" as used herein refers to a therapeutic agent or any substance other than food for use in the prevention, diagnosis, alleviation, treatment or cure of disease.

The term "effective amount" refers to an amount necessary or sufficient to achieve a desired biological effect.

The term "emulsion" as used herein refers to a biphasic system prepared by combining two immiscible liquid vehicles, one of which is uniformly dispersed in the other and consists of globules of equal or greater diameter than the largest colloidal particle. The size of the pellet is critical and must be such that the system achieves maximum stability. Typically, separation of the two phases will occur unless a third material (emulsifier) is incorporated. Thus, the base emulsion contains at least three components, two immiscible liquid carriers and emulsifiers, and an active ingredient. Most emulsions incorporate an aqueous phase into a non-aqueous phase (or vice versa). However, it is possible to prepare substantially anhydrous emulsions, for example, anionic and cationic surfactants, free of the water-immiscible systems glycerol and olive oil.

The term "flowable" as used herein means capable of moving in a stream or stream-like manner by a continuous change in relative position.

The term "granulomatous inflammation" as used herein refers to an inflammatory response characterized by a predominance of normal macrophages relative to epithelial macrophages, with or without multinucleated giant cells and connective tissue.

The term "hydrogel" as used herein refers to a substance that forms a solid, semi-solid, pseudoplastic, or plastic structure containing the necessary aqueous components to form a gel-like or jelly-like mass.

The term "hypertension" as used herein refers to systemic hypertension; the transient or sustained elevation of systemic blood pressure to levels that may cause cardiovascular damage or other adverse consequences.

The term "hypotension" as used herein refers to a lower than normal systemic arterial blood pressure; any kind of pressure or tension drop.

The term "implantation" as used herein refers to the implantation, embedding or insertion of a substance, composition or device into a predetermined location within a tissue.

The term "impregnated," in its various grammatical forms, as used herein, refers to being infused or infiltrated throughout; to fill the gap with a substance.

The term "infarction" as used herein refers to a sudden arterial or venous insufficiency caused by embolism, thrombus, mechanistic factors or pressure in macroscopic areas where necrosis occurs. The term "cerebral infarction" as used herein refers to the loss of brain tissue following a transient or permanent loss of circulation and/or oxygen transport to the brain region of the brain.

The term "inflammation" as used herein refers to the physiological process by which vascularized tissue responds to injury. See, for example, FUNDAMENTAL IMMUNOLOGY, fourth edition, William E.Paul, Lippincott-Raven Publishers, Philadelphia (1999) page 1051-1053, which is incorporated herein by reference. During the inflammatory process, cells involved in detoxification and repair are mobilized by inflammatory mediators to the site of injury. Inflammation is often characterized by a strong infiltration of leukocytes, especially neutrophils (polymorphonuclear cells), at the site of inflammation. These cells promote tissue damage by releasing toxic substances in the vessel wall or undamaged tissue. Traditionally, inflammation is divided into acute and chronic reactions.

The term "damage" as used herein refers to the destruction or injury of a bodily structure or function by an external factor or force, which may be physical or chemical.

The term "ischemia" as used herein refers to a shortage of blood supply and oxygen that occurs when the distal reduced perfusion pressure of an abnormally narrowed (stenotic) blood vessel cannot be compensated for by the autoregulatory dilation of the resistant vessel.

The term "isolated molecule" as used herein refers to a molecule that is substantially pure and free of other substances that are normally present with the molecule in nature or in vivo systems to the extent that it is feasible and appropriate for its intended use.

As used herein, the terms "in vivo", "void volume", "resection pocket", "excavation", "injection site", "deposition site" or "implantation site" or "delivery site" are meant to include without limitation all tissues of the body, and may refer to a cavity formed therein as a result of injection, surgical resection, tumor or tissue removal, tissue damage, abscess formation, or the like, or any other similar cavity, or pocket formed by clinical assessment of behavior, treatment, or physiological response to disease or pathology, as non-limiting examples thereof.

The phrase "localized administration" as used herein refers to the administration of a therapeutic agent at a specific location in the body, which administration can result in either a localized pharmacologic effect (i.e., a pharmacologic effect that is confined to a location) or a diffuse pharmacologic effect (i.e., a pharmacologic effect that is widely spread, dispersed, or dispersed in gaps or surfaces).

The phrase "localized pharmacological effect" as used herein refers to a pharmacological effect that is limited to a location, i.e., in close proximity to a location, place, region, or site.

The term "long-term" release as used herein means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days and possibly up to about 30 days to about 60 days.

As used herein, the term "microthrombolus" (or plurals of microthrombosomes) refers to a small piece of blood clot that causes a vessel to become occluded or blocked.

The term "adjust" as used herein means to adjust, change, adapt or adjust to a degree or proportion.

The term "optionally" as used herein means that the pharmaceutical composition of the invention may or may not contain a pharmaceutically acceptable carrier and includes pharmaceutical compositions comprising a microparticle formulation of a voltage-gated calcium channel blocker and a pharmaceutically acceptable carrier.

The term "parenteral" as used herein means introduction into the body by an injection method (i.e., administration by injection) outside the gastrointestinal tract, and includes, for example, subcutaneous (i.e., injection under the skin), intramuscular (i.e., injection intramuscularly), intravenous (injection into a vein), intrathecal (i.e., injection into the space around the spinal cord or subarachnoid space in the brain), intrasternal injection, or infusion techniques. Compositions for parenteral administration are delivered using a needle (e.g., a surgical needle). The term "surgical needle" as used herein refers to any needle suitable for delivering a fluid (i.e., flowable) composition to a selected anatomical structure. Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.

The term "paresis" as used herein refers to partial or incomplete paralysis.

The term "particle" or "microparticle" as used herein refers to a very small component, e.g., a nanoparticle or microparticle, that may contain, in whole or in part, at least one therapeutic agent as described herein. The particles may contain a therapeutic agent in a core surrounded by a coating. The therapeutic agent may also be dispersed throughout the particle. The therapeutic agent may also be adsorbed in the particles. The particles may have any level of release kinetics including zero order release, first order release, second order release, delayed release, sustained release, rapid release, and the like, and any combination thereof. In addition to the therapeutic agent, the particles may include any material conventionally used in the pharmaceutical and medical arts, including but not limited to erodible, non-erodible, biodegradable, or non-biodegradable materials or combinations thereof. The particles may be microcapsules containing the voltage-gated calcium channel blocker in solution or in a semi-solid state. The particles may be of virtually any shape.

The term "pharmaceutically acceptable carrier" as used herein refers to one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" as used herein refers to a natural or synthetic organic or inorganic ingredient with which the active ingredient is combined to facilitate administration. The ingredients of the pharmaceutical composition can also be mixed in such a way that there are no interactions that would significantly impair the desired pharmacological efficacy.

The term "pharmaceutical composition" is used herein to refer to a composition for preventing, reducing the intensity, curing or treating a condition or disease of interest.

The term "pharmacological effect" as used herein refers to the result or consequence of exposure to an active drug.

The phrase "predominantly localized pharmacological effect" as used herein refers to a pharmacological effect of a drug confined to a site that is at least 1 to 3 orders of magnitude higher than that achieved with systemic administration.

The term "prognosis" as used herein refers to the expected cause and outcome of a disease or condition based on medical knowledge.

The term "reduction" or "reducing" as used herein refers to a reduction, decrease, attenuation, limitation or alleviation of the extent, intensity, extent, size, number, density, number or incidence of a disorder in an individual at risk of developing the disorder.

The term "subacute inflammation" as used herein refers to the tissue reaction commonly seen following an early inflammatory process, characterized by a mixture of neutrophils, lymphocytes and occasionally macrophages and/or plasma cells.

The term "subarachnoid hemorrhage" or "SAH" is used herein to refer to a condition in which blood collects under the arachnoid space. This region, known as the subarachnoid space, usually contains cerebrospinal fluid. The accumulation of blood in the subarachnoid space can lead to stroke, seizures and other complications. In addition, SAH can cause permanent brain damage and many harmful biochemical events in the brain. Causes of SAH include bleeding from cerebral aneurysms, vascular abnormalities, trauma, and extension of primary intracerebral hemorrhage to the subarachnoid space. Symptoms of SAH include, for example, sudden severe headaches, nausea and/or vomiting, symptoms of meningeal irritation (e.g., neck stiffness, lower back pain, bilateral leg pain), photophobia and visual changes, and/or loss of consciousness. SAH is usually secondary to head injury or a vascular defect known as an aneurysm. In some cases, SAH can cause cerebral vasospasm, which may in turn lead to ischemic stroke. A common manifestation of SAH is the presence of blood in the CSF. Subjects with SAH can be identified by a variety of symptoms. For example, a subject with subarachnoid hemorrhage will typically have a significant amount of blood under the arachnoid space. Subjects with subarachnoid hemorrhage can also be identified by intracranial pressure that approaches mean arterial pressure, by a drop in cerebral perfusion pressure, or by a sudden temporary loss of consciousness (sometimes preceded by headache). In about half of the cases, subjects showed severe headaches associated with physical exertion. Other symptoms associated with subarachnoid hemorrhage include nausea, vomiting, memory loss, hemiparesis and aphasia. Subjects with SAH can also be identified by the presence of creatine kinase-BB isozyme activity in their CSF. This enzyme is enriched in the brain but is normally absent in CSF. Thus, its presence in the CSF indicates "leakage" from the brain into the subarachnoid space. Coplin et al describe the assay of creatine kinase-BB isozyme activity in CSF (Coplin et al 1999ArchNeurol 56, 1348-1352). In addition, spinal or lumbar puncture can be used to demonstrate the presence or absence of blood in the CSF, which is a strong marker of subarachnoid hemorrhage. Cranial CT scanning or MRI can also be used to identify blood in the subarachnoid region. Angiography can also be used to determine not only whether bleeding has occurred, but also the location of the bleeding. Subarachnoid hemorrhage is usually the result of rupture of an intracranial cystic aneurysm or malformation of the arteriovenous system within and leading to the brain. Thus, subjects at risk for subarachnoid hemorrhage include subjects with cystic aneurysms as well as subjects with arteriovenous system malformations. Common sites for cystic aneurysms are the apex of the basilar artery and the intersection of the basilar artery with the superior or inferior anterior cerebellar artery. Subjects with subarachnoid hemorrhage may be identified by ophthalmic examination, where slowed eye movement may indicate brain injury. Objects with cystic aneurysms can be identified by conventional medical imaging techniques such as CT and MRI. Cystic or cerebral aneurysms form mushroom-like or berry-like shapes (sometimes referred to as "necked dome" shapes).

The terms "subject" or "individual" or "patient" are used interchangeably to refer to a member of an animal species of mammalian (including human) origin.

The phrase "subject having vasospasm" as used herein refers to a subject exhibiting diagnostic markers and symptoms associated with vasospasm. Diagnostic markers include, but are not limited to, the presence of blood in the CSF and/or a recent history of subarachnoid hemorrhage. Symptoms associated with vasospasm include, but are not limited to, paralysis of one side of the body, inability to speak or understand spoken or written language, and inability to perform tasks requiring spatial analysis. Such symptoms may develop over several days, or their manifestations may fluctuate, or may appear suddenly.

The phrase "subject having angiographic vasospasm" as used herein refers to a subject exhibiting a diagnostic marker associated with vasospasm. Diagnostic markers include, but are not limited to, the presence of blood in the CSF, recent history of SAH and/or the decrease in lumen diameter of cerebral arteries observed upon catheter angiography, computed tomography angiography, or magnetic resonance angiography 1 to 14 days after SAH or TBI. Symptoms associated with vasospasm include, but are not limited to, paralysis of one side of the body, inability to speak or understand spoken or written language, and inability to perform tasks requiring spatial analysis. Such symptoms may develop over several days, or their manifestations may fluctuate, or may appear suddenly. Transcranial doppler ultrasound may also be used to diagnose and monitor the progression of, for example, angiographic vasospasm. CT scanning can be used to detect the presence of blood in the CSF. However, in some cases, the amount of blood is too small to be detected by CT, and lumbar puncture may be used.

The phrase "subject having cerebral vasospasm" as used herein refers to a subject having symptoms of cerebral vasospasm or who has been diagnosed with cerebral vasospasm. A subject at risk for cerebral vasospasm is a subject who has one or more predisposing factors for developing cerebral vasospasm. Predisposing factors include, but are not limited to, the presence of subarachnoid hemorrhage. Subjects who have experienced recent SAH are at significantly higher risk of developing cerebral vasospasm than subjects who have not experienced recent SAH. MR angiography, CT angiography, and catheter angiography can be used to diagnose cerebral vasospasm. Angiography is a technique for introducing a contrast agent into the bloodstream to observe the bloodstream and/or arteries. Since blood flow and/or arteries are sometimes only weakly visible in radiographic films of conventional MR scans, CT scans or catheter angiography, contrast agents are necessary. Suitable contrast agents will vary depending on the imaging technique used. For example, gadolinium is a commonly used contrast agent in MR scans. Other suitable MR contrast agents are known in the art.

As used herein, the phrase "subject suffering from ' late cerebral ischemia ' or ' DCI" refers to a subject exhibiting a diagnostic marker associated with DCI. Diagnostic markers include, but are not limited to, the presence of blood in the CSF and/or a recent history of SAH and/or the appearance of neurological deterioration 1 to 14 days after SAH when it is not due to another cause that can be diagnosed, including, but not limited to, seizures, hydrocephalus, increased intracranial pressure, infection, intracranial hemorrhage or other systemic factors. DCI-related symptoms include, but are not limited to, one-sided physical paralysis, inability to speak or understand spoken or written language, and inability to perform tasks requiring spatial analysis. Such symptoms may develop over several days, or their manifestations may fluctuate, or may appear suddenly.

The phrase "subject having microthrombus emboli" as used herein refers to a subject exhibiting a diagnostic marker associated with microthrombus emboli. Diagnostic markers include, but are not limited to, the presence of blood in the CSF and/or a recent history of SAH and/or the appearance of neurological deterioration 1 to 14 days after SAH when it is not due to another cause that can be diagnosed, including, but not limited to, seizures, hydrocephalus, increased intracranial pressure, infection, intracranial hemorrhage or other systemic factors. An additional diagnostic marker may be an embolic signal detected while the brain conducts aortic transcranial doppler ultrasound. Symptoms associated with microthrombotic emboli include, but are not limited to: one side is physically paralyzed, unable to speak or understand spoken or written language, and unable to complete tasks requiring spatial analysis. Such symptoms may develop over several days, or their manifestations may fluctuate, or may appear suddenly.

The phrase "subject with cortical spreading ischemia" as used herein means a subject with a diagnostic marker associated with cortical spreading ischemia. Diagnostic markers include, but are not limited to, the presence of blood in the CSF and/or a recent history of SAH and/or the appearance of neurological deterioration 1 to 14 days after SAH when it is not due to another cause that can be diagnosed, including, but not limited to, seizures, hydrocephalus, increased intracranial pressure, infection, intracranial hemorrhage or other systemic factors. Another diagnostic marker may be the detection of a propagating wave of depolarization accompanied by vasoconstriction as detected by the cortical electroencephalogram. Symptoms associated with cortical spreading ischemia include, but are not limited to: one side is physically paralyzed, unable to speak or understand spoken or written language, and unable to complete tasks requiring spatial analysis. Such symptoms may develop over several days, or their manifestations may fluctuate, or may appear suddenly.

Subjects at risk for DCI, microthromboemboli, cortical spreading ischemia, or angiographic vasospasm are individuals with one or more predisposing factors for these conditions. Predisposing factors include, but are not limited to, the presence of SAH. Subjects who have experienced recent SAH are at significantly higher risk of developing angiographic vasospasm and DCI than subjects who have not experienced recent SAH. MR angiography, CT angiography, and catheter angiography can be used to diagnose at least one of DCI, microthromboemboli, cortical spreading ischemia, or angiographic vasospasm. Angiography is a technique for introducing a contrast agent into the bloodstream to observe the bloodstream and/or arteries. Since blood flow and/or arteries are sometimes only weakly visible in radiographic films of conventional MR scans, CT scans or catheter angiography, contrast agents are necessary. Suitable contrast agents will vary depending on the imaging technique used. For example, gadolinium is a commonly used contrast agent in MR scans. Other suitable MR contrast agents are known in the art.

The phrase "substantially pure" as used herein refers to a state of a therapeutic agent in which it is substantially separated from the substance with which it is associated in a living system or during synthesis. According to some embodiments, the substantially pure therapeutic agent is at least 70% pure, at least 75% pure, at least 80% pure, at least 85% pure, at least 90% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, or at least 99% pure.

The term "sustained release" (also referred to as "extended release") is used herein in its conventional sense to refer to a pharmaceutical formulation that provides gradual release of the drug over an extended period of time and preferably, although not necessarily, produces substantially constant blood levels of the drug over an extended period of time. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle. Non-limiting examples of sustained release biodegradable polymers include polyesters, polyester polyethylene glycol copolymers, polyamino-derived biopolymers, polyanhydrides, polyorthoesters, polyphosphazenes, SAIBs, photopolymerizable biopolymers, protein polymers, collagen, polysaccharides, chitosan, and alginates.

The term "syndrome" as used herein refers to a pattern of symptoms that is indicative of certain diseases or conditions.

The phrase "systemic administration" as used herein refers to the administration of a therapeutic agent that produces a pharmacological effect throughout the body. Systemic administration includes enteral administration (e.g., oral) via the gastrointestinal tract and parenteral administration (e.g., intravenous, intramuscular, etc.) outside the gastrointestinal tract.

The term "therapeutic amount" or "effective amount" of one or more active agents is an amount sufficient to produce a desired therapeutic effect. In conjunction with the teachings provided herein, by selecting among various active compounds and weighting factors such as potency, relative bioavailability, patient weight, severity of adverse side effects and preferred mode of administration, an effective prophylactic or therapeutic regimen can be planned that does not cause significant toxicity and yet is effective for treating a particular subject. A therapeutically effective amount of active agent that can be employed can generally range from 0.1mg/kg body weight to about 50mg/kg body weight. The therapeutically effective amount for any particular application may vary depending on such factors as the disease or condition being treated, the particular voltage-gated calcium channel blocker being administered, the size of the subject, or the severity of the disease or condition. One skilled in the art can empirically determine an effective amount of a particular inhibitor and/or other therapeutic agent without undue experimentation. It is generally preferred to use the maximum dose, i.e., the highest safe dose according to some medical judgment. However, the dosage level will depend upon a variety of factors including the type of injury, age, weight, sex, medical condition of the patient, severity of the condition, route of administration, and the particular active agent used. Thus, dosage regimens can vary widely, but can be routinely determined by the surgeon using standard methods. "amount" and "dosage" are used interchangeably herein.

The term "therapeutic agent" as used herein refers to a drug, molecule, nucleic acid, protein, composition, or other substance that provides a therapeutic effect. The terms "therapeutic agent" and "active agent" are used interchangeably. The active agent can be a calcium channel inhibitor, a calcium channel antagonist, a calcium channel blocker, a transient receptor potential protein blocker, or an endothelin antagonist.

Therapeutic agents including the calcium channel inhibitors, calcium channel antagonists, calcium channel blockers, transient receptor potential protein blockers, and/or endothelin antagonists can be provided in particulate form.

The term "therapeutic element" as used herein refers to a therapeutically effective dose (i.e., dose and frequency of administration) that eliminates, reduces, or prevents progression of a particular disease manifestation, as a percentage of the population. One example of a commonly used therapeutic element is ED50, which describes the dose that appears therapeutically effective in a particular dose for a particular disease in 50% of the population.

The term "therapeutic effect" as used herein refers to the outcome of a treatment that is judged to be desirable and beneficial. Therapeutic effects may include directly or indirectly preventing, reducing or eliminating disease manifestations. The therapeutic effect may also directly or indirectly include the prevention, reduction or elimination of the development of the disease manifestation.

The term "topical" refers to the application of a composition at or immediately below the point of application. The phrase "topically applying" describes applying to one or more surfaces, including epithelial surfaces. Topical administration generally provides a local effect rather than a systemic effect as compared to transdermal administration.

The term "transient receptor potential protein blocker" as used herein refers to a protein that is structurally different from other calcium channel blockers and blocks the increase in intracellular calcium ions caused by receptor-mediated calcium ion influx.

The term "transient receptor potential protein antagonist" as used herein refers to a protein that is structurally distinct from other calcium channel antagonists and antagonizes the increase in intracellular calcium ion resulting from receptor-mediated calcium ion influx. Transient receptor potential protein blockers and antagonists include, but are not limited to, SK & F96365 (1- (. beta. - [3- (4-methoxy-phenyl) propoxy ] -4-methoxybenzyl ethyl) -1H-imidazole hydrochloride) and LOE 908(RS) - (3, 4-dihydro-6, 7-dimethoxyisoquinoline-1-. gamma.1) -2-phenyl-N, N-bis- [2- (2,3, 4-trimethoxyphenylethyl ] acetamide).

The terms "treat" or "treating" include eliminating, substantially inhibiting, delaying or reversing the progression of a disease, condition, or disorder, substantially ameliorating clinical or aesthetic symptoms of a condition, substantially preventing the appearance of clinical or aesthetic symptoms of a disease, condition, or disorder, and protecting from harmful or unpleasant symptoms. Treatment further refers to achieving one or more of the following: (a) reducing the severity of the condition; (b) limiting the development of symptoms characteristic of the disorder being treated; (c) limiting the worsening of symptoms characteristic of the condition being treated; (d) limiting recurrence of the disorder in a patient who has had the disorder; and (e) limiting the recurrence of symptoms in a patient who has been asymptomatic for the disorder.

The term "vasoconstriction" as used herein refers to the narrowing of a blood vessel caused by the contraction of the muscle wall of the blood vessel. When the blood vessels constrict, the flow of blood is restricted or slowed.

The term "vasodilation" as used herein in contrast to vasoconstriction refers to widening of blood vessels. The term "vasoconstrictor", "vasopressor" or "pressor" as used herein refers to a factor that causes vasoconstriction.

The term "vasospasm" as used herein refers to a decrease in the internal diameter of cerebral arteries due to contraction of smooth muscle in the arterial wall, which causes a decrease in blood flow, but usually without an increase in systemic vascular resistance. Vasospasm leads to decreased cerebral blood flow and increased cerebral vascular resistance. Without being limited by theory, it is generally believed that vasospasm is caused by local damage to the blood vessel, such as that caused by atherosclerosis, and other structural damage including traumatic head injury, aneurysmal subarachnoid hemorrhage, and other causes of subarachnoid hemorrhage. Cerebral vasospasm is a naturally occurring vasoconstriction that can also be triggered by the presence of blood in the CSF, usually after rupture of an aneurysm or traumatic head injury. Due to the interruption of blood supply, cerebral vasospasm can eventually lead to brain cell damage in the form of cerebral ischemia and infarction. The term "cerebral vasospasm" as used herein further refers to narrowing of the large volume arteries at the base of the brain that occurs delayed after subarachnoid hemorrhage, which is often associated with decreased perfusion in the distal region of the affected blood vessels. Cerebral vasospasm may occur at any time after the aneurysm ruptures, but the most common peak occurs 7 days after bleeding and often resolves within 14 days, when blood has been absorbed by the body. Angiographic vasospasm is a consequence of SAH, but can also occur following any pathology with blood deposited in the subarachnoid space. More specifically, the term "angiographic cerebral vasospasm" refers to the narrowing of the large volume arteries at the base of the brain (i.e., cerebral arteries) after bleeding into the subarachnoid space, and resulting in decreased perfusion of the distal brain region.

I. Composition comprising a metal oxide and a metal oxide

In one aspect, the present invention provides a pharmaceutical composition comprising (i) a microparticulate formulation of a voltage-gated calcium channel blocker; and optionally ((ii) a pharmaceutically acceptable carrier.

According to some embodiments, the pharmaceutical composition may prevent or reduce the incidence or severity of at least one delayed complication associated with brain injury in a mammal in need thereof, wherein the brain injury comprises an interruption of at least one cerebral artery. According to some such embodiments, the at least one delayed complication is selected from the group consisting of Delayed Cerebral Ischemia (DCI), intracerebral hematoma, intracerebroventricular hemorrhage, fever, angiographic vasospasm, microthrombus embolus, Cortical Spreading Ischemia (CSI), behavioral deficits, neurological deficits, cerebral infarction, neuronal cell death, or a combination thereof. According to one embodiment, the at least one delayed complication is Delayed Cerebral Ischemia (DCI). According to another embodiment, the at least one delayed complication is an intracerebral hematoma. According to another embodiment, the at least one delayed complication is intracerebroventricular hemorrhage. According to another embodiment, the at least one delayed complication is fever. According to another embodiment, the at least one delayed complication is angiographic vasospasm. According to another embodiment, the at least one delayed complication is Cortical Spreading Ischemia (CSI). According to another embodiment, the at least one delayed complication is microthrombosis. According to another embodiment, the at least one delayed complication is a behavioral deficit. According to another embodiment, the at least one delayed complication is a neurological deficit. According to another embodiment, the at least one delayed complication is cerebral infarction. According to another embodiment, the at least one delayed complication is neuronal cell death.

According to some embodiments, the brain injury is a result of an underlying pathology. Exemplary potential conditions include, but are not limited to, aneurysms, traumatic head injury, subarachnoid hemorrhage (SAH), or combinations thereof. According to one embodiment, the underlying condition is an aneurysm. According to another embodiment, the underlying condition is sudden traumatic head injury. According to another embodiment, the underlying condition is subarachnoid hemorrhage (SAH). According to another embodiment, the underlying condition is a combination of an aneurysm, a traumatic head injury, subarachnoid hemorrhage (SAH).

According to some embodiments, the pharmaceutical composition is effective to prevent or reduce the incidence or severity of at least one late complication associated with brain injury in a mammal in need thereof when administered to a delivery site in the mammal in a therapeutic amount, wherein the brain injury comprises an interruption of at least one cerebral artery. According to one embodiment, the delivery site is a ventricle. According to some embodiments, the ventricle is selected from the group consisting of a lateral ventricle, a third ventricle, a fourth ventricle, or a combination thereof. According to one embodiment, the delivery site is in the subarachnoid space. According to one embodiment, the delivery site is in close proximity to a brain injury. According to another embodiment, the delivery site is in close proximity to a blood vessel affected by brain injury. According to one embodiment, the blood vessel is at least one cerebral artery. According to another embodiment, the blood vessel is at least one cerebral artery affected by brain injury.

According to some embodiments, the delivery site is at a distance of 10mm, less than 9.9mm, less than 9.8mm, less than 9.7mm, less than 9.6mm, less than 9.5mm, less than 9.4mm, less than 9.3mm, less than 9.2mm, less than 9.1mm, less than 9.0mm, less than 8.9mm, less than 8.8mm, less than 8.7mm, less than 8.6mm, less than 8.5mm, less than 8.4mm, less than 8.3mm, less than 8.2mm, less than 8.1mm, less than 8.0mm, less than 7.9mm, less than 7.8mm, less than 7.7mm, less than 7.6mm, less than 7.5mm, less than 7.4mm, less than 7.3mm, less than 7.2mm, less than 7.1mm, less than 7.0mm, less than 6.9mm, less than 6.8mm, less than 6.7.5 mm, less than 6.4mm, less than 6.5mm, less than 5.5mm, less than 6mm, less than 5.5mm, less than 6mm, less than 5.1mm, less than 6mm, less than 6.5mm, less than 6mm, less than 6.5mm, less than 5.3mm, less than 5.2mm, less than 5.1mm, less than 5.0mm, less than 4.9mm, less than 4.8mm, less than 4.7mm, less than 4.6mm, less than 4.5mm, less than 4.4mm, less than 4.3mm, less than 4.2mm, less than 4.1mm, less than 4.0mm, less than 3.9mm, less than 3.8mm, less than 3.7mm, less than 3.6mm, less than 3.5mm, less than 3.4mm, less than 3.3mm, less than 3.2mm, less than 3.1mm, less than 3.0mm, less than 2.9mm, less than 2.8mm, less than 2.7mm, less than 2.6mm, less than 2.5mm, less than 2.4mm, less than 2.3mm, less than 2.2mm, less than 2.1mm, less than 2.0mm, less than 1.9mm, less than 1.8mm, less than 1.7mm, less than 1.5mm, less than 1.0mm, less than 1.9mm, less than 1.0mm, less than 0.1mm, less than 0.09mm, less than 0.08mm, less than 0.07mm, less than 0.06mm, less than 0.05mm, less than 0.04mm, less than 0.03mm, less than 0.02mm, less than 0.01mm, less than 0.009mm, less than 0.008mm, less than 0.007mm, less than 0.006mm, less than 0.005mm, less than 0.004mm, less than 0.003mm, less than 0.002mm, less than 0.001 mm.

According to some embodiments, the delivery site is 10mm, less than 9.9mm, less than 9.8mm, less than 9.7mm, less than 9.6mm, less than 9.5mm, less than 9.4mm, less than 9.3mm, less than 9.2mm, less than 9.1mm, less than 9.0mm, less than 8.9mm, less than 8.8mm, less than 8.7mm, less than 8.6mm, less than 8.5mm, less than 8.4mm, less than 8.3mm, less than 8.2mm, less than 8.1mm, less than 8.0mm, less than 7.9mm, less than 7.8mm, less than 7.7mm, less than 7.6mm, less than 7.5mm, less than 7.4mm, less than 7.3mm, less than 7.2mm, less than 7.1mm, less than 7.0mm, less than 6.9mm, less than 6.6mm, less than 7.5mm, less than 6.4mm, less than 6mm, less than 6.5mm, less than 6mm, less than 6.1mm, less than 8.0mm, less than 6mm, less than 5.6mm, less than 5.5mm, less than 5.4mm, less than 5.3mm, less than 5.2mm, less than 5.1mm, less than 5.0mm, less than 4.9mm, less than 4.8mm, less than 4.7mm, less than 4.6mm, less than 4.5mm, less than 4.4mm, less than 4.3mm, less than 4.2mm, less than 4.1mm, less than 4.0mm, less than 3.9mm, less than 3.8mm, less than 3.7mm, less than 3.6mm, less than 3.5mm, less than 3.4mm, less than 3.3mm, less than 3.2mm, less than 3.1mm, less than 3.0mm, less than 2.9mm, less than 2.8mm, less than 2.7mm, less than 2.6mm, less than 2.5mm, less than 2.4mm, less than 2.3mm, less than 2.2.2 mm, less than 2.1.0 mm, less than 2.0mm, less than 1.7mm, less than 1.6mm, less than 1.0mm, less than 1.5mm, less than 1.0mm, less than 1.1.0 mm, less than 1.6mm, less than 1.0mm, less than 1.9mm, less than 1.0mm, less than 1.6mm, less than 0.4mm, less than 0.3mm, less than 0.2mm, less than 0.1mm, less than 0.09mm, less than 0.08mm, less than 0.07mm, less than 0.06mm, less than 0.05mm, less than 0.04mm, less than 0.03mm, less than 0.02mm, less than 0.01mm, less than 0.009mm, less than 0.008mm, less than 0.007mm, less than 0.006mm, less than 0.005mm, less than 0.004mm, less than 0.003mm, less than 0.002mm, less than 0.001 mm.

According to some embodiments, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life ranging from 1 day to 30 days. According to one embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 1 day. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 2 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 3 days. According to one embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 4 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a 5 day half-life. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 6 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 7 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 8 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 9 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 10 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a 15 day half-life. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 30 days.

According to another embodiment, the release of the voltage-gated calcium channel blocker at the site of delivery is capable of producing a predominantly localized pharmacological effect over a desired time frame. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 1 day. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 2 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 3 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 4 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 5 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 6 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 7 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 8 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 15 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 30 days.

According to another embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a diffuse pharmacologic effect throughout the Central Nervous System (CNS) over a desired time frame. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 1 day. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 2 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) lasting 3 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 4 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 5 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 6 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) lasting 7 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 8 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 15 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 30 days.

According to one embodiment, the localized pharmacologic effect at the delivery site is a reduction in vasospasm, such that the inner diameter of at least one cerebral artery affected by the brain injury is increased as compared to a control. According to one embodiment, the pharmaceutical composition is effective to increase the inner diameter of a cerebral artery affected by brain injury compared to a control.

According to one embodiment, the diffuse pharmacological effect is a reduction of vasospasm such that at least 10mm, at least 9.9mm, at least 9.8mm, at least 9.7mm, at least 9.6mm, at least 9.5mm, at least 9.4mm, at least 9.3mm, at least 9.2mm, at least 9.1mm, at least 9.0mm, at least 8.9mm, at least 8.8mm, at least 8.7mm, at least 8.6mm, at least 8.5mm, at least 8.4mm, at least 8.3mm, at least 8.2mm, at least 8.1mm, at least 8.0mm, at least 7.9mm, at least 7.8mm, at least 7.7mm, at least 7.6mm, at least 7.5mm, at least 7.4mm, at least 7.3mm, at least 7.2mm, at least 7.1mm, at least 7.0mm, at least 6.9mm, at least 6.6mm, at least 7.5mm, at least 7.4mm, at least 7.3mm, at least 7.2mm, at least 6mm, at least 6.5mm, at least 6mm, at least 6.5mm, at least 6mm, an increase in the inner diameter of the blood vessel of at least 5.6mm, at least 5.5mm, at least 5.4mm, at least 5.3mm, at least 5.2mm, at least 5.1mm, at least 5.0 m.

Voltage-gated calcium channel blockers

According to some embodiments, the voltage-gated channel blocker is selected from the group consisting of an L-type voltage-gated calcium channel blocker, an N-type voltage-gated calcium channel blocker, a P/Q-type voltage-gated calcium channel blocker, or a combination thereof.

Non-limiting examples of voltage-gated calcium channel blockers that can be formulated into compositions include, but are not limited to, L-type voltage-gated calcium channel blockers, N-type voltage-gated calcium channel blockers, P/Q-type voltage-gated calcium channel blockers, or combinations thereof.

For example, L-type voltage-gated calcium channel blockers include, but are not limited to: dihydropyridine L-type blockers, such aS nisoldipine, nicardipine and nifedipine, AHFs (such aS (4aR,9aS) - (+) -4 a-amino-1, 2,3,4,4a,9 a-hexahydro-4 aH-fluorene, HCl), isradipine (such aS 4- (4-benzofurazanyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl 1-methylethyl ester), calcium (calcisepine) s (such aS isolated from Dendroaspis polyphylla), H-Arg-Ile-Cys-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Ala-Thr-Cys-Glu-Asn-Thr-Cys-Tyr-Lys-Met) -Phe-Ile-Arg-Thr-Gln-Arg-Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met-Trp-Pro-Tyr-Gln-Thr-Glu-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH, calcein (Calcicludine) species (as isolated from Dongfennese African Bolbilus viridis et al), H-Trp-Gln-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys-Lys-Gln-Phe-Ser-Phe-Tyr-Lys-Trp-Thr-Ala-Ser-Ser-Ser-Gln-Ser-Thr-Gln-Ser-Gln-Ser- -Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-Gly-Cys-Gly-Gly-Asn-Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Cys-Leu-Gly-Lys-OH, sinetidipine (e.g. also known as FRP-8653, an inhibitor of the dihydropyridine type), dilantine (dilatinzem) species (e.g. (2S,3S) - (+) cis-3-acetoxy-5- (2-dimethylaminoethyl) -2, 3-dihydro-2- (4-methoxyphenyl) -1, 5-benzothiazepin-4 (5H) -one hydrochloride, Diltiazem (e.g. benzothiazepine-4 (5H) -one, 3- (acetoxy) -5- [2- (dimethylamino) ethyl) ]2, 3-dihydro-2- (4-methoxyphenyl) - -, (+) -cis-, monohydrochloride), felodipine (e.g. ethyl methyl 4- (2, 3-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinecarboxylate), FS-2 (e.g. isolate from black snake (Dendroaspheroleylpipes polylipis) venom), FTX-3.3 (e.g. isolate from spider funnel (Agelenopsis saperta), neomycin sulphate (e.g. C)₂₃H₄₆N₆O₁₃·3H₂SO₄) Nicardipine (e.g. 1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenylmethyl) -2- [ methyl (phenylmethyl) amino)]-ethyl 3, 5-pyridinedicarboxylate hydrochloride, also known as YC-93), nifedipine (e.g. 1, 4-dihydro-2, 6-dimethyl-4- (2-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl esterEsters), nimodipine (e.g. 2-methoxyethyl-1-methylethyl-4- (3-nitrophenyl) -3, 5-pyridinedicarboxylate 4-methoxyethyl-3, 5-pyridinedicarboxylate) or (isopropyl-2-methoxyethyl-1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylate), nitrendipine (e.g. ethyl methyl-1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) -3, 5-pyridinedicarboxylate), S-Petasin (Petasin) compounds (e.g. (3S,4aR,5R,6R) - [2,3,4,4a,5,6,7, 8-octahydro-3- (2-propenyl) -4a, 5-dimethyl-2-oxo-6-naphthyl]Z-3 ' -methylthio-1 ' -acrylate), phloretins (Phloretin) such as 2 ', 4 ', 6 ' -trihydroxy-3- (4-hydroxyphenyl) propiophenone, and 3- (4-hydroxyphenyl) -1- (2,4, 6-trihydroxy-phenyl) -1-propanone, and b- (4-hydroxyphenyl) -2,4, 6-trihydroxy propiophenone, and protoporphyrins such as C ₂₀H_I9NO₅C1) SKF-96365 (e.g. 1- [ b- [3- (4-methoxyphenyl) propoxy)]-4-methoxybenzyl ethyl]-1H-imidazole, HCl), tetrandrines (e.g. 6,6 ', 7, 12-tetramethoxy-2, 2' -dimethyltetrandrine), (+ -) methoxy verapamil or (+) -verapamil (e.g. 54N- (3, 4-dimethoxyphenylethyl) methylamino]-2- (3, 4-dimethoxyphenyl) -2-isopropylvaleronitrile hydrochloride), and (R) - (+) -Bay K8644 species (e.g. R- (+) -1, 4-dihydro-2, 6-dimethyl-5-nitro-442- (trifluoromethyl) phenyl]-3-pyridinecarboxylic acid methyl ester). The foregoing examples may be specific for L-type voltage-gated calcium channels or may inhibit a broader range of voltage-gated calcium channels, such as N, P/Q, R and T-type.

According to some embodiments, the voltage-gated calcium channel blocker is a dihydropyridine calcium channel blocker. According to one embodiment, the dihydropyridine calcium channel blocker is nimodipine. According to one embodiment, the nimodipine has a half-life of 7-10 days and suitable lipid solubility when formulated as described herein.

According to some embodiments, the voltage-gated calcium channel blocker is an isolated molecule. The term "isolated molecule" as used herein refers to a molecule that is substantially pure and free of other substances with which it is normally found in nature or in vivo systems to the extent feasible and appropriate for its intended use.

According to some embodiments, the voltage-gated calcium channel blocker is admixed with a pharmaceutically acceptable carrier in a pharmaceutical formulation. According to some such embodiments, the voltage-gated calcium channel blocker constitutes only a small percentage by weight of the formulation. According to some embodiments, the voltage-gated calcium channel blocker is substantially pure.

Pharmaceutically acceptable carriers

According to some embodiments, the pharmaceutical composition does not comprise a pharmaceutically acceptable carrier. According to some embodiments, the pharmaceutically acceptable carrier does not include hyaluronic acid.

According to one embodiment, the pharmaceutically acceptable carrier is a solid carrier or excipient. According to another embodiment, the pharmaceutically acceptable carrier is a gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various mono-and polysaccharides (including, but not limited to, hyaluronic acid), starch, cellulose derivatives, gelatin, and polymers. Exemplary carriers may also include saline vehicles, such as Hydroxypropylmethylcellulose (HPMC) in Phosphate Buffered Saline (PBS).

According to some embodiments, the pharmaceutically acceptable carrier imparts adhesiveness to the composition. According to one embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid. According to some embodiments, the pharmaceutically acceptable carrier comprises 0% to 5% hyaluronic acid. According to one embodiment, the pharmaceutically acceptable carrier comprises less than 0.05% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.1% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.2% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.3% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.4% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.6% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.7% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.8% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.9% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.1% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.2% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.3% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.4% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.6% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.7% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.8% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.9% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.1% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.2% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid 2.3% less. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.4% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.6% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.7% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.8% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.9% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 3.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 3.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 4.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 4.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 5.0% hyaluronic acid.

In some embodiments, the pharmaceutically acceptable carrier includes, but is not limited to, a gel sustained release solid or semi-solid compound, optionally as a sustained release gel. In some such embodiments, the voltage-gated calcium channel blocker is embedded in a pharmaceutically acceptable carrier. In some embodiments, the voltage-gated calcium channel blocker is coated on a pharmaceutically acceptable carrier. The coating may be of any desired material, preferably a polymer or a mixture different from a polymer. Optionally, the polymer may be used in a granulation stage to form a matrix with the active ingredient to obtain a desired release pattern of the active ingredient. The gel sustained release solid or semi-solid compound is capable of releasing the active agent over a desired time frame. The gel sustained release solid or semi-solid compound may be implanted into a tissue within the human brain, such as, but not limited to, in close proximity to a blood vessel, such as a cerebral artery.

According to another embodiment, the pharmaceutically acceptable carrier comprises a slow release solid compound. According to one such embodiment, the voltage-gated calcium channel blocker is embedded in or coated on the slow-release solid compound. According to yet another embodiment, the pharmaceutically acceptable carrier comprises slow-release microparticles comprising a voltage-gated calcium channel blocker.

According to another embodiment, the pharmaceutically acceptable carrier is a gel compound, such as a biodegradable hydrogel.

Microparticle formulation

According to some embodiments, the voltage-gated calcium channel blocker is provided in particle form. The term "particle" as used herein refers to a nano-sized or micro-sized (or in some cases larger) particle that may contain, in whole or in part, the calcium channel inhibitor. According to some embodiments, the microparticle formulation comprises a plurality of microparticles impregnated with the voltage-gated calcium channel blocker. According to one embodiment, the voltage-gated calcium channel blocker is comprised inside the core of the particle surrounded by the coating. According to another embodiment, the voltage-gated calcium channel blocker is dispersed throughout the surface of the particle. According to another embodiment, the voltage-gated calcium channel blocker is disposed on or in a microparticle. According to another embodiment, the voltage-gated calcium channel blocker is disposed on the surface of the entire microparticle. According to another embodiment, the voltage-gated calcium channel blocker is adsorbed into the particle.

According to some such embodiments, the microparticles are in a uniform size distribution. According to some embodiments, the uniform distribution of particle sizes is achieved by a homogenization process to form a uniform emulsion comprising the particles. According to some such embodiments, each microparticle comprises a matrix. According to some embodiments, the matrix comprises a voltage-gated calcium channel blocker.

According to some embodiments, the pharmaceutical composition is flowable. According to some embodiments, the microparticle formulation component of the pharmaceutical composition is flowable.

According to some embodiments, the particles are selected from the group consisting of zero order release, first order release, second order release, delayed release, sustained release, rapid release, and combinations thereof. In addition to therapeutic agents, such particles may include any of those materials conventionally used in the medical arts, including but not limited to erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof.

According to some embodiments, the particles are microcapsules containing the voltage-gated calcium channel blocker in solution or in a semi-solid state. According to some embodiments, the particle is a microparticle comprising, in whole or in part, a voltage-gated calcium channel blocker. According to some embodiments, the particle is a nanoparticle comprising, in whole or in part, a voltage-gated calcium channel blocker. According to some embodiments, the particles may be of almost any shape.

According to some embodiments, the particle size is between about 25 μm to about 100 μm. According to some embodiments, the particle size is between about 30 μm to about 80 μm. According to one embodiment, the particle size is at least about 25 μm. According to another embodiment, the particle size is at least about 30 μm. According to another embodiment, the particle size is at least about 35 μm. According to another embodiment, the particle size is at least about 40 μm. According to another embodiment, the particle size is at least about 45 μm. According to another embodiment, the particle size is at least about 50 μm. According to another embodiment, the particle size is at least about 55 μm. According to another embodiment, the particle size is at least about 60 μm. According to another embodiment, the particle size is at least about 65 μm. According to another embodiment, the particle size is at least about 70 μm. According to another embodiment, the particle size is at least about 75 μm. According to another embodiment, the particle size is at least about 80 μm. According to another embodiment, the particle size is at least about 85 μm. According to another embodiment, the particle size is at least about 90 μm. According to another embodiment, the particle size is at least about 95 μm. According to another embodiment, the particle size is at least about 100 μm.

According to another embodiment, the voltage-gated calcium channel blocker may be provided in a thread. The wire may contain a voltage-gated calcium channel blocker in the coated core, or the voltage-gated calcium channel blocker may be dispersed throughout the wire, or a therapeutic agent may be adsorbed within the wire. Such a thread may have any level of release kinetics including zero order release, first order release, second order release, delayed release, sustained release, rapid release, and the like, and any combination thereof. Such a thread may include, in addition to the therapeutic agent, any of those materials conventionally used in the medical arts, including but not limited to erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof.

According to another embodiment, the voltage-gated calcium channel blocker may be provided in at least one sheet. The sheet may contain the voltage-gated calcium channel blocker and at least one additional therapeutic agent in the core surrounded by the coating, or the voltage-gated calcium channel blocker and at least one additional therapeutic agent may be dispersed throughout the sheet, or the voltage-gated calcium channel blocker may be adsorbed in the sheet. The sheet may have any level of release kinetics including zero order release, first order release, second order release, delayed release, sustained release, rapid release, and the like, and any combination thereof. Such a sheet may comprise, in addition to the voltage-gated calcium channel blocker and the at least one additional therapeutic agent, any of those materials conventionally used in the medical arts, including but not limited to erodible, non-erodible, biodegradable or non-biodegradable materials or combinations thereof.

According to some embodiments, the pharmaceutical composition further comprises a preservative. According to some such embodiments, the pharmaceutical composition is in unit dosage form. Exemplary unit dosage forms include, but are not limited to, ampoules or multi-dose containers.

According to some embodiments, the microparticle formulation comprises a suspension of microparticles. According to some embodiments, the pharmaceutical composition further comprises at least one of a suspending agent, a stabilizing agent, and a dispersing agent. According to some such embodiments, the pharmaceutical composition is presented as a suspension. According to some such embodiments, the pharmaceutical composition is now a solution. According to some such embodiments, the pharmaceutical composition is presented as an emulsion.

According to some embodiments, the formulation of the pharmaceutical composition comprises an aqueous solution of the voltage-gated calcium channel blocker in a water-soluble form. According to some embodiments, the formulation of the pharmaceutical composition comprises an oily suspension of the voltage-gated calcium channel blocker. Oily suspensions of the voltage-gated calcium channel blockers can be prepared using suitable lipophilic solvents. Exemplary lipophilic solvents or vehicles include, but are not limited to, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides. According to some embodiments, the formulation of the pharmaceutical composition comprises an aqueous suspension of a voltage-gated calcium channel blocker. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or materials that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the voltage-gated calcium channel blocker may be in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

Suitable liquid or solid pharmaceutical formulations include, for example, microencapsulated forms (and, where appropriate, one or more excipients), helical (encocholated), coated on gold nanoparticles, included in liposomes, pellets for implantation into tissue, or dried on the surface of an object to be rubbed into tissue. The term "microencapsulation" as used herein refers to a process wherein very tiny droplets or particles are surrounded or coated by a continuous film of biocompatible, biodegradable polymeric material or non-polymeric material to produce a solid structure including, but not limited to, spherical particles, globules, crystals, agglomerates, microspheres, or nanoparticles. Such pharmaceutical compositions may also be in the form of granules, beads, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or delayed release formulations of the active compound, wherein formulation excipients and additives and/or adjuvants such as disintegrants, binders, coatings, bulking agents, lubricants or solubilizers are generally used as described above. The pharmaceutical composition is suitable for use in a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer (1990) Science 249, 1527-.

Microencapsulation process

In U.S. Pat. No.5,407,609 (entitled microencapsulation Process and products thereof), U.S. application No.10/553,003 (entitled Process for producing emulsion-based microparticles), U.S. application No.11/799,700 (entitled emulsion-based microparticles and methods of producing the same), U.S. application No.12/557,946 (entitled solvent extraction microencapsulation with tunable extraction rate), U.S. application No.12/779,138 (entitled Hyaluronic Acid (HA) injection vehicle), U.S. application No.12/562,455 (entitled microencapsulation Process Using solvents and salts), U.S. application No.12/338,488 (entitled Process for preparing microparticles with Low solvent residual quantity), U.S. application No.12/692,027 (entitled controlled Release System from Polymer blends), U.S. application No.12/692,020 (entitled Polymer mixtures with polymers comprising different non-repeating units and methods of making and Using the same), U.S. application No.10/565,401 (entitled "controlled release composition"), U.S. application No.12/692,029 (entitled "drying method for modifying properties of microparticles"); U.S. application No.12/968,708 (entitled "emulsion based process for preparing microparticles and workheads for use therewith"); and U.S. application No.13/074,542 (entitled "compositions and methods for improving the residence of pharmaceutical compositions at a topical application site") disclose and describe microencapsulation processes and products; a method for producing emulsion-based microparticles; emulsion-based microparticles and a method for producing the same; solvent extraction microencapsulation with adjustable extraction rate; microencapsulation process using solvent and salt; a continuous double emulsion process for making microparticles; drying methods for modifying the properties of microparticles, controlled release systems from polymer blends; polymer blends having polymers comprising different non-repeating units and methods of making and using the same; and emulsion-based processes for preparing microparticles and examples of workhead assemblies for use therewith. The contents of each of these documents are incorporated herein in their entirety by reference.

According to some embodiments, the delivery of the voltage-gated calcium channel blocker using microparticle technology involves bioabsorbable polymeric particles encapsulating the voltage-gated calcium channel blocker and at least one additional therapeutic agent.

According to one embodiment, the microparticle formulation comprises a polymeric matrix, wherein the voltage-gated calcium channel blocker is impregnated in the polymeric matrix. According to one embodiment, the polymer is a slow release polymer. According to one embodiment, the polymer is poly (D, L-lactide-co-glycolide). According to another embodiment, the polymer is a poly (orthoester). According to another embodiment, the polymer is a poly (anhydride). According to another embodiment, the polymer is polylactide-polyglycolide.

Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for the delivery of the voltage-gated calcium channel blockers. Such polymers may be natural or synthetic polymers. The polymer is selected based on the desired time period of release. Bioadhesive polymers of particular interest include, but are not limited to, bioerodible hydrogels described by Sawhney et al in Macromolecules (1993)26,581-587, the teachings of which are incorporated herein. Exemplary bioerodible hydrogels include, but are not limited to, poly hyaluronic acid, casein, gelatin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (dodecyl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), and poly (octadecyl acrylate). According to one embodiment, the bioadhesive polymer is hyaluronic acid. In some such embodiments, the bioadhesive polymer comprises less than about 2.3% hyaluronic acid.

According to some embodiments, the pharmaceutical composition is formulated for parenteral injection, surgical implantation, or a combination thereof. According to some such embodiments, the pharmaceutical composition is in the form of a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, or a sterile powder for reconstitution into a sterile injectable solution or dispersion. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include, but are not limited to, water, ethanol, dichloromethane, acetonitrile, ethyl acetate, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Suspensions may also include suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide (aluminum metahydroxide), bentonite, agar-agar, tragacanth, and mixtures thereof.

According to some embodiments, the pharmaceutical composition is formulated in an injectable long acting form (depot form). Injectable depot forms are prepared by forming microencapsulated matrices of the voltage-gated calcium channel blockers in biodegradable polymers. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Such depot formulations may be formulated with suitable polymeric or hydrophobic materials (e.g. emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives (e.g. sparingly soluble salts). Examples of biodegradable polymers include, but are not limited to, polylactide-polyglycolide, poly (orthoester), and poly (anhydride). Injectable depot formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a Polyglycolide (PGA) matrix. PGA is a linear aliphatic polyester developed for use in sutures. Studies have reported PGA copolymers formed with trimethylene carbonate, polylactic acid (PLA) and polycaprolactone. Some of these copolymers may be formulated as microparticles for sustained drug release.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a polyester-polyethylene glycol matrix. Polyester-polyethylene glycol compounds can be synthesized; these compounds are soft and can be used for drug delivery.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a poly (amino) -derived biopolymer matrix. Poly (amino) -derived biopolymers may include, but are not limited to, those containing lactic acid and lysine as aliphatic diamines (see, e.g., U.S. patent 5,399,665) and tyrosine-derived polycarbonates and polyacrylates. Modification of the polycarbonate can change the length of the alkyl chain of such an ester (ethyl to octyl), while modification of the polyacrylate can further include changing the length of the alkyl chain of the diacid (e.g., succinic to sebacic acid), which enables great variation in the polymer and great flexibility in polymer properties.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a polyanhydride matrix. Polyanhydrides are prepared by dehydrating two diacid molecules by melt polymerization (see, e.g., U.S. patent 4,757,128). These polymers degrade due to surface attack (as opposed to polyesters that degrade due to bulk attack). The release of the drug may be controlled by the hydrophilicity of the selected monomer.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a photopolymerizable biopolymer matrix. Photopolymerizable biopolymers include, but are not limited to, lactic acid/polyethylene glycol/acrylate copolymers.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a hydrogel matrix. The term "hydrogel" refers to a substance that forms a solid, semi-solid, pseudoplastic, or plastic structure containing the necessary aqueous components to form a gel-like or jelly-like mass. Hydrogels generally include a variety of polymers, including hydrophilic polymers, acrylic acid, acrylamide, and 2-hydroxyethyl methacrylate (HEMA).

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a naturally occurring biopolymer matrix. Naturally occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides, and photopolymerizable compounds.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a protein polymer matrix. Protein polymers have been synthesized from self-assembling protein polymers such as fibroin, elastin, collagen and combinations thereof.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a naturally occurring polysaccharide matrix. Naturally occurring polysaccharides include, but are not limited to, chitin and its derivatives, hyaluronic acid, dextran, and cellulose (which are generally not biodegradable when unmodified) and Sucrose Acetate Isobutyrate (SAIB).

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on the chitin matrix. Chitin is predominantly composed of 2-acetamido-2-deoxy-D-glucosyl groups and is present in yeast, fungi and marine invertebrates (shrimp, crustaceans), where it is the main component of the exoskeleton. Chitin is not water soluble and deacetylated chitin, chitosan, is only soluble in acidic solutions (such as, for example, acetic acid). Studies have reported chitin derivatives that are water soluble, very high molecular weight (greater than 2 million daltons), viscoelastic, non-toxic, biocompatible, and capable of crosslinking with peroxides, glutaraldehyde, glyoxal or other aldehydes, and carbodiimides to form a gel.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a Hyaluronic Acid (HA) matrix. Hyaluronic Acid (HA), consisting of alternating glucuronic acid and glucosamine bonds and present in the vitreous humor, the extracellular matrix of the brain, the synovial fluid, the umbilical cord and the rooster comb of mammals (hyaluronic acid can be isolated and purified therefrom, and can also be produced by fermentation processes).

According to some embodiments, the pharmaceutical composition further comprises an adjuvant. Exemplary adjuvants include, but are not limited to, preservatives, wetting agents, emulsifying agents, and dispersing agents. Preservation of the action of microorganisms can be ensured by various antibacterial and antifungal substances such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example, sugars, sodium chloride, and the like, may also be included. Prolonged absorption of the injectable pharmaceutical form is brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

The formulations can be sterilized, for example, by terminal gamma irradiation, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol, dichloromethane, ethyl acetate, acetonitrile or the like. Acceptable vehicles and solvents that may be used include water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any low-irritation fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Formulations for parenteral (including but not limited to subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intrathecal, intracerebroventricular, and intraarticular) administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions which may contain suspending agents and thickening agents.

According to another embodiment, the pharmaceutical composition is formulated by linking the voltage-gated calcium channel blocker to a polymer that enhances water solubility. Examples of suitable polymers include, but are not limited to, polyethylene glycol, poly- (d-glutamic acid), poly- (l-glutamic acid), poly- (d-aspartic acid), poly- (l-aspartic acid), and copolymers thereof. Polyglutamic acids having a molecular weight between about 5,000 and about 100,000, and a molecular weight between about 20,000 and about 80,000 can be used, as can polyglutamic acids having a molecular weight between about 30,000 and about 60,000. The polymer is attached via an ester linkage to one or more hydroxyl groups of the inventive Epothilone (Epothilone) using a protocol substantially as described in U.S. patent No.5,977,163, incorporated herein by reference. In the case of the 21-hydroxy-derivatives of the invention, specific attachment sites include the hydroxy group off carbon-21. Other attachment sites include, but are not limited to, hydroxyl groups off carbon 3 and/or hydroxyl groups off carbon 7.

Suitable buffers include: acetic acid and salt (1-2% w/v); citric acid and salt (1-3% by weight/volume); boric acid and salts (0.5-2.5% by weight/volume); and phosphoric acid and salts (0.8-2% by weight/volume). Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); nipagin ester (0.01-0.25% by weight/volume) and thimerosal (0.004-0.02% by weight/volume).

Delivery system

In another aspect, the present invention provides a semi-solid (meaning having a certain degree of stable consistency) particulate delivery system for treating delayed complications associated with brain injury in a mammal in need thereof, wherein said brain injury comprises an interruption of at least one cerebral artery, said system comprising (a) a pharmaceutical composition comprising (i) a particulate formulation of a voltage-gated calcium channel blocker; and optionally (ii) a pharmaceutically acceptable carrier; and (b) a device for administering a therapeutic amount of the pharmaceutical composition, wherein the therapeutic amount is effective to reduce the signs or symptoms of at least one delayed complication associated with brain injury.

According to some embodiments, the semi-solid multiparticulate delivery system may prevent or reduce the incidence or severity of late complications associated with brain injury in a mammal in need thereof, wherein the brain injury comprises an interruption of at least one cerebral artery. According to some such embodiments, the at least one delayed complication is selected from the group consisting of Delayed Cerebral Ischemia (DCI), intracerebral hematoma, intracerebroventricular hemorrhage, fever, angiographic vasospasm, microthrombus embolus, Cortical Spreading Ischemia (CSI), behavioral deficits, neurological deficits, cerebral infarction, neuronal cell death, or a combination thereof. According to one embodiment, the at least one delayed complication is Delayed Cerebral Ischemia (DCI). According to another embodiment, the at least one delayed complication is an intracerebral hematoma. According to another embodiment, the at least one delayed complication is intracerebroventricular hemorrhage. According to another embodiment, the at least one delayed complication is fever. According to another embodiment, the at least one delayed complication is angiographic vasospasm. According to another embodiment, the at least one delayed complication is Cortical Spreading Ischemia (CSI). According to another embodiment, the at least one delayed complication is a plurality of microthromboemboli. According to another embodiment, the at least one delayed complication is a behavioral deficit. According to another embodiment, the at least one delayed complication is a neurological deficit. According to another embodiment, the at least one delayed complication is cerebral infarction. According to another embodiment, the at least one delayed complication is neuronal cell death.

According to some embodiments, the brain injury is a result of an underlying pathology. Exemplary potential conditions include, but are not limited to, aneurysms, traumatic head injury, subarachnoid hemorrhage (SAH), and the like. According to some such embodiments, the underlying condition is selected from an aneurysm, a sudden traumatic head injury, subarachnoid hemorrhage (SAH), or a combination thereof. According to one embodiment, the underlying condition is an aneurysm. According to another embodiment, the underlying condition is a sudden traumatic head injury. According to another embodiment, the underlying condition is subarachnoid hemorrhage (SAH).

According to some embodiments, the pharmaceutical composition is administered by parenteral injection or surgical implantation.

According to some embodiments, the semi-solid multi-particulate delivery system comprises a cannula or catheter through which the pharmaceutical composition is delivered, wherein the catheter is inserted into a delivery site within the mammalian body. According to one embodiment, the delivery site is in the ventricle of the brain. According to some embodiments, the ventricle is selected from the group consisting of a lateral ventricle, a third ventricle, a fourth ventricle, or a combination thereof. According to one embodiment, the delivery site is in the subarachnoid space. According to one embodiment, the delivery site is in close proximity to a brain injury. According to another embodiment, the delivery site is in close proximity to a blood vessel affected by brain injury. According to one embodiment, the blood vessel is at least one cerebral artery. According to another embodiment, the at least one cerebral artery is affected by brain injury.

The ventricles may be cannulated or catheterized as is well known in the art and as described in various neurosurgical textbooks. This is known as insertion or drainage of a ventricular catheter or a ventricular ostomy. Holes of different sizes may be drilled in the cranium and the epidura covering the brain cut open. The pia mater is dissected and a catheter (typically a hollow tube made of silicone elastomer of some other biocompatible, non-absorbable compound) is inserted through the brain into the selected ventricle. This is usually a lateral ventricle but any ventricle can be catheterized. The catheter may be used to monitor the pressure inside the head to expel CSF or to administer substances into CSF. Figure 8 shows a schematic of the delivery of a pharmaceutical composition comprising a suspension of voltage-gated calcium channel blocker microparticles to the ventricles of the brain via an intraventricular catheter. Fig. 9 shows a schematic depicting the application of a pharmaceutical composition comprising a voltage-gated calcium channel blocker in or on microparticles carried by CSF flow to each subarachnoid artery.

According to some embodiments, the delivery site is 10mm, less than 9.9mm, less than 9.8mm, less than 9.7mm, less than 9.6mm, less than 9.5mm, less than 9.4mm, less than 9.3mm, less than 9.2mm, less than 9.1mm, less than 9.0mm, less than 8.9mm, less than 8.8mm, less than 8.7mm, less than 8.6mm, less than 8.5mm, less than 8.4mm, less than 8.3mm, less than 8.2mm, less than 8.1mm, less than 8.0mm, less than 7.9mm, less than 7.8mm, less than 7.7mm, less than 7.6mm, less than 7.5mm, less than 7.4mm, less than 7.3mm, less than 7.2mm, less than 7.1mm, less than 7.0mm, less than 6.9mm, less than 6.8mm, less than 6.5mm, less than 6.4mm, less than 6.5mm, less than 6mm, less than 5mm, less than 6.5mm, less than 6mm, less than 5.2mm, less than 6mm, less than 6.1mm, less than 6mm, less than 5.4mm, less than 5.3mm, less than 5.2mm, less than 5.1mm, less than 5.0mm, less than 4.9mm, less than 4.8mm, less than 4.7mm, less than 4.6mm, less than 4.5mm, less than 4.4mm, less than 4.3mm, less than 4.2mm, less than 4.1mm, less than 4.0mm, less than 3.9mm, less than 3.8mm, less than 3.7mm, less than 3.6mm, less than 3.5mm, less than 3.4mm, less than 3.3mm, less than 3.2mm, less than 3.1mm, less than 3.0mm, less than 2.9mm, less than 2.8mm, less than 2.7mm, less than 2.6mm, less than 2.5mm, less than 2.4mm, less than 2.3mm, less than 2.2mm, less than 2.1mm, less than 2.0, less than 1.9mm, less than 1.7mm, less than 1.0mm, less, less than 0.2mm, less than 0.1mm, less than 0.09mm, less than 0.08mm, less than 0.07mm, less than 0.06mm, less than 0.05mm, less than 0.04mm, less than 0.03mm, less than 0.02mm, less than 0.01mm, less than 0.009mm, less than 0.008mm, less than 0.007mm, less than 0.006mm, less than 0.005mm, less than 0.004mm, less than 0.003mm, less than 0.002mm, less than 0.001 mm.

According to some embodiments, the delivery site is 10mm, less than 9.9mm, less than 9.8mm, less than 9.7mm, less than 9.6mm, less than 9.5mm, less than 9.4mm, less than 9.3mm, less than 9.2mm, less than 9.1mm, less than 9.0mm, less than 8.9mm, less than 8.8mm, less than 8.7mm, less than 8.6mm, less than 8.5mm, less than 8.4mm, less than 8.3mm, less than 8.2mm, less than 8.1mm, less than 8.0mm, less than 7.9mm, less than 7.8mm, less than 7.7mm, less than 7.6mm, less than 7.5mm, less than 7.4mm, less than 7.3mm, less than 7.2mm, less than 7.1mm, less than 7.0mm, less than 6.9mm, less than 6.6mm, less than 7.5mm, less than 6.4mm, less than 6mm, less than 6.5mm, less than 6mm, less than 6.1mm, less than 8.0mm, less than 6mm, less than 5.6mm, less than 5.5mm, less than 5.4mm, less than 5.3mm, less than 5.2mm, less than 5.1mm, less than 5.0mm, less than 4.9mm, less than 4.8mm, less than 4.7mm, less than 4.6mm, less than 4.5mm, less than 4.4mm, less than 4.3mm, less than 4.2mm, less than 4.1mm, less than 4.0mm, less than 3.9mm, less than 3.8mm, less than 3.7mm, less than 3.6mm, less than 3.5mm, less than 3.4mm, less than 3.3mm, less than 3.2mm, less than 3.1mm, less than 3.0mm, less than 2.9mm, less than 2.8mm, less than 2.7mm, less than 2.6mm, less than 2.5mm, less than 2.4mm, less than 2.3mm, less than 2.2.2 mm, less than 2.1.0 mm, less than 2.0mm, less than 1.7mm, less than 1.6mm, less than 1.0mm, less than 1.5mm, less than 1.0mm, less than 1.1.0 mm, less than 1.6mm, less than 1.0mm, less than 1.9mm, less than 1.0mm, less than 1.6mm, less than 0.4mm, less than 0.3mm, less than 0.2mm, less than 0.1mm, less than 0.09mm, less than 0.08mm, less than 0.07mm, less than 0.06mm, less than 0.05mm, less than 0.04mm, less than 0.03mm, less than 0.02mm, less than 0.01mm, less than 0.009mm, less than 0.008mm, less than 0.007mm, less than 0.006mm, less than 0.005mm, less than 0.004mm, less than 0.003mm, less than 0.002mm, less than 0.001 mm.

According to some embodiments, the pharmaceutical composition comprising a voltage-gated calcium channel blocker may be delivered to the cerebral ventricles and subsequently carried by cerebrospinal fluid (CSF) flow to at least one cerebral artery of the subarachnoid space to achieve localized release of a therapeutically effective amount of the voltage-gated calcium channel blocker, thereby treating or reducing the incidence or severity of at least one late complication arising from an underlying disease, disorder, condition, or sudden brain injury and improving prognosis. According to one embodiment, the delivery site is in at least one ventricle. Because the voltage-gated calcium channel blocker is delivered locally to the site of brain injury, the dose required to treat or reduce the severity of at least one delayed complication is lower, thus avoiding the unwanted side effects associated with systemic delivery of higher doses, such as hypotension.

According to one embodiment, the pharmaceutical composition comprising the voltage-gated calcium channel blocker may be delivered by inserting a catheter into the cerebral ventricle and injecting the pharmaceutical composition through the catheter such that the pharmaceutical composition is locally emitted from the catheter tip into the cerebral ventricle.

According to another embodiment, the pharmaceutical composition is administered as a bolus injection. According to another embodiment, the injection is repeated after a predetermined period of time. According to some such embodiments, the predetermined period of time may range from 1 minute or more to 10 days or more. For example, repeated injections may be given if monitoring of the patient indicates that the patient still has evidence of angiographic vasospasm and/or DCI. The CSF circulation can carry the pharmaceutical composition from the cerebral ventricles into the subarachnoid space. CSF circulation is usually slowed after SAH and the subarachnoid space contains blood clots. Thus, the pharmaceutical composition may become trapped in the blood clot, whereby there will be a localized release of the agent from the composition, which/they will exert a pharmacological effect in the adjacent arteries and brain.

More generally, the semi-solid multiparticulate delivery system of the present invention provides a number of advantages over systemic administration orally or by infusion. As an example, nimodipine must currently be administered every 2 to 4 hours either by continuous intravenous infusion or by oral administration in a bolus. In CSF where the voltage-gated calcium channel blocker acts locally, the blocker is present in higher concentrations and in lower plasma concentrations than when the voltage-gated calcium channel blocker is administered orally or intravenously. This results in a localized pharmacological effect in the cerebral arteries and/or brain, but less in vivo. Side effects in the body, such as hypotension, are unlikely to occur. Some agents do not cross the blood brain barrier after systemic administration. Administration directly into the ventricles of the brain overcomes this problem. The total dose of administered voltage-gated calcium channel blockers is much lower than that administered systemically, so that other and unknown side effects are lower.

According to some embodiments, the pharmaceutical composition comprising a voltage-gated calcium channel blocker is comprised in a controlled release system. To prolong the effect of a drug, it is often desirable to slow the absorption of the drug. This can be achieved by using a liquid suspension of a poorly water soluble crystalline or amorphous material. The rate of absorption of the drug then depends on its rate of dissolution, which in turn depends on crystal size and crystal form. For example, according to some embodiments, the SABER including a high viscosity matrix component such as Sucrose Acetate Isobutyrate (SAIB)^TMThe delivery system is used to provide controlled release of the voltage-gated calcium channel blocker. (see U.S. Pat. No.5,747,058 and U.S. Pat. No.5,968,542, incorporated herein by reference). When the high viscosity SAIB is mixed with drug and biocompatible excipientWhen formulated with other additives, the resulting formulation is a liquid sufficient for easy injection with a standard syringe and needle. In-injection SABER^TMAfter formulation, the excipient diffused away, leaving a viscous reservoir.

According to some embodiments, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life ranging from 1 day to 30 days. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 1 day. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 2 days. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 3 days. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 4 days. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a 5 day half-life. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 6 days. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a 7 day half-life. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 8 days. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a 9 day half-life. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a 10 day half-life. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a 15 day half-life. According to another embodiment, the controlled release system is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 30 days.

According to some embodiments, the controlled release system comprises a long-term sustained release implant that may be particularly suitable for treating chronic conditions. The term "long-term" release as used herein means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, preferably from about 30 to about 60 days. Long-term sustained release implants are well known to those skilled in the art and include some of the delivery systems described above.

According to another embodiment, the release of the voltage-gated calcium channel blocker at the site of delivery is capable of producing a predominantly localized pharmacological effect over a desired time frame. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 1 day. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 2 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 3 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 4 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 5 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 6 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 7 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 8 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 15 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 30 days.

According to another embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a diffuse pharmacologic effect throughout the Central Nervous System (CNS) over a desired time frame. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 1 day. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 2 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) lasting 3 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 4 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 5 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 6 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) lasting 7 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 8 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 15 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 30 days.

According to one embodiment, the localized pharmacologic effect at the delivery site is a reduction in vasospasm, such that the inner diameter of at least one cerebral artery affected by the brain injury is increased as compared to a control. According to one embodiment, the pharmaceutical composition is effective to increase the inner diameter of a cerebral artery affected by brain injury compared to a control.

According to one embodiment, the diffusible pharmacological effect is a reduction in vasospasm whereby at least 10mm, at least 9.9mm, at least 9.8mm, at least 9.7mm, at least 9.6mm, at least 9.5mm, at least 9.4mm, at least 9.3mm, at least 9.2mm, at least 9.1mm, at least 9.0mm, at least 8.9mm, at least 8.8mm, at least 8.7mm, at least 8.6mm, at least 8.5mm, at least 8.4mm, at least 8.3mm, at least 8.2mm, at least 8.1mm, at least 8.0mm, at least 7.9mm, at least 7.8mm, at least 7.7mm, at least 7.6mm, at least 7.5mm, at least 7.4mm, at least 7.3mm, at least 7.2mm, at least 7.1mm, at least 7.0mm, at least 6.9mm, at least 6.6mm, at least 6.5mm, at least 6.6mm, at least 6mm, at least 6.5mm, at least 6mm, at least 6.3mm, at least 6mm, an increase in the inner diameter of the blood vessel in the range of at least 5.7mm, at least 5.6mm, at least 5.5mm, at least 5.4mm, at least 5.3mm, at least 5.2mm, at least 5.1mm, at least 5.0 mm.

Means of administration

According to one embodiment, the means for administering is (1) by surgical injection, whereby the formulation is positioned in close proximity to a cerebral artery affected by the brain injury, thereby delivering a therapeutic amount of the pharmaceutical composition into the subarachnoid space.

According to another embodiment, the means for administering is (2) locally administering into the cerebral ventricle via a catheter, thereby carrying the formulation from the CSF circulation to contact the cerebral arteries affected by the brain injury, thereby delivering a therapeutic amount of the pharmaceutical composition into the subarachnoid space.

Pharmaceutical composition

Voltage-gated calcium channel blockers

According to some embodiments, the voltage-gated channel blocker is selected from the group consisting of an L-type voltage-gated calcium channel blocker, an N-type voltage-gated calcium channel blocker, a P/Q-type voltage-gated calcium channel blocker, or a combination thereof.

Non-limiting examples of voltage-gated calcium channel blockers that can be formulated into compositions include, but are not limited to, L-type voltage-gated calcium channel blockers, N-type voltage-gated calcium channel blockers, P/Q-type voltage-gated calcium channel blockers, or combinations thereof.

For example, L-type voltage-gated calcium channel blockers include, but are not limited to: dihydropyridine L-type blockers, such aS nisoldipine, nicardipine and nifedipine, AHFs (such aS (4aR,9aS) - (+) -4 a-amino-1, 2,3,4,4a,9 a-hexahydro-4 aH-fluorene, HCl), isradipine (such aS 4- (4-benzofurazanyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl 1-methylethyl ester), calcium (calcisepine) s (such aS isolated from Dendroaspis polyphylla), H-Arg-Ile-Cys-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Ala-Thr-Cys-Glu-Asn-Thr-Cys-Tyr-Lys-Met) -Phe-Ile-Arg-Thr-Gln-Arg-Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met-Trp-Pro-Tyr-Gln-Thr-Glu-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH, calcein (Calcicludine) species (as isolated from Dongfennese African Bolbilus viridis et al), H-Trp-Gln-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys-Lys-Gln-Phe-Ser-Phe-Tyr-Lys-Trp-Thr-Ala-Ser-Ser-Ser-Gln-Ser-Thr-Gln-Ser-Gln-Ser- -Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-Gly-Cys-Gly-Gly-Asn-Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Cys-Leu-Gly-Lys-OH, sinetidipine (e.g. also known as FRP-8653, an inhibitor of dihydropyridines), dilantine (dilatinzem) species (e.g. (2S,3S) - (+) cis-3-acetoxy-5- (2-dimethylaminoethyl) -2, 3-dihydro-2- (4-methoxyphenyl) -1, 5-benzothiazepin-4 (5H) -one hydrochloride, Diltiazem (e.g. benzothiazepine-4 (5H) -one, 3- (acetoxy) -5- [2- (dimethylamino) ethyl) ]2, 3-dihydro-2- (4-methoxyphenyl) - -, (+) -cis-, monohydrochloride), felodipine (e.g. ethyl methyl 4- (2, 3-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinecarboxylate), FS-2 (e.g. isolate from black snake (Dendroaspheroleylpipes polylipis) venom), FTX-3.3 (e.g. isolate from spider funnel (Agelenopsis saperta), neomycin sulphate (e.g. C)₂₃H₄₆N₆O₁₃·3H₂SO₄) Nicardipine (e.g. 1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) methyl-2- [ methyl (phenylmethyl) amino)]-ethyl 3, 5-pyridinedicarboxylate hydrochloride, also known as YC-93), nifedipine (such as dimethyl 1, 4-dihydro-2, 6-dimethyl-4- (2-nitrophenyl) -3, 5-pyridinedicarboxylate), nimodipine (such as 2-methoxyethyl-1-methylethyl 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) -3, 5-pyridinedicarboxylate) or (isopropyl 2-methoxyethyl 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylate), nitrendipine (such as 1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) -3, 5-ethylmethylpyridinedicarboxylate), S-petasins (Petasins) (e.g. 3S,4aR,5R,6R) - [2,3,4,4a,5,6,7, 8-octahydro-3- (2-propenyl) -4a, 5-dimethyl-2-oxo-6-naphthalenyl]Z-3 ' -methylthio-1 ' -acrylate), phloretins (Phloretin) such as 2 ', 4 ', 6 ' -trihydroxy-3- (4-hydroxyphenyl) propiophenone, and 3- (4-hydroxyphenyl) -1- (2,4, 6-trihydroxy-phenyl) -1-propanone, and b- (4-hydroxyphenyl) -2,4, 6-trihydroxy propiophenone, and protoporphyrins such as C ₂₀H_I9NO₅C1) SKF-96365 (e.g. 1- [ b- [3- (4-methoxyphenyl) propoxy)]-4-methoxybenzyl ethyl]-1H-imidazole, HCl), tetrandrines (e.g. 6,6 ', 7, 12-tetramethoxy-2, 2' -dimethyltetrandrine), (+ -) methoxy verapamil or (+) -verapamil (e.g. 54N- (3, 4-dimethoxyphenylethyl) methylamino]-2- (3, 4-dimethoxyphenyl) -2-isopropylvaleronitrile hydrochloride), and (R) - (+) -Bay K8644 species (e.g. R- (+) -1, 4-dihydro-2, 6-dimethyl-5-nitro-442- (trifluoromethyl) phenyl]-3-pyridinecarboxylic acid methyl ester). The foregoing examples may be specific for L-type voltage-gated calcium channels or may inhibit a wider range of voltage-gated calcium channels, such as N, P/Q, R and T-type.

According to some embodiments, the voltage-gated calcium channel blocker is a dihydropyridine calcium channel blocker. According to one embodiment, the dihydropyridine calcium channel blocker is nimodipine. According to one embodiment, the nimodipine has a half-life of 7-10 days and suitable lipid solubility when formulated as described herein.

According to some embodiments, the voltage-gated calcium channel blocker is an isolated molecule. The term "isolated molecule" as used herein refers to a molecule that is substantially pure and free of other substances with which it is normally found in nature or in vivo systems to the extent feasible and appropriate for its intended use.

According to some embodiments, the voltage-gated calcium channel blocker is admixed with a pharmaceutically acceptable carrier in a pharmaceutical formulation. According to some such embodiments, the voltage-gated calcium channel blocker constitutes only a small percentage by weight of the formulation. According to some embodiments, the voltage-gated calcium channel blocker is substantially pure.

Pharmaceutically acceptable carriers

According to some embodiments, the pharmaceutical composition does not comprise a pharmaceutically acceptable carrier. According to some embodiments, the pharmaceutically acceptable carrier does not include hyaluronic acid.

According to one embodiment, the pharmaceutically acceptable carrier is a solid carrier or excipient. According to another embodiment, the pharmaceutically acceptable carrier is a gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various mono-and polysaccharides (including, but not limited to, hyaluronic acid), starch, cellulose derivatives, gelatin, and polymers. Exemplary carriers may also include saline vehicles, such as Hydroxypropylmethylcellulose (HPMC) in Phosphate Buffered Saline (PBS).

According to some embodiments, the pharmaceutically acceptable carrier imparts adhesiveness. According to one embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid. According to some embodiments, the pharmaceutically acceptable carrier comprises 0% to 5% hyaluronic acid. According to one embodiment, the pharmaceutically acceptable carrier comprises less than 0.05% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.1% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.2% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.3% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.4% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.6% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.7% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.8% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.9% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.1% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.2% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.3% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.4% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.6% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.7% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.8% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.9% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.1% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.2% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid 2.3% less. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.4% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.6% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.7% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.8% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.9% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 3.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 3.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 4.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 4.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 5.0% hyaluronic acid.

In some embodiments, the pharmaceutically acceptable carrier includes, but is not limited to, a gel sustained release solid or semi-solid compound, optionally as a sustained release gel. In some such embodiments, the voltage-gated calcium channel blocker is embedded in a pharmaceutically acceptable carrier. In some embodiments, the voltage-gated calcium channel blocker is coated on a pharmaceutically acceptable carrier. The coating may be of any desired material, preferably a polymer or a mixture different from a polymer. Optionally, the polymer may be used in a granulation stage to form a matrix with the active ingredient to obtain a desired release pattern of the active ingredient. The gel sustained release solid or semi-solid compound is capable of releasing the active agent over a desired time period. The gel sustained release solid or semi-solid compound may be implanted into a tissue within the human brain, such as, but not limited to, in close proximity to a blood vessel, such as a cerebral artery.

According to another embodiment, the pharmaceutically acceptable carrier comprises a slow release solid compound. According to one such embodiment, the voltage-gated calcium channel blocker is embedded in or coated on a slow-release solid compound. According to yet another embodiment, the pharmaceutically acceptable carrier comprises slow-release microparticles comprising a voltage-gated calcium channel blocker.

According to another embodiment, the pharmaceutically acceptable carrier is a gel compound, such as a biodegradable hydrogel.

Microparticle formulation

According to some embodiments, the voltage-gated calcium channel blocker is provided in particle form. The term "particle" as used herein refers to a nano-sized or micro-sized (or in some cases larger) particle that may contain, in whole or in part, the calcium channel inhibitor. According to some embodiments, the microparticle formulation comprises a plurality of microparticles impregnated with the voltage-gated calcium channel blocker. According to one embodiment, the voltage-gated calcium channel blocker is comprised inside the core of the particle surrounded by the coating. According to another embodiment, the voltage-gated calcium channel blocker is dispersed throughout the surface of the particle. According to another embodiment, the voltage-gated calcium channel blocker is disposed on or in a microparticle. According to another embodiment, the voltage-gated calcium channel blocker is disposed on the surface of the entire microparticle. According to another embodiment, the voltage-gated calcium channel blocker is adsorbed into the particle.

According to some such embodiments, the microparticles are in a uniform size distribution. According to some embodiments, the uniform distribution of particle sizes is achieved by a homogenization process to form a uniform emulsion comprising the particles. According to some such embodiments, each microparticle comprises a matrix. According to some embodiments, the matrix comprises a voltage-gated calcium channel blocker.

According to some embodiments, the pharmaceutical composition is flowable. According to some embodiments, the microparticle formulation component of the pharmaceutical composition is flowable.

According to some embodiments, the particles are selected from the group consisting of zero order release, first order release, second order release, delayed release, sustained release, rapid release, and combinations thereof. In addition to the therapeutic agent, such particles may include any of those materials conventionally used in the medical arts, including but not limited to erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof.

According to some embodiments, the particles are microcapsules containing the voltage-gated calcium channel blocker in solution or in a semi-solid state. According to some embodiments, the particle is a microparticle comprising, in whole or in part, a voltage-gated calcium channel blocker. According to some embodiments, the particle is a nanoparticle comprising, in whole or in part, a voltage-gated calcium channel blocker. According to some embodiments, the particles may be of almost any shape.

According to some embodiments, the particle size is between about 25 μm to about 100 μm. According to some embodiments, the particle size is between about 30 μm to about 80 μm. According to one embodiment, the particle size is at least about 25 μm. According to another embodiment, the particle size is at least about 30 μm. According to another embodiment, the particle size is at least about 35 μm. According to another embodiment, the particle size is at least about 40 μm. According to another embodiment, the particle size is at least about 45 μm. According to another embodiment, the particle size is at least about 50 μm. According to another embodiment, the particle size is at least about 55 μm. According to another embodiment, the particle size is at least about 60 μm. According to another embodiment, the particle size is at least about 65 μm. According to another embodiment, the particle size is at least about 70 μm. According to another embodiment, the particle size is at least about 75 μm. According to another embodiment, the particle size is at least about 80 μm. According to another embodiment, the particle size is at least about 85 μm. According to another embodiment, the particle size is at least about 90 μm. According to another embodiment, the particle size is at least about 95 μm. According to another embodiment, the particle size is at least about 100 μm.

According to another embodiment, the voltage-gated calcium channel blocker may be provided in a thread. The wire may contain a voltage-gated calcium channel blocker in the coated core, or the voltage-gated calcium channel blocker may be dispersed throughout the wire, or a therapeutic agent may be adsorbed within the wire. Such a thread may have any level of release kinetics including zero order release, first order release, second order release, delayed release, sustained release, rapid release, and the like, and any combination thereof. Such a thread may include, in addition to the therapeutic agent, any of those materials conventionally used in the medical arts, including but not limited to erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof.

According to another embodiment, the voltage-gated calcium channel blocker may be provided in at least one sheet. The sheet may contain the voltage-gated calcium channel blocker and at least one additional therapeutic agent in the core surrounded by the coating, or the voltage-gated calcium channel blocker and at least one additional therapeutic agent may be dispersed throughout the sheet, or the voltage-gated calcium channel blocker may be adsorbed in the sheet. The sheet may have any level of release kinetics including zero order release, first order release, second order release, delayed release, sustained release, rapid release, and the like, and any combination thereof. Such a sheet may comprise, in addition to the voltage-gated calcium channel blocker and the at least one additional therapeutic agent, any of those materials conventionally used in the medical arts, including but not limited to erodible, non-erodible, biodegradable or non-biodegradable materials or combinations thereof.

According to some embodiments, the pharmaceutical composition further comprises a preservative. According to some such embodiments, the pharmaceutical composition is in unit dosage form. Exemplary unit dosage forms include, but are not limited to, ampoules or multi-dose containers.

According to some embodiments, the microparticle formulation comprises a suspension of microparticles. According to some embodiments, the pharmaceutical composition further comprises at least one of a suspending agent, a stabilizing agent, and a dispersing agent. According to some such embodiments, the pharmaceutical composition is presented as a suspension. According to some such embodiments, the pharmaceutical composition is presented as a solution. According to some such embodiments, the pharmaceutical composition is presented as an emulsion.

According to some embodiments, the formulation of the pharmaceutical composition comprises an aqueous solution of the voltage-gated calcium channel blocker in a water-soluble form. According to some embodiments, the formulation of the pharmaceutical composition comprises an oily suspension of the voltage-gated calcium channel blocker. Oily suspensions of the voltage-gated calcium channel blockers can be prepared using suitable lipophilic solvents. Exemplary lipophilic solvents or vehicles include, but are not limited to, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides. According to some embodiments, the formulation of the pharmaceutical composition comprises an aqueous suspension of a voltage-gated calcium channel blocker. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or materials that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the voltage-gated calcium channel blocker may be in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

Suitable liquid or solid pharmaceutical formulations include, for example, microencapsulated forms (and, where appropriate, one or more excipients), helical (encocholated), coated on fine gold particles, included in liposomes, pellets for implantation into tissue, or dried on the surface of an object to be rubbed into tissue. The term "microencapsulation" as used herein refers to a process wherein very tiny droplets or particles are surrounded or coated by a continuous film of biocompatible, biodegradable polymeric material or non-polymeric material to produce a solid structure including, but not limited to, spherical particles, globules, crystals, agglomerates, microspheres, or nanoparticles. Such pharmaceutical compositions may also be in the form of granules, beads, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or delayed release formulations of the active compound, wherein formulation excipients and additives and/or adjuvants such as disintegrants, binders, coatings, bulking agents, lubricants or solubilizers are generally used as described above. The pharmaceutical composition is suitable for use in a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer (1990) Science 249, 1527-.

Microencapsulation process

In U.S. Pat. No.5,407,609 (entitled microencapsulation Process and products thereof), U.S. application No.10/553,003 (entitled Process for producing emulsion-based microparticles), U.S. application No.11/799,700 (entitled emulsion-based microparticles and methods of producing the same), U.S. application No.12/557,946 (entitled solvent extraction microencapsulation with tunable extraction rate), U.S. application No.12/779,138 (entitled Hyaluronic Acid (HA) injection vehicle), U.S. application No.12/562,455 (entitled microencapsulation Process Using solvents and salts), U.S. application No.12/338,488 (entitled Process for preparing microparticles with Low solvent residual quantity), U.S. application No.12/692,027 (entitled controlled Release System from Polymer blends), U.S. application No.12/692,020 (entitled Polymer mixtures with polymers comprising different non-repeating units and methods of making and Using the same), U.S. application No.10/565,401 (entitled "controlled release composition"), U.S. application No.12/692,029 (entitled "drying method for modifying properties of microparticles"); U.S. application No.12/968,708 (entitled "emulsion-based process for making microparticles and workheads for use therewith"); and U.S. application No.13/074,542 (entitled "compositions and methods for improving the residence of pharmaceutical compositions at a topical application site") disclose and describe microencapsulation processes and products; a method for producing emulsion-based microparticles; emulsion-based microparticles and a method for producing the same; solvent extraction microencapsulation with adjustable extraction rate; microencapsulation process using solvent and salt; a continuous double emulsion process for making microparticles; drying methods for modifying the properties of microparticles, controlled release systems from polymer blends; polymer blends having polymers comprising different non-repeating units and methods of making and using the same; and examples of emulsion-based methods for preparing microparticles and workhead assemblies for use therewith. The contents of each of these documents are incorporated herein in their entirety by reference.

According to some embodiments, the delivery of the voltage-gated calcium channel blocker using microparticle technology involves bioabsorbable polymeric particles encapsulating the voltage-gated calcium channel blocker and at least one additional therapeutic agent.

According to one embodiment, the microparticle formulation comprises a polymeric matrix, wherein the voltage-gated calcium channel blocker is impregnated in the polymeric matrix. According to one embodiment, the polymer is a slow release polymer. According to one embodiment, the polymer is poly (D, L-lactide-co-glycolide). According to another embodiment, the polymer is a poly (orthoester). According to another embodiment, the polymer is a poly (anhydride). According to another embodiment, the polymer is polylactide-polyglycolide.

Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for the delivery of the voltage-gated calcium channel blockers. Such polymers may be natural or synthetic polymers. The polymer is selected based on the desired time period of release. Bioadhesive polymers of particular interest include, but are not limited to, bioerodible hydrogels as described by Sawhney et al in Macromolecules (1993)26,581-587, the teachings of which are incorporated herein. Exemplary bioerodible hydrogels include, but are not limited to, poly hyaluronic acid, casein, gelatin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (dodecyl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), and poly (octadecyl acrylate). According to one embodiment, the bioadhesive polymer is hyaluronic acid. In some such embodiments, the bioadhesive polymer comprises less than about 2.3% hyaluronic acid.

According to some embodiments, the pharmaceutical composition is formulated for parenteral injection, surgical implantation, or a combination thereof. According to some such embodiments, the pharmaceutical composition is in a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, or a sterile powder for reconstitution into a sterile injectable solution or dispersion. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include, but are not limited to, water, ethanol, dichloromethane, acetonitrile, ethyl acetate, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Suspensions may also include suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and mixtures thereof.

According to some embodiments, the pharmaceutical composition is formulated in an injectable long-acting form. Injectable depot forms are prepared by forming microencapsulated matrices of the voltage-gated calcium channel blockers in biodegradable polymers. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Such depot formulations may be formulated with suitable polymeric or hydrophobic materials (e.g. emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives (e.g. sparingly soluble salts). Examples of biodegradable polymers include, but are not limited to, polylactide-polyglycolide, poly (orthoester), and poly (anhydride). Injectable depot forms can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a Polyglycolide (PGA) matrix. PGA is a linear aliphatic polyester developed for use in sutures. Studies have reported PGA copolymers formed with trimethylene carbonate, polylactic acid (PLA) and polycaprolactone. Some of these copolymers may be formulated as microparticles for sustained drug release.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a polyester-polyethylene glycol matrix. Polyester-polyethylene glycol compounds can be synthesized; these compounds are soft and can be used for drug delivery.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a poly (amino) -derived biopolymer matrix. Polyamino-derived biopolymers may include, but are not limited to, those containing lactic acid and lysine as aliphatic diamines (see, e.g., U.S. patent 5,399,665) and tyrosine-derived polycarbonates and polyacrylates. Modification of the polycarbonate can change the length of the alkyl chain of such an ester (ethyl to octyl), while modification of the polyacrylate can further include changing the length of the alkyl chain of the diacid (e.g., succinic to sebacic acid), which enables great variation in the polymer and great flexibility in polymer properties.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a polyanhydride matrix. Polyanhydrides are prepared by dehydrating two diacid molecules by melt polymerization (see, e.g., U.S. patent 4,757,128). These polymers degrade due to surface attack (as opposed to polyesters that degrade due to bulk attack). The release of the drug may be controlled by the hydrophilicity of the selected monomer.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a photopolymerizable biopolymer matrix. Photopolymerizable biopolymers include, but are not limited to, lactic acid/polyethylene glycol/acrylate copolymers.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a hydrogel matrix. The term "hydrogel" refers to a substance that forms a solid, semi-solid, pseudoplastic, or plastic structure containing the necessary aqueous components to form a gel-like or jelly-like mass. Hydrogels generally include a variety of polymers, including hydrophilic polymers, acrylic acid, acrylamide, and 2-hydroxyethyl methacrylate (HEMA).

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a naturally occurring biopolymer matrix. Naturally occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides, and photopolymerizable compounds.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a protein polymer matrix. Protein polymers have been synthesized from self-assembling protein polymers such as fibroin, elastin, collagen and combinations thereof.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a naturally occurring polysaccharide matrix. Naturally occurring polysaccharides include, but are not limited to, chitin and its derivatives, hyaluronic acid, dextran, and cellulose (which are generally not biodegradable when unmodified) and Sucrose Acetate Isobutyrate (SAIB).

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on the chitin matrix. Chitin is predominantly composed of 2-acetamido-2-deoxy-D-glucosyl groups and is present in yeast, fungi and marine invertebrates (shrimp, crustaceans), where it is the main component of the exoskeleton. Chitin is not water soluble and deacetylated chitin, chitosan, is only soluble in acidic solutions (such as, for example, acetic acid). Studies have reported chitin derivatives that are water soluble, very high molecular weight (greater than 2 million daltons), viscoelastic, non-toxic, biocompatible, and capable of crosslinking with peroxides, glutaraldehyde, glyoxal or other aldehydes, and carbodiimides to form a gel.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a Hyaluronic Acid (HA) matrix. Hyaluronic Acid (HA), which consists of alternating glucuronic acid and glucosamine bonds and is present in the vitreous humor, the extracellular matrix of the brain, the synovial fluid, the umbilical cord and the rooster comb of mammals, from which it can be isolated and purified, can also be produced by fermentation processes.

According to some embodiments, the pharmaceutical composition further comprises an adjuvant. Exemplary adjuvants include, but are not limited to, preservatives, wetting agents, emulsifying agents, and dispersing agents. Preservation of the action of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example, sugars, sodium chloride, and the like, may also be included. Prolonged absorption of the injectable pharmaceutical form is brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

The formulations can be prepared, for example, by terminal gamma irradiation, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol, dichloromethane, ethyl acetate, acetonitrile or the like. Acceptable vehicles and solvents that may be used include water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any low-irritation fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Formulations for parenteral (including but not limited to subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intrathecal, intracerebroventricular, and intraarticular) administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions which may contain suspending agents and thickening agents.

According to another embodiment, the pharmaceutical composition is formulated by linking the voltage-gated calcium channel blocker to a polymer that enhances water solubility. Examples of suitable polymers include, but are not limited to, polyethylene glycol, poly- (d-glutamic acid), poly- (l-glutamic acid), poly- (d-aspartic acid), poly- (l-aspartic acid), and copolymers thereof. Polyglutamic acids having a molecular weight between about 5,000 and about 100,000, and a molecular weight between about 20,000 and about 80,000 can be used, as can polyglutamic acids having a molecular weight between about 30,000 and about 60,000. The polymer is attached via an ester linkage to one or more hydroxyl groups of the inventive Epothilone (Epothilone) using a protocol substantially as described in U.S. patent No.5,977,163, incorporated herein by reference. In the case of the 21-hydroxy-derivatives of the invention, specific attachment sites include the hydroxy group of carbon-21. Other attachment sites include, but are not limited to, hydroxyl groups at carbon 3 and/or hydroxyl groups at carbon 7.

Suitable buffers include: acetic acid and salt (1-2% w/v); citric acid and salt (1-3% by weight/volume); boric acid and salts (0.5-2.5% by weight/volume); and phosphoric acid and salts (0.8-2% by weight/volume). Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); nipagin ester (0.01-0.25% by weight/volume) and thimerosal (0.004-0.02% by weight/volume).

According to another embodiment, the semi-solid multi-particle delivery system comprises, in part or in whole, a biocompatible, biodegradable viscous semi-solid, wherein the semi-solid comprises a hydrogel, wherein the hydrogel comprises the voltage-gated calcium channel blocker. The term "hydrogel" as used herein refers to a substance that forms a solid, semi-solid, pseudoplastic, or plastic structure containing the necessary aqueous components to form a gel-like or jelly-like mass. Consolidation of the hydrogel with retention of a large amount of H₂O, will eventually reach equilibrium levels in the presence of water. In one embodiment, glyceryl monooleate (hereinafter GMO) is the desired semi-solid delivery system or hydrogel. However, many hydrogels, polymers, hydrocarbon compositions and fatty acid derivatives with similar physical/chemical properties in terms of viscosity/rigidity can function as semi-solid delivery systems.

In one embodiment, the gel system is created by heating the GMO above its melting point (40-50 ℃) and by adding a heated water-based buffer or electrolyte, such as phosphate buffer or physiological saline, to form a three-dimensional structure. The aqueous-based buffer may include other aqueous solutions or combinations that contain semi-polar solvents.

GMO provides a predominantly lipid-based hydrogel with the ability to bind lipophilic materials. The term "lipophilic" as used herein means that a non-polar environment is more favored or has an affinity for a non-polar environment than a polar or aqueous environment. GMO further provides an internal aqueous pathway to bind and deliver hydrophilic compounds. The term "hydrophilic" as used herein refers to a material or substance that has an affinity for a polar substance (such as water). It is believed that at room temperature (-25 ℃), the gel system may exhibit different phases including a wide range of viscosity values.

In one embodiment, two gel system phases are used due to their performance at room and physiological temperatures (about 37 ℃) and pH (about 7.4). Within the two gel system phases, the first phase is a lamellar phase, wherein H₂The O content is from about 5% to about 15% and the GMO content is from about 95% to about 85%. The lamellar phase is a moderately viscous liquid that can be easily handled, poured and injected. The second phase is a cubic phase consisting of a water content of about 15% to about 40% and a GMO content of about 85% to 60%. It has an equilibrium water content of about 35% to about 40% by weight. The term "equilibrium moisture content" as used herein refers to the maximum moisture content in the presence of excess water. Thus, the cubic phase comprises from about 35% to about 40% by weight of water. The cubic phase is highly viscous. The viscosity is in excess of 120 kilo-centipoise (cp) when measured with a Brookfield viscometer; with 120 ten thousand cp being the largest measurement available through the cup and bob configuration of a Brookfield viscometer. In some such embodiments, the therapeutic agent may be included in a semi-solid, thereby providing a system for sustained continuous delivery. In some such embodiments, the therapeutic agent is a calcium channel blocker. In some such embodiments, the therapeutic agent is a dihydropyridine calcium channel blocker. In some such embodiments, the therapeutic agent is nimodipine. In some such embodiments, other therapeutic agents, bioactive agents, drugs, medicaments, and inactivators may be included in the semi-solid for providing a localized biological, physiological, or therapeutic effect at various release rates in vivo.

In some embodiments, other semisolids, modified formulations, and manufacturing methods are employed to alter the lipophilic nature of the semisolids, or alternatively, alter the aqueous channels included within the semisolids. Thus, different concentrations of various therapeutic agents may diffuse from the semi-solid at different rates, or from the semi-solid over time through its aqueous channelsAnd (4) releasing. Hydrophilic substances can be used to alter the semi-solid concentration or the release of therapeutic agents by altering the viscosity, fluidity, surface tension or polarity of the aqueous component. For example, Glycerol Monostearate (GMS) is structurally identical to GMO, except that there are double bonds instead of single bonds at carbon 9 and carbon 10 positions of the fatty acid moiety; like GMO, GMS does not gel when heating and adding aqueous ingredients. However, because GMS is a surfactant, GMS is in H₂Miscible in O up to about 20% w/w. The term "surfactant" as used herein means a surfactant in H₂O and a surface active substance which is miscible with the polar substance in a limited concentration. 80% H when heated and stirred₂The O/20% GMS combination produced a spreadable paste with a similar consistency to hand cream. This paste was then combined with melted GMO to form a cubic phase gel with the high viscosity mentioned above.

According to another embodiment, a hydrolyzed gel such as Gelfoam, which is commercially available, is used^TMThe aqueous component is changed. Gelfoam in a concentration of about 6.25% to about 12.50% by weight may be added^TMRespectively placing in about 93.75% to about 87.50% by weight of H₂O or other water-based buffer. While heating and stirring, H₂O (or other aqueous buffer)/Gelfoam^TMThe combination produced a viscous, gelatinous material. Combining the obtained substance with GMO; the product thus formed swells and forms a highly viscous, translucent gel that is less malleable than neat GMO gel alone.

According to another embodiment, polyethylene glycol (PEG) may be used to modify the aqueous component to aid in drug solubilization. PEG at a concentration of about 0.5% to 40% by weight (depending on the PEG molecular weight) can be placed in about 99.5% to about 60% by weight of H, respectively₂O or other water-based buffer. With heating and stirring, H₂The O (or other aqueous buffer)/PEG combination forms a viscous liquid to a semi-solid substance. The resulting material was combined with GMO and the product thus formed swelled and formed a highly viscous gel.

According to some embodiments, the voltage-gated calcium channel blocker is released from the semi-solid by diffusion in a biphasic manner. The first stage involves, for example, diffusion of the lipophilic drug contained within the lipophilic membrane from there into the aqueous channel. The second stage comprises diffusion of the drug from the aqueous channel into the external environment. Due to its lipophilic nature, the drug can self-orient within the proposed lipid bilayer structure inside the GMO gel. Thus, including more than about 7.5% drug by weight in GMO results in a loss of integrity of this three-dimensional structure, so that the gel system no longer maintains the semi-solid cubic phase and reverses to a viscous lamellar phase liquid. In some such embodiments, the therapeutic agent is nimodipine. In some such embodiments, the therapeutic agent is a calcium channel blocker. In some such embodiments, the therapeutic agent is a transient receptor potential protein blocker. According to another embodiment, from about 1% to about 45% by weight of the therapeutic agent is included in the GMO gel at physiological temperatures without disrupting the normal three-dimensional structure. As a result, the system has the ability to provide significantly increased flexibility in the dosage. Because the delivery system is malleable, it can be delivered to and manipulated at an implantation site, for example, adjacent a cerebral artery or subarachnoid space, to adhere to and conform to the contours of the walls, cavities, or other spaces in the body and completely fill all existing cavities. The delivery system ensures drug distribution and uniform drug delivery throughout the implantation site. The ease of delivery and handling of the delivery system within a cavity such as, but not limited to, the subarachnoid space is facilitated by a semi-solid delivery device. The semi-solid delivery device facilitates targeted and controlled delivery of the delivery system.

Alternatively, the present invention provides a semi-solid delivery system that functions as a vehicle for the topical delivery of therapeutic agents, comprising a lipophilic, hydrophilic or amphiphilic, solid or semi-solid substance that is heated above its melting point and thereafter added with a hot aqueous component to produce a gelatinous composition having a different viscosity based on water content. The therapeutic agent is combined and dispersed in the molten lipophilic component or aqueous buffer component prior to mixing or forming the semi-solid system. The gelatinous composition is placed within the semi-solid delivery device for subsequent placement or deposition. Being malleable, the gel system is easily delivered to and manipulated at the implantation site by the semi-solid delivery device where it adheres and conforms to the contours of the implantation site, cavity or other void in the body and completely fills all voids present. Alternatively, multiparticulate compositions comprised of biocompatible polymer or non-polymer systems are used to prepare microspheres having therapeutic agents encapsulated therein. After the final treatment process, the microspheres are incorporated into the semi-solid system and then placed in the semi-solid delivery device for easy delivery therefrom to the implantation site or equivalent cavity, whereby the therapeutic agent is subsequently released therefrom by a drug release mechanism.

Method III

In another aspect, the present invention provides a method for treating a delayed complication associated with a brain injury in a mammal in need thereof, wherein the brain injury comprises at least one interruption of a cerebral artery, the method comprising:

(a) there is provided a pharmaceutical composition comprising

(i) Microparticle formulations of voltage-gated calcium channel blockers; and optionally

(ii) A pharmaceutically acceptable carrier; and

(b) administering a therapeutic amount of the pharmaceutical composition via a device for administering the therapeutic amount of the pharmaceutical composition to an administration site, wherein the therapeutic amount is effective to reduce the signs or symptoms of at least one delayed complication associated with brain injury.

According to one embodiment, in step (b), the means for administering a therapeutic amount of the pharmaceutical composition is a surgical injection device and the site of administration is a site in close proximity to a cerebral artery affected by the brain injury.

According to another embodiment, in step (b), the means for administering a therapeutic amount of the pharmaceutical composition is a catheter and the site of administration is local access to the cerebral ventricles, such that the microparticulate formulation component of the composition is carried by the CSF circulation to contact cerebral arteries affected by brain injury.

According to some such embodiments, the at least one delayed complication is selected from the group consisting of Delayed Cerebral Ischemia (DCI), intracerebral hematoma, intracerebroventricular hemorrhage, fever, angiographic vasospasm, microthrombus embolus, Cortical Spreading Ischemia (CSI), behavioral deficits, neurological deficits, cerebral infarction, neuronal cell death, or a combination thereof. According to one embodiment, the at least one delayed complication is Delayed Cerebral Ischemia (DCI). According to another embodiment, the at least one delayed complication is an intracerebral hematoma. According to another embodiment, the at least one delayed complication is intracerebroventricular hemorrhage. According to another embodiment, the at least one delayed complication is fever. According to another embodiment, the at least one delayed complication is angiographic vasospasm. According to another embodiment, the at least one delayed complication is Cortical Spreading Ischemia (CSI). According to another embodiment, the at least one delayed complication is microthrombosis. According to another embodiment, the at least one delayed complication is a behavioral deficit. According to another embodiment, the at least one delayed complication is a neurological deficit. According to another embodiment, the at least one delayed complication is cerebral infarction. According to another embodiment, the at least one delayed complication is neuronal cell death.

According to some embodiments, the brain injury is a result of an underlying pathology. Exemplary potential conditions include, but are not limited to, aneurysms, traumatic head injury, subarachnoid hemorrhage (SAH), and the like. According to some such embodiments, the underlying condition is selected from an aneurysm, a sudden traumatic head injury, subarachnoid hemorrhage (SAH), or a combination thereof. According to one embodiment, the underlying condition is an aneurysm. According to another embodiment, the underlying condition is sudden traumatic head injury. According to another embodiment, the underlying condition is subarachnoid hemorrhage (SAH).

According to some embodiments, the pharmaceutical composition is effective to prevent or reduce the incidence or severity of late complications associated with brain injury in a mammal in need thereof, when administered to a delivery site in the mammal in a therapeutic amount, wherein the brain injury comprises an interruption of at least one cerebral artery. According to one embodiment, the delivery site is a ventricle. According to some embodiments, the ventricle is selected from the group consisting of a lateral ventricle, a third ventricle, a fourth ventricle, or a combination thereof. According to one embodiment, the delivery site is in the subarachnoid space. According to one embodiment, the delivery site is in close proximity to a brain injury. According to another embodiment, the delivery site is in close proximity to a blood vessel affected by brain injury. According to one embodiment, the blood vessel is at least one cerebral artery. According to another embodiment, the blood vessel is at least one cerebral artery affected by brain injury.

According to some embodiments, the pharmaceutical composition is administered by parenteral injection or surgical implantation.

The ventricles may be cannulated or catheterized as is well known in the art and as described in various neurosurgical texts. This is known as insertion or drainage of a ventricular catheter or a ventricular ostomy. Holes of different sizes may be drilled in the cranium and the epidura covering the brain cut open. The pia mater is dissected and a catheter (typically a hollow tube made of silicone elastomer of some other biocompatible, non-absorbable compound) is inserted through the brain into the selected ventricle. This is usually a lateral ventricle but any ventricle can be catheterized. The catheter may be used to monitor the pressure inside the head to expel CSF or to administer substances into CSF.

According to some embodiments, the delivery site is 10mm, less than 9.9mm, less than 9.8mm, less than 9.7mm, less than 9.6mm, less than 9.5mm, less than 9.4mm, less than 9.3mm, less than 9.2mm, less than 9.1mm, less than 9.0mm, less than 8.9mm, less than 8.8mm, less than 8.7mm, less than 8.6mm, less than 8.5mm, less than 8.4mm, less than 8.3mm, less than 8.2mm, less than 8.1mm, less than 8.0mm, less than 7.9mm, less than 7.8mm, less than 7.7mm, less than 7.6mm, less than 7.5mm, less than 7.4mm, less than 7.3mm, less than 7.2mm, less than 7.1mm, less than 7.0mm, less than 6.9mm, less than 6.8mm, less than 6.5mm, less than 6.4mm, less than 6.5mm, less than 6mm, less than 5mm, less than 6.5mm, less than 6mm, less than 5.2mm, less than 6mm, less than 6.1mm, less than 6mm, less than 5.4mm, less than 5.3mm, less than 5.2mm, less than 5.1mm, less than 5.0mm, less than 4.9mm, less than 4.8mm, less than 4.7mm, less than 4.6mm, less than 4.5mm, less than 4.4mm, less than 4.3mm, less than 4.2mm, less than 4.1mm, less than 4.0mm, less than 3.9mm, less than 3.8mm, less than 3.7mm, less than 3.6mm, less than 3.5mm, less than 3.4mm, less than 3.3mm, less than 3.2mm, less than 3.1mm, less than 3.0mm, less than 2.9mm, less than 2.8mm, less than 2.7mm, less than 2.6mm, less than 2.5mm, less than 2.4mm, less than 2.3mm, less than 2.2mm, less than 2.1mm, less than 2.0, less than 1.9mm, less than 1.7mm, less than 1.0mm, less, less than 0.2mm, less than 0.1mm, less than 0.09mm, less than 0.08mm, less than 0.07mm, less than 0.06mm, less than 0.05mm, less than 0.04mm, less than 0.03mm, less than 0.02mm, less than 0.01mm, less than 0.009mm, less than 0.008mm, less than 0.007mm, less than 0.006mm, less than 0.005mm, less than 0.004mm, less than 0.003mm, less than 0.002mm, less than 0.001 mm.

According to some embodiments, the delivery site is 10mm, less than 9.9mm, less than 9.8mm, less than 9.7mm, less than 9.6mm, less than 9.5mm, less than 9.4mm, less than 9.3mm, less than 9.2mm, less than 9.1mm, less than 9.0mm, less than 8.9mm, less than 8.8mm, less than 8.7mm, less than 8.6mm, less than 8.5mm, less than 8.4mm, less than 8.3mm, less than 8.2mm, less than 8.1mm, less than 8.0mm, less than 7.9mm, less than 7.8mm, less than 7.7mm, less than 7.6mm, less than 7.5mm, less than 7.4mm, less than 7.3mm, less than 7.2mm, less than 7.1mm, less than 7.0mm, less than 6.9mm, less than 6.6mm, less than 7.5mm, less than 6.4mm, less than 6.5mm, less than 6mm, less than 6.2mm, less than 6mm, less than 6.5mm, less than 6, less than 5.5mm, less than 5.4mm, less than 5.3mm, less than 5.2mm, less than 5.1mm, less than 5.0mm, less than 4.9mm, less than 4.8mm, less than 4.7mm, less than 4.6mm, less than 4.5mm, less than 4.4mm, less than 4.3mm, less than 4.2mm, less than 4.1mm, less than 4.0mm, less than 3.9mm, less than 3.8mm, less than 3.7mm, less than 3.6mm, less than 3.5mm, less than 3.4mm, less than 3.3mm, less than 3.2mm, less than 3.1mm, less than 3.0mm, less than 2.9mm, less than 2.8mm, less than 2.7mm, less than 2.6mm, less than 2.5mm, less than 2.4mm, less than 2.3mm, less than 2.2mm, less than 2.1mm, less than 2.0mm, less than 1.0mm, less than 1.9mm, less than 1.0mm, less than 1.1.0 mm, less than 1.1.06 mm, less than 1.0mm, less than 1.1.0 mm, less than 1.06 mm, less than 1.9mm, less than 1.0mm, less than 1.9mm, less than 1.1.1., less than 0.03mm, less than 0.02mm, less than 0.01mm, less than 0.009mm, less than 0.008mm, less than 0.007mm, less than 0.006mm, less than 0.005mm, less than 0.004mm, less than 0.003mm, less than 0.002mm, less than 0.001 mm.

According to some embodiments, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life ranging from 1 day to 30 days. According to one embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 1 day. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 2 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 3 days. According to one embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 4 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a 5 day half-life. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 6 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 7 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 8 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 9 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 10 days. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a 15 day half-life. According to another embodiment, the pharmaceutical composition is capable of releasing the voltage-gated calcium channel blocker at the delivery site within a half-life of 30 days.

Therapeutic action

According to another embodiment, implantation of the pharmaceutical composition into the injured brain may improve appetite.

According to another embodiment, the implantation of the pharmaceutical composition into the damaged brain may improve ataxia or paresis.

According to another embodiment, the release of the voltage-gated calcium channel blocker at the site of delivery is capable of producing a predominantly localized pharmacological effect over a desired time frame. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 1 day. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 2 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 3 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 4 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 5 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 6 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 7 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 8 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a predominantly localized pharmacological effect for 15 days. According to one embodiment, the release of the voltage-gated calcium channel blocker at the site of delivery produces a predominantly localized pharmacologic effect for 30 days.

According to another embodiment, the release of the voltage-gated calcium channel blocker at the delivery site produces a diffuse pharmacologic effect throughout the Central Nervous System (CNS) over a desired time frame. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 1 day. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 2 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) lasting 3 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 4 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 5 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 6 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) lasting 7 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 8 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 15 days. According to another embodiment, the release of the voltage-gated calcium channel blocker may produce a diffuse pharmacological effect throughout the Central Nervous System (CNS) for 30 days.

According to one embodiment, the localized pharmacologic effect at the site of delivery is a reduction in vasospasm such that the inner diameter of at least one cerebral artery affected by the brain injury is increased as compared to a control. According to one embodiment, the pharmaceutical composition is effective to increase the inner diameter of a cerebral artery affected by brain injury compared to a control.

According to one embodiment, the diffusible pharmacological effect is a reduction in vasospasm whereby at least 10mm, at least 9.9mm, at least 9.8mm, at least 9.7mm, at least 9.6mm, at least 9.5mm, at least 9.4mm, at least 9.3mm, at least 9.2mm, at least 9.1mm, at least 9.0mm, at least 8.9mm, at least 8.8mm, at least 8.7mm, at least 8.6mm, at least 8.5mm, at least 8.4mm, at least 8.3mm, at least 8.2mm, at least 8.1mm, at least 8.0mm, at least 7.9mm, at least 7.8mm, at least 7.7mm, at least 7.6mm, at least 7.5mm, at least 7.4mm, at least 7.3mm, at least 7.2mm, at least 7.1mm, at least 7.0mm, at least 6.9mm, at least 6.6mm, at least 6.5mm, at least 6.6mm, at least 6mm, at least 6.5mm, at least 6mm, at least 6.6mm, at least 6mm, at least 6.3mm, at least 8.2mm, an increase in the inner diameter of the blood vessel in the range of at least 5.7mm, at least 5.6mm, at least 5.5mm, at least 5.4mm, at least 5.3mm, at least 5.2mm, at least 5.1mm, at least 5.0 mm.

According to some embodiments, the pharmaceutical composition is injected into the cerebral ventricle through a catheter or tube inserted into one of the lateral, third or fourth cerebral ventricles, or subarachnoid pools, of the brain.

Voltage-gated calcium channel blockers

According to some embodiments, the voltage-gated channel blocker is selected from the group consisting of an L-type voltage-gated calcium channel blocker, an N-type voltage-gated calcium channel blocker, a P/Q-type voltage-gated calcium channel blocker, or a combination thereof.

Non-limiting examples of voltage-gated calcium channel blockers that can be formulated into compositions include, but are not limited to, L-type voltage-gated calcium channel blockers, N-type voltage-gated calcium channel blockers, P/Q-type voltage-gated calcium channel blockers, or combinations thereof.

For example, L-type voltage-gated calcium channel blockers include, but are not limited to: dihydropyridine L-type blockers, such aS nisoldipine, nicardipine and nifedipine, AHFs (such aS (4aR,9aS) - (+) -4 a-amino-1, 2,3,4,4a,9 a-hexahydro-4 aH-fluorene, HCl), isradipine (such aS 4- (4-benzofurazanyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl 1-methylethyl ester), calcium (calcisepine) s (such aS isolated from Dendroaspis polyphylla), H-Arg-Ile-Cys-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Ala-Thr-Cys-Glu-Asn-Thr-Cys-Tyr-Lys-Met) -Phe-Ile-Arg-Thr-Gln-Arg-Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met-Trp-Pro-Tyr-Gln-Thr-Glu-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH, calcein (Calcicludine) species (as isolated from Dongfennese African Bolbilus viridis et al), H-Trp-Gln-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys-Lys-Gln-Phe-Ser-Phe-Tyr-Lys-Trp-Thr-Ala-Ser-Ser-Ser-Gln-Ser-Thr-Gln-Ser-Gln-Ser- -Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-Gly-Cys-Gly-Gly-Asn-Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Cys-Leu-Gly-Lys-OH, sinidipine (e.g. also known as FRP-8653, an inhibitor of the dihydropyridines), dilantine (dilatinzem) species (e.g. (2S,3S) - (+) cis-3-acetoxy-5- (2-dimethylamino) species Ethyl) -2, 3-dihydro-2- (4-methoxyphenyl) -1, 5-benzothiazepin-4 (5H) -one hydrochloride, diltiazem (e.g. benzothiazepin-4 (5H) -one, 3- (acetoxy) -5- [2- (dimethylamino) ethyl ] ketone]2, 3-dihydro-2- (4-methoxyphenyl) - -, (+) -cis-, monohydrochloride), felodipine (e.g. 4- (2, 3-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinecarboxylic acid ethylmethyl ester), FS-2 (e.g. isolates from the venom of the black-man snake (Dendroaspherococcus polylipis), FTX-3.3 (e.g. isolates from the funnel-web spider (Agelenopsis saperta)), neomycin sulphate (e.g. C)₂₃H₄₆N₆O₁₃·3H₂SO₄) Nicardipine (e.g. 1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) methyl-2- [ methyl (phenylmethyl) amino)]-ethyl 3, 5-pyridinedicarboxylate hydrochloride, also known as YC-93), nifedipine (such as dimethyl 1, 4-dihydro-2, 6-dimethyl-4- (2-nitrophenyl) -3, 5-pyridinedicarboxylate), nimodipine (such as 2-methoxyethyl-1-methylethyl 4, 6-pyridinedicarboxylate) or (isopropyl 2-methoxyethyl 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylate), nitrendipine (such as 1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) -3, 5-ethylmethylpyridinedicarboxylate), S-petasins (Petasins) (e.g. 3S,4aR,5R,6R) - [2,3,4,4a,5,6,7, 8-octahydro-3- (2-propenyl) -4a, 5-dimethyl-2-oxo-6-naphthalenyl ]Z-3 ' -methylthio-1 ' -acrylate), phloretins (Phloretin) such as 2 ', 4 ', 6 ' -trihydroxy-3- (4-hydroxyphenyl) propiophenone, and 3- (4-hydroxyphenyl) -1- (2,4, 6-trihydroxy-phenyl) -1-propanone, and b- (4-hydroxyphenyl) -2,4, 6-trihydroxy propiophenone, and protoporphyrins such as C₂₀H_I9NO₅C1) SKF-96365 (e.g. 1- [ b- [3- (4-methoxyphenyl) propoxy)]-4-methoxybenzyl ethyl]-1H-imidazole, HCl), tetrandrines (e.g. 6,6 ', 7, 12-tetramethoxy-2, 2' -dimethyltetrandrine), (+ -) methoxy verapamil or (+) -verapamil (e.g. 54N- (3, 4-dimethoxyphenylethyl) methylamino]-2- (3, 4-dimethoxyphenyl) -2-isopropylvaleronitrile hydrochloride), and (R) - (+) -Bay K8644 species (e.g. R- (+) -1, 4-dihydro-2, 6-dimethyl-5-nitro-442- (trifluoromethyl) phenyl]-3-pyridinecarboxylic acid methyl ester). The foregoing examplesMay be specific for L-type voltage-gated calcium channels or may inhibit a broader range of voltage-gated calcium channels, such as N, P/Q, R and T-type.

According to some embodiments, the voltage-gated calcium channel blocker is a dihydropyridine calcium channel blocker. According to one embodiment, the dihydropyridine calcium channel blocker is nimodipine. According to one embodiment, the nimodipine has a half-life of 7-10 days and suitable lipid solubility when formulated as described herein.

According to some embodiments, the voltage-gated calcium channel blocker is an isolated molecule. As used herein, an "isolated molecule" refers to a molecule that is substantially pure and free of other substances that are normally present with the molecule in nature or in vivo systems to the extent feasible and appropriate for its intended use.

According to some embodiments, the voltage-gated calcium channel blocker is admixed with a pharmaceutically acceptable carrier in a pharmaceutical formulation. According to some such embodiments, the voltage-gated calcium channel blocker constitutes only a small percentage by weight of the formulation. According to some embodiments, the voltage-gated calcium channel blocker is substantially pure.

Pharmaceutically acceptable carriers

According to some embodiments, the pharmaceutical composition does not comprise a pharmaceutically acceptable carrier. According to some embodiments, the pharmaceutically acceptable carrier does not include hyaluronic acid.

According to one embodiment, the pharmaceutically acceptable carrier is a solid carrier or excipient. According to another embodiment, the pharmaceutically acceptable carrier is a gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various mono-and polysaccharides (including, but not limited to, hyaluronic acid), starch, cellulose derivatives, gelatin, and polymers. Exemplary carriers may also include saline vehicles, such as Hydroxypropylmethylcellulose (HPMC) in Phosphate Buffered Saline (PBS).

According to some embodiments, the pharmaceutically acceptable carrier imparts adhesiveness. According to one embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid. According to some embodiments, the pharmaceutically acceptable carrier comprises 0% to 5% hyaluronic acid. According to one embodiment, the pharmaceutically acceptable carrier comprises less than 0.05% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.1% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.2% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.3% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.4% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.6% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.7% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.8% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 0.9% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.1% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.2% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.3% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.4% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.6% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.7% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.8% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 1.9% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.1% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.2% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid 2.3% less. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.4% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.6% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.7% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.8% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 2.9% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 3.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 3.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 4.0% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 4.5% hyaluronic acid. According to another embodiment, the pharmaceutically acceptable carrier comprises less than 5.0% hyaluronic acid.

In some embodiments, the pharmaceutically acceptable carrier includes, but is not limited to, a gel sustained release solid or semi-solid compound, optionally as a sustained release gel. In some such embodiments, the voltage-gated calcium channel blocker is embedded in a pharmaceutically acceptable carrier. In some embodiments, the voltage-gated calcium channel blocker is coated on a pharmaceutically acceptable carrier. The coating may be of any desired material, preferably a polymer or a mixture of different polymers. Optionally, the polymer may be used in a granulation stage to form a matrix with the active ingredient to obtain a desired release pattern of the active ingredient. The gel sustained release solid or semi-solid compound is capable of releasing the active agent over a desired time period. The gel sustained release solid or semi-solid compound may be implanted into a tissue within the human brain, such as, but not limited to, in close proximity to a blood vessel, such as a cerebral artery.

According to another embodiment, the pharmaceutically acceptable carrier comprises a slow release solid compound. According to one such embodiment, the voltage-gated calcium channel blocker is embedded in or coated on a slow-release solid compound. According to yet another embodiment, the pharmaceutically acceptable carrier comprises slow-release microparticles comprising a voltage-gated calcium channel blocker.

According to another embodiment, the pharmaceutically acceptable carrier is a gel compound, such as a biodegradable hydrogel.

Microparticle formulation

According to some embodiments, the voltage-gated calcium channel blocker is provided in particle form. The term "particle" as used herein refers to a nano-sized or micro-sized (or in some cases larger) particle that may contain, in whole or in part, the calcium channel blocker. According to some embodiments, the microparticle formulation comprises a plurality of microparticles impregnated with the voltage-gated calcium channel blocker. According to one embodiment, the voltage-gated calcium channel blocker is comprised inside the core of the particle surrounded by the coating. According to another embodiment, the voltage-gated calcium channel blocker is dispersed throughout the surface of the particle. According to another embodiment, the voltage-gated calcium channel blocker is disposed on or in a microparticle. According to another embodiment, the voltage-gated calcium channel blocker is disposed on the surface of the entire microparticle. According to another embodiment, the voltage-gated calcium channel blocker is adsorbed into the particle.

According to some such embodiments, the microparticles are in a uniform size distribution. According to some embodiments, the uniform distribution of particle sizes is achieved by a homogenization process to form a uniform emulsion comprising the particles. According to some such embodiments, each microparticle comprises a matrix. According to some embodiments, the matrix comprises a voltage-gated calcium channel blocker.

According to some embodiments, the pharmaceutical composition is flowable. According to some embodiments, the microparticle formulation component of the pharmaceutical composition is flowable.

According to some embodiments, the particles are selected from the group consisting of zero order release, first order release, second order release, delayed release, sustained release, rapid release, and combinations thereof. In addition to therapeutic agents, such particles may include any of those materials conventionally used in the medical arts, including but not limited to erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof.

According to some embodiments, the particles are microcapsules containing the voltage-gated calcium channel blocker in solution or in a semi-solid state. According to some embodiments, the particle is a microparticle comprising, in whole or in part, a voltage-gated calcium channel blocker. According to some embodiments, the particle is a nanoparticle comprising, in whole or in part, a voltage-gated calcium channel blocker. According to some embodiments, the particles may be of almost any shape.

According to some embodiments, the particle size is between about 25 μm to about 100 μm. According to some embodiments, the particle size is between about 30 μm to about 80 μm. According to one embodiment, the particle size is at least about 25 μm. According to another embodiment, the particle size is at least about 30 μm. According to another embodiment, the particle size is at least about 35 μm. According to another embodiment, the particle size is at least about 40 μm. According to another embodiment, the particle size is at least about 45 μm. According to another embodiment, the particle size is at least about 50 μm. According to another embodiment, the particle size is at least about 55 μm. According to another embodiment, the particle size is at least about 60 μm. According to another embodiment, the particle size is at least about 65 μm. According to another embodiment, the particle size is at least about 70 μm. According to another embodiment, the particle size is at least about 75 μm. According to another embodiment, the particle size is at least about 80 μm. According to another embodiment, the particle size is at least about 85 μm. According to another embodiment, the particle size is at least about 90 μm. According to another embodiment, the particle size is at least about 95 μm. According to another embodiment, the particle size is at least about 100 μm.

According to another embodiment, the voltage-gated calcium channel blocker may be provided in a thread. The wire may contain a voltage-gated calcium channel blocker in the coated core, or the voltage-gated calcium channel blocker may be dispersed throughout the wire, or a therapeutic agent may be adsorbed within the wire. Such a thread may have any level of release kinetics including zero order release, first order release, second order release, delayed release, sustained release, rapid release, and the like, and any combination thereof. Such a thread may include, in addition to the therapeutic agent, any of those materials conventionally used in the medical arts, including but not limited to erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof.

According to another embodiment, the voltage-gated calcium channel blocker may be provided in at least one sheet. The sheet may contain the voltage-gated calcium channel blocker and at least one additional therapeutic agent in a core surrounded by a coating, or the voltage-gated calcium channel blocker and at least one additional therapeutic agent may be dispersed throughout the sheet, or the voltage-gated calcium channel blocker may be adsorbed in the sheet. The sheet may have any level of release kinetics including zero order release, first order release, second order release, delayed release, sustained release, rapid release, and the like, and any combination thereof. Such a sheet may comprise, in addition to the voltage-gated calcium channel blocker and the at least one additional therapeutic agent, any of those materials conventionally used in the medical arts, including but not limited to erodible, non-erodible, biodegradable or non-biodegradable materials or combinations thereof.

According to some embodiments, the pharmaceutical composition further comprises a preservative. According to some such embodiments, the pharmaceutical composition is in unit dosage form. Exemplary unit dosage forms include, but are not limited to, ampoules or multi-dose containers.

According to some embodiments, the microparticle formulation comprises a suspension of microparticles. According to some embodiments, the pharmaceutical composition further comprises at least one of a suspending agent, a stabilizing agent, and a dispersing agent. According to some such embodiments, the pharmaceutical composition is presented as a suspension. According to some such embodiments, the pharmaceutical composition is presented as a solution. According to some such embodiments, the pharmaceutical composition is presented as an emulsion.

According to some embodiments, the formulation of the pharmaceutical composition comprises an aqueous solution of the voltage-gated calcium channel blocker in a water-soluble form. According to some embodiments, the formulation of the pharmaceutical composition comprises an oily suspension of the voltage-gated calcium channel blocker. Oily suspensions of the voltage-gated calcium channel blockers can be prepared using suitable lipophilic solvents. Exemplary lipophilic solvents or vehicles include, but are not limited to, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides. According to some embodiments, the formulation of the pharmaceutical composition comprises an aqueous suspension of a voltage-gated calcium channel blocker. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or materials that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the voltage-gated calcium channel blocker may be in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

Suitable liquid or solid pharmaceutical formulations include, for example, microencapsulated forms (and, where appropriate, one or more excipients), helical (encocholated), coated on fine gold particles, included in liposomes, pellets for implantation into tissue, or dried on the surface of an object to be rubbed into tissue. The term "microencapsulation" as used herein refers to a process wherein very tiny droplets or particles are surrounded or coated by a continuous film of biocompatible, biodegradable polymeric material or non-polymeric material to produce a solid structure including, but not limited to, spherical particles, globules, crystals, agglomerates, microspheres, or nanoparticles. Such pharmaceutical compositions may also be in the form of granules, beads, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or delayed release formulations of the active compound, wherein formulation excipients and additives and/or adjuvants such as disintegrants, binders, coatings, bulking agents, lubricants or solubilizers are generally used as described above. The pharmaceutical composition is suitable for use in a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer (1990) Science 249, 1527-.

Microencapsulation process

In U.S. Pat. No.5,407,609 (entitled microencapsulation Process and products thereof), U.S. application No.10/553,003 (entitled Process for producing emulsion-based microparticles), U.S. application No.11/799,700 (entitled emulsion-based microparticles and methods of producing the same), U.S. application No.12/557,946 (entitled solvent extraction microencapsulation with tunable extraction rate), U.S. application No.12/779,138 (entitled Hyaluronic Acid (HA) injection vehicle), U.S. application No.12/562,455 (entitled microencapsulation Process Using solvents and salts), U.S. application No.12/338,488 (entitled Process for preparing microparticles with Low solvent residual quantity), U.S. application No.12/692,027 (entitled controlled Release System from Polymer blends), U.S. application No.12/692,020 (entitled Polymer mixtures with polymers comprising different non-repeating units and methods of making and Using the same), U.S. application No.10/565,401 (entitled "controlled release composition"), U.S. application No.12/692,029 (entitled "drying method for modifying properties of microparticles"); U.S. application No.12/968,708 (entitled "emulsion based process for preparing microparticles and workheads for use therewith"); and U.S. application No.13/074,542 (entitled "compositions and methods for improving the residence of pharmaceutical compositions at a topical application site") disclose and describe microencapsulation processes and products; a method for producing emulsion-based microparticles; emulsion-based microparticles and a method for producing the same; solvent extraction microencapsulation with adjustable extraction rate; microencapsulation process using solvent and salt; a continuous double emulsion process for making microparticles; drying methods for tuning the properties of microparticles, controlled release systems from polymer blends; polymer blends having polymers comprising different non-repeating units and methods of making and using the same; and emulsion-based processes for preparing microparticles and working head assemblies for use therewith. The contents of each of these documents are incorporated herein in their entirety by reference.

According to some embodiments, the delivery of the voltage-gated calcium channel blocker using microparticle technology involves bioabsorbable polymeric particles encapsulating the voltage-gated calcium channel blocker and at least one additional therapeutic agent.

According to one embodiment, the microparticle formulation comprises a polymeric matrix, wherein the voltage-gated calcium channel blocker is impregnated in the polymeric matrix. According to one embodiment, the polymer is a slow release polymer. According to one embodiment, the polymer is poly (D, L-lactide-co-glycolide). According to another embodiment, the polymer is a poly (orthoester). According to another embodiment, the polymer is a poly (anhydride). According to another embodiment, the polymer is polylactide-polyglycolide.

Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for the delivery of the voltage-gated calcium channel blockers. Such polymers may be natural or synthetic polymers. The polymer is selected based on the desired time period of release. Bioadhesive polymers of particular interest include, but are not limited to, bioerodible hydrogels as described by Sawhney et al in Macromolecules (1993)26,581-587, the teachings of which are incorporated herein. Exemplary bioerodible hydrogels include, but are not limited to, poly hyaluronic acid, casein, gelatin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (dodecyl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), and poly (octadecyl acrylate). According to one embodiment, the bioadhesive polymer is hyaluronic acid. In some such embodiments, the bioadhesive polymer comprises less than about 2.3% hyaluronic acid.

According to some embodiments, the pharmaceutical composition is formulated for parenteral injection, surgical implantation, or a combination thereof. According to some such embodiments, the pharmaceutical composition is in a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, or a sterile powder for reconstitution into a sterile injectable solution or dispersion. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include, but are not limited to, water, ethanol, dichloromethane, acetonitrile, ethyl acetate, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Suspensions may also include suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and mixtures thereof.

According to some embodiments, the pharmaceutical composition is formulated in an injectable long-acting form. Injectable depot forms are prepared by forming microencapsulated matrices of the voltage-gated calcium channel blockers in biodegradable polymers. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Such depot formulations may be formulated with suitable polymeric or hydrophobic materials (e.g. emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives (e.g. sparingly soluble salts). Examples of biodegradable polymers include, but are not limited to, polylactide-polyglycolide, poly (orthoester), and poly (anhydride). Injectable depot formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a Polyglycolide (PGA) matrix. PGA is a linear aliphatic polyester developed for use in sutures. Studies have reported PGA copolymers formed with trimethylene carbonate, polylactic acid (PLA) and polycaprolactone. Some of these copolymers may be formulated as microparticles for sustained drug release.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a polyester-polyethylene glycol matrix. Polyester-polyethylene glycol compounds can be synthesized; these compounds are soft and can be used for drug delivery.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a poly (amino) -derived biopolymer matrix. Polyamino-derived biopolymers may include, but are not limited to, those containing lactic acid and lysine as aliphatic diamines (see, e.g., U.S. patent 5,399,665) and tyrosine-derived polycarbonates and polyacrylates. Modification of the polycarbonate can change the length of the alkyl chain of such an ester (ethyl to octyl), while modification of the polyacrylate can further include changing the length of the alkyl chain of the diacid (e.g., succinic to sebacic acid), which enables great variation in the polymer and great flexibility in polymer properties.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a polyanhydride matrix. Polyanhydrides are prepared by dehydrating two diacid molecules by melt polymerization (see, e.g., U.S. patent 4,757,128). These polymers degrade due to surface attack (as opposed to polyesters that degrade due to bulk attack). The release of the drug may be controlled by the hydrophilicity of the selected monomer.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a photopolymerizable biopolymer matrix. Photopolymerizable biopolymers include, but are not limited to, lactic acid/polyethylene glycol/acrylate copolymers.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a hydrogel matrix. The term "hydrogel" refers to a substance that forms a solid, semi-solid, pseudoplastic, or plastic structure containing the necessary aqueous components to form a gel-like or jelly-like mass. Hydrogels generally include a variety of polymers, including hydrophilic polymers, acrylic acid, acrylamide, and 2-hydroxyethyl methacrylate (HEMA).

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a naturally occurring biopolymer matrix. Naturally occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides, and photopolymerizable compounds.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a protein polymer matrix. Protein polymers have been synthesized from self-assembling protein polymers such as fibroin, elastin, collagen and combinations thereof.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a naturally occurring polysaccharide matrix. Naturally occurring polysaccharides include, but are not limited to, chitin and its derivatives, hyaluronic acid, dextran, and cellulose (which are generally not biodegradable when unmodified) and Sucrose Acetate Isobutyrate (SAIB).

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on the chitin matrix. Chitin is predominantly composed of 2-acetamido-2-deoxy-D-glucosyl groups and is present in yeast, fungi and marine invertebrates (shrimp, crustaceans), where it is the main component of the exoskeleton. Chitin is not water soluble and deacetylated chitin (chitosan) is only soluble in acidic solutions (such as, for example, acetic acid). Studies have reported chitin derivatives that are water soluble, very high molecular weight (greater than 2 million daltons), viscoelastic, non-toxic, biocompatible, and capable of crosslinking with peroxides, glutaraldehyde, glyoxal or other aldehydes, and carbodiimides to form a gel.

According to some embodiments, the voltage-gated calcium channel blocker is impregnated in or on a Hyaluronic Acid (HA) matrix. Hyaluronic Acid (HA), which consists of alternating glucuronic acid and glucosamine bonds and is present in the vitreous humor, the extracellular matrix of the brain, the synovial fluid, the umbilical cord and the rooster comb of mammals, from which it can be isolated and purified, can also be produced by fermentation processes.

According to some embodiments, the pharmaceutical composition further comprises an adjuvant. Exemplary adjuvants include, but are not limited to, preservatives, wetting agents, emulsifying agents, and dispersing agents. Preservation of the action of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example, sugars, sodium chloride, and the like, may also be included. Prolonged absorption of the injectable pharmaceutical form is brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

The formulations may be prepared, for example, by terminal gamma irradiation, filtration through a bacteria-retaining filter, or by incorporating the disinfecting agent in the form of a sterile solid composition which may be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol, dichloromethane, ethyl acetate, acetonitrile or the like. Acceptable vehicles and solvents that may be used include water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any low-irritation fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Formulations for parenteral (including but not limited to subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intrathecal, intracerebroventricular, and intraarticular) administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions which may contain suspending agents and thickening agents.

According to another embodiment, the pharmaceutical composition is formulated by linking the voltage-gated calcium channel blocker to a polymer that enhances water solubility. Examples of suitable polymers include, but are not limited to, polyethylene glycol, poly- (d-glutamic acid), poly- (l-glutamic acid), poly- (d-aspartic acid), poly- (l-aspartic acid), and copolymers thereof. Polyglutamic acids having a molecular weight between about 5,000 and about 100,000, and a molecular weight between about 20,000 and about 80,000 can be used, as can polyglutamic acids having a molecular weight between about 30,000 and about 60,000. The polymer is attached via an ester linkage to one or more hydroxyl groups of the inventive Epothilone (Epothilone) using a protocol substantially as described in U.S. patent No.5,977,163, incorporated herein by reference. In the case of the 21-hydroxy-derivatives of the invention, specific attachment sites include the hydroxy group of carbon-21. Other attachment sites include, but are not limited to, hydroxyl groups at carbon 3 and/or hydroxyl groups at carbon 7.

Suitable buffers include: acetic acid and salt (1-2% w/v); citric acid and salt (1-3% by weight/volume); boric acid and salts (0.5-2.5% by weight/volume); and phosphoric acid and salts (0.8-2% by weight/volume). Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); nipagin ester (0.01-0.25% by weight/volume) and thimerosal (0.004-0.02% by weight/volume).

As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to a "polypeptide" refers to one or more polypeptides

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, or any intermediate value in the stated range, between the upper and lower limit of that range and any other stated or stated range, unless the context clearly dictates otherwise, is encompassed within the invention. The upper and lower limits of these smaller ranges, independently included in the smaller ranges, are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such publication by virtue of prior invention. In addition, the dates of publication provided may also be different from the actual publication dates which may need to be independently verified.

Examples

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all experiments or experiments performed only. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees celsius, and pressure is at or near atmospheric.

Example 1 preliminary study 1-Effect of nimodipine formulations on cerebral vasospasm in a subarachnoid hemorrhage (SAH) canine model

Materials and methods

Preparation

Test formulations of particulate nimodipine formulations with uniform particle size distribution were prepared by combining a polymer solution (e.g., a 50-50 glycolide-lactide blend) with a solvent in the presence of nimodipine. The mixture is added to an aqueous solution containing a surfactant to form an emulsion, and the solvent is separated to produce a flowable particulate nimodipine formulation. The initial drug loading was 65%, i.e., 65% nimodipine and 35% polymer. The average particle size was about 52 μ.

The particulate nimodipine formulation is combined with a pharmaceutical carrier to form the pharmaceutical composition of the present invention. When the device for delivery is a surgical injection apparatus and the site of delivery is in close proximity to the cerebral artery in the subarachnoid space, a vehicle (e.g., saline (hydroxypropyl methylcellulose (HPMC) in Phosphate Buffered Saline (PBS)) is mixed with the particulate nimodipine formulation.

Treatment group

A total of 6 male dogs were assigned to the study as shown in table 1.

TABLE 1 treatment set distribution

Administration of

Control (microparticulate placebo formulation) and test article (low dose microparticulate nimodipine formulation or high dose microparticulate nimodipine formulation) were administered 1 time during day 1 surgery by injection into the cisterna magna (enlarged subarachnoid space between the caudal side of the cerebellum and the dorsal surface of the medulla oblongata). The dose level in the treatment group was 10mg or 30mg in a fixed dose volume of 0.25mL (microparticle placebo formulation), 0.17mL or 0.18mL (low dose microparticle nimodipine formulation) or 0.46mL (high dose microparticle nimodipine formulation). Filling the provided syringes with 16mg of low dose microparticle nimodipine formulation and 40mg of high dose microparticle nimodipine formulation, respectively; this allows for the overfill required to fill the dead volume in the delivery system. When these substances are administered according to the reconstitution/injection method, the delivered dose is approximately 10mg and 30 mg. The control group received the control (particulate placebo formulation) in the same manner as the treatment group.

For reconstitution/injection, a syringe containing the diluent is connected to a syringe containing the particulate nimodipine formulation by a linker. The plunger is cycled to draw the vehicle into the microparticle formulation. The resulting pharmaceutical composition is then pushed into the left syringe disconnected from the adapter. For delivery, the composition is injectable through a surgical needle or may be loaded onto or injected through a cannula or catheter of any suitable size.

Surgical operation

On day 1, dogs were weighed, baseline blood was collected and blood pressure, temperature, heart rate oxygen and blood gas were monitored throughout the surgery. Cerebrovascular angiography is performed through a vertebral artery. For each angiogram, images were captured using the same exposure factor and magnification. An internal amplification standard was included in each angiogram.

After angiography, the animals were turned to the prone position and the cisterna magna was punctured transdermally with a # 18 spinal needle. A target volume of 0.3mL/kg CSF was spontaneously shed, after which 0.5mL/kg fresh autologous arterial non-heparinized blood was withdrawn from the femoral artery catheter and injected into the cerebellar medullary basin at a rate of approximately 5 mL/min. Approximately half of the blood volume was injected, followed by administration of either placebo or nimodipine formulation at a rate of approximately 5 mL/min. When administration of the particulate placebo or nimodipine formulation (low and high dose) was completed, the remaining blood was injected. The needle is withdrawn immediately after injection. The animals were tilted 30 ° head down during the cerebral pool blood injection and held in this position for 15 minutes after completion of the injection. The animal was then turned supine, the femoral catheter removed, and the femoral artery connected. The incision is closed in a standard manner.

On day 3, dogs were placed under general anesthesia and cerebral cistern blood injections were repeated. On days 8 and 15, the animals were anesthetized, the angiography repeated and the removal of CSF from the cisterna magna. Animals were not allowed to recover from anesthesia after day 15 angiography. They were euthanized under anesthesia, perfused with phosphate buffered saline and then neutral buffered formalin, and brains were histologically analyzed as described above.

Vasospasm was assessed by comparing the diameter of the basilar artery on days 1, 8 and 15. The angiographic data was analyzed independently by four panelists blinded to the animal group. The 5 mean lumen diameters for each animal were averaged to obtain the mean lumen diameter for each animal at each time. For each animal, the individual vasospasm percentage was measured on days 8 and 15 using formula (1):

for each group, the average vasospasm percentage on days 8 and 15 was also measured. Figure 10 shows the percent change (%) from baseline in mean basilar artery diameter after treatment with low dose (10mg) nimodipine formulation, high dose (30mg) formulation and placebo in the cisterna magna in the subarachnoid space. Table 2 summarizes the mean, standard error, median and standard deviation of the vasospasm percentages.

Table 2: summary of the percentage of vasospasm data from angiographic examination

On day 8, mean basilar artery diameter was reduced by 24% in control animals compared to baseline. Animals treated with low dose nimodipine microparticles had an average reduction in the basilar artery diameter of-9.9% compared to baseline. Animals treated with high dose nimodipine microparticles had an average increase in the basilar artery diameter of 1.2% compared to baseline.

On day 15, the mean basilar artery diameter reduction in control animals (placebo-treated) was-17.3% compared to baseline. Animals treated with low dose nimodipine microparticles had an average decrease in basilar artery diameter of-24% compared to baseline. Animals treated with high dose nimodipine microparticles had an average increase in the basilar artery diameter of 0.7% compared to baseline. Due to the small number of animals studied, no statistical analysis was performed.

This example shows that: (1) on day 8, the control group had the highest narrowing of the basal artery, followed by the low dose group, and the high dose group was the lowest; and (2) on day 15, the basal artery narrowing was highest in the control group, followed by the low dose group, and lowest in the high dose group. Due to the small number of animals in this study, the change in the basilar artery was within the expected statistical range of variation in the low dose group on day 15.

Clinical findings associated with the study approach are believed to be limited to the observation of decreased activity and loss of appetite. The activity reduction was significant in all 6 animals during study week 1 and in 1 placebo-treated and 1 low dose nimodipine microparticle treated animals during week 2. Appetite loss was evident in 5 of 6 animals during week 1 and 4 of 6 animals during week 2. These findings were present in animals from all dose groups and were therefore considered relevant to the study procedure.

Behavioral observations

For all animals, observations were made twice daily for morbidity, mortality, injury and food and water availability. Body weights were measured and recorded weekly before randomization and during the study. A full set of physical examinations was performed on all animals by an assistant veterinarian pretest.

Behavioral observations were made daily by an assistant veterinarian on each animal enrolled in the study. Each animal was examined daily by an assistant veterinarian. Behavior scores were given for behaviors belonging to the categories of appetite, activity and neurological deficit behavior according to tables 3-5.

Table 3 provides the behavior scores given for appetite.

TABLE 3 behavior scoring for appetite

Table 4 provides the behavior scores for activity.

TABLE 4 behavior scoring for Activity

Table 5 provides the behavioral scores for neurological deficit. Neurological impairment assessed as a result of inability to walk due to ataxia or paresis

TABLE 5 behavior scoring for neurological deficits

Figure 11 shows a graph of mean behavioral scores of dogs suffering from subarachnoid hemorrhage treated with placebo, a low dose (10mg) microparticle nimodipine formulation, or a high dose (30mg) microparticle nimodipine formulation.

There was no consistent or significant change in appetite or activity and no change in neurological function.

Both the study method and the treatment with placebo or nimodipine microparticles were not associated with any substantial body weight change. There was no significant difference in hematological parameters between nimodipine microparticle dose and placebo.

Serum analysis

Analysis of nimodipine in serum samples showed higher concentrations at day 3 and detectable nimodipine levels were still present at day 15 (figure 7, table 6). Table 6 lists serum drug concentrations (ng/mL) in dogs suffering from subarachnoid hemorrhage when treated with placebo, low dose (10mg) microparticle nimodipine formulation or high dose (30mg) microparticle nimodipine formulation. Figure 12 shows a graph of serum drug concentration (ng/mL) over time in dogs suffering from subarachnoid hemorrhage when treated with placebo, a low dose (10mg) microparticle nimodipine formulation, or a high dose (30mg) microparticle nimodipine formulation.

Serum concentrations of nimodipine were higher in animals treated with high doses of nimodipine microparticles. In placebo animals, no nimodipine was detected at any time point.

TABLE 6 serum drug concentration (ng/mL)

Cerebrospinal fluid (CSF) analysis

Analysis of CSF samples found that high concentrations of nimodipine continued on days 3 and 8, and lower concentrations were present on day 15 after administration of low doses of nimodipine microparticles. Table 7 lists the drug concentration (ng/mL) in CSF from dogs suffering from subarachnoid hemorrhage when treated with placebo, low dose (10mg) microparticle nimodipine formulation or high dose (30mg) microparticle nimodipine formulation.

In the case of low and high dose nimodipine microparticles, CSF nimodipine concentration was significantly higher than serum concentration and there was still a detectable concentration at day 15. One of the samples on day 3 of the high dose was above the limit of quantitation (>500(ng/mL) and could not be retested due to the absence of additional samples.

TABLE 7 CSF nimodipine concentration (ng/mL) for each treatment group

Observation by microscope

Figure 13 shows the histopathology of dogs suffering from subarachnoid hemorrhage (SAH) when treated with placebo (a) and when treated with low dose microparticle nimodipine formulation (B). Figure 14 shows a profile used in a dog model experiment. The only microscopic observations included a slight to mild granulomatous inflammation within the subarachnoid space of the pons and/or medulla in both animals from the low dose microparticle nimodipine formulation group and in both animals from the high dose microparticle nimodipine formulation group. Inflammation is characterized by the accumulation of giant cells that phagocytose foreign substances. Minor subacute inflammation or perivascular infiltration of lymphocytes was also evident in some animals between groups. The latter observation is closely related to granulomatous inflammation.

Minor to mild degeneration was also evident in both animals from the placebo group and in both animals from the low dose nimodipine microparticle group. Degeneration is present in the ventral portion of the pons and/or medulla and is characterized by cavitation of the lacunae, small vessel hyperplasia, and an increase in the number of glia/astrocytes that are partially filled with hemorrhage. Foam vacuolated cells are occasionally present. Axonal swelling/degeneration is present in adjacent brain tissue. This observation is believed to be related to the method of injection and not to the effect of the injected composition.

Meningeal bleeding and/or fibroplasia are evident in most animals examined and may be associated with necropsy and/or injection procedures.

Microscopic studies showed that in all treatment groups, i.e., placebo, low (10mg) and high (30mg) microparticle nimodipine formulations, there was minimal to mild granulomatous inflammation, minimal to mild degeneration and meningeal bleeding and/or fibrosis within the subarachnoid space.

Example 2 study 2-Effect of nimodipine formulations on cerebral vasospasm in a subarachnoid hemorrhage (SAH) canine model

Materials and methods

Preparation

Test formulations comprising particulate nimodipine formulations with a uniform distribution of particle size were prepared by combining a polymer solution (e.g., a 50-50 glycolide-lactide blend) with a solvent in the presence of nimodipine. The mixture is added to an aqueous solution containing a surfactant to form an emulsion, and the solvent is separated to produce a flowable particulate nimodipine formulation. The initial drug loading was 65%, i.e., 65% nimodipine and 35% polymer. The average particle size was about 52 μ.

The particulate nimodipine formulation is combined with a pharmaceutical carrier to form the pharmaceutical composition of the present invention. When the device for delivery is a surgical injection apparatus and the site of delivery is in close proximity to the cerebral artery in the subarachnoid space, a vehicle that imparts adhesion (e.g., hyaluronic acid) is mixed with the microparticle nimodipine formulation ("nimodipine formulation 1"). For the microparticle nimodipine formulation 2 ("nimodipine formulation 2"), the vehicle that imparts adhesion is not used as a pharmaceutically acceptable carrier. Placebo formulations contain microparticles plus vehicle but no nimodipine.

Treatment group

A total of 30 dogs were assigned to the study shown in table 8.

TABLE 8 assignment of treatment groups

Administration of

The microparticle nimodipine formulation (formulation 1) was administered to treatment groups 2 and 3 by surgical injection within the cisterna magna of the subarachnoid space, accompanied by a vehicle such as hyaluronic acid. The microparticle nimodipine formulation (formulation 2) was administered to treatment group 4 via a catheter into the ventricle by syringe (nos. 14 to 18) without vehicle. The particulate placebo formulation was administered to treatment group 1 (oral control) by surgical injection within the cisterna magna of the subarachnoid space, accompanied by vehicle (e.g., hyaluronic acid). Treatment group 1 (oral control) subsequently received oral nimodipine capsules (0.86mg/kg) 6 times daily until day 21 after administration of the particulate placebo formulation on day 1. The microparticulate placebo formulation was also administered by surgical injection to a placebo control group in the subarachnoid space inside the cisterna magna in the presence of a vehicle (e.g., hyaluronic acid). (data not shown). The dose levels delivered for treatment groups 2, 3 and 4 are as shown in table 8 above. Filling the syringe with the pharmaceutical composition takes into account the overfill required to fill the dead volume in the delivery system. The delivered dose was approximately 40mg (dose 1) and 100mg (dose 2). The oral control group and the placebo group received the control preparation in the same manner as the treatment group.

For reconstitution/injection, a syringe containing the diluent is connected to a syringe containing the particulate nimodipine formulation by a linker. In the case of treatment groups 1, 2 and 3, the plunger was cycled to draw the vehicle into the microparticle formulation. The resulting pharmaceutical composition is then pushed into the syringe on the left side disconnected from the adapter. For delivery, the composition is injectable through a surgical needle or may be loaded onto and injected through a cannula or catheter of any suitable size.

Surgical operation

On day 1, dogs were weighed, baseline blood was collected and blood pressure, temperature, heart rate oxygen and blood gas were monitored throughout the surgery. Cerebrovascular angiography is performed through a vertebral artery. For each angiogram, images were captured using the same exposure coefficients and magnification. An internal amplification standard is included in each angiogram.

In the case of treatment groups 1, 2 and 3, after angiography, the animals were turned to the prone position and the cisterna magna was punctured transdermally with a 14 gauge spinal needle. A target volume of 0.3mL/kg CSF was spontaneously shed, after which 0.5mL/kg fresh autologous arterial non-heparinized blood was withdrawn from the femoral artery catheter and injected into the cerebellar medullary basin at a rate of approximately 5 mL/min. Approximately half of the blood volume was injected, followed by administration of either the particulate placebo or particulate nimodipine formulation at a rate of approximately 5 mL/min. When administration of placebo or nimodipine formulations (dose 1 and dose 2) was completed, the remaining blood was injected. The needle is withdrawn immediately after injection. The animals were tilted 30 ° head down during the cerebral pool blood injection and held in this position for 15 minutes after completion of the injection. The animal was then turned supine, the femoral catheter removed, and the femoral artery connected. The incision is closed in a standard manner.

In the case of treatment group 4, the microparticle nimodipine formulation was administered into the lateral ventricle in a single injection through a catheter (No. 14) at a rate of 5 mL/min.

On day 3, dogs were placed under general anesthesia and either cerebral cistern blood injection (in the case of treatment groups 1, 2 and 3) or intraventricular administration (in the case of treatment group 4) was repeated. On days 8 and 15, the animals were anesthetized, the angiography repeated and the removal of CSF from the cisterna magna. Animals were not allowed to recover from anesthesia after day 15 angiography. They were euthanized under anesthesia, perfused with phosphate buffered saline and then with neutral buffered formalin, and brains were subjected to histological analysis as described above.

Vasospasm was assessed by comparing the diameter of the basilar artery on days 1, 8 and 15. The angiographic data was analyzed independently by two panelists who were blinded to the animal group. The 5 mean lumen diameters for each animal were averaged to obtain the mean lumen diameter for each animal at each time point. For each animal, the individual vasospasm percentage was measured on days 8 and 15 using formula (1):

for each group, the average vasospasm percentage on days 8 and 15 was also measured. Figure 15 shows the percent change (%) of mean basilar artery diameter from baseline after treatment with nimodipine formulation 1 at dose 1(40mg), nimodipine formulation 1 at dose 2(100mg) and oral controls in the cisterna magna of the subarachnoid space, and following administration of nimodipine formulation 2 at dose 2(100mg) to the ventricles of the brain. Table 9 summarizes the mean, standard error, median and standard deviation of the percent vasospasm.

Table 9: summary of the percentage of vasospasm data from angiographic examination

This example shows that on day 8, by intraventricular delivery, control animals treated with oral nimodipine had the highest reduction in the basilar artery diameter when compared to baseline, followed by animals treated with 40mg dose of formulation 1, followed by animals treated with 100mg dose of formulation 1, and followed by animals treated with 100mg dose of formulation 2. Animals treated with 100mg dose of formulation 2 by intracerebroventricular delivery showed the lowest reduction in the diameter of the basilar artery. All three formulations were statistically significant on day 8 compared to the control. On day 15, the control and 100mg dose of formulation 1 had a similar decrease in basal artery diameter compared to baseline, the 40mg dose of formulation 1 was lower, and the 100mg dose of formulation 2 had no decrease or slight enlargement in basal artery diameter. On day 15, only the 100mg dose of formulation 2 was statistically significant compared to the control. This example shows that all 3 formulations were able to reduce vasospasm at day 7 compared to the oral nimodipine control, and that at day 15, formulation 2 at a dose of 100mg was able to reduce vasospasm compared to the oral nimodipine control.

Behavioral observations (study 2)

For all animals, observations were made twice daily for morbidity, mortality, injury and food and water availability. Body weights were measured and recorded weekly before randomization and during the study. A full set of physical examinations was performed on all animals by an assistant veterinarian pretest.

Behavioral observations were made daily by an assistant veterinarian on each animal enrolled in the study. Behavioral examinations were performed daily on each animal by an assistant veterinarian. Behavior scores were given for behaviors belonging to the categories of appetite, mobility, and neurologic deficit behaviors according to tables 3-5 above.

There was no consistent or significant change in appetite or activity and no change in neurological function.

Serum analysis (study 2)

Tables 10a-10g list the serum drug concentrations (ng/mL) in dogs suffering from subarachnoid hemorrhage after treatment with nimodipine formulation 1 at dose 1(40mg), nimodipine formulation 1 at dose 2(100mg), and oral controls, and subsequent administration of nimodipine formulation 2 at dose 2(100mg) to the ventricles. Figure 16 shows a graph of serum drug concentration (ng/mL) over time in dogs suffering from subarachnoid hemorrhage after treatment with nimodipine formulation 1 at dose 1(40mg), nimodipine formulation 1 at dose 2(100mg), and an oral control, and following administration of nimodipine formulation 2 at dose 2(100mg) to the ventricles.

Figure 16 and tables 10a-10g show that both the 40mg dose and the 100mg dose of formulation 1 exhibited peak plasma concentrations at day 3, the 100mg dose of formulation 2 exhibited peak plasma concentrations at day 4, and the control oral nimodipine had peak plasma concentrations at day 7. 40mg of formulation 1 had the lowest peak concentration (8.3(ng/mL), while 100mg of formulation 1, 100mg of formulation 2, and the oral nimodipine control all had approximately equal peak concentrations (13.6 ng/mL, 14.6ng/mL, and 14.6ng/mL, respectively). this example demonstrates that all formulations had plasma concentrations at or below the maximum plasma concentration seen in the control with oral nimodipine.

TABLE 10 serum drug concentration (ng/mL) (study 2)

Cerebrospinal fluid (CSF) analysis (study 2)

Tables 11a-11b list CSF drug concentrations (ng/mL) in dogs suffering from subarachnoid hemorrhage after treatment with nimodipine formulation 1 at dose 1(40mg), nimodipine formulation 1 at dose 2(100mg), and oral controls, and subsequent administration of nimodipine formulation 2 at dose 2(100mg) to the ventricles. Figure 17 shows a graph of CSF drug concentration (ng/mL) over time in dogs suffering from subarachnoid hemorrhage after treatment with nimodipine formulation 1 at dose 1(40mg), nimodipine formulation 1 at dose 2(100mg), and an oral control, and subsequent administration of nimodipine formulation 2 at dose 2(100mg) to the ventricles.

Figure 17 and tables 11a-11b show that on day 3, oral nimodipine control, formulation at the 0mg dose, formulation at the 100mg dose, and formulation 2 at the 100mg dose all had CSF nimodipine peak concentrations. Oral nimodipine control has a CSF nimodipine peak concentration of 1.6ng/mL, 40mg dose of formulation 1 has a CSF nimodipine peak concentration of 1763.5ng/mL, 100mg dose of formulation 1 has a CSF nimodipine peak concentration of 3028.5ng/mL, and 100mg dose of formulation 2 has a CSF nimodipine peak concentration of 1896.5 ng/mL. Oral nimodipine controls had detectable CSF concentrations up to day 8, 40mg doses and 100mg doses of formulation 1 had detectable CSF concentrations up to day 35, and 100mg doses of formulation 2 had detectable CSF concentrations up to day 42. This example shows that both formulation 1 and formulation 2 are able to have significantly higher CSF nimodipine concentrations than the control with oral nimodipine and are able to maintain these concentrations for a longer period of time. This example shows that both formulation 1 and formulation 2 are capable of producing high CSF nimodipine concentrations while maintaining plasma nimodipine concentrations at or below the highest levels seen with control oral nimodipine. This example demonstrates that high levels of CSF nimodipine concentration achieved with microparticle nimodipine formulations can reduce vasospasm in subarachnoid bleeding dogs when administered topically (either by intracisternal or by intraventricular administration).

Table 11: CSF nimodipine concentration (ng/mL) of each treatment group (study 2)

Identity of

While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims.

1. A method for treating a delayed complication associated with a brain injury in a mammal in need thereof, wherein the brain injury comprises at least one interruption of a cerebral artery, the method comprising:

(a) a pharmaceutical composition is provided, which comprises

(i) Microparticle formulations of voltage-gated calcium channel blockers; and optionally

(ii) A pharmaceutically acceptable carrier; and

(b) administering a therapeutic amount of the pharmaceutical composition to an administration site via a device for administering a therapeutic amount of the pharmaceutical composition,

wherein the therapeutic amount is effective to reduce at least one sign or symptom of a delayed complication associated with brain injury, an

Wherein the at least one delayed complication is at least one of Delayed Cerebral Ischemia (DCI), a plurality of microthromboemboli, Cortical Spreading Ischemia (CSI), and angiographic vasospasm.

2. The method of embodiment 1, wherein in step (b), the means for administering is a surgical injection device and the site of administration is in close proximity to at least one cerebral artery affected by the brain injury.

3. The method of embodiment 1, wherein in step (b), the means for administering is a surgical injection device and the site of administration is a cerebral ventricle.

4. The method of embodiment 2, wherein the surgical injection apparatus is a needle, a cannula, a catheter, or a combination thereof.

5. The method of embodiment 3, wherein the microparticulate formulation is carried by cerebrospinal fluid to contact the cerebral artery affected by brain injury.

6. The method of embodiment 1, wherein the therapeutic amount is effective to increase the inner diameter of the cerebral artery affected by the brain injury as compared to a control.

7. The method of embodiment 1, wherein the brain injury is the result of an aneurysm, a sudden traumatic head injury, subarachnoid hemorrhage (SAH), or a combination thereof.

8. The method of embodiment 7, wherein the brain injury is the result of subarachnoid hemorrhage.

9. The method of embodiment 1, wherein the at least one delayed complication associated with brain injury further comprises at least one of an intracerebral hematoma, intracerebroventricular hemorrhage, fever, behavioral deficits, neurological deficit, cerebral infarction, and neuronal cell death.

10. The method of embodiment 9, wherein the behavioral deficit is ameliorated such that the improved behavioral deficit comprises increased appetite.

11. The method of embodiment 9, wherein improving the neurological deficit is such that the improved neurological deficit comprises improvement in ataxia or paresis.

12. The method of embodiment 1, wherein said pharmaceutical composition exerts a predominantly localized pharmacological effect in the treatment of said at least one delayed complication associated with brain injury.

13. The method of embodiment 1, wherein said pharmaceutical composition exerts a diffuse pharmacological effect throughout the brain in treating said at least one delayed complication associated with brain injury.

14. The method of embodiment 1, wherein the microparticle formulation comprises a plurality of microparticles, wherein the microparticles are in a uniform size distribution, and wherein each microparticle comprises a matrix.

15. The method of embodiment 1, wherein said microparticle formulation further comprises a plurality of microparticles impregnated with said voltage-gated calcium channel blocker.

16. The method of embodiment 1, wherein the microparticle formulation comprises a liquid suspension of microparticles.

17. The method of embodiment 1, wherein the ventricle is a lateral ventricle, a third ventricle, a fourth ventricle, or a combination thereof.

18. The method according to embodiment 1, wherein the microparticulate formulation of the voltage-gated calcium channel blocker comprises a slow-release compound.

19. The method of embodiment 18, wherein the sustained release compound is a polymer.

20. The method of embodiment 19, wherein the voltage-gated calcium channel blocker is disposed on or in the sustained release polymer.

21. The method according to embodiment 20, wherein the microparticulate formulation of a voltage-gated calcium channel blocker comprises poly (D, L-lactide-co-glycolide).

22. The method according to embodiment 20, wherein the microparticulate formulation of a voltage-gated calcium channel blocker comprises a poly (orthoester).

23. The method of embodiment 20, wherein the microparticulate formulation of a voltage-gated calcium channel blocker comprises a polyanhydride.

24. The method according to embodiment 1, wherein the voltage-gated calcium channel blocker is selected from the group consisting of an L-type voltage-gated calcium channel blocker, an N-type voltage-gated calcium channel blocker, a P/Q-type voltage-gated calcium channel blocker, or a combination thereof.

25. The method according to embodiment 1, wherein the voltage-gated calcium channel blocker is a dihydropyridine calcium channel blocker.

26. The method of embodiment 25, wherein the dihydropyridine calcium channel blocker is nimodipine.

27. The method of embodiment 1, wherein the pharmaceutically acceptable carrier comprises a gel compound.

28. The method of embodiment 27, wherein the gel compound is a biodegradable hydrogel.

29. The method of embodiment 1, wherein the pharmaceutical composition does not include the pharmaceutically acceptable carrier.

30. The method of embodiment 1, wherein the pharmaceutically acceptable carrier does not comprise hyaluronic acid.

31. The method of embodiment 1, wherein the pharmaceutically acceptable carrier comprises hyaluronic acid.

32. The method according to embodiment 31, wherein the pharmaceutically acceptable carrier comprises hyaluronic acid in the range of 0% to 5%.

33. The method according to embodiment 33, wherein the pharmaceutically acceptable carrier comprises less than 2.3% hyaluronic acid.

34. The method according to embodiment 33, wherein the pharmaceutically acceptable carrier comprises less than 5% hyaluronic acid.

35. A semi-solid multi-particle delivery system for treating delayed complications associated with brain injury in a mammal in need thereof, wherein the brain injury comprises at least one interruption of a cerebral artery, the system comprising:

(a) a pharmaceutical composition comprising

(i) Microparticle formulations of voltage-gated calcium channel blockers; and optionally

(ii) A pharmaceutically acceptable carrier; and

(b) a device for administering a therapeutic amount of the pharmaceutical composition to an application site;

wherein the therapeutic amount is effective to reduce the signs or symptoms of at least one delayed complication associated with the brain injury.

36. The system according to embodiment 35, wherein the at least one delayed complication is at least one of Delayed Cerebral Ischemia (DCI), a plurality of microthromboemboli, Cortical Spreading Ischemia (CSI), and angiographic vasospasm. The system of embodiment 31, wherein the means for administering is a surgical injection device and the site of administration is in close proximity to at least one cerebral artery affected by the brain injury.

37. The system of embodiment 35, wherein the means for administering is a surgical injection device and the administration site is a cerebral ventricle.

38. The system of embodiment 37, wherein the surgical injection device is a needle, a cannula, a catheter, or a combination thereof.

39. The system of embodiment 35, wherein the microparticulate formulation is capable of being carried by cerebrospinal fluid to contact the cerebral artery affected by the brain injury.

40. The system of embodiment 35, wherein the therapeutic amount is effective to increase the inner diameter of the cerebral artery affected by the brain injury as compared to a control.

41. The system of embodiment 35, wherein the brain injury is a result of an aneurysm, a traumatic sudden head injury, subarachnoid hemorrhage (SAH), or a combination thereof.

42. The system of embodiment 41, wherein the brain injury is a result of subarachnoid hemorrhage.

43. The system of embodiment 35, wherein the at least one delayed complication associated with brain injury further comprises at least one of an intracerebral hematoma, intracerebroventricular hemorrhage, fever, behavioral deficits, neurological deficit, cerebral infarction, and neuronal cell death.

44. The system of embodiment 43, wherein the behavioral deficit is ameliorated such that the improved behavioral deficit comprises increased appetite.

45. The system of embodiment 43, wherein improving the neurological deficit is such that the improved neurological deficit comprises improvement in ataxia or paresis.

46. The system according to embodiment 35, wherein said pharmaceutical composition exerts a predominantly localized pharmacological effect in the treatment of said at least one delayed complication associated with brain injury.

47. The system of embodiment 35, wherein the pharmaceutical composition exerts a diffuse pharmacologic effect throughout the brain in treating the at least one delayed complication associated with brain injury.

48. The system of embodiment 35, wherein the microparticle formulation comprises a plurality of microparticles, wherein the microparticles are in a uniform size distribution, and wherein each microparticle comprises a matrix.

49. The system according to embodiment 35, wherein the microparticle formulation further comprises a plurality of microparticles impregnated with the voltage-gated calcium channel blocker.

50. The system of embodiment 35, wherein the microparticle formulation comprises a liquid suspension of microparticles.

51. The system of embodiment 35, wherein the ventricle is a lateral ventricle, a third ventricle, a fourth ventricle, or a combination thereof.

52. The system according to embodiment 35, wherein the microparticulate formulation of the voltage-gated calcium channel blocker comprises a slow-release compound.

53. The system of embodiment 52, wherein the sustained release compound is a polymer.

54. The system of embodiment 53, wherein the voltage-gated calcium channel blocker is disposed on or in the sustained release polymer.

55. The system of embodiment 52, wherein the microparticulate formulation of the voltage-gated calcium channel blocker comprises poly (D, L-lactide-co-glycolide).

56. The system of embodiment 55, wherein the microparticulate formulation of a voltage-gated calcium channel blocker comprises a poly (orthoester).

57. The system according to embodiment 55, wherein the microparticulate formulation of a voltage-gated calcium channel blocker comprises a polyanhydride.

58. The system according to embodiment 35, wherein the voltage-gated calcium channel blocker is selected from the group consisting of an L-type voltage-gated calcium channel blocker, an N-type voltage-gated calcium channel blocker, a P/Q-type voltage-gated calcium channel blocker, or a combination thereof.

59. The system according to embodiment 35, wherein the voltage-gated calcium channel blocker is a dihydropyridine calcium channel blocker.

60. The system of embodiment 59, wherein the dihydropyridine calcium channel blocker is nimodipine.

61. The system according to embodiment 35, wherein the pharmaceutically acceptable carrier comprises a gel compound.

62. The system of embodiment 61, wherein the gel compound is a biodegradable hydrogel.

63. The system according to embodiment 35, wherein the pharmaceutical composition does not include the pharmaceutically acceptable carrier.

64. The system of embodiment 35, wherein the pharmaceutically acceptable carrier does not comprise hyaluronic acid.

65. The system according to embodiment 35, wherein the pharmaceutically acceptable carrier is hyaluronic acid.

66. The system according to embodiment 64, wherein the pharmaceutically acceptable carrier comprises hyaluronic acid ranging between 0% and 5%.

67. The method according to embodiment 66, wherein the pharmaceutically acceptable carrier comprises less than 2.3% hyaluronic acid.

68. The method according to embodiment 66, wherein the pharmaceutically acceptable carrier comprises less than 5% hyaluronic acid.

Claims (20)

1. Use of a particulate pharmaceutical composition in the manufacture of a medicament for reducing the severity and incidence of late complications associated with brain injury accumulating blood within the subarachnoid space, wherein the brain injury comprises an interruption of at least one cerebral artery and the late complications are selected from the group consisting of late cerebral ischemia (DCI) caused by microthromboembolism, microthromboembolus formation or Cortical Spreading Ischemia (CSI) and Cortical Spreading Ischemia (CSI), comprising:

(a) a microparticle formulation of a therapeutic amount of a voltage-gated calcium channel blocker, wherein the microparticle formulation comprises a suspension of uniformly sized microparticles formed from a polymer matrix impregnated with the voltage-gated calcium channel blocker; and

(b) pharmaceutically acceptable carriers

Wherein

(i) The pharmaceutical composition is flowable;

(ii) the pharmaceutical composition is formulated for parenteral injection into the subarachnoid space of the brain;

(iii) the pharmaceutical composition has a release profile such that the voltage-gated channel blocker is released from the composition in vivo from day 1 to day 30 in the second half of delivery;

(iv) the therapeutic amount of the voltage-gated calcium channel blocker is effective to maintain a cerebrospinal fluid (CSF) concentration of the voltage-gated calcium channel blocker within a therapeutic range to treat the delayed complication, while the plasma concentration is below the therapeutic range; thereby avoiding the unwanted side effects associated with systemic delivery; and

(v) A therapeutic amount of contact and flow around the cerebral artery in the subarachnoid space is effective to reduce signs or symptoms of delayed complications associated with brain injury.

2. The use of claim 1, wherein the brain injury that accumulates blood within the subarachnoid space is the result of an aneurysm, a traumatic head injury, subarachnoid hemorrhage (SAH), or a combination thereof.

3. The use of claim 2, wherein the brain injury that accumulates blood within the subarachnoid space is the result of subarachnoid hemorrhage.

4. The use according to claim 1, wherein the delayed complications associated with brain injury that accumulates blood within the subarachnoid space further include intracerebral hematoma, intracerebroventricular hemorrhage, fever, behavioral deficits, neurological deficit, cerebral infarction, and neuronal cell death.

5. Use according to claim 4, wherein the behavioural deficit is ameliorated such that the improved behavioural deficit comprises increased appetite.

6. The use of claim 4, wherein improving the neurological deficit is such that the improved neurological deficit comprises improvement in ataxia or paresis.

7. The use according to claim 1, wherein the voltage-gated calcium channel blocker is disposed in the polymer matrix.

8. Use according to claim 1, wherein the polymer matrix is selected from:

(i) poly (D, L-lactide-co-glycolide);

(ii) poly (ortho esters); and

(iii) a polyanhydride.

9. The use according to claim 1, wherein the voltage-gated calcium channel blocker is selected from the group consisting of an L-type voltage-gated calcium channel blocker, an N-type voltage-gated calcium channel blocker, a P/Q-type voltage-gated calcium channel blocker, or a combination thereof.

10. The use according to claim 9, wherein the L-type voltage-gated calcium channel blocker is a dihydropyridine calcium channel blocker.

11. The use according to claim 10, wherein the dihydropyridine calcium channel blocker is nimodipine.

12. The use of claim 1, wherein the pharmaceutically acceptable carrier comprises a gel compound.

13. The use according to claim 12, wherein the gel compound is a biodegradable hydrogel.

14. The use of claim 1, wherein the pharmaceutically acceptable carrier comprises hyaluronic acid.

15. The use of claim 1, wherein the pharmaceutically acceptable carrier comprises less than 2.3% -5% hyaluronic acid.

16. The use according to claim 1, wherein a therapeutic amount of the pharmaceutical composition is effective to increase the internal diameter of a cerebral artery affected by a brain injury that accumulates blood within the subarachnoid space as compared to a control.

17. The use according to claim 11, wherein the microparticle formulation comprises 65% nimodipine and 35% polymer.

18. Use according to claim 1, wherein the microparticles have an average size of about 52 μm.

19. The use of claim 1, wherein the brain injury results in decreased brain perfusion.

20. The use of claim 1, wherein the microparticles have a size of about 25 μ ι η to about 100 μ ι η.