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Definitions

• the invention relates to topical regional neuro-affective therapy (“TRNA THERAPY”) with cannabinoids, such as cannabidiol (CBD) on mammals other than humans. This is accomplished via administration of effective amounts of these agents on the back of the neck region, and in certain embodiments also in proximity to the painful site or problem area.
• TRNA THERAPY topical regional neuro-affective therapy
• CBD cannabidiol
• the approximate 21 ⁇ 2 pound human brain is comprised of the most complex material known to man.
• the neuron the primary functional cell of the nervous system, operates on the basis of electrical impulses that result in the release of neurochemical substances (neurotransmitters) at specific receptors: dopamine, serotonin, acetylcholine, norepinephrine, gamma-amino butyric acid (GABA), and many others.
• neurochemical substances neurochemical substances
• GABA gamma-amino butyric acid
• the brainstem serves as the vital pathway for relay and processing of neural impulses flowing continuously between the brain and the rest of the body. It is about the size of the thumb and contains the most dense and complicated wiring systems in the human body. In addition to the axons and dendrites (wires) that carry nerve impulses, the brainstem also contains critical nuclei that function as electrical generators and relays. Some of the nuclei are related to cranial nerve function while others serve as generators and impulse centers for pain perception, the autonomic system “fight or flight” response, wakefulness and alertness, as well as cardio-respiratory and related autonomic functions. The brainstem in mammals other than humans, while somewhat different than humans, is also responsible for these tasks.
• the endocannabinoid system is involved in regulating a variety of physiological processes including appetite, pain and pleasure sensation, immune system, mood, and memory.
• Endocannabinoid receptors in the brain interact with cannabinoids from different sources, including (endocannabinoids (brain derived, e.g., from foods (Omega-3s and Omega-6s); phytocannabinoids (plant derived, e.g., from buds, tinctures, extracts, including tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN),etc.); and synthetic cannabinoids (such as tetrahydrocannabinol (THC)).
• endocannabinoids brain derived, e.g., from foods (Omega-3s and Omega-6s)
• phytocannabinoids plant derived, e.g., from buds, tinctures, extracts, including tetrahydrocannabin
• Cannabinoids are a diverse class of chemical compounds that act on cannabinoid receptors on cells and influence neurotransmitter release in brain. These receptor proteins include endocannabinoids produced naturally in humans and animals, phytocannabinoids in cannabis and some other plants, and chemically manufactured synthetic cannabinoids.
• Phytocannabinoid ⁇ 9-tetrahydrocannabinol (THC) is the primary psychoactive compound of cannabis.
• Cannabidiol (CBD) is another major constituent of the plant, and comprises up to 40% extracts of plant resin. At least 85 different cannabinoids isolated from cannabis exhibit varied effects.
• U.S. Pat. No. 6,630,507 is held by the United States Department of Health and Human Services, covering use of cannabinoids for treating a wide range of diseases. It is directed to a method of treating diseases caused by oxidative stress comprising administering a therapeutically effective amount of a cannabinoid (e.g., cannabidiol) that has substantially no binding to the NMDA receptor to a subject who has a disease caused by oxidative stress.
• a cannabinoid e.g., cannabidiol
• the present invention is directed in part to a method of treating a disease state or condition in mammals via topical regional neuro-affective (TRNA) or regional neuro-affective (RNA) therapy via administration of a drug at the back of the neck region, optionally also at the spine region.
• the drug is one or more cannabinoids, administered at the back of the neck region in proximity to and under or on the area of skin above the brain stem to provide regional neuro-affective therapy to mammals, and optionally also at the spine region.
• the mammals are not human.
• the method is directed in part to treating a disease state or condition in mammals other than humans via topical regional neuro-affective (TRNA) or regional neuro-affective (RNA) therapy via administration of a cannabinoid drug(s) at the spine region, to provide regional neuro-affective therapy to mammals, including humans but preferably other than humans.
• TRNA topical regional neuro-affective
• RNA regional neuro-affective
• the administration may be along part or all of the spine, depending on the disease state or condition and/or the location of the injured area on the mammal.
• the cannabinoid drug(s) is derived from an endocannabinoid, a phytocannabinoid, a synthetic cannabinoid, or mixtures of any of the foregoing.
• the cannabinoid comprises cannabidiol.
• the cannabinoid drug mixture concentrate includes from about 0 to about 3% tetrahydrocannabinol, from about 0 to about 1% tetrahydrocannabinolic acid, from about 20 to about 100% cannabidiol, from about 0 to about 1% cannabidiolic acid, and from about 0 to about 1% cannabinol, for a total active cannabinoid level of from about 20% to about 50%.
• the remaining cannabinoids included in the mixture may be substantially therapeutically inactive.
• the cannabinoid drug(s) are incorporated into a pharmaceutically acceptable topical formulation.
• the cannabinoid drug(s) in the topical pharmaceutical formulation are at a concentration from about 0.75% to about 5%, by weight.
• the unit dose of the cannabinoid drug(s) includes from about 1 mg to about 200 mg cannabinoid drug(s) and the cannabinoid drug(s) comprise at least 80% cannabidiol.
• a unit dose of the topical pharmaceutical formulation comprises from about 3 mg to about 50 mg cannabidiol.
• the pharmaceutically acceptable topical formulation comprises a topical aqueous-based carrier, with an optional penetration enhancer.
• the topical aqueous-based carrier is a mousse, gel, or cream, and most preferably a mousse.
• the method further comprises applying a sufficient amount of the topical pharmaceutical formulation to the back of the neck region (and optionally also at the spine region) of mammals other than humans such that the onset of a therapeutic effect occurs in less than about 30 minutes, or in less than 15 minutes.
• the topical pharmaceutical formulation may be administered (applied to the back of the neck region) on a once a day basis, a twice a day basis, or even three times per day.
• the mammal has been administered multiple doses of the topical pharmaceutical formulation and has realized a therapeutic benefit from the cannabinoid drug therapy
• the administration of the topical pharmaceutical formulation will no longer be necessary after an initial course of therapy, as the mammal would no longer be suffering from the underlying condition and may be in essence “cured”.
• the mammal is a canine. In other preferred embodiments, the mammal is a feline. In other preferred embodiments, the mammal is a horse or other equine. In other embodiments, the mammal is a goat, sheep, lamb, pig, wolf, cattle, etc. In yet other embodiments, the mammal is a monkey or a hominoid ape.
• the disease or condition to be treated in the mammal includes lameness and gait issues; elbow dysplasia; hip dysplasia; back and hind leg problems; arthritis; seizures; encephalopathy, including lethargy, focus/attentional problems, and cognitive issues: spasticity; epilepsy; cancer; weakness; pain; numbness; anxiety and other mood disorders; hypertension; tremors; peripheral neuropathy; bowel and bladder control issues; inactivity; poor appetite; tumors (e.g., pituitary tumors); Cushing's disease; aggressive behavior; lethargy; personality change; as well as any other disease or condition in a mammal other than humans that may be treated with a cannabinoid.
• lameness and gait issues includes lameness and gait issues; elbow dysplasia; hip dysplasia; back and hind leg problems; arthritis; seizures; encephalopathy, including lethargy, focus/attentional problems, and cognitive issues: spasticity; epilepsy; cancer; weakness; pain;
• the method further comprises further comprises topically administering at the back of the neck region (and optionally also at the spine region) together with, sequentially, or simultaneously but in separate formulations, an additional drug(s) selected from the group consisting of: an anti-epileptic, an anxiolytic, a neuroleptic, an anti-psychotic, an analgesic, an anti-inflammatory, an anti-Parkinson's disease/syndrome drug, a drug for the treatment of dystonia, a drug for the treatment of spastic conditions, a drug for the treatment of benign essential/familial tremor, a drug for the treatment of tremor related to MS, a drug for the treatment of chronic encepahalopathies, a drug for the treatment of congenital CNS degeneration conditions/cerebral palsy, a drug for the treatment of cerebellar degeneration syndromes, a drug for the treatment of neuropathic and/or neurogenic pain, a drug for appetite suppression, a drug for neurode
• the additional drug(s) is a dopamine agonist selected from the group consisting of apomorphine, pramipexole, ropinirole, bromocriptine, cabergoline, pergolide, rotigotine, entacapone, tocapone, seligiline, dopamine, and mixtures of any of the foregoing.
• the disease state or condition is Parkinson's disease and/or related syndromes/diseases.
• the additional drug(s) is selected from the group consisting of the drug is a dopamine agonist, COMT inhibitors, MAO-B inhibitors, and mixtures of any of the foregoing.
• the additional drug(s) is an anti-epileptic drug selected from the group consisting of Valproic acid, Leviteracetem, Lamotrigene, Topiramate, Pregabalin, Gabapentin, Carbamazepine, Oxcarbazepine, Phenobarbital and other barbiturates, Tiagabine, Retigabine, Lacosamide, Perampanel, and mixtures of any of the foregoing; or the additional drug(s) is an anxiolytic, a neuroleptic and/or an antipsychotic; or the additional drug(s) is an analgesic and/or an anti-inflammatory; or the additional drug(s) is used in the treatment of neuropathic and/or neurogenic pain; or the additional drug(s) is for multiple sclerosis; or the additional drug(s) is for insomnia; or the additional drug(s) is for fatigue; or the additional drug(s) is for vertigo, nausea and/or dizziness; or the additional drug(s) is a
• the drug is formulated in a pharmaceutically acceptable (immediate release) topical carrier.
• the topical carrier is aqueous based, and may be a cream or gel or mousse.
• the method further comprises formulating the cannabinoid drug(s) in a pharmaceutically acceptable immediate release aqueous-based carrier.
• the cannabinoid drug(s) is administered in a topical pharmaceutical formulation comprising liposomes.
• the method further comprises applying a sufficient amount to the back of the neck region of the mammal such that the onset of clinical effect occurs in less than about 30 minutes, and in certain preferred embodiments in less than about 15 minutes.
• the therapeutically effective amount of the cannabinoid drug(s) is applied as a unit dose comprising from about 0.25 mg to about 500 mg.
• the cannabinoid drug(s) is incorporated into a sustained release transdermal delivery system which is capable of delivering from about 0.25 mg to about 5000 mg of the cannabinoid drug(s) through the skin of a mammal other than humans over a 24 hour period, the transdermal delivery system being capable of delivering the cannabinoid drug(s) in such amounts for a time period from about 1 to about 7 days.
• the cannabinoid drug(s) is administered via implantation or injection at the back of the neck region, or is administered via injection in an immediate release pharmaceutically acceptable carrier for injection. In certain embodiments, the cannabinoid drug(s) is administered via injection or implantation in a controlled release carrier to provide a prolonged effect of the cannabinoid drug(s). In certain embodiments, the cannabinoid drug(s) is administered to create a depot under the skin at the back of the neck region.
• Certain embodiments of the invention are directed to a topical formulation, comprising a cannabinoid drug(s) in a pharmaceutically acceptable aqueous-based carrier, the cannabinoid drug(s) being incorporated into the carrier in at least one unit dose comprising from about 0.25 mg to about 80 mg cannabinoid drug(s).
• a topical formulation when applied in a unit dose to the back of the neck of a mammal other than humans the topical formulation provides an onset of clinical effect occurs in less than about 30 minutes.
• the invention is also directed to a topical formulation, comprising a cannabinoid drug in a formulation suitable for administration at the back of the neck region in proximity to and under or on the area of skin above the brain stem of a mammal other than a human to provide regional neuro-affective therapy to the patient.
• the topical formulation may be prepared as an immediate, controlled or sustained release formulation.
• the drug formulations useful in the present invention may be in a form selected from a topical formulation (e.g, a mousse, cream, ointment or gel); a transdermal device; or an implantable or injectable formulation.
• the invention is further directed to the use of a cannabinoid drug in the preparation of a medicament for providing regional neuro-affective therapy to a mammal other than a human, wherein the cannabinoid drug(s) is administered at the back of the neck region and spine.
• the regional neuro-affective therapy can be described as administration of the cannabinoid drug(s) in proximity to and at or on the back of the neck region, e.g., on the area of skin above the brain stem or in an area running from around the pole to around or beyond the withers (for four-legged mammals), to provide regional neuro-affective therapy to the mammalian patient.
• the cannabinoid drug(s) is also administered to the mammal at or in proximity to an injured area on the mammal.
• the cannabinoid drug(s) may also be administered to the leg or hip area. If the four-legged mammal has an injury to its hip, the cannabinoid drug(s) may also be administered directly to the hip region.
• the cannabinoid drug(s) is applied to the posterior cervical region of the mammal in order to initiate the brainstem afferent stimulation therapy.
• the topical formulation or topical therapeutic system is applied to the back of the neck region, preferably near to or on the area of skin above the brain stem and/or along (part or all of) the spine.
• the cannabinoid drug is administered via implantation or injection at the back of the neck region and/or along the spine.
• the therapy is accomplished via the availability of the drug(s) at the free nerve endings under the epidermis.
• the drug may be incorporated into an implantation device or may be incorporated into a carrier such as a gel or matrix that will provide a prolonged release/effect of the cannabinoid drug(s) at the site.
• the carrier may be a hydrophilic or hydrophobic material, a colloidal material, and may be in a state ranging from a viscous liquid to a solid polymeric insert.
• Certain embodiments of the invention are directed to a method of treatment, comprising delivering a cannabinoid drug(s) through regional neuro-affective therapy by application as a cream/gel or a sustained release patch applied at the back of the neck region and/or along the spine, or via administration under the skin at the back of the neck region via an implantable or injectable drug formulation or device.
• the method further provides for a therapeutically effective treatment through topical regional neuro-affective (TRNA) therapy by application of a drug(s) as a cream/gel or a sustained release patch applied at the back of the neck region without the side-effects and the other draw-backs of the current injection method.
• TRNA topical regional neuro-affective
• the cannabinoid drug(s) is administered at the back of the neck region in an immediate release topical formulation in a dose comprising from about 0.25 mg to about 500 mg of the cannabinoid drug(s), and in certain embodiments more preferably from about 1 to about 100 mg of the cannabinoid drug(s).
• the cannabinoid drug(s) are in a more potent form (e.g., crystallized CBD from a herbal source), and the dose is from about 10 mg to about 50 mg.
• the (e.g., immediate release) topical formulation includes from about 1 mg to about 30 mg CBD when the CBD is provided as purified crystallized CBD from a herbal source.
• the method of treatment further comprises administering the cannabinoid drug(s) to other areas of the spine and/or peripheral nerves in addition to administration on or at the back of the neck region, in order to provide an additive or synergistic effect and further modulate afferent neural input to the brain to affect efferent outflow for relief of symptoms.
• the method of treatment further comprises topically administering at the back of the neck together with, sequentially, or simultaneously but in separate formulations, one or more additional active agents (“drugs”) which may be chosen from the following: an anti-epileptic, an anxiolytic, a neuroleptic, an anti-psychotic, an analgesic, an anti-inflammatory, an anti-Parkinson's disease/syndrome drug, a drug for the treatment of dystonia, a drug for the treatment of spastic conditions, a drug for the treatment of benign essential/familial tremor, a drug for the treatment of tremor related to MS, a drug for the treatment of chronic encepahalopathies, a drug for the treatment of congenital CNS degeneration conditions/cerebral palsy, a drug for the treatment of cerebellar degeneration syndromes, a drug for the treatment of neuropathic and/or neurogenic pain, a drug for appetite suppression, a drug for neurodegenerative conditions, a drug
• drugs which may
• the term “back of the neck region” is intended to encompass the area or region extending from (behind) one ear to the other ear of the mammal (other than a human patient) and from the back of the head (i.e., above the neck) to below the neck at the torso of the mammal.
• the back of the neck region refers to the area extending from the poll to the withers and beyond, e.g., along the spine.
• the poll is a name of the part of an animal's head, alternatively referencing a point immediately behind or right between the ears.
• the withers is the ridge between the shoulder blades of a four-legged mammal.
• a “topical formulation” includes, for example, ointments, creams, lotions, pastes, gels, etc., which releases one or more drugs (e.g., cannabinoid drug(s)s) at a predetermined rate over a defined period of time to a defined site of application.
• drugs e.g., cannabinoid drug(s)s
• an “injectable” formulation includes, for example, an injectable solution, suspension, gel or the like and may be in immediate release form or may provide a controlled or sustained release of the drug at the site of administration.
• immediate release means that the cannabinoid drug(s) is administered at the site of application (e.g., the back of the neck) and is available for immediate absorption at the site of application.
• immediate release is meant to convey in terms of a topical formulation the fact that there is nothing in the formulation (e.g., a sustained release carrier) that would delay or slow the availability of the drug at the site of application (in contrast to, e.g., a transdermal device or patch).
• an “implantable” formulation includes, for example, a solid, semisolid or liquid drug formulation which can be administered at the back of the neck region either via injection and/or via surgical implantation.
• the solid may comprise microspheres, microcapsules, pellets, discs, and the like.
• the implantable formulations of the invention may provide a controlled or sustained release of the drug at the site of administration.
• a “transdermal therapeutic system” is defined as a drug-containing device (including e.g., patch, disc, etc.) which releases one or more drugs at a predetermined rate over a defined period of time to a defined site of application.
• transdermal delivery is the delivery by passage of a drug through the skin and into the bloodstream (“traditional” transdermal delivery) and is termed “transdermal systemic drug delivery (TSD therapy).
• topical neuro-affective therapy is synonomous with the more accurately termed topical regional neuro-affective therapy (or “TRNA therapy”).
• TRNA therapy topical regional neuro-affective therapy
• This term describes important aspects of this delivery method: topical, regional (near brainstem and cervical spinal cord), and affecting the free nerve endings of the afferent nervous system, thereby not requiring the presence of drug in the blood, as with systemic therapies which includes the transdermal patch wherein the skin is used to have drug enter into the bloodstream through a continuous application patch.
• an ionotophoretic electric current generator may be required to cause drug entry into blood against a concentration gradient.
• therapeutically effective or “effective” amount is meant to be a nontoxic but sufficient amount of a cannabinoid compound(s) to provide the desired therapeutic effect.
• an “effective” amount of a permeation enhancer as used herein means an amount that will provide the desired increase in skin permeability and, correspondingly, the desired depth of penetration, rate of administration, and amount of drug to be delivered.
• the term “delivers” when used with respect to the topical formulation or transdermal therapeutic system means that the formulation or system provides a mean relative release rate or flux of the drug out of the formulation or system and through the skin of the patient.
• “Penetration enhancement” or “permeation enhancement” for purposes of the present invention relates to an increase in the permeability of skin to a pharmacologically active agent, i.e., so as to increase the rate at which the drug permeates through the skin and enters the bloodstream.
• the enhanced permeation effected through the use of such enhancers can be observed by measuring the rate of diffusion of drug through animal (mammal) skin using a diffusion cell apparatus.
• the drug may be in the form of the base, or may be provided as a pharmaceutically acceptable salt (inorganic or organic) or complex. It may be in an optically pure form or a mixture of stereoisomers.
• the therapeutically active agents used in the formulations and methods of the invention comprise cannabinoid drug(s).
• Cannabinoids are a diverse class of chemical compounds that act on cannabinoid receptors on cells and influence neurotransmitter release in brain. These receptor proteins include endocannabinoids produced naturally in humans and animals, phytocannabinoids in cannabis and some other plants, and chemically manufactured synthetic cannabinoids. Endo, phyto and/or synthetic cannabinoids cause neurotransmitter release which results in nerve transmission.
• Phytocannabinoid ⁇ 9-tetrahydrocannabinol (THC) is primary psychoactive compound of cannabis.
• Cannabidiol (CBD) is another major constituent of the plant, up to 40% extracts of plant resin.
• Cannabidiol is one of many active cannabinoids in cannabis.
• the cannabinoid may be derived from endocannabinoids (derived, e.g., from foods (Omega-3s and Omega-6s); phytocannabinoids (plant derived, e.g., from buds, tinctures, extracts, including tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN),etc.); and synthetic cannabinoids (such as tetrahydrocannabinol (THC)).
• THC tetrahydrocannabinol
• CBD cannabinol
• CBN cannabinol
• THC cannabinol
• the cannabinoid drug(s), or are not psychoactive or are substantially not psychoactive meaning that if included in the formulation, they are not in sufficient amount that a unit dose of the formulation would cause the patient to have a psychoactive effect).
• the cannabinoid drug is actually a mixture of two or more cannabinoids (e.g., CBD and THC together in a CBD:THC ratio that provides a therapeutic effect while substantially not psychoactive or not psychoactive at all).
• ECS The endocannabinoid system
• ECS endocannabinoid system
• cannabinoid receptors located in mammalian brain and throughout the central and peripheral nervous systems. These entail neuromodulatory lipids and their associated receptors.
• ECS cannabinoid system
• ECS is involved in a variety of physiological processes including neurological functions dealing with pain, mood, memory; and, movement, and sensation.
• the body's immune function and cell homeostasis is also maintained by ECS. It mediates the psychoactive effects of the cannabis (marijuana) plant.
• Cannabinoids are a diverse class of compounds that include many of the unique compounds found in marijuana.
• Cannabinoids produce physiological and behavioral effects through interaction with specific membrane-bound receptors.
• Two primary endocannabinoid receptors have been identified in humans: CB1 and CB2.
• CB1 receptors are found predominantly in brain (specifically in basal ganglia and limbic system, including hippocampus) and nervous system, as well as in peripheral organs and tissues. These are acted on by the endocannabinoid binding molecule Anandamide.
• GPCR G protein-coupled type receptors
• cannabinoid receptors are the most plentiful.
• CB1 receptors responsible for euphoric and anti-convulsive effects of cannabis.
• CB2 receptors found only in peripheral nervous system appear responsible for anti-inflammatory effect such as pain relief.
• One other main endocannabinoid is 2-Arachidonoylglycerol (2-AG), active at both CB1 and CB2 cannabinoid receptors.
• 2-AG 2-Arachidonoylglycerol
• Its mimetic phytocannabinoid is cannabidiol (CBD)
• CBD cannabidiol
• THC responsible for psycho-active effects.
• 2-AG and CBD are involved in regulation of appetite, immune system functions and pain management.
• Tetrahydrocannabinol has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest.
• innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study.
• Cannabidiol is considered the “medical component” of cannabis and hemp. CBD is considered to have a wide scope of medical applications. It acts as 5-HT1A receptor agonist which may explain its antidepressant, anxiolytic, and neuroprotective effects. Cannabidiol modulates opioid receptors involved with pain perception. CBD is not psychoactive and relieves convulsion, inflammation, anxiety, and nausea. It has also been found to play a role in preventing short-term memory loss from THC. Antipsychotic effects of cannabidiol represent potential treatment of schizophrenia. Oral CBD formulation received orphan drug status in US as treatment for Dravet syndrome, an intractable seizure disorder also known as Severe Myoclonic Epilepsy of Infancy (SMEI). Nabiximols, trade name Sativex, is an aerosolized mist for oral administration containing 1:1 ratio of CBD and THC approved 2005 in Canada for multiple sclerosis associated pain. CBD has a greater affinity for CB2 than CB1 receptor.
• CBD acts as serotonin (5-HT1A) receptor agonist which may explain its antidepressant, anxiolytic, and neuroprotective effects.
• CBD modulates opioid receptors involved with pain perception.
• CBD is not psychoactive and relieves convulsion (seizures), inflammation, anxiety, and nausea. It has been found to play a role in preventing short-term memory loss from THC.
• Antipsychotic effects of cannabidiol represents potential treatment of schizophrenia.
• CBD has a greater affinity for CB2 than CB1 receptors.
• the formulations of the invention contain more than one cannabinoid compound, which provide an “entourage effect.”
• CBD has anti-psychotic effects which may counteract psychotomimetic effects of THC, euphoric and hallucinogenic component of cannabis. Reports show CBD safe and well-tolerated alternative treatment for schizophrenia.
• a double blind trial comparing purified cannabidiol to atypical antipsychotic amisulpride in acute paranoid schizophrenia showed both treatments were associated with significant decrease in psychotic symptoms after 2 weeks; but cannabidiol was associated with significantly fewer side effects.
• cannabidiol affects limbic system, decreasing symptoms of social anxiety and isolation.
• Cannabidiol has demonstrated antidepressant-like effects in animal models of depression.
• the cannabinoid is not psychoactive, or only mildly psychoactive.
• Cannabidiol CBD is not psychoactive, and therefore in certain preferred embodiments, the active cannabinoid drug comprises cannabidiol, or consists essentially of cannabidiol, or consists of cannabidiol. In other preferred embodiments, cannabidiol comprises from about 5% to about 99.9% of the total amount of cannabinoid drug(s) included in the formulations and treatments of the present invention.
• cannabidiol comprises about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or more, or greater than about 95% of the total amount of cannabinoid drug(s) included in the formulations and treatments of the present invention.
• the CBD is derived from crystalline powder, such that the powder is about 95% pure CBD or greater.
• cannabidiol comprises at least about 20% of the total amount of cannabinoid drug(s) included in the formulations and treatments of the present invention.
• the cannabinoid drug comprises cannabinol (which is only mildly psychoactive).
• the cannabinoid drug(s) contained in the formulations of the invention is hemp CBD.
• the cannabinoid drug(s) is cannabis-based and comprises a THC-CBD (and optionally other cannabinoid combinations derived from cannabis).
• CBD and THC have different mechanisms of action, they may act synergistically, e.g., to control seizures. In such embodiments, the therapeutic effect may be via the “entourage effect”.
• the drug is a cannabinoid such as an endocannabinoids (derived, e.g., from foods (Omega-3s and Omega-6s); a phytocannabinoid (plant derived, e.g., from buds, tinctures, extracts, including tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN),etc.); and synthetic cannabinoids (such as tetrahydrocannabinol (THC)), mixtures thereof, and the like.
• endocannabinoids derived, e.g., from foods (Omega-3s and Omega-6s)
• a phytocannabinoid plant derived, e.g., from buds, tinctures, extracts, including tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN),etc.
• synthetic cannabinoids such as te
• cannabinoids useful in the present invention include cannabigerol (CBG), cannabichchromene (CBC), cannabicyclol (CBL), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol (Dronabinol), cannabigerol monomethyl ether (CBGM), nabilone, rimonabant (SR141716, a selective cannabinoid (CB I ) receptor inverse agonist), JWH-018, JWH-073, CP-55940, dimethylheptylpyran, HU-331, SR 144528 (a selective CB 2 receptor agonist), levonantradol, AM-2201, beta-caryophyllene, lipophilic alkamides (alycer
• a synthetic cannabinoid is used.
• Synthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, including the nonclassical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles, qualene17p, and arylsulfonamides, as well as eicosanoids related to the endocannabinoids.
• Cannabigerol (“CBG”) is non-psychotomimetic but still impacts the overall effects and affects of cannabis.
• CBG acts as a alpha2-adrenergic receptor agonist, 5-HT1A receptor antagonist, CB1 receptor antagonist, and also binds to the CB2 receptor.
• CBC is non-psychoactive, and exhibits anti-inflammatory and analgesic properties. Evidence suggests that CBC may play a role in anti-inflammatory and anti-viral effects, may have antidepressant effects, may promote neurogenesis, and may contribute to the overall analgesic effects of cannabis.
• Delta-9-tetrahydrocannabinol (Dronabinol; commercially available in the U.S. under the tradename Marinol) is used as an appetite stimulant, anti-emetic, and analgesic.
• Nabilone (Cesamet, Canemes), a synthetic cannabinoid and an analog of Marinol; Rimonabant (SR141716), a selective CB1 receptor inverse agonist once used as an anti-obesity drug under the tradename Acomplia, and was also used for smoking cessation.
• the cannabinoid drug(s) is industrial hemp or a non-psychoactive hemp product.
• the cannabinoid drug(s) comprises a natural cannabinoid compound, a synthetic cannabinoid compound, a semi-synthetic cannabinoid compound, or mixtures thereof.
• cannabinoids or cannabinoid analogues selected from the group consisting of cannabinol, cannabidiol, delta 9-tetrahydrocannabinol, delta 8-tetrahydrocannabinol, hydroxy-tetrahydrocannabinol, 11-hydroxy-9-tetrahydrocannabinol, levonantradol, delta 11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol, amandamide, nabilone, a natural or synthetic analogue thereof, a natural or synthetic molecule with a basic cannabinoid structure, and mixtures of any of the foregoing.
• the cannabinoid drug(s) included in the treatment and/or formulations of the present invention comprise a ligand that binds to the CB I or the CB 2 receptor.
• Cannabis terpenoids e.g., limonene, myrcene, a-pinene, linalool, ⁇ -caryophyllene, caryophyllene oxide, nerolidol and phytol
• terpenoids are quite potent, and affect animal and even human 18qualene when inhaled from ambient air at serum levels in the single digits ng ⁇ M1-1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts.
• the formulations and treatments of the present invention include an active drug component which comprises both a phytocannabinoid(s) and a terpenoid(s).
• Phytocannabinoid-terpenoid interactions may produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus ).
• the cannabinoid drug formulations of the present invention are preferably applied at the back of the neck region of the mammal other than a human patient.
• the term “back of the neck region” is intended to encompass the area or region extending from (behind) one ear to the other ear of the mammal and from the back of the head (i.e., above the neck) to the withers or beyond (four-legged mammals), and below shoulder level (monkeys, huminoid apes, etc.).
• the majority of mammals have seven cervical vertebrae, including humans, bats, giraffes and whales.
• the administration of the cannabinoid drug(s) may be located more directly at the back of the neck in the area in mammals above the cervical nerve roots, C1-C4 (and optionally including C5) such that administration of the cannabinoid drug(s) are in the area at or above the skin where the afferent components of trigeminal nerve system, cervical sympathetic nerves, and vagus nerve are located.
• a cannabinoid drug(s) at the back of the neck for mammals is a novel way to deliver cannabinoids. This is believed to be accomplished by activation of cutaneous afferent pathways through neuro-chemical receptors existing on free nerve-endings.
• the hypothesis of this therapeutic modality is based on presence of numerous (hundreds of thousands to millions) of free nerve-endings below the skin surface (stratum corneum) at upper posterior cervical region, the back of the neck or “nuchal” region.
• Modulated CNS efferent neural outflow in response to afferent activation manifests as improvement in clinical symptoms of MS and other conditions of brain and spinal cord impairment.
• the inventor has observed rapid therapeutic onset of action, generally, less than 10 to15 minutes administration of cannabinoid drug(s) at the back of the neck, with maximal benefit noted well within 30 minutes.
• a prolonged therapeutic effect has been noted, e.g., about 4 to about 12 hours or more, depending on condition and severity of the condition being treated.
• the peripheral nervous system communicates with central nervous system (CNS, consisting of brain, brainstem, and spinal cord) through dorsal root ganglia which reside just outside the spine and act as neural relay areas between PNS and CNS.
• CNS central nervous system
• Mammalian skin has free nerve endings just below the skin surface (stratum corneum), which are the peripheral end components of spinal dorsal root ganglia.
• stratum corneum are the peripheral end components of spinal dorsal root ganglia.
• As skin and CNS are both derived from the same embryological tissue, neuro-ectoderm, receptors to neurotransmitters and other substances used in neural communication are similarly represented on both free nerve endings and CNS. This makes sense as the skin needs to communicate directly with CNS with respect to external stimuli.
• these receptors are on the cell surface of skin free nerve endings, making them readily accessible to compounded drug applications to the skin for neural effect, “topical neuro-affective therapy.”
• the binding of the topically administered cannabinoid drug(s) to these receptors results in electrical action potential generation and propagation to CNS, causing therapeutic effects to occur.
• these same drug compounds do not need to enter the bloodstream to reach their sites of activity, as it is with systemic delivery. Systemic side effects and drug activity at sites other than intended are therefore not present. Further, by working through established neural pathways than through the blood stream, the therapeutic effects are rapid, generally with 15-30 minutes or less.
• TRNA TRNA
• RNA RNA therapy in CNS drug delivery for brainstem related disorders lies in the anatomy of the region.
• the free nerve endings with receptors for the neuro-chemicals dopamine, serotonin, norepinephrine, and others are located just below the surface of the skin, easily assessable to drugs compounded in an appropriate dermal penetration enhancing medium and topically applied to the skin.
• peripheral neural afferent stimulation therapy As it applies to the brainstem and how topical drug delivery to the back of the neck works requires a review of the neuro-anatomy and the neuro-physiology of the region. As indicated above, this area of the nervous system is very complicated, compact and highly inter-active and inter-related.
• the Trigeminal Nerve System is a component of the brainstem which coordinates pain input from the face, head, and the back of the neck. As such, it intimately influences the production of other symptoms associated with syndromes attributed to dysfunction within the trigeminal complex. These include the photophobia, phonophobia, nausea, anxiety, allodynia, and other focal sensory symptoms which may accompany a migraine attack. Similarly, episodes of trigeminal neuralgia (tic douloreux) frequently involve significant affective (emotional) and visceral components. Because of proximity and connections to other structures in the brainstem, abnormalities of temperature regulation, thirst, alertness, and mood are common. Some of these symptoms may be as equally disabling as the head and face pain.
• the trigeminal system receives similar input from the soft tissues of the posterior cervical region.
• the free nerve endings in the back of the neck are just below the surface of the skin, easily accessible to topically delivered drugs formulated in an appropriate dermal penetration enhancing compounding medium.
• the free nerve endings, via the small un-myelinated and myelinated “C-fibers” (pain fibers) carry pain impulses through afferent sensory nerves back to the Trigeminal Nucleus Caudalis (TNC).
• TNC is the pain processing center extending from the pons through the entire extent of the brainstem to the upper cervical spinal cord. After synapsing at the thalamus, pain impulses from TNC travel to the somatosensory cortex, where pain is perceived.
• Afferent input is defined as any neural impulses coming back to the brain from the body. As such it provides information to the brain for processing and interpretation: pain, sensation, autonomic functions.
• Efferent output on the other hand, consists of impulses originating in the central nervous system (brain, brainstem, and spinal cord) flowing to the body for function: movement, response, action.
• the vagus nerve includes both efferent and afferent fibers and is attached to the lower brainstem (medulla oblongata) via 8-10 radicles. Other mammals also have a vagus nerve which is somewhat similar.
• the afferent fibers arise in the jugular and the nodose vagus ganglia.
• the somatic afferent fibers terminate in the nucleus of the trigemino-spinal tract (TNC). Both the jugular and the nodose ganglia are connected with the superior cervical sympathetic gangion through inter-communicating rami.
• the superior cervical sympathetic ganglion is located between the internal carotid artery and the jugular vein on the ventral aspects of the transverse processes of the 2 nd , 3 rd , and the 4 th cervical vertebrae. It is the largest of the sympathetic trunk ganglia.
• the sympathetic innervation of the head includes fibers which join the plexi on the common carotid and the vertebrtal arteries.
• the one on the vertebral artery is continuous with the plexus on the basilar artery.
• Rami derived from the internal carotid plexus join the trigeminal nerve and the cavernous plexus in addition to the other structures such as the abducens and deep petrosal nerves.
• cervical nerve function is intimately related to vagal afferents and afferents from the face, head, and the dura of cranial fossae associated with migraine and other head and face pain syndromes.
• VNS vagal nerve stimulation
• CNS central nervous system
• the proposed delivery operates through direct nerve connections between skin peripheral nerves at the back of the neck, region and brainstem structures.
• Active drug compounded in an appropriate “dermal penetration enhancing” medium topically applied to the skin at the back of neck has effect on the free nerve endings of peripheral nerves located immediately below the skin surface.
• Receptors to dopamine, serotonin, norepinephrine, and other neuro-transmitters/neuro-chemicals involved with neural transmission are located on these free nerve endings.
• topically applied drug has near immediate therapeutic effect as direct neural impulses are involved—the concept of brainstem afferent stimulation through topical regional neuro-affective (TRNA) therapy.
• TRNA topical regional neuro-affective
• All prior art and methods of drug delivery to the CNS have involved blood flow and therapeutic drug blood level requirements.
• the inventive method does not require such, which are the source of undesirable systemic and CNS side-effects.
• the present drug delivery process operates on the principle of an electrical capacitor whereas the prior relied on those fluid dynamics and reservoir principles.
• the factors which determine the success of TRNA therapy include: the drug being considered, the compounding substance (surfactant/dermal penetration enhancer), the disease process, and the location of application.
• the free nerve endings in the skin at the back of the neck area are important components of the cervical nerves with rich connections to the trigeminal, vagal, and sympathetic systems communicating with brainstem structures and other components of the central nervous system. These are the areas pain and other symptoms related to neuro-chemical release are processed and perceived.
• These cervical nerves (the wires) have their cell bodies (their generators) within the Nucleus Caudalis (Spinal Nucleus) of the Trigeminal Nerve in the cervical spinal cord and the brainstem. Accordingly, they have direct neural connections with brainstem processing areas.
• the peripheral nerve receptor sites for these nerves, the free nerve endings reside under the skin surface at the back of the neck.
• the nerves in the soft tissues of the back of the neck representing the C1, C2, and C3 segments of the cervical spinal cord are unique in that they have intimate connections with pathways directly affecting brainstem and autonomic system function.
• There are direct connections with the Trigeminal Nerve system of the brainstem which provides for pain and other sensory input and interpretation from the head, face, sinus cavities, the dural covering of the brain, and the back of the neck.
• skin is embryologically derived from neuro-ectoderm which is also responsible for the formation of the brain and other aspects of the CNS.
• the nerves in the human skin have a particularly direct relationship with these structures. This provides for the efficacy noted with TRN/back of the neck therapy.
• systemic and other CNS side-effects are reduced or avoided.
• drugs topically applied to the skin in this region have ready access to brainstem and other CNS structures without the requirement of drug in the bloodstream reaching target sites.
• TRNA therapy at the back of the neck region delivery differs from traditional therapy (whether oral, injection, nasal spray, inhalation, or rectal) in that it has no reliance on the systemic or cerebral blood flow. Nor does it require therapeutic blood levels of drug. These latter factors are responsible for systemic and CNS side-effects as drug is delivered to areas not intended to be affected in the therapeutic process.
• Transdermal systemic delivery by patch although similarly applied to the skin as in TRNA therapy, differs significantly in its reliance on a drug concentration gradient for absorption into the systemic capillary and venous blood.
• TRNA therapy is unaffected by dermal vessels or systemic blood flow. It relies solely on the function of the free nerve endings of cutaneous nerves and their connections at the point of application of compounded drug.
• transdermal drug delivery by patch and TRNA are both “transdermal” in that in both, drug penetrates the skin (epidermis) for eventual clinical effect.
• the difference lies in the fact that in “traditional” transdermal patch therapy, drug enters the systemic circulation through a concentration gradient and establishes a therapeutic drug blood level.
• measuring a blood level gives assurance drug is being taken or delivered systemically, allowing for checking compliance, it is also the source of undesirable side-effects and drug interactions.
• drug applied to the skin surface must be absorbed through the small vessels in the dermis for eventual presence in the systemic venous blood for measurement of drug level.
• the cannabinoid drug(s) need only be available at the free nerve endings under the epidermis. No concentration gradients or systemic blood levels are necessary. Drug delivery is unaffected by cardiac output or cerebral blood flow factors. Of significance, persons afflicted with Parkinson's disease are typically elderly with concomitant cardiac and cerebral vascular disease.
• the methods and formulations of the invention deliver an amount of drug (e.g., cannabinoid drug(s)) in the TRNA therapy that would provide sub-therapeutic plasma levels if administered orally, but which is therapeutically effective when administered via TRNA therapy at the back of the neck region.
• drug e.g., cannabinoid drug(s)
• TRNA therapy is rapid in the onset of clinical effect (e.g., less than about 10 -15 minutes) for is that it operates through an “electro-chemical” process.
• Active drug compounded in an appropriate dermal penetration enhancing medium acts at free nerve endings, changing the neurochemistry of receptors at the neural synapse: apomorphine (dopamine and norepinephrine agonist), increasing dopamine and norepinephrine levels and improving neural transmission.
• neural (electrical) impulses are generated back to neuronal cell bodies residing in the spinal cord and brainstem: “afferent feed-back”.
• the nervous system functions through neurons generating electrical impulses and the release of neurochemicals/neuro-transmitters (serotonin, norepinephrine, dopamine, and acetylcholine, being the major ones) at neural receptor sites called “synaptic clefts”. Accordingly, the process in TRNA therapy may be considered analogous to an electrical capacitor discharging to perform a function, such as turning on a light switch. Viewed from this perspective, the rapid onset of clinical effect observed in TRNA therapy makes sense.
• transdermal systemic patch delivery operates on the principles of chemical gradients and fluid dynamics. These processes have variability and inherent idiosyncrasies, fluctuating heart function as a pump for blood flow being one. Thus, despite the advantage of measurable drug levels, a more circuitous route with slower clinical effect is observed. This makes systemic transdermal patch delivery inappropriate for acute therapy.
• cannabinoids in mammals include but are not limited to the treatment of lameness and gait issues; elbow dysplasia; hip dysplasia; back and hind leg problems; arthritis; seizures; encephalopathy, including lethargy, focus/attentional problems, and cognitive issues: spasticity; epilepsy; cancer; weakness; pain; numbness; anxiety and other mood disorders; hypertension; tremors; peripheral neuropathy; bowel and bladder control issues; inactivity; poor appetite; tumors (e.g., pituitary tumors); Cushing's disease; aggressive behavior; pruritis; dermatitis; vomiting; lethargy; dystonia; personality change; as well as any other disease or condition in a mammal other than humans that may be treated with a cannabinoid.
• a representative cannabinoid drug mixture concentrate may include with respect to total active cannabinoids, for example, from about 0 to about 3% tetrahydrocannabinol, from about 0 to about 1% tetrahydrocannabinolic acid, from about 20 to about 50% cannabidiol, from about 0 to about 1% cannabidiolic acid, and from about 0 to about 1% cannabinol, for a total active cannabinoid level of from about 20% to about 50%.
• total active cannabinoids for example, from about 0 to about 3% tetrahydrocannabinol, from about 0 to about 1% tetrahydrocannabinolic acid, from about 20 to about 50% cannabidiol, from about 0 to about 1% cannabidiolic acid, and from about 0 to about 1% cannabinol, for a total active cannabinoid level of from about 20% to about 50%.
• a particular cannabinoid concentrate useful in the formulations of the present invention may include, e.g., about 0.84% tetrahydrocannabinol, about 0.23% tetrahydrocannabinolic acid, about 26.41% cannabidiol, about 0% cannabidiolic acid, and about 0.09% cannabinol, for a total active cannabinoid level of about 27.58%, as detected using full spectrum cannabinoid profiling and analysis utilizing High Performance Liquid Chromatography (HPLC/UV), and is commercially available from CannaVest.
• HPLC/UV High Performance Liquid Chromatography
• Such a cannabinoid drug mixture may provide the afore-mentioned entourage effect.
• the cannabinoid(s) is administered together with (e.g., in the same formulation), or simultaneously (but separately) or sequentially with an additional active agent(s) (“drug(s)”) suitable for treating the patient's disease state or condition.
• additional active agent(s) include, but are not limited to:
• Anti-Epileptic drugs examples include Valproic acid (Depacon®/Depakot®e), Leviteracetem (Keppra®), Lamotrigene (Lamictal®), Topiramate (Topamax®), Pregabalin (Lyrica®), Gabapentin (Neurontin®), Carbamazepine (Tegretol®), Oxcarbazepine (Trileptal®), Phenobarbital and other barbiturates, Tiagabine (Gabatril®), RetigabineTM (Valeant Pharmaceuticals), Lacosamide® (Schwarz Biosciences), and Perampanel® (Eisai) are in development as anti-epileptics and neuromodulators for other associated neurological, pain, and psychiatric conditions.
• Anxiolytic drugs Benzodiazepines: Examples include lorazepam (Ativan®), diazepam (Valium®), clonazepam (Klonopin®), chlordiazepoxide (Librium®), and alprazolam (Xanax®). 3.
• Neuroleptics/Anti-Psychotic drugs Examples include chlorpromazine (Thorazine®), haloperidol (Haldol®), risperidone (Risperdal®), olanzapine (Zyprexa®) and quetiapine (Seroquel®). 4.
• Analgesics/Anti-Inflammatory drugs examples include prednisone, solumedrol, and other steroids, naproxen, aspirin, acetaminophen, voltaren, ketoprofen, ibuprofen, other NSAID's. 5.
• Parkinson's Disease/Similar or Related Syndrome drugs Examples include dopamine agonists such as apomorphine. 6.
• drugs include dopamine agonists such as apomorphine.
• Neuropathic/Neurogenic pain drugs Examples include carbamazepine, gabapentin, topiramate, zonisamide, phenytoin, desipramine, amitriptyline, imipramine, doxepin, protriptyline, pentoxifylline, and hydroxyzine.
• Smoking Cessation drugs examples include drugs such as varenicline. 10.
• Appetite Suppressant drugs examples include drugs such as Sibutramine.
• Neurodegenerative Diseases examples include drugs such as Aricept/donepezil, Exelon/rivastigmine, Reminyl/Razadyne/galantamine, and Namenda/memantine and their naturally occurring counterparts, as well as NMDA antagonists.
• MS Multiple Sclerosis
• Insomnia examples include drugs such as zolpidem.
• Fatigue Examples include drugs such as pemoline and Modafinil. 15.
• Vertigo, Nausea and/or Dizziness examples include drugs such as meclizine, dimenhydrinate, prochlorperazine, scopolamine and diphenhydramine. 16.
• the additional drug(s) includes a dopamine agonist such as apomorphine (Apokyn®, APO-go®), pramipexole (Mirapexin®), ropinirole (Requip®), bromocriptine (Parlodel®), cabergoline (Cabaser®, Dostinex®), pergolide (Permax®, Celance®) rotigotine (Neupro®), mixtures of any of the foregoing, or other dopamine agonists known to those skilled in the art.
• a dopamine agonist such as apomorphine (Apokyn®, APO-go®), pramipexole (Mirapexin®), ropinirole (Requip®), bromocriptine (Parlodel®), cabergoline (Cabaser®, Dostinex®), pergolide (Permax®, Celance®) rotigotine (Neupro®), mixtures of any of the foregoing, or
• dopamine agonists other than apomorphine may be used in the formulations and methods of the present invention, and all such agents are meant to be encompassed by the term “dopamine agonists.”
• drugs include, but are not limited to, carbidopa (Sinemet®), dopamine agonists (Requip®, Rotigotine®, Mirapex®), COMT inhibitors (Entacapone®, Tocapone), rasagiline (Azilect®) (MAO inhibitors) and MAO-B inhibitors (Selegiline (Eldepryl®).
• the additional drug(s) includes an opioid such as morphine, codeine, dihydrocodeine, hydrocodone, hydromorphone, nicomorphine, oxycodone, oxymorphone, fentanyl, alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl, ohmefentanyl, thebaine, oripavine, diacetylmorphine (heroin), phenylpiperidines such as pethidine (meperidine) and ketobemidone, allylprodine, prodine, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, methadone, dipipanone, levomethadyl Acetate (LAAM), loperamide, diphenoxylate, dezocine, pentazocine, phenazocine, buprenorphine, dihydroetorphine, e
• an opioid
• the additional drug(s) is tarpentadol (a centrally acting oral analgesic having two mechanisms of action combining mu-opioid receptor agonism and norepinephrine reuptake inhibition).
• the additional drug(s) is a selective norepinephrine reuptake inhibitor, such as Atomoxetine (Strattera®), Mazindol (Mazanor®, Sanorex®), Nisoxetine (LY-94939), Reboxetine (Edronax®, Vestra®), Viloxazine (Vivalan®), mixtures thereof, and the like.
• the additional drug(s) is a benzodiazepine, such as lorazepam (Ativan®), diazepam (Valium®), clonazepam (Klonopin®), chlordiazepoxide (Librium®), alprazolam (Xanax®), temazepam (Restoril®), mixtures thereof, and the like.
• the drug is a neuroleptic or psychotropic such as chlorpromazine (Thorazine®), haloperidol (Haldol®), risperidone (Risperdal®), olanzapine (Zyprexa®) and quetiapine (Seroque®).
• the additional drug(s) is an agent that treats depression and/or anxiety, for example, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), sertraline (Zoloft®), venlafaxine (Effexor®), citalopram (Celexa®), parocetine (Paxil), mixtures thereof, and the like (such as trazodone (Desyrel)), and/or serotonin-norepinephrine reuptake inhibitors (SNRI), such as Desvenlafaxine (Pristiq®), Duloxetine (Cymbalta®), Milnacipran (Ixel®, Savella®), Venlafaxine (Effexor®), mixtures thereof, and the like.
• SSRIs selective serotonin reuptake inhibitors
• SSRIs selective serotonin reuptake inhibitors
• SSRIs selective serotonin reuptake inhibitors
• the additional drug(s) is a norepinephrine-dopamine reuptake inhibitor (NDRI), such as Amineptine (Survector®), an aminoketone antidepressant such as Bupropion (Wellbutrin®, Zyban®), Dexmethylphenidate (Focalin), Methylphenidate (Ritalin®, Concerta®), Nomifensine (Merital®), a phenylpiperazine antidepressant such as nefazodone (Serzone®), a piperazino-azepine antidepressant such as mirtazapine (Remeron®), mixtures thereof, and the like.
• NDRI norepinephrine-dopamine reuptake inhibitor
• the additional drug(s) may be an NMDA receptor antagonist.
• Phencyclidine, ketamine, and dextromethorphan are used as recreational drugs. At subanesthetic doses, however, these drugs have mild stimulant effects, and these agents have shown promise for the treatment of conditions that involve excitotoxicity, including traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's.
• the additional drug(s) may be an agent that treats neuropathic/neurogenic pain (pain that arises from nerve dysfunction and not as a result of injury, e.g., trigeminal neuralgia), such as carbamazepine, gabapentin, topiramate, zonisamide, phenytoin, desipramine, amitriptyline, imipramine, doxepin, protriptyline, pentoxifylline, and hydroxyzine.
• neuropathic/neurogenic pain pain that arises from nerve dysfunction and not as a result of injury
• trigeminal neuralgia such as carbamazepine, gabapentin, topiramate, zonisamide, phenytoin, desipramine, amitriptyline, imipramine, doxepin, protriptyline, pentoxifylline, and hydroxyzine.
• the additional drug(s) treats insomnia, such as zolpidem (Ambien®).
• the additional drug(s) treats fatigue.
• Such drugs include central nervous system stimulants such as pemoline (Cylert®) and Modafinil (Provigil®).
• the additional drug(s) treats vertigo, nausea and/or dizziness, such as meclizine (Antivert®), dimenhydrinate (32qualene32), prochlorperazine (32qualene32®), scopolamine (Transderm®) and diphenhydramine (Benadryl®).
• the drug is a serotonin-norepinephrine reuptake inhibitor (SNRI), such as Desvenlafaxine (Pristiq®), Duloxetine (Cymbalta®), Milnacipran (Ixel®, Savella®), Venlafaxine (Effexor®), mixtures thereof, and the like.
• SNRI serotonin-norepinephrine reuptake inhibitor
• the additional drug(s) is a tricyclic antidepressant (TCA), such as Amitriptyline (Elavil®), Butriptyline (Evadene®, Evadyn®e), Clomipramine (Anafranil®), Desipramine (Norpramin®, Pertofrane), Dosulepin (Prothiade), Doxepin (Adapin, Sinequan), Imipramine (Tofranil®), Lofepramine (Feprapax®, Gamanil®, Lomont®), Nortriptyline (Aventyl®, Nortrilen®, Pamelor®), Protriptyline (Vivacti®1), Trimipramine (Surmontil®), mixtures thereof, and the like.
• TCA tricyclic antidepressant
• the additional drug(s) is a tetracyclic antidepressant, such as Amoxapine (Asendin®), Maprotiline (Ludiomil®), Mianserin (Tolvon®), mixtures thereof, and the like.
• a tetracyclic antidepressant such as Amoxapine (Asendin®), Maprotiline (Ludiomil®), Mianserin (Tolvon®), mixtures thereof, and the like.
• the additional drug(s) is an atypical antipsychotic, such as Ziprasidone (Geodon®, Zeldox®), Nefazodone (Serzone®), and the like.
• the additional drug(s) is an anti-convulsant or anti-epileptic drug such as arylsulfonimide analogues such as Acetazolimide (Diamox)®, tricyclic iminostilbene derivatives such as carbamazepine (Tegreto®), benzodiazepines such as clonazepam (Klonopin®), clorazepate dipotassium (Tranxene®), lorazepam (Ativan®) and diazepam (Valium®), carboxylic acid derivatives such as valproic acid (Depakene®) and divalproex sodium (Depakote®), succinimide derivatives such as ethosuximide (Zarontin®), carbamate esters of 2-phenyl-1,3-propanediol such as felbamate (felbatol®), hydantoins such as phenytoin (Dilantin®),
• Additional drugs such as Retigabine® (Valeant Pharmaceuticals), Lacosamide® (Schwarz Biosciences), and Perampanel® (Eisai) are in development as anti-epileptics and neuromodulators for other associated neurological, pain, and psychiatric conditions, and thus are further examples of potentially useful drugs in the present invention.
• the additional drug(s) is an analgesic/anti-inflammatory agent such as acetaminophen; prednisone, solumedrol, and other steroids; naproxen, aspirin, voltaren, ketoprofen, ibuprofen, nabumetone, and other NSAID's.
• the NSAID may be COX-1, COX-2 or mixed COX-1/COX-2 inhibitors.
• COX-2 inhibitors include oxicam, meloxicam, and the more selective celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib.
• corticosteroids include methylprednisolone, prednisolone, dexamethasone, and adreno-corticotrophic hormone (ACTH), corticotropin.
• the additional drug(s) may be an agent that treats neuropathic/neurogenic pain (pain that arises from nerve dysfunction and not as a result of injury, e.g., trigeminal neuralgia), such as carbamazepine, gabapentin, topiramate, zonisamide, phenytoin, desipramine, amitriptyline, imipramine, doxepin, protriptyline, pentoxifylline, and hydroxyzine, mixtures thereof, and the like.
• neuropathic/neurogenic pain e.g., trigeminal neuralgia
• trigeminal neuralgia such as carbamazepine, gabapentin, topiramate, zonisamide, phenytoin, desipramine, amitriptyline, imipramine, doxepin, protriptyline, pentoxifylline, and hydroxyzine, mixtures thereof, and the like.
• the additional drug(s) is 4-aminopyridine (4-AP; also known as Fampridine®) or a pharmaceutically acceptable derivative thereof.
• This drug has been shown to have the ability to improve the communication between damaged nerves, which may result in increased neurological function in the treatment of conditions such as multiple sclerosis (MS).
• An example of another such drug is 3,4 diaminopyridine.
• the additional drug(s) is useful for the treatment of Dementia/Alzheimer's disease, such as Aricept®/donepezil, Exelon®/rivastigmine, Reminyl®/Razadyne®/galantamine, and Namenda®/memantine, their naturally occurring counterparts, and mixtures thereof.
• Dementia/Alzheimer's disease such as Aricept®/donepezil, Exelon®/rivastigmine, Reminyl®/Razadyne®/galantamine, and Namenda®/memantine, their naturally occurring counterparts, and mixtures thereof.
• the cannabinoid drug(s) is formulated in a vehicle that allows for the drug to be immediately absorbable and available for the free nerve endings of the trigeminal nervous system which reside under the skin surface in the form of a mousse, cream, gel or ointment.
• the topical or implantable cannabinoid drug(s) formulation can be administered in the form that provides a prolonged release at the back of the neck region, for example, in the form of a transdermal patch.
• the cannabinoid drug(s) is applied (i) in a topical form that provides a therapeutically effective dose of the cannabinoid drug(s) immediately absorbable at the site (e.g., back of the neck region and/or along the spine), and (ii) a further therapeutically effective dose(s) in a prolonged or sustained release formulation (e.g., a transdermal patch or contained in liposomes) that releases the cannabinoid drug(s) over time such that the cannabinoid drug(s) is absorbed in therapeutically effective amounts over a span of multiple dosage time intervals (e.g., 1-7 days).
• a prolonged or sustained release formulation e.g., a transdermal patch or contained in liposomes
• the topical cannabinoid formulation of the present invention is administered at the back of the neck region and/or spine on the mammal and a therapeutic effect is preferably provided within about 45 minutes, preferably within about 30 minutes, or 25 minutes, or 20 minutes, or 15 minutes, or 10 minutes after the administration. In certain preferred embodiments, a therapeutic effect is noticed within about 10 to about 15 minutes after the administration (e.g., application of the topical formulation to the back of the neck region).
• the topical cannabinoid formulation is administered on an “as needed” basis. In other embodiments, the topical cannabinoid formulation is administered on a once a day basis, or on a twice a day basis, or on a three times a day basis, or on a four times a day basis. In other embodiments, particularly where the mammal has been administered multiple doses of the topical pharmaceutical formulation and has realized a therapeutic benefit from the cannabinoid drug therapy, it is possible to reduce the frequency of the dosing to less than once per day, e.g., once every two or three days, once a week, biweekly, or monthly. In certain instances, it is contemplated that the administration of the topical pharmaceutical formulation will no longer be necessary after an initial course of therapy, as the mammal would no longer be suffering from the underlying condition and may be in essence “cured” or no longer in need of chronic treatment.
• a unit dose of the topical cannabinoid drug(s) formulation provides a cannabinoid (e.g., CBD) unit dose from about 0.1 mg to about 500 mg, or from about 0.25 mg to about 80 mg, or from about 1 mg to about 100 mg.
• the unit dose of cannabinoid (e.g., CBD) is from about 3 mg to about 50 mg or from about 7.5 mg to about 30 mg. This may be administered in a topical mousse cream, ointment, gel or the like.
• a unit dose of the topical formulation(s) of cannabinoid drug(s) used in accordance with the present invention preferably includes at least 80% cannabidiol, in certain preferred embodiments at least 90% cannabidiol, and in certain further preferred embodiments at least 95% cannabidiol.
• the amount of psychoactive cannabinoid drug(s) present in the topical formulations of the present invention is less than 20%, more preferably less than 10% or less than 5% of the total active cannabinoids in the topical formulation.
• the topical formulation may be administered as a unit dose in an amount from about 0.5 g to about 1 g at a cannabinoid (e.g., CBD) concentration from about 0.1% to about 5% (or more).
• a cannabinoid e.g., CBD
• a topical mousse formulation containing the cannabinoid drug(s) is particularly beneficial because of the ease of application and greater likelihood of the application remaining at the site while the cannabinoid drug(s) is being absorbed.
• the formulations of the present invention are prepared such that the drug(s) may be delivered acutely as single dose applications as mousse/cream/gel/ointment or as a sustained release topical patch, depending on the condition treated and associated symptom complex in the individual patient.
• the critical point again, is in the location of the application: at the back of neck at the hair-line for access to posterior cervical afferents with free nerve endings under the surface of the skin. Through feedback connections with vagal and trigeminal afferent systems, this results in ultimate effect on brainstem structures.
• the disease state/condition to be treated may be treated much faster and more effectively than such prior art modes of administration.
• the method of treating a human patient comprises applying a topical formulation which comprises a drug suitable for topical administration, which is useful for the treatment of a disease state or condition treatable via the topical brainstem afferent stimulation (de-afferentation) drug therapy described herein.
• a topical formulation which comprises a drug suitable for topical administration, which is useful for the treatment of a disease state or condition treatable via the topical brainstem afferent stimulation (de-afferentation) drug therapy described herein.
• the methods of the present invention may also, if desired, involve pre-treatment of the skin with an enhancer to increase the permeability of the skin to the applied drug.
• the methods of the present invention may include pre-treatment or “prepping” of the skin area with a substance that opens up the skin pores. Additionally, the methods of the present invention may include, if desired, pre-treatment or “prepping” of the skin with an alcohol swab or the like to rid the area of dirt, make-up, oil, and the like, prior to application of the drug.
• the topical formulation of the present invention comprises a drug in an amount which is therapeutically effective when administered topically at the at the back of neck at the hair-line for access to posterior cervical afferents with free nerve endings under the surface of the skin, but which provides a plasma concentration which is subtherapeutic if orally administered.
• topical formulations of the present invention e.g., mousse, ointment, gel, cream, or the like
• must be suitable for topical administration of a drug i.e., must contain pharmaceutically acceptable excipients compatible with application to the skin tissue, and may optionally contain a sufficient amount of an enhancer composition as described hereinafter.
• the topical formulations and/or transdermal therapeutic systems of the present invention may include at least one adjuvant such as a penetration enhancer, anti-oxidant, stabilizer, carrier, or vehicle. Additionally or alternatively, the present invention may include the application of electric current (iontophoresis) for enhancing permeation of the cannabinoid drug(s).
• a penetration enhancer such as a penetration enhancer, anti-oxidant, stabilizer, carrier, or vehicle.
• the present invention may include the application of electric current (iontophoresis) for enhancing permeation of the cannabinoid drug(s).
• Suitable penetration enhancers useful in the formulations of the present invention include but are not limited to isostearic acid, octanoic acid, oleic acid, oleyl alcohol, lauryl alcohol, ethyl oleate, isopropyl myristate, butyl stearate, methyl laurate, diisopropyl adipate, glyceryl monolaurate, tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethyl ethers, polyethylene oxide dimethyl ethers, dimethyl sulfoxide, glycerol, ethyl acetate, acetoacetic ester, N-alkylpyrrolidone, and terpenes.
• the topical formulations comprising a drug in an ointment, gel, cream or the like, will typically contain on the order of about 0.001 to about 80% by weight, preferably 0.01 wt. % to 50 wt. % drug (i.e., cannabinoid drug(s) plus optional additional drugs as described herein), and about 0 wt. % to about 50.0 wt. %, preferably from about 1 wt. % to about 30 wt. % of a permeation enhancer composition, with the remainder of the composition comprising a carrier or vehicle.
• drug i.e., cannabinoid drug(s) plus optional additional drugs as described herein
• a permeation enhancer composition preferably from about 1 wt. % to about 30 wt. % of a permeation enhancer composition, with the remainder of the composition comprising a carrier or vehicle.
• the drug is included in a cream or gel or ointment in a concentration of, e.g., 1 mg drug/ml of carrier (e.g., Lipoderm).
• carrier e.g., Lipoderm
• the drug is applied as a unit dose at the back of the neck region in immediate release form (e.g., cream, ointment or gel) for acute treatment with a cannabinoid drug as would be beneficial to a human patient.
• the concentration of cannabinoid drug(s) included in the unit dose is from about 1 mg to about 100 mg, based on cannabidiol, or an therapeutically equivalent amount of another cannabinoid drug(s) as described herein.
• a unit dose of cannabinoid e.g., CBD
• CBD cannabinoid
• the topical formulation may be administered as a unit dose in an amount from about 0.5 g to about 1 g at a cannabinoid (e.g., CBD) concentration from about 0.1% to about 5% (or more).
• CBD is provided as purified crystallized CBD (e.g., about 95% pure) from a herbal source, the amount of CBD (cannabinoid drugs in total) may be reduced.
• the topical formulations comprising a cannabinoid drug(s) with or without additional drugs (collectively referred to herein as “drug(s)”) in an ointment, gel, cream or the like, will typically contain on the order of about 0.001 to about 80% by weight, preferably 0.01 wt. % to 50 wt. % drug(s) or from about 0.5% to about 5% drug(s); and about 0 wt. % to about 50.0 wt. %, preferably from about 1 wt. % to about 30 wt. % of a permeation enhancer composition, with the remainder of the composition comprising a carrier or vehicle.
• the drug comprises CBD and is included in a cream or gel or ointment in a concentration of, e.g., 1 mg drug/ml of carrier (e.g., Lipoderm).
• carrier e.g., Lipoderm
• one skilled in the art can increase the amount of carrier or change the carrier and maintain or improve efficacy of the topical formulation for TRNA therapy.
• Suitable (optional) permeation enhancers may also be included in the formulations.
• Such enhancers include, but are not limited to, dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C10 MSO), polyethylene glycol monolaurate (PEGML), propylene glycol (PG), PGML, glycerol monolaurate (GML), lecithin, the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone® from Whitby Research Incorporated, Richmond, Va.), alcohols, and the like.
• the permeation enhancer may also be a vegetable oil as described in U.S. Pat. No. 5,229,130 to Sharma.
• oils include, for example, safflower oil, cotton seed oil and corn oil.
• Additional optional enhancers for use in conjunction with the present invention are lipophilic compounds having the formula [RCOO]n R′, wherein n is 1 or 2 and R is C1-C16 alkyl optionally substituted with 1 or 2 hydroxyl groups, and R′ is hydrogen or C1-C16 alkyl optionally substituted with 1 or 2 hydroxyl groups.
• a first subset of compounds are represented by the formula [CH3 (CH 2)m COO]n R′ in which m is an integer in the range of 8 to 16, n is 1 or 2, and R′ is a lower alkyl (C1-C3) residue that is either unsubstituted or substituted with one or two hydroxyl groups.
• Preferred enhancers within this group include an ester which is a lower alkyl (C1-C3) laurate (i.e., m is 10 and n is 1) such as “PGML”.
• PGML a lower alkyl
• PGML propylene glycol monolaurate
• PGML propylene glycol monolaurate
• esters of fatty alcohols represented by the formula CH3 (CH2)m—O—CO—CHR1 R2, in which R1 and R2 are independently hydrogen, hydroxyl, or lower alkyl (C1-C3), and m is as above.
• Particularly preferred enhancers within this group are lauryl lactate and myristyl lactate.
• a third subset of compounds within this group are analogous fatty acids, i.e., acids having the structural formula CH3 (CH2)m COOH where m is as above.
• a particularly preferred acid is lauric acid.
• enhancer compositions are wherein a lipophilic compound as just described, particularly PGML is combined with a hydrophilic compound, such as a C2-C6 alkanediol.
• a hydrophilic compound such as a C2-C6 alkanediol.
• One preferred hydrophilic enhancer within this group is 1,3-butanediol.
• Another hydrophilic enhancer that may be included in these compositions is an ether selected from the group consisting of diethylene glycol monoethyl ether (Transcutol) and diethylene glycol monomethyl ether.
• Such enhancer compositions are described in detail in U.S. Pat. Nos. 5,053,227 and 5,059,426 to Chiang et al., the disclosures of which are herein incorporated by reference.
• compositions may include mixture or combinations of any of the aforementioned enhancers, and the like.
• One preferred topical formulation comprises the cannabinoid drug(s) in oil, together with a suitable amount of a penetration enhancer, dimethyl sulfoxide and a base.
• a formulation may include the CBD oil, and about 3 ml dimethyl sulfoxide in 30 g of base.
• the CBD can be incorporated at a concentration of, e.g., from about 0.5% to about 5% of the topical formulation in a preferred embodiment, and most preferably from about 1.5% to about 3% in a certain embodiment.
• the dose of such a formulation would be, e.g., from about 0.5 g to about 1 g applied topically on the back of the neck of the human patient.
• U.S. Patent Publication No. 2008011289 hereby incorporated by reference, describes a room temperature stable aqueous cannabinoid formulation comprising an effective amount of a cannabinoid in a semi-aqueous solution buffered to a pH of about 5-1, the solution comprising water and an effective amount of an organic cosolvent to maintain the physical stability of the formulation, which may be incorporated into a pharmaceutically acceptable carrier.
• the topical formulation may include at least one water-insoluble, pharmacologically approved, alkyl cellulose or hydroxyalkyl cellulose, and the like.
• Alkyl cellulose or hydroxyalkyl cellulose polymers for use in this invention include ethyl cellulose, propyl cellulose, butyl cellulose, cellulose acetate, hydroxypropyl cellulose, hydroxybutyl cellulose, and ethylhydroxyethyl cellulose, alone or in combination.
• a plasticizer or a cross linking agent may be used to modify the polymer's characteristics.
• esters such as dibutyl or diethyl phthalate, amides such as diethyldiphenyl urea, vegetable oils, fatty acids and alcohols such as acid oleic and myristyl may be used in combination with the cellulose derivative.
• the topical formulation may further include hydrocarbons such as liquid paraffin, qualene, solid paraffin, microcrystalline wax, etc.; higher aliphatic alcohols such as cetyl alcohol, hexadecyl, alcohol, stearyl alcohol, oleyl alcohol, etc.; esters of higher fatty acids with higher alcohols such as beeswax, etc.; esters of higher fatty acids with lower alcohols such as isopropyl myristate, isopropyl palmitate, etc.; vegetable oils, modified vegetable oils, hydrous lanolin and its derivative, squalene, 4lqualene; higher fatty acids such as palmitic acid, stearic acid, etc. and the like.
• hydrocarbons such as liquid paraffin, qualene, solid paraffin, microcrystalline wax, etc.
• higher aliphatic alcohols such as cetyl alcohol, hexadecyl, alcohol, stearyl alcohol, oleyl alcohol, etc.
• the topical formulation may further include emulsifiers and dispersing agents which include, for example, anionic, cationic and nonionic surfactants.
• Nonionic surfactants are preferred because of their low levels of irritation to skin.
• Typical of nonionic surfactants are fatty acid monoglycerides such as glyceryl monostearate, etc.; sorbitan fatty acid esters such as sorbitan monolaurate, etc.; sucrose fatty acid esters; polyoxyethylene fatty acid esters such as polyoxyethylene stearate, etc.; and polyoxyethylene higher alcohol ethers such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, etc.
• the topical TRNA formulation is aqueous-based.
• the topical formulation may include a gelling agent such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl-cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carbomer, and the like.
• a gelling agent such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl-cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carbomer, and the like.
• examples of pharmaceutical compositions which rely upon an aqueous gel composition as a vehicle for the application of a drug are U.S. Pat. Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760; and 5,318,780, the disclosures of which are herein incorporated by reference.
• the topical formulation may further include one or more preservatives, stabilizers, or anti-oxidants.
• preservatives examples include, but are not limited to, bacteriostatic compounds and other preservatives suitable for topical administration including various alcohols, sorbic acid and salts and derivatives thereof, ethylenediamine, monothioglycerol, and thimerosal.
• stabilizers examples include pH buffers suitable for topical administration, complexing agents, chelating agents and the like.
• anti-oxidants examples include ascorbic acid and its derivatives, e.g., ascorbyl palmitate, as well as butylated hydroxyanisole, butylated hydroxytoluene, sodium bisulfite, sodium metabisulfite, and others.
• adjuvants that may be included in the drug formulation include carriers, tackifiers, pigments, dyes, and other additives that do not adversely affect the mechanical or adhesive properties of the formulation.
• Carriers” or “vehicles” as used herein refer to carrier materials suitable for transdermal drug administration, and include any such materials known in the art, e.g., any liquid, gel, emulsion, solvent, liquid diluent, solubilizer, or the like, which is nontoxic and which does not interact with other components of the composition in a deleterious manner.
• carrier or “vehicle” as used herein may also refer to stabilizers, crystallization inhibitors, dispersing agents or other types of additives useful for facilitating transdermal drug delivery. It will be appreciated that compounds classified as “vehicles” or “carriers” may sometimes act as permeation enhancers, and vice versa, and, accordingly, these two classes of chemical compounds or compositions may sometimes overlap.
• Carrier materials suitable for use in the instant compositions include those well-known for use in the cosmetic and medical arts as bases for ointments, lotions, salves, aerosols, suppositories and the like.
• Suitable carriers include, for example, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions.
• suitable carriers herein include for example alcohols, including both monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.
• alcohols including both monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol
• the carrier is an aqueous based cannabidiol cream is produced using Lipoderm® as the carrier.
• Lipoderm®/LIP is a whitish cream with no smell, commercially marketed compounding agent (from PCCA, Pharmaceutical Compounding Centers of America) having the following ingredients: Ethoxydiglycol, Water (Aqua), Glycerin, C 12-15 Alkyl Benzoate, Glyceryl Stearate, Dimethicone, Cetearyl Alcohol, Cetearyl Glucoside, Polyacrylamide, Cetyl Alcohol, Magnesium Aluminum Silicate, Xanthan Gum, Aloe Vera (Aloe Barbadensis), Tocopheryl Acetate (Vitamin E Acetate), Prunus Amygadalus Amara (Bitter Almond) Kernel Oil, Vitis Vinifera (Grape) Seed Extract, Triticum Vulgare (Wheat) Germ Oil, Retinyl Palmitate (Vitamin A
• part or all of the dose of cannabinoid drug(s) may be encapsulated within liposomes.
• U.S. Patent Publication No. 2015/0302148 hereby incorporated by reference, describes fast-acting liposomal and micelle formulations of cannabinoids which are prepared by (a) dissolving one or more cannabinoids or cannabinoid analogues in ethanol to obtain an ethanol cannabinoid solution; (b) adding a phospholipid to the ethanol cannabinoid solution to obtain an ethanol-phospholipid cannabinoid solution; (c) injecting the ethanol-phospholipid cannabinoid solution into distilled water to obtain a liposomal cannabinoid suspension; and (d) removing the ethanol from the liposomal cannabinoid suspension, thereby producing a stable liposomal suspension of one or more cannabinoids or cannabinoid analogue.
• the method further comprises the step of adding sodium alginate to the liposomal suspension of one or more cannabinoids or cannabinoid analogues to obtain an alginate liposomal cannabinoid suspension that has a final alginate concentration of 2% w/v, followed by the addition of calcium chloride to the alginate liposomal cannabinoid suspension to obtain a calcium alginate-encapsulated liposomal cannabinoid suspension.
• This suspension is then cold-pressed and air-dried to remove the water so as to obtain a dry cannabinoid powder.
• the dry cannabinoid powder can be re-suspended in citrate buffer to obtain an aqueous cannabinoid solution.
• the amount of cannabinoid or cannabinoid analogue in the aqueous cannabinoid solution is greater than 40%.
• the formulations of the present invention may be formulated as a transdermal delivery system (also referred to herein as a transdermal therapeutic system) such as a transdermal patch, a transdermal plaster, a transdermal disc, iontophoretic transdermal device, or the like.
• a transdermal delivery system also referred to herein as a transdermal therapeutic system
• Such formulations are recognized by those skilled in the art as providing a release of drug and absorption into the skin of the patient in a sustained manner over an extended period of time (e.g., 1-7 days).
• the transdermal delivery system comprises, e.g., a cannabinoid drug(s) contained in a reservoir or a matrix, and an adhesive which allows the transdermal patch to adhere to the skin, allowing the passage of the active agent from the transdermal patch through the skin of the patient.
• the transdermal patch is applied topically at the back of the neck so as to achieve topical regional neuro-affective therapy (“TRNA THERAPY”) as described herein.
• the drug in embodiments in which the drug is contained in a transdermal patch, it is contemplated that the drug will be absorbed more slowly and the transdermal patch will provide a sustained release and prolonged therapeutic effect, as compared, e.g., to a cream or ointment intended to provide an immediate release of the drug and rapid onset of the TRNA therapy.
• the dose of cannabinoid drug(s) may be that which is sufficient to provide a therapeutically effective dose to the back of the neck (e.g., non-systemic dose) over the course of e.g., from about 1, 2, 3, 4, 5, 6 or 7 days.
• the dose of cannabinoid drug(s) contained in the transdermal delivery system is from about 0.5 mg to about 1000 mg. In certain preferred embodiments, the dose of the cannabinoid drug is from about 1 mg to about 100 mg. In certain preferred embodiments in which the cannabinoid drug is cannabidiol, the dosage is from about 8 mg to about 80 mg, and in certain preferred embodiments, about 40 mg.
• the methods and formulations of the present invention provide reduced side effects as compared to a systemic administration of the same drug.
• the transdermal delivery devices as well as other transdermal delivery systems in accordance with the invention can be made in the form of an article such as a tape, a patch, a sheet, a dressing or any other form known to those skilled in the art.
• the device will be in the form of a patch of a size suitable to deliver a unit dose of serotonin agonist through the skin.
• the drug may be introduced into a transdermal therapeutic system in different forms (solid, in solution, in dispersion); it may also be microencapsulated.
• the present invention provides a transdermal therapeutic system comprising a cannabinoid drug(s) in an amount that would provide sub-therapeutic plasma levels if administered orally, but is therapeutically effective when administered via transdermal delivery at the back of the neck.
• a transdermal delivery system for use in accordance with the present invention can also be constructed with an enhancer composition and other ingredients described hereinabove with respect to the topical formulation.
• the transdermal delivery system is formulated for the prolonged delivery of the cannabinoid drug(s).
• the targeted skin flux for delivery of the cannabinoid drug(s) can be achieved by adjusting vehicle composition and vehicle loading, as well as by adjusting the surface area through which the compositions are administered to skin.
• the transdermal delivery system (e.g., patch) is formulated to deliver from about 1 mg to about 800 mg of the cannabinoid drug(s) per each 24 hours through the skin of the patient, based on cannabidiol (CBD), or a therapeutically equivalent amount of a suitable alternative cannabinoid(s) as described herein.
• CBD cannabidiol
• the transdermal delivery system (e.g., patch) is formulated to provide a flux rate over the useful life of the system such that a similar amount (e.g., mean dose) is delivered on a daily basis until the system is removed and replaced with a fresh system.
• transdermal delivery system used in the present invention may be prepared, for example, in accordance with U.S. Patent Nos. 5,069,909; 4,806,341; 5,026,556; 4,588,580; 5,016,652; 3,598,122; 4,144,317; 4,201,211; 4,262,003; and 4,379,454; all of which are incorporated herein by reference.
• transdermal delivery system used in the present invention may be in accordance with U.S. Patent No. 6,689,379, hereby incorporated by reference, which system is a matrix or reservoir system which comprises at least one pharmaceutical active agent and a pressure-sensitive adhesive comprising a polyacrylate polymer, wherein said polyacrylate polymer has a polyacrylate backbone containing monomer units selected from the group consisting of acrylic acid, methacrylic acid and ester derivatives of acrylic or methacrylic acid, and said monomer units comprise at least 50% (w/w) relative to a mean polymer mass of said polyacrylate polymer, a total amount of monomers selected from the group consisting of non-esterified acrylic acid and non-esterified methacrylic acid is 0.5 to 10.0% (w/w) relative to the mean polymer mass of said polyacrylate polymer, and the carboxyl groups of said non-esterified acrylic and methacrylic acid monomers are present stoichiometrically at 5 to 100% in the form of alkali
• the dosage form can be a transdermal patch comprising a laminated composite for administering the drug (e.g., cannabinoid drug(s)) to an individual transdermally comprising: (a) a polymer backing layer that is substantially impermeable to the cannabinoid drug(s); and (b) a reservoir layer comprising a water-base acrylate pressure-sensitive adhesive, 1 to 12% by weight serotonin agonist and 2 to 25% by weight of a permeation enhancer comprising propylene glycol monolaurate in combination with capric acid or oleic acid, wherein the skin contact area of the composite is 10 to 100 cm2.
• a transdermal patch comprising a laminated composite for administering the drug (e.g., cannabinoid drug(s)) to an individual transdermally comprising: (a) a polymer backing layer that is substantially impermeable to the cannabinoid drug(s); and (b) a reservoir layer comprising a water-base acrylate pressure
• the dosage form can be a transdermal patch comprising (a) a polar solvent material selected from the group consisting of C3-C4 diols, C3-C6 triols, and mixtures thereof; and (b) a polar lipid material selected from the group consisting of fatty alcohol esters, fatty acid esters, and mixtures thereof; wherein said polar solvent material and said polar lipid material are present in a weight ratio of solvent material:lipid material of from about 60:40 to about 99:1.
• the dosage form also comprises a transdermal plaster comprising: (1) a film layer which comprises a polyester film of 0.5 to 4.9 microns thickness, 8 to 85 g/mm strength, respectively in the two directions intersecting substantially at right angles, 30 to 150% elongation, in the two directions intersecting substantially at right angles and an elongation ratio of A to B of 1.0 to 5.0, wherein A and B represent data in two directions intersecting at right angles, and A is greater than B, and wherein said polyester film comprises 0.01 to 1.0% by weight, based on the total weight of said polyester film, of solid fine particles in which (a) the average particle size is 0.001 to 3.0 microns, and (b) the average particle size is substantially not more than 1.5 times the thickness of said polyester film; and (2) an adhesive layer (a) which is composed of an adhesive containing said serotonin agonist and further wherein said adhesive layer (a) is laminated on said film layer over the surface in a 2 to 60 microns thickness.
• a transdermal plaster comprising:
• the dosage form can be a transdermal disc comprising: (a) a backing layer which is substantially impervious to the cannabinoid drug(s); and (b) a polymer matrix disc layer which is adhered to said backing layer and which has microdispersed therein said serotonin agonist, said polymer being bioacceptable and permitting said serotonin agonist to be transmitted for transdermal absorption, the cannabinoid drug(s) being stable in said polymer matrix.
• topical formulation or transdermal therapeutic system may further comprise another active ingredient in combination with the first drug (e.g., as previously described herein).
• the present invention is contemplated to encompass all transdermal formulations, e.g., the technologies described above, with the inclusion of the cannabinoid drug(s), such that the administration of a drug useful for treatment of disease state or condition in humans via topical brainstem afferent stimulation (de-afferentation) therapy via topical administration. Therefore, modifications of the invention via, e.g., the choice and/or amount of drug are considered to be obvious variations of this disclosure and within the scope of the appended claims.
• the present invention also contemplates the administration of the cannabinoid drug (s) directly below the skin to affect direct brainstem afferent stimulation to the free nerve endings under the epidermis.
• Such administration may be effected as an injection (e.g., subcutaneous injection) or implantation of the drug in immediate release or sustained release form. It will be appreciated by those skilled in the art that providing the drug in sustained release form and administering it in a suitable form below the skin may provide benefits, including less frequent administration (e.g., in chronic therapy).
• the cannabinoid drug(s) can be formulated for controlled or sustained delivery at the back of the neck via incorporation into a biocompatible and implantable polymer which can be in the form of microparticles or an implantable insert, or a liquid that forms a gel or colloid or a semi-solid after injection (thereby encapsulating the drug and allowing it to be released in a prolonged and controlled manner at the desired site).
• a biocompatible and implantable polymer which can be in the form of microparticles or an implantable insert, or a liquid that forms a gel or colloid or a semi-solid after injection (thereby encapsulating the drug and allowing it to be released in a prolonged and controlled manner at the desired site).
• a drug depot or reservoir may be created under the skin at the back of the neck, which then provides a sustained release of the drug in proximity to the desired nerve endings and which may be replenished or replaced at the end of the dosing interval.
• administrations of the drug may provide a prolonged therapeutic effect for at least about 3
• Implants are placed subcutaneously by making an incision in the skin and forcing the implants between the skin and the muscle. At the end of their use, if not dissolved, these implants are surgically removed.
• U.S. Pat. No. 4,244,949 hereby incorporated by reference, describes an implant which has an outer matrix of an inert plastic such as polytetrafluoroethylene resin. Examples of this type of implantable therapeutic system are Progestasert IUD and Ocusert system. It is contemplated that such systems can be appropriately modified by one skilled in the art for use in conjunction with the present invention.
• Norplant® which is an implant having a core containing levonorgestrel as the active substance, and where the core it surrounded by a membrane of a silicone elastomer of poly(dimethylsiloxane) (PDMS).
• PDMS poly(dimethylsiloxane)
• Jadelle® Another preparation of this kind is Jadelle®, in which the core is a poly(dimethylsiloxane) based matrix with levonorgestrel dispersed therein.
• the membrane is an elastomer made from PDMS and silica filler, which, besides giving necessary strength properties to the membrane, also retards the permeation of the active agent through the membrane.
• U.S. Pat. No. 3,854,480 hereby incorporated by reference, describes a drug delivery device, e.g.
• the device has a core of a matrix in which the drug is dispersed.
• the core is surrounded by a membrane that is insoluble in body fluids.
• the core matrix as well as the membrane are permeable to the drug by diffusion.
• the materials of the core and the membrane are chosen so that the drug diffuses through the membrane at a lesser rate than through the core matrix.
• the membrane controls the release rate of the drug.
• a suitable polymer for the core matrix is mentioned poly(dimethylsiloxane) (PDMS), and as suitable polymers for the membrane are mentioned polyethylene and a copolymer of ethylene and vinyl acetate (EVA). It is contemplated that the above systems may be adapted by one skilled in the art to deliver the cannabinoid drug(s) in accordance with the present invention.
• U.S. Pat. No. 5,968,542 (Tipton), hereby incorporated by reference, which describes a high viscosity liquid controlled delivery system as a medical or surgical device is provided that includes: (i) a non-polymeric, non-water soluble liquid carrier material (HVLCM) of viscosity of at least 5,000 Cp at 37° C. that does not crystallize neat under ambient or physiological conditions; and, optionally, (ii) a substance to be delivered.
• HVLCM non-polymeric, non-water soluble liquid carrier material
• compositions suitable for injectable use in accordance with this invention include sterile aqueous solutions or dispersions and sterile powders or lyopholysates for the extemporaneous preparation of sterile injectable solutions or dispersions.
• the dosage forms must be sterile and it must be stable under the conditions of manufacture and storage.
• the carrier for injectable formulations is typically water but can also include ethanol, a polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), mixtures thereof, and vegetable oil.
• Injectable formulations used in the present invention can also be formulated as injectable prolonged release formulations in which the active compound is combined with one or more natural or synthetic biodegradable or biodispersible polymers such as carbohydrates, including starches, gums and etherified or esterified cellulosic derivatives, polyethers, polyesters, polyvinyl alcohols, gelatins, or alginates.
• Such dosage formulations can be prepared for example in the form of microsphere suspensions, gels, or shaped polymer matrix implants that are well-known in the art for their function as “depot-type” drug delivery systems that provide prolonged release of the biologically active components.
• Such compositions can be prepared using art-recognized formulation techniques and designed for any of a wide variety of drug release profiles.
• apomorphine derivatives and the physiologically acceptable salts thereof as well as formulations thereof are described which provide a prolonged duration of action.
• the apomorphine pro-drugs can be suspended (as a neat oil or as crystals, or dissolved in a suitable and pharmaceutically acceptable solvent (e.g. water, ethanol, DMSO, i-PrOH or benzylbenzoate)) in a pharmaceutically acceptable depot oil (e.g.
• viscoleo, sesame oil or olive oil and injected subcutaneously or intramuscularly with a syringe or a “pen injector”.
• these drugs may, in a suitable composition and with a suitable vehicle (penetration enhancer), be applied to a patch for transdermal administration.
• the composition could include also a local anesthetic (e.g. lidocaine) to avoid injection pain, in particular at intramuscular injections.
• the composition is in the form of a patch or an ointment for transdermal administration.
• the patch or ointment preferably also comprises stabilizers, solubilizers and permeation activators to facilitate the passage of the active principle through the skin.
• the composition is in the form of a depot preparation for subcutaneous or intramuscular administration comprising the cannabinoid drug(s) dissolved or suspended in an oil.
• the formulation in addition to the apomorphine derivative, further contains a local anesthetic.
• the formulations described in the '503 patent can be modified as understood by one skilled in the art to contain other active drugs as described herein for use at the back of the neck region.
• An injectable depot formulation is a dosage form, which is generally intended to have a therapeutic activity for 2 to 4 weeks after administration (e.g. in sesame oil). In order to maintain effective drug plasma levels the dosage form should release the drug at a more or less constant rate during the desired dosing interval.
• the difference between such prior art depots and depots used in the present invention is that the in accordance with the present invention, the drug is not needed to be absorbed into the systemic circulation.
• a suitable form of depot preparation is the subcutaneous or intramuscular administration of an oil solution and/or oil suspension of a lipophilic drug. This gives a slow transport over the oil-biofluid interface and a slow dissolution in the biophase.
• a polar solvent e.g. oils
• the drug has to be transported over the oil/water interface.
• the oil/water partition coefficient is high, the transport will be slow.
• the release from the oil phase may last for up to several weeks.
• the use of depot preparations such as those described herein may be used to deliver the drugs described herein at the back of the neck region.
• the maximum volume of an oil solution/suspension to be injected intramuscularly or subcutaneously is 2-4 Ml.
• the cannabinoid drug(s) may be dissolved or dispersed in 1 Ml of an oil (sesame oil, Viscoleo or another approved oil) and the mixture gently heated (max 50° C.) shaken in a test tube shaker and ultrasonicated for a short time (minutes) until the mixture becomes a homogeneous solution or suspension.
• the cannabinoid drug(s) may first be dissolved in 50-300 ⁇ l DMSO, water, t-BuOH, PEG, benzylbenzoate, or another suitable and approved solvent or mixtures thereof, before adding the oil to a total volume of 1 Ml.
• U.S. Pat. No. 5,601,835 (Sabel, et al.), hereby incorporated by reference, which describes a polymeric drug delivery system for delivery of any substance to the central nervous system.
• the delivery system is preferably implanted in the central nervous system for delivery of the drug directly to the central nervous system.
• implantable devices can be used, for example, to achieve continuous delivery of dopamine, which cannot pass the blood brain barrier, directly into the brain for an extended time period.
• the implantable devices display controlled, “zero-order” release kinetics, a life time of a minimum of several weeks or months even when the devices contain water soluble, low molecular weight compounds, biocompatibility, and relative non-invasiveness.
• the polymeric devices are said to be applicable in the treatment of a variety of central nervous system disorders including Parkinson's disease, Alzheimer's dementia, Huntington's disease, epilepsy, trauma, stroke, depression and other types of neurological and psychiatric illnesses, and one skilled in the art can adapt that drug delivery system for delivering the drugs contemplated herein at the back of the neck region.
• the delivery device is a two-phase system that is manufactured using standard techniques such as blending, mixing or the equivalent thereof, following selection of the biologically active material to be delivered and an appropriate polymer for formation of the matrix.
• the general method of solvent casting as disclosed by Siegel and Langer, “Controlled release of polypeptides and other macromolecules”, Pharmaceutical Research 1, 2-10 (1984), is modified so that drug is dispersed within the devices to create channels and pores to the surface for release of the drug at the desired rate.
• a coating impermeable to the drug is placed over a portion of the drug containing polymer matrix to further regulate the rate of release.
• One skilled in the art can adapt that drug delivery system for delivering the drugs contemplated herein at the back of the neck region.
• the drug is encapsulated within a compartment that is enclosed by a rate-limiting polymeric membrane.
• the drug reservoir may contain either drug particles or a dispersion (or solution) of solid drug in a liquid or a matrix type dispersing medium.
• the polymeric membrane may be fabricated from a homogeneous or a heterogeneous nonporous polymeric material or a microporous or semipermeable membrane.
• the encapsulation of the drug reservoir inside the polymeric membrane may be accomplished by molding, encapsulation, microencapsulation, or other techniques.
• the implants release drugs by dissolution of the drug in the inner core and slow diffusion across the outer matrix.
• the drug release from this type of implantable therapeutic system should be relatively constant and is largely dependent on the dissolution rate of the drug in the polymeric membrane or the diffusion rate across or a microporous or semipermeable membrane.
• the inner core may substantially dissolve over time; however, in devices currently in use, the outer matrix does not dissolve.
• the drug reservoir is formed by the homogeneous dispersion of drug particles throughout a lipophilic or hydrophilic polymer matrix.
• the dispersion of drug particles in the polymer matrix may be accomplished by blending the drug with a viscous liquid polymer or a semisolid polymer at room temperature, followed by cross-linking of the polymer, or by mixing the drug particles with a melted polymer at an elevated temperature. It can also be fabricated by dissolving the drug particles and/or the polymer in an organic solvent followed by mixing and evaporation of the solvent in a mold at an elevated temperature or under vacuum. The rate of drug release from this type of delivery device is not constant.
• Examples of this type of implantable therapeutic system are the contraceptive vaginal ring and Compudose implant.
• PCT/GB 90/00497 describes slow release glassy systems for formation of implantable devices.
• the described implants are bioabsorbable and need not be surgically removed.
• One skilled in the art can adapt these drug delivery systems for delivering the drugs contemplated herein at the back of the neck region.
• the drug reservoir which is a suspension of drug particles in an aqueous solution of a water-miscible polymer, forms a homogeneous dispersion of a multitude of discrete, unleachable, microscopic drug reservoirs in a polymer matrix.
• the microdispersion may be generated by using a high-energy-dispersing technique. Release of the drug from this type of drug delivery device follows either an interfacial partition or a matrix diffusion-controlled process.
• An example of this type of drug delivery device is the Syncro-Mate-C Implant.
• compositions and methods for releasing a bio-active agent or a drug within a biological environment in a controlled manner are described in U.S. Pat. No. 6,287,588 (Shih , et al.), hereby incorporated by reference, which describes a composition and method for releasing a bio-active agent or a drug within a biological environment in a controlled manner.
• the composition is a dual phase polymeric agent-delivery composition comprising a continuous biocompatible gel phase, a discontinuous particulate phase comprising defined microparticles and an agent to be delivered.
• a microparticle containing a bio-active agent is releasably entrained within a biocompatible polymeric gel matrix.
• the bio-active agent release may be contained in the microparticle phase alone or in both the microparticles and the gel matrix.
• the release of the agent is prolonged over a period of time, and the delivery may be modulated and/or controlled.
• a second agent may be loaded in some of the microparticles and/or the gel matrix.
• transdermal transport device includes a reservoir for holding a formulation of an active principle, and a needle with a bore extending along the length of the needle from a first end of the needle to a second end of the needle. The second end is substantially aligned to a plane parallel to a body surface of a biological body when the device is placed on the body surface.
• the device also includes an actuator which pumps the formulation through the bore of the needle between a target area of the body and the reservoir.
• the cannabinoid drug(s) is infused into the patient at the back of the neck using technology known to be useful for infusing other drugs, such as an insulin pump.
• U.S. Pat. No. 7,354,420 (Steil, et al.), hereby incorporated by reference, describes a closed loop infusion system controls the rate that fluid is infused into the body of a user.
• the closed loop infusion system includes a sensor system, a controller, and a delivery system.
• the sensor system includes a sensor for monitoring a condition of the user.
• the sensor produces a sensor signal, which is representative of the condition of the user.
• the sensor signal is used to generate a controller input.
• the controller uses the controller input to generate commands to operate the delivery system.
• the delivery system infuses a liquid into the user at a rate dictated by the commands from the controller.
• the sensor system monitors the glucose concentration in the body of the user, and the liquid infused by the delivery system into the body of the user includes insulin.
• the present invention is contemplated to encompass all implantable or injectable formulations, e.g., the technologies described above, with the inclusion of a drug(s) (e.g., cannabinoid drug(s)(s)), such that the administration of a drug useful for treatment of disease state or condition in humans via topical brainstem afferent stimulation (de-afferentation) therapy. Therefore, modifications of the invention via, e.g., the choice and/or amount of drug are considered to be obvious variations of this disclosure and within the scope of the appended claims.
• a drug(s) e.g., cannabinoid drug(s)(s)
• de-afferentation topical brainstem afferent stimulation
• Lipoderm®/LIP is a commercially marketed compounding agent (from PCCA, Pharmaceutical Compounding Centers of America) having the following ingredients: Ethoxydiglycol, Water (Aqua), Glycerin, C 12-15 Alkyl Benzoate, Glyceryl Stearate, Dimethicone, Cetearyl Alcohol, Cetearyl Glucoside, Polyacrylamide, Cetyl Alcohol, Magnesium Aluminum Silicate, Xanthan Gum, Aloe Vera (Aloe Barbadensis), Tocopheryl Acetate (Vitamin E Acetate), Prunus Amygadalus Amara (Bitter Almond) Kernel Oil, Vitis Vinifera (Grape) Seed Extract, Triticum Vulgare (Wheat) Germ Oil, Retinyl Palmitate (Vitamin A Palmitate), Ascorbyl Palmitate (Vitamin C Palmitate),
• the concentration is 4 mg of CBD in 1 ml of Lipoderm.
• Lipoderm is a whitish cream with no smell.
• the cannabinoid drug(s) are incorporated into the Lipoderm cream in the form of a CBD oil product as described herein.
• a 60 g topical formulation of CBD is prepared by incorporating 2.2 g CBD (CBD-RSHO-Clear 43.5%), 20 g Pluronic 20%, 40 g Carbomer hydroalcoholic gel and 1 ml ethyl alcohol to obtain a CBD topical formulation having a 1.6% concentration of CBD.
• a 30 g topical formulation of CBD is prepared by incorporating CBD oil, Dimethyl sulfoxide 3 ml and enough base for total quantity of 30 grams.
• the CBD is incorporated in a concentration sufficient to yield an end product having a CBD concentration of 0.75%, 1%, 1.5%, 2% and 3%.
• the topical formulation is in the form of a cream.
• the oil-based CBD includes CBD oil commercially available from CannaVest.
• a unit dose of the topical CBD cream is from about 0.5 to about 1 g, with respect to formulations having a CBD concentration from 1.5% - 3%.
• the topical CBD formulation can be applied to the back of the neck of the human patient once a day, twice a day, three times a day, or four times a day depending on the condition to be treated and its severity.
• a 60 g topical formulation of CBD is prepared utilizing CBD crystalline powder (95%+pure CBD).
• the CBD is incorporated into the topical formulation of Example 2 having a CBD concentration between 0.75% to about 10% CBD.
• Example 5 a total of 7 dogs suffering from a variety of diseases/conditions were treated with a 30 mg topical cannabidiol (CBD) formulation administered on the back of the neck and spine on each of these dogs.
• CBD cannabidiol
• Table 1 reports the subject demographics and condition/disease state of each dog, as well as the subject response to treatment.
• hypotheses of the inventor provided throughout the specification are for possible explanation purposes only, and are not meant to be limiting in any way.

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• 2016
  • 2016-03-02 CN CN201680025420.2A patent/CN107530318A/zh active Pending
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  • 2016-03-02 EP EP16759411.8A patent/EP3265081A4/en not_active Withdrawn
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• 2017
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• 2018
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