HK1070588A - Pharmaceutical compositions of 5,7,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]-hexadeca-2(11)3,5,7,9-pentaene - Google Patents

Description

Pharmaceutical composition of 5, 7, 14-triazatetracyclo [10.3.1.0(2, 11) 0(4, 9) ] -hexadeca-2 (11)3, 5, 7, 9-pentaene

The invention relates to 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadec-2 (11)3, 5, 7, 9-pentaene (1) and related compounds in Controlled Release (CR) oral pharmaceutical dosage forms and to methods of using them to reduce nicotine addiction or to assist in the cessation or reduction of tobacco use while reducing nausea as an adverse reaction. The present invention also relates to Immediate Release (IR) low dose compositions having a stable formulation with uniform drug distribution and efficacy.

Background

Compound 1, also known as 7, 8, 9, 10-tetrahydro-6, 10-methylene-6H-pyrazino [2, 3-H ] [3] -benzazepine, binds to neuronal nicotinic acetylcholine specific receptor sites and is used to modulate cholinergic function. Thus, the compounds are useful for treating inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum, and crohn's disease), irritable bowel syndrome, tonic-tension disorder, chronic pain, acute pain, sprue, capsulitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorder, ejaculatory depression, Amyotrophic Lateral Sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, arrhythmia, hyperacidity, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical and addiction (e.g., nicotine (and/or tobacco products), alcohol, benzodiazepine, barbiturates, opioids or cocaine dependency or addiction), headache, migraine, stroke, Traumatic Brain Injury (TBI), headache, Obsessive Compulsive Disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, difficulty reading, schizophrenia, multi-infarct and necrotizing dementia, age-related cognitive decline, epilepsy including non-epileptic seizures, Alzheimer's Disease (AD), Parkinson's Disease (PD), Attention Deficit Hyperactivity Disorder (ADHD) and Tourette's syndrome.

Compound 1 and its pharmaceutically reducible acid addition salts are disclosed in international patent publication No. WO 99/35131, published on 15.7.1999, the entire contents of which are incorporated herein by reference.

When an Immediate Release (IR) dosage form of the above compounds, i.e. a dosage form for providing a drug in dissolved form in less than about 30 minutes upon swallowing, produces therapeutically useful drug levels in the blood and brain, significant levels of nausea have been observed in patients, especially at sufficiently high doses to be therapeutically useful for certain patients. Since nausea can result in poor patient compliance with dosing regimens, there is a need for a dosage form of 1 that reduces the incidence of nausea.

Thus, the present invention provides a CR dosage form that reduces or eliminates nausea while maintaining therapeutic levels of the drug in the blood and Central Nervous System (CNS) of 1. Although examples exist in the art suggesting that CR dosage forms may in some cases alleviate such side effects as nausea (e.g., oxycodone (j.r. caldwell et al, j.of rhematology 1999, 26, 862-869), venlafaxine (r.entsuah and r.chitra, psychopharmacogenetic Bulletin, 1997, 33, 671-676) and paroxetine (r.n.golden et al, j.clin.psychiatry, 2002, 63, 577-584), there are also opposite examples which suggest that CR dosage forms are sometimes not preferred over immediate release dosage forms which may reduce nausea and thus teach no use of CR dosage forms as a way to reduce side effects.examples of such teachings include morphine sulfate (t.d.walsh et al, j.clin.oncology, 1992, 15, 268), hydrophenone (h.clysone et al, yang @, 74, 1808, 57-zhuo-ba-1999, zu-r et al, zu-k et al, zu-kogaku-k et al, zu-k-r-kola-k, zu et al, zu, european Neurology, 1997, 37, 23-27). Furthermore, in many cases, CR dosage forms result in decreased bioavailability compared to IR dosage forms, thereby necessitating increased dosing or even making it impractical to utilize CR dosage forms. Thus, it was not possible to predict in advance that drugs exhibiting nausea would actually benefit from a CR dosage form. In addition, the rate of drug, i.e., the dissolution rate of the drug, is achieved over a wide range somewhat slower than for IR dosage forms for delivery over an extended period of time (up to about 24 hours). The inventors have discovered that, with respect to 1, CR dosage forms having a range of transport rates can provide treatment of blood and CNS drug levels while reducing the incidence of nausea compared to IR dosage forms. The inventors have also discovered a particularly preferred manner of formulation 1 to achieve the desired rate of administration. The inventors have also discovered a preferred dosing regimen that provides therapeutic drug levels while maintaining low levels of nausea.

The high efficacy of compound 1 as a nicotinic receptor ligand makes it possible to use low dosing concentrations. For ease of handling, manufacture and convenience for the patient, low dose concentrations of the drug are typically formulated with high dilution of excipients. However, unique challenges are also faced during the preparation and storage of such dilute formulations. First, high dilution can cause significant degradation of the excipient, and even excipient impurities, during storage. Examples of excipient characteristics that can affect Drug degradation include moisture and moisture migration (see J.T. Carstensen, Drug Stability: Principles and Practices, 2ndEd, Marcel Dekker, NY, 1995, 449-452) and excipient acidity (see K.Waterman et al, Pharm Dev. Tech., 2002, 7(2), 113-146) that affects the local pH microenvironment. Examples of excipient impurities that affect drug degradation include trace metals, peroxides, and formic acid (see k.waterman et al, pharm.dev.tech., 2002, 7(1), 1-32). Although the chemical structure and identification of the reacting moieties under consideration can be used to infer possible degradation pathways, it is still not possible to predict in advance whether a particular excipient can form an acceptable stable formulation with a given drug. In addition, 1 has been observed to react with many commonly used excipients and excipient impurities. There thus remains a need to provide excipients and excipient combinations (such as tablettable properties) that can be made into acceptable formulations, while providing suitable stability to 1. The inventors have found a particularly preferred way of obtaining formulation 1 with the required stability. More specifically, with respect to film coated tablets, the inventors have discovered specific formulations and methods to achieve the desired stability.

A second problem sometimes observed with effective drugs prepared at high dilution is variability in efficacy due to separation and sticking to equipment during manufacture. This problem has been found to be a problem with the formulation of 1. One recently reported method for achieving uniform drug distribution in low dose drug blends utilizes the carrier excipient lactose to form an ordered mixture with the micronized drug (l.wu et al, AAPS pharmcitech, 2000, 1(3), article 26). While the manual scrubbing step can be effectively performed to recover active components that are fluidized or adhered to the metal surfaces of small-scale equipment, manual scrubbing is neither effective nor desirable in a production-scale environment. The liquid method can reduce the problem of medicine loss in the production process of the medicine product to the minimum; however, morphologically altered compounds (e.g., polymorph, hydrate, or solvate changes) make it difficult to perform liquid processes while maintaining stability (both physical and chemical) of the pharmaceutical composition. Although many techniques have been applied to address these common problems, it is not yet possible to expect a particular technique to be effective for a given set of drugs and excipients. Thus, since 1 must be highly diluted when used, there is a need for a process suitable for commercialization of 1 so that sufficient uniformity of efficacy can be maintained from dosage form (e.g., tablet) to dosage form and from lot to lot. The inventors have also discovered a preferred way of processing the formulation to obtain the desired uniform drug potency and uniform drug distribution 1.

Summary of The Invention

The present invention is directed to certain Controlled Release (CR) pharmaceutical dosage forms of 1 or a pharmaceutically acceptable salt thereof for administration to a subject in need thereof, said CR dosage forms comprising said compound or a pharmaceutically acceptable salt thereof and means for delivering said compound or pharmaceutically acceptable salt thereof to said subject at a rate of less than about 6 mg/hr (wherein mgA refers to milligrams of active agent equivalent to the free base) such that at least about 0.1mgA of said compound or pharmaceutically acceptable salt thereof is administered over a 24-hour period. In certain subjects, it may be advantageous to administer an Immediate Release (IR) dosage form comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, after administration of a panel of doses of a CR dosage form.

The invention particularly relates to methods of treatment using CR pharmaceutical dosage forms that result in a reduction in nausea 1 as a side effect. Such CR dosage forms are characterized by providing the drug in the Gastrointestinal (GI) tract in a dissolved form at a rate of from about 0.03 mgA/hr to about 6 mgA/hr, more preferably from about 0.06 mgA/hr to about 3 mgA/hr, and most preferably from about 0.10 mgA/hr to about 1 mgA/hr. The invention also provides a CR dosage form that provides a mean maximum blood concentration (C) to a subject when said dosage is first administered to said subject_max) Reduction of mean C for immediate release bolus initially administered_max10-80%, more preferably 30-70%. The invention also provides for increasing the time T required to reach this maximum blood concentration_maxThe dosage form of (1). In particular, an average T has been found to be found for immediate release boluses_maxComparative mean T_maxAn increase of 50% may reduce nausea. The present invention also provides a dosage form wherein a release rate of 1 as determined by dissolution method USP type II provides a release rate of less than 6 mgA/hour and a dissolution time of 50% w/w of said drug of from 1 to 15 hours, more preferably from 2 to 10 hours.

The invention also provides pharmaceutical compositions for achieving these transport rates. The invention is particularly directed to dosage forms of 1 comprising delivery devices such as hydrophilic matrices, hydrophobic matrices, coated CR tablets and multiparticulates, buccal systems, transdermal systems, suppositories and depot systems. Among the coated tablets, a particularly preferred dosage form is an asymmetric membrane technology system (as described in U.S. Pat. Nos. 5,612,059 and 5,698,220, the contents of which are incorporated herein by reference).

The present invention further provides such a controlled release dosage form which is a combination of a delayed + sustained release dosage form having a delay period of up to 8 hours before the onset of sustained release, wherein during the delay period said pentaene is released at a rate of not more than about 0.1 mgA/hr and wherein the delay period is controlled by the transit or space of location in the gastrointestinal tract.

It is another object of the invention to provide a reduction in nausea when compound 1 is administered to a patient by initiating a treatment course with a CR dosage form followed by a treatment course with an IR dosage form.

The term "controlled release" (CR) as used herein refers to a dosage form that slowly releases or transports the drug to a patient at a rate such that at least some of the drug is not available within the first 1 hour. CR systems can provide drug at a constant rate (zero order), at a steadily decreasing rate (first order), or at unequal or pulsatile rates. Drug delivery may also include a delay time after the initial drug release. This delay may be brief or related to the location of the drug in the body. For example, CR dosage forms may be prepared by using an enteric coating wherein the drug is released upon reaching intestinal pH following oral administration.

In the present invention, a suitable CR dosage form of 1 can be determined by one or both of two methods:

(1) the first method involves determining the characteristics of the drug in the dosage form (creating a pharmacokinetic profile) by sampling and analyzing the blood after the drug is initially administered to the subject. Initial administration refers to administration to a subject for the first time or at least 4 days since the previous administration of any dosage form 1. It has been found that a particularly important aspect of reducing nausea with 1 is the maximum blood concentration of 1 (C) achieved after initial administration of the drug_max) And the time (T) required to reach maximum blood concentration_max). In the determination of C_maxAnd T_maxOne skilled in the art recognizes that there is significant variability between administrations and between subjects. To obtain C_maxAnd T_maxIn order to make a sufficient comparison between the two and thereby determine whether the administered dosage forms can achieve the desired nausea reduction, it is necessary to determine these parameters for at least 10 subjects in a crossover experiment (i.e., each subject receives both dosage forms, IR and CR) with at least 7 days between experiments. It was particularly found that to reduce nausea, an initial average C was required_maxThe reduction value is 10-80%, more preferably 30-70% obtained using IR bolus administration. Just T_maxIn particular, the initial mean T of the CR dosage form is greater than that of the IR bolus_maxThe increase should be at least 50% (i.e., the number of hours for the average CR dose is 1.5 times the number of hours for the average IR bolus dose).

(2) The second method of analyzing a CR dosage form to determine whether it can reduce nausea involves in vitro testing. The inventors have found that plotting 1 percent of dissolution versus time is the best way to determine the time required for 50% of the drug to dissolve. The data required to make this figure is obtained using a standard USP (United states Pharmacopeia) type II dissolution apparatus (50 rpm; 500mL of 0.01N hydrochloric acid; 37 ℃), such as Hanson SR 8. Samples were analyzed using reverse phase HPLC. It has been found that nausea is reduced when the dosage form shows a total dose of 50% w/w which dissolves in about 1-15 hours, preferably 2-10 hours.

Thus, the present invention further relates to an immediate release dosage form suitable for administration to a subject that provides dosage form stability and uniform drug distribution and efficacy, comprising a drug core comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent that is substantially free of reducing sugars. The invention particularly provides such immediate release dosage forms wherein the IR dosage form comprises 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-L-tartrate or citrate of hexadeca-2 (11)3, 5, 7, 9-pentaene.

As used herein, "substantially free of reducing sugars" refers to less than 20 w/w% reducing sugars (including, but not limited to, lactose). Preferably, the dosage forms prepared according to the present invention contain less than 10 w/w% reducing sugars, and more preferably less than 5 w/w% reducing sugars.

The immediate release dosage form of the present invention may further comprise a glidant, a disintegrant and/or a lubricant. The invention also relates to a method for producing these immediate release dosage forms.

The immediate release dosage form of the present invention may further comprise a film coating. The invention also relates to a process for the production of these film coated immediate release dosage forms.

The present invention also provides formulations suitable for film coating immediate release dosage forms of 1, wherein the polymeric binder used for such coating comprises predominantly cellulosic polymers. A particularly preferred cellulosic polymer is Hydroxypropylmethylcellulose (HPMC). The coating material further comprises an opacifier (particularly titanium dioxide), a plasticizer and/or a glidant, each of which contains less than about 20% w/w of a reducing sugar. Particularly preferred coating formulations include HPMC, titanium dioxide, and triacetin or PEG.

The present invention also provides a method of producing blends with good efficacy and content uniformity as described herein. These methods include geometric dilution of the drug with excipients prior to tableting. These methods also include the application of moderate shear blending. The preferred blending method uses a "bin mixer"; however, other mixers that produce similar shear are also used.

The disclosed method of treatment using a CR drug dosage form that reduces nausea by 1 as a side effect is characterized by providing the drug in the Gastrointestinal (GI) tract in a dissolved form at a rate of from about 0.03 mgA/hr to about 8 mgA/hr, more preferably from about 0.06 mgA/hr to about 3 mgA/hr, and most preferably from about 0.10 mgA/hr to about 1 mgA/hr.

The invention particularly provides methods for reducing nicotine addiction or aiding in the cessation or reduction of tobacco use in a subject, comprising administering to said subject an amount of 1A release formulation or an immediate release formulation, said amount effective to reduce nicotine addiction or aid in the cessation or reduction of tobacco use. The invention particularly provides such methods wherein the CR or IR dosage form comprises 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-L-tartrate or citrate of hexadeca-2 (11)3, 5, 7, 9-pentaene.

The invention further provides a method of treating a disease or condition in a subject in need of such treatment, comprising administering to said subject a controlled release dosage form or an immediate release dosage form of 1 in an amount effective to treat such disease or condition, wherein said disease or condition is selected from the group consisting of: inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, crohn's disease, irritable bowel syndrome, tonic dystonia, chronic pain, acute pain, sprue, capsulitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, ejaculatory retardation (jet lag), Amyotrophic Lateral Sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmia, hyperacidity, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependence and addiction; nicotine, tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine dependence or addiction; headache, stroke, Traumatic Brain Injury (TBI), Obsessive Compulsive Disorder (OCD), psychosis, huntington's chorea, tardive dyskinesia, hyperkinesia, difficulty reading, schizophrenia, multi-infarct, necrobium dementia, age-related cognitive decline, epilepsy, seizures without seizures, alzheimer-like senile dementia (AD), Parkinson's Disease (PD), Attention Deficit Hyperactivity Disorder (ADHD), and tourette's syndrome. The invention particularly provides such methods wherein the CR or IR dosage form comprises 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-L-tartrate or citrate of hexadeca-2 (11)3, 5, 7, 9-pentaene.

The invention also provides pharmaceutical compositions that achieve these rates of administration. The invention is particularly directed to dosage forms of 1, including delivery devices such as hydrophilic matrices, hydrophobic matrices, osmotic systems, multiparticulates, permeable coated controlled release dosage forms, suppositories, oral systems, transdermal systems, and implantable systems. Among osmotic systems, a particularly preferred dosage form is an asymmetric membrane technology system (as described in U.S. Pat. Nos. 5,612,059 and 5,698,220, the contents of which are incorporated herein by reference).

The present invention also provides a method of administration that results in reduced nausea as a side effect when compound 1 is administered to a patient by initiating a course of treatment with a CR dosage form followed by a course of treatment with an IR dosage form.

As used herein, an "immediate release" (IR) dosage form refers to a dosage form that provides a drug in a form that is substantially absorbed over about 1 hour when the drug is administered orally.

By "matrix" system is meant a particular CR dosage form in which the drug is mixed with excipients, usually in a compressible or extrudable form, such that release of the drug from the dosage form is controlled by a combination of erosion and diffusion. Aggressive control of drug delivery involves the slow removal of matrix material by the GI fluid to gradually expose and release the drug from the matrix. Diffusion control of drug transport involves diffusion of the soluble drug through the matrix excipient network in a controlled manner. In fact, many matrix dosage forms include some degree of combination of both structures.

A "hydrophilic matrix" is a matrix CR dosage form in which water-soluble or water-swellable polymers form a drug-containing network. The rate of diffusion of the drug to the surface of the dosage form and the rate of disintegration of the matrix control the rate at which the GI system gains drug.

A "hydrophobic matrix" is a matrix CR dosage form in which a water-insoluble or only partially water-soluble material slows the rate at which the drug contacts the liquid environment of the GI system, thereby controlling the rate of drug available for absorption.

"Permeability coating" CR systems refer to various coating materials on tablets or granules that act as barriers to the release of drug from the tablet or to the passage of water through the drug. These coating materialsIncluding enteric coating materials that permeate as the pH increases when the dosage form is present in the stomach. Examples of such coating materials include Eudragits sold by Rohm GmbHPharma Polymers (Darmstadt, Germany)^TMAnd hydrogen Cellulose Acetate Phthalate (CAP) sold by eastman chemical (Kingsport, TN). One group of such coated CR systems includes osmotic systems. Such CR dosage forms include a semipermeable membrane surrounding a drug core having sufficient osmotic pressure to allow water to pass through the membrane in the GI system. The osmotic pressure then forces the drug out of the core through holes or pores previously formed or created in situ in the coating layer. Such systems typically include added agents (osmogens) for increasing the osmotic pressure within the core. An overview describing such systems can be found in g.santus j.control.rel, 1995, 35, 1-21 of r.w.baker.

"asymmetric membrane technology" AMT describes a specific osmotic CR system in which a porous coating layer is prepared by a phase separation process during the coating operation as described in U.S. Pat. Nos. 5,612,059 and 5,698,220, the contents of both of which are incorporated herein by reference.

A "transdermal delivery system" is a drug delivery device for providing systemic drugs to a patient through the skin. Such systems typically include a layer of drug-containing material over a backing material that includes an adhesive to attach the material to the subject's skin.

An "oral delivery system" is a dosage form that provides a means of drug absorption through the tissues of the oral cavity (inner cheek).

A "long acting formulation" is a controlled release pharmaceutical dosage form for subcutaneous or intramuscular injection of a drug and suitable excipients and formation of a bolus (matrix) that slowly provides the drug to the circulatory system.

Drug 1 for the purposes of the present invention refers to the parent drug and all pharmaceutically acceptable salts and prodrugs thereof.

The term "mgA" refers to milligrams of active agent based on the free base of the agent.

The term "pharmaceutically acceptable" refers to a substance or composition that must be chemically, physically, and/or toxicologically compatible with the other components included in the formulation and/or the mammal being treated therewith.

The term "active ingredient" refers to therapeutically active compounds and prodrugs thereof, and pharmaceutically acceptable salts, hydrates, and solvates of the compounds and prodrugs.

The term "suitable time period" or "suitable time period" refers to a time period necessary to achieve a desired effect or result. For example, the mixture may be blended until the efficacy profile is within an acceptable qualitative range for the administration application or application of the blended mixture.

The term "unit dose" as used herein refers to a physically discrete unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect. The unit dose can be in the form of a tablet, capsule, sachet, or the like, referred to herein as a "unit dosage form".

Detailed Description

The preparation of compound 1 is described in U.S. Pat. No. 6,410,550, the contents of which are incorporated herein by reference; in contrast, WO01/62736 describes a process for the resolution of racemic mixtures. According to the present invention, it is desirable that 1 of the CR pharmaceutical composition may be administered in a dose of about 0.1mgA to about 6 mgA/day, more preferably about 0.5 to 4 mgA/day, and most preferably about 1 to 4 mgA/day, in single or divided doses, although these doses will necessarily vary depending on the body weight and condition of the subject to be treated. Dosage levels below the lower limit of the aforesaid range may exceed adequate levels depending on individual response, while in other cases still larger doses may be employed without causing any harmful side effects.

Although any pharmaceutically acceptable form of 1 related to the present invention may be used, it is preferable to use a salt form of the drug. A particularly preferred salt form of the medicament is the L-tartrate salt.

In order to control nausea using a CR dosage form of 1, the release rate of the drug must be such that the drug is metered into the GI system in a form that achieves drug absorption at a significantly lower rate than the IR dosage form. Using fractionated IR doses in clinical trials it was found that: if the drug is released at a rate equivalent to about 12 mgA/hr (total dose 3mgA), then the incidence of nausea is reported to be over 50% in the tested subjects. In contrast, when administered at a rate equivalent to about 8 mgA/hr (2mgA total dose), the incidence of nausea dropped to about 13%. This result establishes an upper limit of 8 mgA/hr of dosing rate required for a CR dosage form to reduce nausea. It is expected that even greater improvements in reducing nausea can be achieved by using slower release rates in accordance with the present invention. It is generally expected that oral CR dosage forms will allow no more than about 18 hours of drug absorption, depending on the mobility of the dosage form for the individual. The total dosage of the required drug is expected to be about 0.5mgA to 6 mgA/day based on the blood concentration required for efficacy. Based on this result, the lower limit of the administration rate is considered to be about 0.03 mgA/hr. Although these extreme data may provide some of the beneficial effects described herein, the inventors have discovered that in order to achieve the desired therapeutic plasma levels while maintaining a reduction in nausea, the drug is administered at a rate of about 0.06-3 mgA/hr and more preferably 0.1-1 mgA/hr.

A number of devices have been found to produce such CR systems that achieve the desired rate of administration. One such device is a substrate. In particular, matrix tablets or matrix multiparticulates can be prepared according to the invention. In the case of multiparticulates, the dosage form in its final form may be prepared by incorporating the particles into a capsule or into a sachet or other such form. These matrix dosage forms may be made using conventional techniques, such as by compression with a tablet press or by methods such as extrusion or melt congealing. Two types of matrix dosage forms are suitable for 1: hydrophilic and hydrophobic matrices. Matrix formulations of hydrophilic matrices generally consist of a mixture of high and low molecular weight water-soluble polymers. In particular, these matrix materials are composed of Hydroxypropylmethylcellulose (HPMC), polyethylene oxide (PEO), Hydroxypropylcellulose (HPC), polyacrylates, xanthan gum (xan) of different molecular weightstham gum), alginate, and other combinations of such polymers. Particularly preferred polymers include HPMC and PEO. A particularly preferred formulation is sold under the trade name K4MMethocel^TMHPMC (available from Dow Corp., Midland, Mich.) is sold under the trade name D-tab^TMA mixture of marketed dibasic calcium phosphates (available from rhodia inc., Cranbury, NJ). The hydrophobic base formulation of 1 can be prepared by using hydrophobic materials to slow down the contact of water with 1 accordingly. Particularly preferred hydrophobic materials include carnauba wax, glyceryl behenate, and stearic acid. However, it will be appreciated by those skilled in the art that other similar wax-like substances function in an equivalent manner.

Osmotic dosage forms may also provide a desired release rate of 1. Examples of such dosage forms are described in j.control.rel, 1995, 35, 1-21 of g.santus and r.w.baker, which are incorporated herein by reference. A particularly preferred osmotic dosage form of 1 is in the form of an AMT system such as described in U.S. patent nos. 5,612,059 and 5,698,220. (see, e.g., also S.M.Herbig, J.control.Rel., 1995, 35, 127-. Such systems allow for a well controlled release of the drug throughout the GI system. The inventors have found that a preferred formulation consists of a core made of the L-tartrate salt of the drug, mannitol, microcrystalline cellulose, dibasic calcium phosphate and magnesium stearate. These cores may be prepared by direct compression, wet granulation (using high or low shear wet or fluid bed granulators), extrusion granulation, rotary granulation or roller compaction. Roller compaction is particularly preferred due to its ability to prevent drug separation while maintaining stability of the drug (as opposed to aqueous wet granulation, which can lead to formation of drug hydrates). Tablets can be prepared with a standard tablet press (rotary). The cores were then coated using a pan coater. The coating material advantageously consists of a mixture of acetone and water-coated Cellulose Acetate (CA) and polyethylene glycol (PEG). The proportions of the components are selected so that the CA/PEG combination produces a porous semipermeable coating material that can be administered at a desired rate through pores in the GI tract. Most preferably, the ratio of CA to PEG is selected such that the PEG and CA are in a single phase, since it has been found that phase separated PEG can degrade the drug in the final dosage form at elevated temperatures. The phase compatibility for the purposes of the present invention can be determined using a standard differential scanning calorimeter on the desired blend of CA and PEG. The absence of a PEG melting transition between 30 ℃ and 50 ℃ is an indication of a single phase and thus that such proportions would form a preferred film. Therefore, it is most preferred that the CA/PEG ratio be maintained above about 4.

Non-oral CR systems may also provide a reduction in nausea while maintaining efficacy at dosing 1. These systems include suppositories, transdermal systems, oral systems, drug depots, and implantable devices. In order to act to reduce nausea, these devices must provide controlled release characteristics as described above. A particularly preferred non-oral dosage form is a transdermal dosage form.

Since all CR dosage forms are used, it is preferred to transport the drug at a rate of about 0.06 to 3 mgA/hr and more preferably 0.1 to 1 mgA/hr. Suitability for the present invention can be determined by in vivo or in vitro testing. It is particularly preferred to use the starting average C_maxDown to the starting mean C obtained with IR bolus administration_maxA value of 10 to 80%, more preferably 30 to 70%. Just T_maxIn particular, the initial mean T of the CR dosage forms is preferred_maxInitial mean T with IR bolus_maxAt least 50% greater. Preferred dosage forms of the invention provide 50% w/w total dose dissolution between about 1-15 hours, more preferably 2-10 hours.

The CR systems of the invention may include a delay period or lag period between administration of the dose and absorption of the drug. Such delays may be temporary or related to the location of the gastrointestinal tract. These systems are effective for the purposes of the present invention provided that once they begin to take up the drug, the rate falls within the above defined range. Particularly preferred delayed release systems are enteric coated tablets or multiparticulates. Preferred enteric systems may be prepared by coating tablets or multiparticulates with a material such as cellulose acetate phthalate or an enteric polyacrylic acid such as those sold under the trade name Eudragit (available from Rohm Pharmaceuticals).

The formulations used in the present invention can be prepared using a number of materials and methods well known in the art. However, the present inventors have found that the presence of reducing sugars is detrimental to the stability of the drug on storage. It is particularly preferred that the reducing sugar in the CR formulation is less than 20% w/w; more preferably the CR formulation contains less than 10% w/w reducing sugars; and most preferably the CR formulation contains less than 5% w/w reducing sugars. The particular reducing sugar that should preferably be avoided is lactose.

For the preparation of controlled release dosage forms and immediate release dosage forms, the active ingredient itself or in the form of its pharmaceutically acceptable salts, solvates and/or hydrates can be used. The active ingredient may be used as such or in the form of a pharmaceutically acceptable salt, solvate and/or hydrate thereof. The term "pharmaceutically acceptable salts" refers to non-toxic acid addition salts derived from inorganic and organic acids. Suitable salt derivatives include halides, thiocyanates, sulfates, bisulfates, sulfites, bisulfites, arylsulfonates, alkylsulfates, phosphonates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, alkanoates, cycloalkylalkanoates, arylalkanoates, adipates, alginates, aspartates, benzoates, fumarates, glucoheptonates, glycerophosphates, lactates, maleates, nicotinates, oxalates, palmitates, pectinates, picrates, pivalates, succinates, tartrates, citrates, camphorates, camphorsulfonates, digluconates, trifluoroacetates, and the like.

The final pharmaceutical composition is processed into unit dosage forms (e.g., tablets, capsules, or sachets) and then packaged for distribution. The processing steps vary depending on the particular unit dosage form. For example, tablets are typically compressed under pressure into a desired shape and capsules or sachets are filled using a simple filling operation. The procedures for producing different unit dosage forms are well known to those skilled in the art.

The active ingredient blend of the immediate release dosage form generally comprises one or more pharmaceutically acceptable excipients, carriers or diluents. The particular carrier, diluent or excipient employed will depend upon the mode and purpose for which the active ingredient is to be administered. Generally, immediate release tablets include materials such as diluents, binders, lubricants, glidants, disintegrants and mixtures thereof. Although many such excipients are well known to those skilled in the art, the present inventors have discovered that only a small fraction of them can be made into the most stable formulations. The inventors have particularly found that preferred formulations contain less than about 20% w/w reducing sugars. Reducing sugars are saccharides and their derivatives containing a free aldehyde group or a free ketone group capable of acting as a reducing agent by donating electrons. Examples of reducing sugars include monosaccharides and disaccharides and more specifically include lactose, glucose, fructose, maltose, and other similar sugars. The inventors have further found that formulations containing dibasic calcium phosphate are particularly stable. More specifically, more than about 20% w/w calcium dibasic phosphate is used to produce a stable formulation. Other acceptable excipients include starch, mannitol, kaolin, calcium sulfate, inorganic salts (e.g., sodium chloride), powdered cellulose derivatives, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers such as polyethylene oxide, and hydroxypropyl methylcellulose. To ensure homogeneity of the contents of the blend, it is preferred to use a volume average diameter of the drug substance particle size of less than or equal to about 30 microns. Preferred diluents are microcrystalline cellulose (e.g., Avicel * PH200, PH102 or PH101, available from FMC Pharmaceutical, Philadelphia, Pa.) and dibasic calcium phosphate or phosphate (e.g., A-Tab * available from Rhodia, Chicago Heights, IL.). The average particle size of the microcrystalline cellulose is generally in the range of about 90 μm to about 200 μm. Suitable grades of dibasic calcium phosphate include anhydrous (average about 135-180 μm, available from PenWest Pharmaceuticals Co., Patterson, NY or Rhodia, Cranbury, NJ) and dihydrate (about 180 μm, available from PenWest Pharmaceuticals Co., Patterson, NY or Rhodia, Cranbury, NJ). Generally, the microcrystalline cellulose is present in an amount of about 10% to about 70% by weight and the dibasic calcium phosphate is present in an amount of about 10% to about 50% by weight, more preferably the microcrystalline cellulose is present in an amount of about 30% to about 70% by weight and the dibasic calcium phosphate is present in an amount of about 20% to about 40% by weight.

If desired, a binder may be added. Suitable binders include materials such as cellulose (e.g., cellulose, methylcellulose, ethylcellulose, hydroxypropyl cellulose, and hydroxymethyl cellulose), polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, starch, natural and synthetic gums (e.g., acacia, alginate, and gum arabic), and waxes.

Lubricants are commonly used in tablets to prevent sticking of the tablet and punch to the die. Suitable lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and the like. A preferred lubricant is magnesium stearate. Magnesium stearate is typically present in an amount of about 0.25% to about 4.0% by weight.

Disintegrants may also be added to the composition to break the dosage form and release the compound. Suitable disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch and calcium alginate. Of these, croscarmellose sodium and sodium starch glycolate are preferred, and croscarmellose sodium is most preferred. Croscarmellose sodium is typically present in an amount of about 0.5% to about 6.0% by weight. The amount of disintegrant included in the dosage form depends on several factors, including the nature of the dispersion, the porosity (described below), and the disintegrant properties selected. Generally, the disintegrant comprises from 1 wt% to 15 wt%, preferably from 1 wt% to 10 wt% of the dosage form.

Examples of glidants include silicon dioxide, talc, and corn starch.

Film coatings on immediate release dosage forms result in ease of swallowing, may reduce unpleasant taste or odor during administration, improve lightfastness by the use of opacifiers, provide improved dexterity, reduce friction during high speed packaging, or act as a barrier between incompatible substances (g.cole, j.hogan and m.ulton, Pharmaceutical coating technology. taylor and Francis Ltd, Ch1, 1995). The present inventors have found that a coating layer comprising a high amount of cellulose-based polymer provides excellent chemical stability to the drug. Cellulosic products are polymers derived from cellulose. Examples of polymers include cellulose preparations such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, and sodium carboxymethyl cellulose. The preferred polymer is hydroxypropyl methylcellulose. The coating layer of the present invention comprises a polymer, an opacifier, a plasticizer, a pharmaceutically acceptable diluent/filler and optionally a colorant. Opacifiers are excipients that help reduce the transmission of light through the coating to the core. Examples of opacifiers are titanium dioxide and talc. A preferred opacifier is titanium dioxide. Plasticizers are materials that lower the glass transition temperature of a polymer, thereby generally improving physical properties. Examples of plasticizers include polyhydric alcohols, such as glycerol and polyethylene glycols and acetates, such as triacetin (triacetin) and triethyl citrate. The compositions of the present invention may optionally include a colorant. Such colorants are commercially available from a number of commercial suppliers and are well known to those skilled in the art. Particularly preferred coating formulations include HPMC, triacetin and titanium dioxide or HPMC, PEG and titanium dioxide.

In order to obtain a uniform distribution of the drug in the blend before tablet or capsule production, two methods have been invented. In the first method, a geometric dilution method is used. In this method, a pre-blend of drug and a portion of the excipients is prepared and then further diluted with the remaining excipients in 2-5 additional steps. In the first dilution step, the drug is mixed with 10-30 wt% of the excipient. During the second dilution, the first preblend is further diluted with 10-40 wt% of excipients. During the 3 rd to 5 th dilutions, the second diluted blend was further diluted with 10-75 wt% of excipients to form the final blend. A preferred dilution scheme involves a first dilution of the drug with dibasic calcium phosphate in two increments, followed by combining the blend with the remaining excipients.

A second method for obtaining uniform drug distribution involves blending the formulation with a specific level of shear force. The inventors have surprisingly found that either too high or too low shear can result in poor uniformity and overall efficacy. The inventors have found that the desired shearing effect is obtained using a bin mixer or high shear mixer operating at low shear conditions (below 200 rpm). Typical blending times for blending in a bin blender range from about 20 minutes to about 30 minutes. Although blending times of 30 minutes or more may be used, careful consideration is given to not stratify the blend. After the initial blending step, the active ingredient blend may be sieved using a conical mill (Comil 197, Quadro Engineering, inc., Waterloo, Ontario, Canada) fitted with a 0.8mm sieve. The lubricant is then added to the active ingredient blend and blended in a double shell "V" or bin blender for about 3 minutes, after which dry granulation is conducted.

The above method allows for effective mixing and more uniform distribution of the active ingredients without significant degradation of the active ingredients; however, the loss of active ingredient due to the separation or binding of the compound to the metal surfaces of the equipment (e.g., sieve and pipe surfaces) again presents challenges for formulations especially at low doses (e.g., less than 4mg per unit dose). The inventors have found that a third method of achieving acceptable blend efficacy involves the use of an abrasive excipient, such as dibasic calcium phosphate. More specifically, preferred formulations contain 10-50 wt% dibasic calcium phosphate.

The pharmaceutical compositions may be used to produce unit dosage forms containing from about 0.1mg to about 10.0mg of active ingredient per unit dose, preferably from about 0.2mg to about 5.0mg of active ingredient per unit dose. Tablet sizes (i.e., unit dosage forms) are generally about 100mg to about 600 mg.

Tablets are generally prepared by compression in a rotary tablet press. However, the particular method used for the tablets is non-limiting and well known to those skilled in the art. After forming the tablets, the tablets are typically coated with one or more coating materials. The tablets may be coated with a coating material that masks the odor, acts as a sealant, and/or acts as a recipient of a logo or trademark printed on the surface of the tablet. Alternatively, the tablets may be coated with a film-forming protecting agent to modify the dissolution characteristics of the tablet. For example, tablets may be coated with a film-forming coating that is resistant to dissolution for a predetermined period of time, thereby providing delayed or extended release of the active ingredient. Suitable film forming protective agents include cellulose (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose), polyvinylpyrrolidone, and ethyl acrylate-methyl methacrylate copolymer. The coating formulation may also include additives such as plasticizers (e.g., polyethylene glycol or triacetin), preservatives, sweeteners, flavoring agents, colorants, and other additives known to provide an elegant form of medication. Preferred coating formulations contain 40-70 wt% cellulosic polymers. Preferred aqueous coating materials for the immediate release dosage forms of the present invention include Opadry * (YS-1-18202-A) and Opadry clear * (YS-2-19114-A) manufactured by Colorcon, West Point, Pennsylvania. Opadry *, used as a sunscreen coating, contained hydroxypropyl methylcellulose, titanium dioxide, and polyethylene glycol or triacetin. OpadryClear *, which was used as a polishing coating agent, contained hydroxypropyl methylcellulose and triacetin.

The inventors have found that a preferred formulation consists of a core made of the L-tartrate salt of the drug, mannitol, microcrystalline cellulose, dibasic calcium phosphate and magnesium stearate. More preferred formulations consist of a core made of the L-tartrate salt of the drug, microcrystalline cellulose, dibasic calcium phosphate and magnesium stearate. Even more preferred formulations consist of a drug core made of the L-tartrate salt of the drug, microcrystalline cellulose, dibasic calcium phosphate, croscarmellose sodium, silicon dioxide and magnesium stearate. These cores may be prepared by direct compression, wet granulation (using high or low shear wet or fluid bed granulators), extrusion granulation, rotary granulation or roller compaction. Roller compaction is particularly preferred due to its ability to prevent drug separation while maintaining stability of the drug (as opposed to aqueous wet granulation, which can lead to formation of drug hydrates). Tablets can be prepared with a standard tablet press (rotary). The cores were then coated using a pan coater. Preferred coating layers consist of a mixture of hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol or triacetin and optionally a colorant.

Alternatively, the active drug blend may be filled into hard capsules, also known as dry-filled capsules (DFC). The capsules and production method are similar to the reported tablet core formulations and production methods. Hard capsules may consist of gelatin and water or hydroxypropylmethyl cellulose, water and gelatin (gelan gum or carrageenan).

The pharmaceutical composition (or formulation) may be packaged in various ways. Generally, the dispensing article comprises a container containing a pharmaceutical composition in a suitable dosage form. Suitable containers are well known to those skilled in the art and include materials such as vials (plastic and glass), sachets, blister foil packets, and the like. Tamper-proof components may also be included in the container to prevent easy access to the package contents. In addition, the surface of the container is typically coated with a label that describes the contents of the container and any appropriate warnings or instructions.

Pharmaceutical compositions containing compound 1 described herein are particularly useful for treating or preventing inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum, and crohn's disease), irritable bowel syndrome, tonic-tension disorder, chronic pain, acute pain, sprue, capsulitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, ejaculatory retardation (jet lag), Amyotrophic Lateral Sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, arrhythmia, hyperacidity, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependence and addiction (e.g., nicotine (and/or tobacco products), alcohol, benzodiazepine, barbiturates, opioids or cocaine dependence or addiction), Headache, migraine, stroke, Traumatic Brain Injury (TBI), Obsessive Compulsive Disorder (OCD), psychosis, huntington's chorea, tardive dyskinesia, hyperkinesia, difficulty reading, schizophrenia, multi-infarct, dementia at death, age-related cognitive decline, epilepsy including non-epileptic seizures, alzheimer-like senile dementia (AD), Parkinson's Disease (PD), Attention Deficit Hyperactivity Disorder (ADHD), and tourette's syndrome.

Accordingly, the pharmaceutical formulations and methods described herein containing compound 1 can be used to prepare medicaments for the above-mentioned therapeutic applications.

A therapeutically effective amount of the prepared medicament may be administered to a human in need of such treatment or prevention. The term "therapeutically effective amount" as used herein refers to an amount of active ingredient that is capable of inhibiting or preventing the various pathological conditions referred to above, or the symptoms and sequelae thereof. The term "inhibit" refers to preventing, treating, ameliorating, stopping, suppressing, slowing the progression of, reversing, or alleviating the severity of a pathological condition or symptom associated with or resulting from the respective disease being treated. As such, the pharmaceutical formulations may be used for therapeutic (acute or chronic) and/or prophylactic (prophylactic) administration as appropriate. The dosage, frequency and duration will vary with such factors as the nature and severity of the disease being treated, the age and general health of the host, and the degree of tolerance of the host to the active ingredient. The pharmaceutical composition or medicament may be administered in a single daily dose, multiple doses, daily or even weekly. The regimen may last from about 2-3 days to several weeks or more. Generally, the composition is administered to a human patient once or twice daily in a unit dose of about 0.25mg to about 10.0mg, and the above dose may be appropriately changed depending on the age, body weight and medical condition of the patient and the type of administration.

The following examples are for illustrative purposes and are not to be construed as limiting the scope of the invention.

The substances used in the examples listed below can be prepared or obtained from corresponding sources:

compound 1 (L-tartrate) may be prepared by the methods described in patent application WO9935131a1 or WO0162736a1, which are incorporated herein by reference.

Microcrystalline cellulose (Avicel)^TMPH200) was obtained from FMC Pharmaceutical (philiadelphia, PA).

Mannitol (granule 2080) was purchased from SPI Polyols, Inc (New Castle, DE).

Anhydrous dibasic calcium phosphate (A-tab)^TM) Purchased from Rhodia Inc.

Croscarmellose sodium (Ac-Di-SoI)^TM) Purchased from FMC BioPolymer (Philadelphia, PA).

Sodium starch glycolate (Explotab)^TM) From Penwest (Patterson, NJ).

Colloidal silicon dioxide (Cab-O-Sil)^TM) Available from Cabot Corporation (Boston, MA).

Silicified microcrystalline cellulose (ProSolv)^TM) From Penwest (Patterson, NJ).

Hydroxypropyl cellulose (Klucel)^TM) Purchased from Hercules, Inc (Hopewell, VA).

Anhydrous lactose was purchased from Quest International (Norwich, NY).

Magnesium stearate of animal or vegetable origin is purchased from Mallinckrodt (st. louis, MO).

Film coating material Opadry^TMFrom Colorcon, West Point, Pa.).

Cellulose acetate (398-10NF) was purchased from Eastman Chemicals (Kingsport, TN).

Polyethylene glycol (PEG3350) was purchased from Union Carbide Corp (subsidiary of Dow Chemical co., Midland, MI).

Hydroxypropyl methylcellulose (HPMC, K4M, methocel)^TM) Purchased from Dow Chemical co., Midland, MI.

Example 1

Preparation of AMT CR dosage form of L-tartrate salt of 1

A 3kg batch of compressed tablets was prepared as follows: 450g of microcrystalline cellulose and 1602g of dibasic calcium phosphate were mixed in an 8-quart V-blender for 10(f0) minutes. Half of the blend was placed in a polyethylene bag and the remaining half of the blend was left in the mixer. 450g of mannitol and 10.3g of the drug were added to a 1250-cc glass bottle. Using Turbula^TMA mixer (available from Geln Mills inc., Clifton, NJ) blends the mixture. This material was added to a V-blender containing the above material. Additional 450g of mannitol was added to the vial followed by 5 minutes blending using Turbula to rinse out any drug from the vial. The material was then added to the V-blender and the mixture was blended for 20 minutes. The material that had been placed in the polyethylene bag was then added to the V-blender and the mixture blended for an additional 20 minutes. An aliquot of 22.5g magnesium stearate was then added to the V-blender and the mixture blended for 5 minutes. The mixture was rolled using a TF-mini roller compactor (from Vector Corp., Marion, IA) with DSP rollers using a roller pressure of 30kg/cm²The drum speed was 4.0rpm and the screw conveyor speed was 15.6 rpm. The resulting strands were milled at 300rpm using an M5A mill (available from Fitzpatrick corp., Elmhurst, IL) with an 18 mesh Conidur mill screen. The powder was then placed back into the V-blender and 15g of magnesium stearate was added, followed by blending for an additional 5 minutes.

The granules were compressed using a Kilian T100 (available from Kilian & co.inc., Horsham, PA) tablet press using an 9/32 "(11 mm) SRC knife to give 250 mg/tablet tablets (0.5 mgA). The precompression force used was 2.8kN and the main compression force was 8kN, operating at 74rpm, with a feed agitation speed of 20 rpm. The resulting tablets exhibited a hardness of 7-9kp, but no measurable friability.

Tablets were coated by first preparing a coating solution consisting of 538g cellulose acetate and 134.5g PEG dissolved in 4506g acetone and 1547g water. HCT-30EX Hicoater (available from Vector Corp., Marian, IA) was used for coating. A spray rate of 20.0 g/min and an exit temperature of 28 ℃ was maintained until a target coating add-on weight of 27.5% was obtained. The tablets were then pan dried in an oven at 40 ℃ for 24 hours.

Tablets using a USP type II dissolution system (37 ℃, stirred at 50rpm, analyzed by HPLC potency test) showed pH independent dissolution profiles in vitro. The percentage of drug dissolved in the dissolution medium as a function of time is as follows: 2 hours, 1%; 5 hours, 8%; 8 hours, 35%; 10 hours, 52%; 12 hours, 65%; 16 hours, 81%; 24 hours, 95%. Thus, the system was transported at 0.03 mg/hour after a 5 hour delay.

Example 2

Results of a clinical trial of nausea with AMT from example 1

In a single clinical dose study with an IR dosage form of 1 in fasting non-smokers, nausea was reported to occur in 50% of subjects (2/4) at the 1mgA dose and in 75% of subjects (3/4) at the 3mgA dose. If a multiple dose study is used, 1mgA per day is well tolerated; however, very uncomfortable persistent nausea (7/12 subjects) occurred with 2 mgA/day, thereby terminating this study arm. In a single dose test on a fed healthy smoker, nausea or related symptoms were reported to occur in 2 of 16 subjects receiving the maximum dose of 2mgA of IR. In contrast, for the AMT dosage forms described above, the 3mgA and 4mgA doses produced similar levels of nausea as observed with the lower dose IR dosage forms (2/16 in each case). The extent of nausea in the multiple dose study using 3mgA AMT tablets was comparable to and significantly better than the results obtained with 1mgAIR tablets administered twice daily.

Example 3

Preparation of AMT CR dosage form of L-tartrate salt of preferred 1

A 7kg batch of compressed tablets was prepared as follows: 1050g of microcrystalline cellulose and 3340g of dibasic calcium phosphate were mixed in a 16-quart V-blender for 20 minutes. To an 8-quart V-blender was added 2450g mannitol and 71.8g of the drug. The mixture was mixed for 30 minutes. The material was added to a 16-quart V-blender (containing the blend from the first blending process) and the mixture blended for 30 minutes (the blend could be used to flush the blender to ensure complete handling). An aliquot of 22.5g magnesium stearate was then added to the V-blender and the mixture blended for 5 minutes. The mixture was rolled using a TF-mini roller compactor with DSP rollers using a roller pressure of 30kg/cm²The drum speed was 4.0rpm and the screw speed was 15rpm, resulting in a bar having a thickness of 0.06-0.08 ". The resulting strands were milled at 300rpm using an M5A mill (available from Fitzpatrick corp., Elmhurst, IL) with an 18 mesh Conidur mill screen. The powder was then placed back into the V-blender and 35g of magnesium stearate was added, followed by blending for an additional 5 minutes.

The granules were compressed using a Kilian T100 (available from Kilian & co.inc., Horsham, PA) tablet press using an 9/32 "(11 mm) SRC knife to give 250 mg/tablet tablets (1.5 mgA). The precompression force used was 1.2kN and the main compression force was 8kN, operating at 74rpm, with a feed agitation speed of 20 rpm. The resulting tablets exhibited a hardness of 5-8kp, but no measurable friability.

Tablets were coated by first preparing a coating solution consisting of 4095g cellulose acetate and 405g PEG dissolved in 30.6kg acetone and 9.9kg water. Coating was carried out using HCT-60EX Hicoater (available from Vector Corp., Marian, IA) for 40,000-48,000 tablets per batch. The spray rate was maintained at 180 g/min and the exit temperature at 27 ℃ until a target coating add-on of 13% was obtained. The tablets were then tray dried in an oven at 40 ℃ for 16 hours.

Tablets using a USP type II dissolution system (37 ℃, stirred at 50rpm, analyzed by HPLC potency test) showed pH independent dissolution profiles in vitro. The percentage of drug dissolved in the dissolution medium as a function of time is as follows: 2 hours, 5%; 5 hours, 30%; 7 hours, 50%; 10 hours, 70%; 12 hours, 80%; 24 hours, 97%. Thus, the system was transported at 0.1 mg/hour after a delay of 2 hours.

Example 4

Preparation of hydrophilic matrix CR dosage forms of L-tartrate salt of 1

HPMC K4M (45.000g) and 50.575g dibasic calcium phosphate were blended in a Turbula bottle for 10 minutes. About 10g of this blend was combined with 3.425g of L-tartrate salt of 3.425g 1 and blended with Turbula for 10 minutes. The remaining powder from the first mixing was then added to the drug containing blend and the mixture was blended with Turbula for 20 minutes. Magnesium stearate (1.000g) was then added and the mixture blended for an additional 3 minutes. Tablets were prepared using a Manesty F-Press (a single punch tablet Press available from Manesty Corporation, Liverpool, UK) employing an 1/4 "SRC cutter. The average tablet weight was 102 mg/tablet, corresponding to 0.5mgA, and the hardness of the tablet was 5 to 7 kp. In vitro dissolution experiments were performed using artificial intestinal fluid (pH6.8) at 37 ℃ using a cage with a sinker on a tablet and paddle rotation at 50 rpm. The amount of drug dissolved over time was determined using the HPLC potency assay and the results are as follows: 2 hours, 59%; 4 hours, 85%; 8 hours, 94%; 16 hours, 97%. Thus, the system was transported at 0.10 mg/hour.

Example 5

1 preparation of L-tartrate hydrophobic matrix CR dosage forms

A mixture of 0.86g of 1 and 42.25g mannitol was passed through a #30 sieve and then blended with Turbula for 2 minutes. Carnauba wax (6.04g) and stearic acid (0.61g) were added to a beaker and melted using a water bath at 90 ℃. Upon mixing, mannitol and the drug blend are added to the melted wax and stearic acid mixture. The warm material was then sieved through a #20 sieve and subsequently allowed to cool overnight. This material was combined with 0.09g of silica and blended with Turbula for 2 minutes. Magnesium stearate (0.17g) was added followed by blending for an additional 0.5 minutes. Blending with Turbula. Tablets were prepared using an F-tablet press employing 5/16 "SRC knives to give a tablet weight of 200mg (2 mgA).

Example 6

Method selection based on tablet stability and production characteristics

This example compares conventional direct compression and wet granulation processes with dry granulation as the preferred processing method. Dry granulation is described using binary and ternary diluent formulations.

Dry granulation:

the following ingredients were added to a bin blender, with the drug dispersed in a layer between the excipients:

	diluent system
			Components	Two elements	Ternary element
1-L-tartrate salt	0.87％	0.57％
			Mannitol	0％	26.02％
Microcrystalline cellulose (PH200)	62.55％	33.33％

Dibasic calcium phosphate	33.33％	33.33％
			Croscarmellose sodium	2.00％	5.00％
Silicon dioxide (colloidal state)	0.50％	0.50％
			Magnesium stearate	0.25％	0.75％
Magnesium stearate	0.50％	0.50％

The mixture was blended for 30 minutes. Magnesium stearate was added to the mixture and then blended for 3 minutes. Using 30kg/cm²Cylinder pressure of 4roller speed at rpm and screw conveyor speed at 15rpm (lubricated blend was rolled into a bar using a TF-Small roller compactor (available from VectorCorp., Marion, IA.). the bar was ground through a 20 mesh screen (vector Rotary Granulator) to produce granules.10 minutes were blended the granules were added to a second portion of magnesium stearate and blended for 3 minutes.A Kilian T100 tablet press (Kilian T100) equipped with a standard round concave punch of 5/16 inches was used&Co., inc., Horsham, PA) the final blend was compressed into 200mg tablets.

Direct compression (comparative method)

Binary diluted formulations (i.e. microcrystalline cellulose and dibasic calcium phosphate) were prepared using the following components:

8.68g of 1-L-tartrate

Microcrystalline cellulose 621.27g

333.30g of dibasic calcium phosphate

Croscarmellose sodium 20.00g

Silica (colloidal state) 5.00g

Two different blends were prepared and are referred to as "excipient pre-blend" and "active ingredient pre-blend". An "excipient preblend" consists of microcrystalline cellulose, silicon dioxide, and croscarmellose sodium. These components were added to a V-blender and blended for 20 minutes. The active ingredient pre-blend consists of the drug and half-dibasic calcium phosphate. The active ingredient pre-blend was added to the V-blender and blended for 30 minutes and let out. Half of the "excipient preblend" was added to an appropriately sized mixer, followed by the addition of the entire "active ingredient preblend" and then blended for 20 minutes. The second portion of dibasic calcium phosphate was added to the empty mixer used to mix the "active ingredient preblend" and mixed for 5 minutes. This portion and a second portion of the "excipient preblend" are added to the mixer containing the active ingredient. The mixture was blended for 20 minutes. To this mixture was added magnesium stearate (5.00g) and then blended for 5 minutes. The final blend was compressed into 200mg tablets using a Kilian T100 tablet press (Kilian & co., inc., Horsham, PA) fitted with an 5/16 inch standard round female punch.

Wet granulation (comparative formulation and Process)

The wet granulation process was evaluated using two different granulating agents, including water and isopropanol. The formulations prepared with each granulating agent are listed below:

granulating agent

Components		Isopropanol (I-propanol)
			1-L-tartrate salt	5.70g	5.70g
Mannitol	255.20g	260.20g
			Silicified microcrystalline cellulose	333.30g	-
Microcrystalline cellulose (PH200)	-	333.30g
			Dibasic calcium phosphate	333.30g	333.30g
Hydroxypropyl cellulose	10.00g	-
			Croscarmellose sodium	50.00g	50.00g
Water (W)	533.30g	-
			Isopropanol (I-propanol)	-	533.30g
Silicon dioxide (colloidal state)	5.00g	5.00g
			Magnesium stearate	7.50g	12.50g

The above inactive ingredients in the formula table were granulated (water or isopropanol) into a high shear mixer and dry mixed for 1 minute at 100rpm impeller speed. Half of the excipient blend was removed from the barrel and the total amount of 1-L-tartrate was added to the mixer and the removed blend was overlaid. The blend was blended at 100rpm for 1 minute. When blending was continued, the granulating agent was added over 1 minute at a chopper speed of 1000rpm and an impeller speed of 300 rpm. The wet granulation was mixed for an additional 15 seconds and then water or isopropanol was added. The wet mass was dried in an oven at 50 ℃ until the moisture was within 1% of the starting value, after which granulation was carried out. The dried granules were milled through a conical mill (Comil, Quadro Engineering, inc., Waterloo, Ontario, Canada) fitted with a 0.050 inch screen and a round-edged impeller set at 1770 rpm. To the granules was added colloidal silica and blended in a V-blender for 20 minutes. Magnesium stearate was added to the blend and blended for 5 minutes. The final blend was compressed into 300mg tablets using a Kilian T100 tablet press (Kilian & co., inc., Horsham, PA) fitted with an 11/32 inch standard round female punch.

The blend homogeneity of direct compression and dry granulation is compared below. The batch used the same incoming drug substance lot number, drug load (0.868%) and tablet size (200 mg). The potency and variability of direct compression versus dry granulation are summarized in table 5-1 below. The effect of dry granulation on the formulation on blend homogeneity was demonstrated by the variability from 8.0% down to 1.8% RSD.

TABLE 6-1

Production method	Dry granulation (binary)	Direct compression
			Percent drug loading	0.868	0.868
Tablet size (mg)	200	200
			Final blend efficacy (mean)	99.2	99.4
Final blend efficacy (% RSD)	1.8	8

The high variability of potency (8% RSD) of the final blend before direct compression into tablets is the basis for selecting dry granulation as the preferred method.

Wet granulation was compared to dry granulation by granulation blend and production characteristics of tablet potency and variability (percent relative standard deviation or% RSD). These batches used the same incoming drug substance lot number, drug load (0.57%) and tablet size (300 mg). The efficacy and variability data for the three granulation methods evaluated herein are summarized in table 6-2 below.

TABLE 6-2

Production methodMethod of	Dry granulation (binary)	Wet granulation with water	Wet granulation with IPO
				Percent drug loading	0.57	0.57	0.57
Tablet size (mg)	300	300	300
				Efficacy of granulation (average value)	91.3	101.3	93.6
Granulation efficacy (% RSD)	4.2	4.0	1.8
				Tablet potency (mean) onset intermediate Final	94.595.096.0	99.0100.899.8	93.796.194.8

Tablet (% RDS) start intermediate end

1.20.41.2

2.50.92.6

2.30.41.0

Granulation and tablet potency values are closest to 100% expected for wet granulation with water as the granulating agent. Dry granulation produces similar production characteristic results as wet granulation using an isopropanol process.

The tablet stability results of 6 weeks storage under accelerated conditions and analysis of the wet granulation process and the dry granulation process by HPLC are summarized in table 6-3 below.

Tables 6 to 3

Production method	Dry granulation (binary)	Wet granulation with water	Wet granulation with IPO
				Percent drug loading	0.57	0.57	0.57
Tablet size (mg)	300	300	300
				Percentage of total impurities after 6 weeks
At 5 deg.C	ND	0.08	0.30
				At 25 ℃/60% RH	ND	NA	NA
At 30 ℃/60% RH	NA	0.10	0.35
				At 40 ℃/75% RH	0	0.12	0.40
At 50 ℃/60% RH	NA	0.20	0.35
				In-process pharmaceutical forms	Without water	Hydrate of calcium and magnesium	Without water

Wet granulation using water as granulating agent was found to be physically unstable due to the transition of 1-L-tartrate from the anhydrous to hydrated state. The hydrate then loses water during the drying stage to form an anhydrous pharmaceutical form. These physical stabilities change during wet granulation and dry granulation using water which helps in the selection of the preferred process. Dry granulation and wet granulation using isopropanol are preferred ways to process the 1-L-tartrate salt. The method of minimizing the total impurity level is dry granulation followed by wet granulation using water, and then followed by wet granulation using isopropanol.

Thus, the most preferred granulation method for preparing 1-L-tartrate tablets based on stability, blend uniformity and production characteristics is dry granulation.

Example 7

Diluent selection based on tablet stability

The diluent used to prepare the 1-L-tartrate tablet is selected based on chemical stability and manufacturing characteristics. These diluents (dibasic calcium phosphate, microcrystalline cellulose and mannitol) were evaluated using the preferred dry granulation method and included two (binary) or three (ternary) diluents in the formulation.

	Diluent
			Components	Dibasic calcium phosphate/MCC/mannitol	MCC/mannitol
1-L-tartrate salt	0.57％	0.57％
			Mannitol	26.02％	42.68％
Microcrystalline cellulose (PH200)	33.33％	50.00％
			Dibasic calcium phosphate	33.33％	0.0％
Croscarmellose sodium	5.00％	5.00％
			Silicon dioxide (colloidal state)	0.50％	0.50％
Magnesium stearate	0.75％	0.75％
			Magnesium stearate	0.50％	0.50％

The tablet stability, prepared by a dry granulation process using a ternary or binary (without dibasic calcium phosphate) formulation, stored under accelerated conditions for 3 months and analyzed by HPLC, is summarized in table 7-1 below.

TABLE 7-1

Production method	Dry granulation (ternary)	Dry granulation (binary MCC/mannitol-calcium phosphate dibasic free)
			Percent drug loading	0.57	0.57
Tablet size (mg)	300	300
			Total impurity percentage after 6 weeks/3 months:
at 5 deg.C	ND/0	0/0.05
			At 25 ℃/60% RH	ND/0	NA
At 30 ℃/60% RH	NA	0.13/0.12
			At 40 ℃/75% RH	0/0.10	0.28/0.34
At 50 ℃/20% RH	NA	0.23/0.58

NA indicates no application

ND means not detected

Formulations processed by dry granulation that minimize total impurity levels employ calcium phosphate dibasic. Preferred formulations prepared by dry granulation contain a dibasic or tribasic diluent of calcium phosphate dibasic, microcrystalline cellulose and mannitol. The most preferred formulation prepared by dry granulation contains dibasic calcium phosphate as one of the primary diluents.

The results of tablet stability under accelerated conditions for the three binary and ternary diluent formulations prepared using the preferred dry granulation process, stored for 6-12 weeks and analyzed by HPLC, are summarized in table 7-2 below.

TABLE 7-2

Binary diluent	MCC/dibasic calcium phosphate	Mannitol/dibasic calcium phosphate	Lactose/dibasic calcium phosphate	Ternary (dibasic calcium phosphate/MCC/mannitol)
					Percentage of drug	0.86	0.86	0.86	0.86
Tablet size (mg)	200	200	200	300
					Total impurity percentage after 6 and 12 weeks:
at 5 ℃/75% RH	0/0	0/0	0/NA	0/0
					At 30 ℃/60% RH	0.1/0.1	0/0	0.2/NA	0.1/0.1
At 40 ℃/75% RH	0.1/0.3	0.1/0.2	2.6/NA	0.1/0.3
					At 50 ℃/20% RH	0.2/0.3	0.1/0.2	1.3/NA	0.2/0.3

The lactose/dibasic calcium phosphate binary diluent formulation was found to be less stable under accelerated temperature/humidity conditions. The microcrystalline cellulose/dibasic calcium phosphate and mannitol/dibasic calcium phosphate binary tablets exhibited similar total impurity levels as the original ternary formulation, as shown in table 7-2. Accordingly, tribasic and MCC/dibasic calcium phosphate and mannitol/dibasic calcium phosphate systems are preferred embodiments of the present invention.

Example 8

Diluent selection based on tablet production characteristics and content uniformity

The two binary formulations listed in example 7 (MCC/dibasic calcium phosphate and mannitol/dibasic calcium phosphate) are suitable formulations of 1-L-tartrate based on chemical stability alone. To select a more preferred composition, production evaluations were performed using a Kilian T-100 tablet press with 3 configurations of 5/16 inch SRC knives. Tablets were compressed at 4, 8, 12, 16 and 20kN forces and tested for tablet weight, thickness, hardness, disintegration time and% friability under each condition. These data are listed in Table 8-1 below.

TABLE 8-1

Batch number	Suppression power (kN)	Tablet weight (mg)	Thickness (inch)	Hardness (kP)	Disintegration time (minutes: seconds)	Brittleness (%)
							Mannitol/dibasic calcium phosphate	4.53	199.8	0.150	＜1	00:17	35.48％(a)
7.91	200.7	0.146	1.81	00:21	0.59％
						11.65		200.1	0.141	2.73	00:19	0.34％
16.32	200.8	0.138	2.71	00:16	1.20％(b)
						19.69		201.0	0.136	2.88	00:20	100％(c)
MCC/dibasic calcium phosphate	3.94	201.5	0.156	＜1	00:04								100％(d)
						7.89	201.8	0.146	3.05	00:09	0.21％
	11.51	202.0	0.139	4.84	00:12							0.11％
						16.08	202.7	0.136	7.17	00:23	0.14％
	17.56	201.5	0.135	7.91	00:13							0.067％

(a) Both tablets were broken up completely after testing.

(b) Two tablets capped during the test.

(c) All tablets capped during the test.

(d) All tablets were broken during the test.

The mannitol/dibasic calcium phosphate binary formulation showed severe capping problems and could not be compressed to hardness above 3kP, whereas the target range of such processing sizes was 6-9 kP. At these hardnesses, tablets based on high friability% (less than 0.2% is required) have poor mechanical integrity. MCC/dibasic calcium phosphate binary tablets, on the other hand, yield hardness and friability values within the targeted range. Thus, a more preferred binary formulation based on production evaluation is microcrystalline cellulose/calcium dibasic phosphate. Ternary formulations are preferred formulations based on stability and manufacturing characteristics and are also embodiments of the present invention.

Example 9

Disintegrant selection based on tablet stability

Tablets containing Sodium Starch Glycolate (SSG) as disintegrant were analyzed for purity and compared to tablets containing Croscarmellose Sodium (CS). The tablets were placed into 60cc HDPE/HIS bottles at 5 ℃/75% RH, 40 ℃/75% RH and 50 ℃/20% RH for analysis at 6 and 12 weeks. The purity results at 6 weeks and 12 weeks are shown in Table 9-1.

TABLE 9-1

Stability ofCondition	Time of acquisition	Croscarmellose sodium	Sodium starch glycolate
				5℃/75％RH	6 weeks and 12 weeks	0％0％	0.3％0.3％
40℃/75％RH	6 weeks and 12 weeks	0.1％0.3％	0.6％0.9％
				50℃/20％RH	6 weeks and 12 weeks	0.2％0.3％	0.9％1.1％

The degradation of the SSG tablets (0.3-1.1%) is greater than that observed for CS as a disintegrant. When lactose is not present in the tablets, these CS-containing tablets never show more than 0.3% overall degradation at any condition of 6 or 12 weeks. For this reason, croscarmellose sodium has been chosen as a more desirable disintegrant for 1-L-tartrate tablets based on improved chemical stability compared to sodium starch glycolate.

Example 10

Flow aid incorporated to reduce cohesiveness of blends

In this case, the effect of adding the glidant colloidal silicon dioxide to the tablet on the characteristic flowability was evaluated using a standard powder disintegration test. For this evaluation, a binary formulation placebo was used with a drug load below 1%. This formulation is listed in Table 10-1. These tablets were prepared by dry granulation as described in example 6.

TABLE 10-1

Components	Content of glidant
			0％	0.5％
	Microcrystalline cellulose (PH200)	63.42％			62.92％
Dibasic calcium phosphate			33.33％	33.33％
	Croscarmellose sodium	2.00％			2.00％
Silicon dioxide (colloidal state)			0.0％	0.50％
	Magnesium stearate	0.75％			0.75％
Magnesium stearate			0.50％	0.50％

The blend and granules were sampled for analysis immediately prior to each lubrication step. Cohesiveness, flow variability and particle size were evaluated and the results are shown in table 10-2. The particle sizes of the two batches of granules are very similar and therefore should not have an influence on the powder disintegration results. The presence of silica improves cohesiveness and flow variability. Its addition reduces the cohesiveness of the blend from a ' low ' to a ' very low ' grade and the cohesiveness of the granules from a high ' to a ' low ' grade. The presence of 0.50% silica also reduced the level of flow variability of the particles from medium to low.

TABLE 10-2

Characteristics of	0.5% silica blend		0.5% silica particles		0% silica blend		0% silica particles
									Adhesion Property	3.9	Very low adhesion	4.5	Low adhesion	4.5	Low adhesion	6.1	High adhesion
Variability of flow	40.7	Moderate flow variability	31.1	Low variability of flow	41.0	Moderate flow variability	41.1	Moderate flow variability
									D[4，3]	191.5μm		161.0μm		155.5μm		160.5μm

During the tabletting process, the ejection force was monitored as a function of pressure. Tables 10-3 list the ejection forces generated by pressures in the 5-20kN range for 0 and 0.5% silica formulations.

Tables 10-3

Pressure (kN)	0％	0.5％
			Jetting force (N)	Jetting force (N)
	6.38.912.214.318.6	29.5627.4725.8821.0821.56
5.79.111.415.018.6				16.6425.4022.5819.9723.56

Tablets containing 0.50% Cab-O-Sil over most of this pressure range exhibited slightly lower ejection forces. 1-L-tartrate tablets containing glidants are considered to be a more preferred formulation based on the positive characteristics of cohesiveness, flow variability and reduced ejection force.

Example 11

Basal dry tablet stabilityFilm coating material selection of

The preferred white film coating material for the 1-L-tartrate tablet is selected based on chemical stability using accelerated attack conditions. 4 Opadry white film coating systems were used on one of the more preferred dry granulated tablets.

The tablet cores were prepared using a geometric dilution blending protocol prior to roller compaction and contained the following ingredients:

10.62g of 1-L-tartrate

Microcrystalline cellulose 744.42g

399.96g of dibasic calcium phosphate

Cross-linked sodium carboxymethyl cellulose 24.00g

Silica (colloidal state) 6.00g

Magnesium stearate 9.00g

Magnesium stearate 6.00g

Two different blends were prepared and are referred to as "excipient pre-blend" and "active ingredient pre-blend". An "excipient preblend" consists of microcrystalline cellulose, silicon dioxide, and croscarmellose sodium. These components were added to a V-blender and blended for 20 minutes. The "active ingredient pre-blend" consists of the drug and half-dibasic calcium phosphate. The "active ingredient pre-blend ingredients" were added to the V-blender and blended for 30 minutes and let out. Half of the "excipient preblend" was added to an appropriately sized mixer, followed by the addition of the entire "active ingredient preblend" and then blended for 20 minutes. The second portion of dibasic calcium phosphate was added to the empty mixer used to mix the "active ingredient preblend" and blended for 5 minutes. Pre-mixing the fraction with a second fraction of excipientBlend "is added to the mixer containing the active ingredient. The mixture was blended for 20 minutes. To this mixture a first portion of magnesium stearate was added and then blended for 5 minutes. Using 30kg/cm²Roller pressure of 4rpm, Roller speed of 4rpm and screw conveyor speed of 15rpm (Vector TF Mini Roller compressor) the lubricated blend was rolled into a bar. The strands were ground through a 20 mesh screen (Vector Rotary Granulator) to produce granules. The granules were blended for 10 minutes. A second portion of magnesium stearate was added to the granules and blended for 5 minutes. Kilian T100 tablet press (Kilian) fitted with a standard round female punch of 5/16 inches was used&Co., inc., Horsham, PA) the final blend was compressed into 200mg tablets.

The qualitative composition of the 4 coating systems is presented in Table 11-1. The coating composition listed as batch a consisted of lactose, hydroxypropylmethyl cellulose or HPMC, titanium dioxide and triacetin. The main difference between the lactose-free coating systems B-D is the polymer type (hydroxypropylmethylcellulose or HPMC versus polyvinyl alcohol or PVA) and the plasticizer type (polyethylene glycol or PEG and triacetin). The PVA coating layer also contains talc. The final dosage form was coated to contain 4 wt% of the white coating layer and 0.5 wt% of the clear coating layer. The film coated tablets were placed into 60ccHDPE/HIS bottles and challenged at 5 ℃ and 70 ℃/75% RH for 10 days and then evaluated for purity. Uncoated tablet cores were also evaluated for comparison. Placebo tablets were prepared and analyzed for purity at the starting time point as a control. Purity results are shown in Table 11-2.

TABLE 11-1

Coating batch number	Coating composition
		A	LactoseMonohydrate hydroxypropyl methylcellulose titanium dioxide triacetin
B	Hydroxypropyl methylcellulose titanium dioxide triacetin
		C	Hydroxypropyl methylcellulose titanium dioxide polyethylene glycol
D	Polyvinyl alcohol titanium dioxide polyethylene glycol talc

Lactose-free film-coated tablets containing HPMC (B and C) were found to be chemically more stable than lactose/HPMC (a) or pva (d) film-coated tablets. The total degradation rates of HPMC batches were found to be 0.4-1.2% and 0.5-1.0% for PEG and triacetin as plasticizers, respectively. At the same time, the total degradation rates of the lactose control and PVA batches were as high as 3.5% and 2.9%, respectively. The preferred film coating layers in formulations B and C are believed to consist of HPMC, titanium dioxide, and triacetin or PEG, respectively, based on improved chemical stability.

TABLE 11-2

Determination of film coating	Placebo	Uncoated tablets	A	B	C	D
							At 5 deg.C	0.0*	0.00	0.44	0.41	0.52	0.06
At 70 ℃/75% RH	NA	1.07	3.54	1.29	0.96	2.95

Indicates that the analysis was performed only at the initial time point

Example 12

Method-content uniformity of Dry granulation

This example demonstrates a more preferred blending method to achieve blend and tablet efficacy and uniformity. V-blending (with and without geometric dilution), bin blending (with and without baffles and rotation of straight line versus angle of rotation), and high shear blending were evaluated. The formulation consists of a binary diluent system of dibasic calcium phosphate and microcrystalline cellulose, as follows:

composition (I)	By weight%
		1-L-tartrate salt	0.885
Microcrystalline cellulose (PH200)	62.035
		Second generation calcium phosphate (A-Tab)	33.330
Croscarmellose sodium	2.00
		Silicon dioxide (colloidal state)	0.50
Magnesium stearate	0.75
		Magnesium stearate	0.50

V-blending using geometric dilution

The formulation and method for the tablet core are described as provided in example 11.

V-blending in a single step

Blending 3 the mixture (without lubricant)And 0 minute. To this mixture a first portion of magnesium stearate was added and then blended for 5 minutes. Using 30kg/cm²Roller pressure of 4rpm, roller speed of 4rpm and screw conveyor speed of 15rpm (Vector TF Mini roller compressor) the lubricated blend was rolled into a bar. The strands were ground through a 20 mesh screen (Vector Rotary Granulator) to produce granules. The granules were blended for 10 minutes. A second portion of magnesium stearate was added to the granules and blended for 5 minutes. Kilian T100 tablet press (Kilian) fitted with a standard round female punch of 5/16 inches was used&Co., inc., Horsham, PA) the final blend was compressed into 200mg tablets.

Blending in silo

The components (without lubricant) were added to a bin mixer with the drug dispersed in the middle layer. The mixer configuration (with and without the use of baffles and linear pair rotation angles) was set. The mixture was blended for 30 minutes. To this mixture a first portion of magnesium stearate was added and then blended for 5 minutes. Using 30kg/cm²Roller pressure of 4rpm, Roller speed of 4rpm and screw conveyor speed of 15rpm (Vector TF Mini Roller compressor) the lubricated blend was rolled into a bar. The noodles were ground through a 20 mesh screen (vector rotary granulator) to produce granules. The granules were blended for 10 minutes. A second portion of magnesium stearate was added to the granules and blended for 5 minutes. Kilian T100 tablet press (Kilian) fitted with a standard round female punch of 5/16 inches was used&Co., inc., Horsham, PA) the final blend was compressed into 200mg tablets.

High shear blending

The components (without lubricant) were added to a high shear mixer with the drug dispersed in the middle layer. The mixture was blended for 10 minutes at an impeller speed of 200rpm and a chopper speed of 0 rpm. The first portion of lubricant was added and blended for 5 minutes. Using 30kg/cm²Roller pressure of (3), roller speed of 4rpm and screw conveyor speed of 15 rpm: (Vector TF mini roller compressor) the lubricated blend was rolled into a bar. The noodles were ground through a 20 mesh screen (vector rotary granulator) to produce granules. The granules were blended in a V-blender for 10 minutes. A second portion of magnesium stearate was added to the granules and blended for 5 minutes. Kilian T100 tablet press (Kilian) fitted with a standard round female punch of 5/16 inches was used&Co., inc., Horsham, PA) the final blend was compressed into 200mg tablets.

The efficacy and uniformity results for the granules and tablets are listed in Table 12-1. The single step V-blending and high shear blending process minimizes the efficacy value of the particles. The more preferred blending methods are blending using geometric dilution and bin blending using arbitrarily configured baffles and rotation based on the particle and tablet potency and uniformity results. High shear mixers operating at low impeller speeds (low to moderate shear on the mixer) are also more preferred embodiments of the present invention.

TABLE 12-1

Blending process	Granules		Tablet formulation
					Efficacy	％RSD	Efficacy	％RSD
	Make itV-blending with geometric dilution	98.3	0.3	98.8					0.8
V-blending in a single step					94.5	7.3	103.4	1.2
	Blending in a bin mode; no baffle, rotating linearly	99.1	1.2	101.7					0.8
Blending in a bin mode; with baffles, rotating linearly					100.3	0.7	102.7	1.4
	Blending in a bin mode; with baffles, angular rotation	98.3	1.0	102.1					0.6
High shear blending					91.1	0.4	96.2	2.3

Example 13

Diluent selection based on particle content uniformity

The preferred diluent for the geometric dilution blending method in the "active ingredient pre-blend" is selected based on the granule and tablet potency and uniformity. The carrier excipient characteristics of the combination of the two primary diluents (dibasic calcium phosphate and mannitol) in the adjuvant formulation were studied. The components and concentrations for the ternary tablets (same composition as in example 7) were blended according to the geometric dilution scheme described in example 11. Half of the mannitol (13A) or dibasic calcium phosphate (13B) was used in the "active ingredient preblend". In this example, the drug was jet pulverized to about half the original particle size, and thereafter processed using excipients.

	Diluent in "active ingredient preblend
			Components	Mannitol (13A)	Second generation calcium phosphate (13B)
1-L-tartrate (jet-milled)	0.86％	0.86％
			Mannitol	25.95％	25.95％
Microcrystalline cellulose (PH200)	33.22％	33.22％
			Second generation calcium phosphate (A-Tab)	33.22％	33.22％
Croscarmellose sodium	5.00％	5.00％
			Silicon dioxide (colloidal state)	0.50％	0.50％
Magnesium stearate	0.75％	0.75％
			Magnesium stearate	0.50％	0.50％

For each tablet, two were preparedDifferent blends are known as "excipient pre-blend" and "active ingredient pre-blend". An "excipient preblend" consists of microcrystalline cellulose, silicon dioxide, croscarmellose sodium, and dibasic calcium phosphate or mannitol. These components were added to a V-blender and blended for 20 minutes. The active ingredient pre-blend consists of the drug and about half of mannitol (12A) or dibasic calcium phosphate (12B). The "active ingredient pre-blend" components were added to the V-blender and blended for 30 minutes and let out. Half of the "excipient preblend" was added to an appropriately sized mixer, followed by the addition of the entire "active ingredient preblend" and then blended for 20 minutes. To the empty mixer used to mix the "active ingredient pre-blend" was added a second portion of mannitol or dibasic calcium phosphate and blended for 5 minutes. This portion and a second portion of the "excipient preblend" are added to the mixer containing the active ingredient. The mixture was blended for 20 minutes. To this mixture a first portion of magnesium stearate was added and then blended for 5 minutes. Using 30kg/cm²Roller pressure of 4rpm, roller speed of 4rpm and screw conveyor speed of 15rpm (vector TF mini roller compressor) the lubricated blend was rolled into a bar. The noodles were ground through a 20 mesh screen (vector rotary granulator) to produce granules. A second portion of magnesium stearate was added to the granules and blended for 5 minutes. Kilian T100 tablet press (Kilian) fitted with a standard round female punch of 11/32 inches was used&Co., inc., Horsham, PA) the final blend was compressed into 300mg tablets. The results of the potency and variability (expressed as% RSD) of the final granules and tablets are listed in table 13-1.

TABLE 13-1

Carrier vehicle	13A	13B
			Granular mannitol 2080	Anhydrous dibasic calcium phosphate
	Efficacy of the particles	In total: 95.9% RSD: 0.2 percent of			In total: 96.3% RSD: 1.0 percent
Tablet efficacy			In total: 95.1% RSD: 2.4 percent of	In total: 97.2% RSD: 0.8 percent

The potency values for the granules were similar for mannitol and calcium phosphate "active ingredient pre-blend" diluents. However, when dibasic calcium phosphate was used instead of mannitol as the "active ingredient preblend" diluent used in the geometric dilution blending method, the efficacy value of the tablets increased from 95.1% to 97.2%. Thus, a more preferred diluent for the "active ingredient pre-blend" used in the geometric dilution blending process is calcium dibasic phosphate.

Claims (15)

1. Controlled release dosage forms suitable for administration to a subject comprising 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadec-2 (11)3, 5, 7, 9-pentaene or a pharmaceutically acceptable salt thereof and means for administering said compound or salt to said subject at a rate of less than about 6 mg/hour, whereby at least about 0.1mg of said compound or pharmaceutically acceptable salt thereof is administered over a 24 hour period.

2. The controlled release dosage form of claim 1, wherein the means for administering the compound or pharmaceutically acceptable salt thereof comprises a matrix tablet, multiparticulates, or coated multiparticulates.

3. The controlled release dosage form of claim 2, wherein the matrix tablet or multiparticulates comprise a hydrophilic matrix.

4. The controlled release dosage form of claim 1, wherein the means for administering the compound or pharmaceutically acceptable salt thereof comprises a coated tablet.

5. The controlled release dosage form of claim 1, wherein the pharmaceutically acceptable salt is L-tartrate or citrate.

6. The controlled release dosage form of claim 1, wherein the subject is a human.

7. Controlled release dosage forms suitable for administration to a subject comprising 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadeca-2 (11)3, 5, 7, 9-pentaene, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which dosage form, when administered to said subject, provides a maximum plasma concentration (C) of said pentaene during initial administration to said subject_max) Average is the corresponding C determined for a medium dose of said pentaene in an immediate release bolus dosage form_max10-80% of the total weight of the composition.

8. Controlled release dosage forms suitable for administration to a subject comprising 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadec-2 (11)3, 5, 7, 9-pentaene or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, when administered to said subject, provides a time (T) for said drug to reach maximum plasma concentration during initial administration to said subject_max) Comparing the corresponding T determined for an equivalent dose of the pentaene in an immediate release bolus dosage form_maxMean increase of 50％。

9. Controlled release dosage forms suitable for administration to a subject comprising 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadeca-2 (11)3, 5, 7, 9-pentaene or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form releases said pentaene in vitro at a rate of less than 6 mgA/hr when subjected to a dissolution test using a USP-2 apparatus, such that 50 w/w% of said drug substance has a dissolution time of about 1 to 15 hours.

10. An immediate release dosage form suitable for administration to a subject comprising a compound containing 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadec-2 (11)3, 5, 7, 9-pentaene or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the total concentration of reducing sugars is less than 20 wt%.

11. The immediate release dosage form of claim 10, wherein the excipient comprises about 77 w/w% to about 91 w/w% and is selected from the group consisting of mannitol, xylitol, sorbitol, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers such as polyethylene oxide, and hydroxypropylmethylcellulose.

12. The immediate release dosage form of claim 10, wherein the excipients are mannitol, dibasic calcium phosphate and microcrystalline cellulose.

13. To a subject in need thereof 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadec-2 (11)3, 5, 7, 9-pentaene or a pharmaceutically acceptable salt thereof, said method comprising: administering in a first phase a controlled release dosage form comprising said compound or pharmaceutically acceptable salt thereof and means for administering said compound or pharmaceutically acceptable salt thereof, such that said compound or pharmaceutically acceptable salt thereof(ii) releases the pharmaceutically acceptable salt into the subject at a rate of less than about 6 mg/hour, thereby administering at least about 0.1mg of the compound or pharmaceutically acceptable salt thereof over a 24 hour period after administration of a group dose; and administering in a second phase an immediate release dosage form comprising a drug core containing said compound or a pharmaceutically acceptable salt thereof; wherein said first phase comprises a period of about 1 day to about 30 days and a second phase is initiated after said first phase.

14. A method for reducing nicotine addiction in a subject or aiding in the cessation or reduction of tobacco use, comprising administering to said subject an amount of the controlled release dosage form of claim 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, or 12, wherein said amount is effective to reduce nicotine addiction or aid in the cessation or reduction of tobacco use.

15. A method of treating a disease or disorder in a subject in need thereof according to the method comprising administering to the subject the dosage form of claim 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, or 12 in an amount effective to treat such disease or disorder, wherein the disease or disorder is selected from the group consisting of: inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, crohn's disease, irritable bowel syndrome, tonic dystonia, chronic pain, acute pain, sprue, capsulitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, ejaculatory retardation (jetlag), Amyotrophic Lateral Sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmia, hyperacidity, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependence and addiction; nicotine, tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine dependence or addiction; headache, stroke, Traumatic Brain Injury (TBI), Obsessive Compulsive Disorder (OCD), psychosis, huntington's chorea, tardive dyskinesia, hyperkinesia, difficulty reading, schizophrenia, multi-infarct, necrobium dementia, age-related cognitive decline, epilepsy, seizures without seizures, alzheimer-like senile dementia (AD), Parkinson's Disease (PD), Attention Deficit Hyperactivity Disorder (ADHD), and tourette's syndrome.