WO2009027786A2

WO2009027786A2 - Matrix dosage forms of varenicline

Info

Publication number: WO2009027786A2
Application number: PCT/IB2008/002165
Authority: WO
Inventors: Michael B. Fergione; Barbara A. Johnson; Ernest S. Quan; Neha B. Vatsaraj
Original assignee: Pfizer Inc.
Priority date: 2007-08-29
Filing date: 2008-08-18
Publication date: 2009-03-05
Also published as: WO2009027786A3

Abstract

The present invention provides matrix dosage form comprising varenicline or a pharmaceutically acceptable salt thereof, at least one high molecular weight water soluble polymer; and at least one water-insoluble, hydrophilic excipient.

Description

MATRIX DOSAGE FORMS OF VARENICLINE

FIELD OF THE INVENTION

The present invention relates to pharmaceutical dosage formulations for medicinal uses thereof. BACKGROUND ART

Varenicline (1) has the structure:

Varenicline and pharmaceutically acceptable acid addition salts thereof are referred to in PCT International Patent Publication No. WO99/35131 , published July 15, 1999, the contents of which are hereby incorporated herein by reference.

Varenicline binds to neuronal nicotinic acetylcholine specific receptor sites and is useful in modulating cholinergic function. Accordingly, this compound is useful in the treatment of various conditions or diseases including, but not limited to, inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome.

Varenicline is a highly potent compound such that dosage forms are necessarily highly diluted with excipients. The excipients provide dosage forms with adequate stability, while also providing for such desirable features as controlling the drug dissolution (e.g., either fast dissolving or slow dissolving in a controlled-release system as described in co-pending applications U.S. Patent Publication No. 2003-0180360 A1, published Sept. 25, 2003, and U.S. Serial No. 10/848,464, filed May 18, 2004, the contents of which are hereby incorporated by reference in their entirety), masking bad taste, and providing appropriate properties for preparation of the dosage form (i.e., compression properties for tablets). Finally, because of the high dilution with excipients, reactivity of varenicline with the excipients themselves or with trace impurities (i.e., degradants) of the excipients can be especially problematic.

The immediate release (IR) tablet dosage form of varenicline has shown, in some instances, a certain level of nausea in patients. There is a need to reduce these side effects. A gradual release of the varenicline such as would be the case from a controlled release matrix tablet composition might prove to be useful towards reducing the incidence of nausea and enhance the desirability of the drug to a larger patient population requiring its use. Additionally, it is likely there would be a higher compliance rate if a patient had available a controlled release matrix tablet that delivers therapeutically useful levels of active ingredient over the course of a day or a longer period of time rather than taking a tablet twice daily. Accordingly, there is a need for providing matrix tablet controlled release dosage forms of varenicline.

Hydrophilic and hydrophobic controlled release (CR) matrix formulations of varenicline or its pharmaceutically acceptable salts have been disclosed in US Patent Application US 2003/0180360A1 which is hereby incorporated as reference. However, novel hydrophilic matrix controlled release formulations of varenicline and its pharmaceutically acceptable salts are disclosed in this invention. The improved hydrophilic matrix formulations of the present invention differ from US 2003/0180360A1 in that the matrix composition is comprised of a high-molecular weight water soluble gel forming polymer; and a water-insoluble, hydrophilic excipient. The incorporation of the water-insoluble, hydrophilic excipient surprisingly and unexpectedly produces a more preferred, varenicline release profile in humans.

SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical dosage formulation suitable for administration to a subject comprising (a) varenicline, or a pharmaceutically acceptable salt thereof, (b) at least one high-molecular weight water soluble gel forming polymer; and, (c) at least one water- insoluble, hydrophilic excipient. In particular embodiments, the invention provides such a pharmaceutical dosage formulation comprising a matrix tablet. In preferred embodiments of the invention, said pharmaceutically acceptable salt is the tartrate salt.

In the pharmaceutical dosage formulations of the invention, the high molecular weight water soluble gel forming polymer is selected from the group consisting of hydroxypropyl methylcellulose (hypromellose or HPMC), carboxymethylcellulose sodium (carmellose sodium), carbomer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene oxide, hydroxypropyl cellulose (HPC), sodium alginate, and hydroxyethyl cellulose (HEC). In particular embodiments, the high molecular weight water soluble gel forming polymer comprises HPMC. More specifically, the HPMC is preferably selected from the group consisting of hydroxypropyl methylcellulose 2208 USP 100 cps, hydroxypropyl methylcellulose 2208 USP 4,000 cps, hydroxypropyl methylcellulose 2208 USP 15,000 cps, hydroxypropyl methylcellulose 2208 USP 100,000 cps, hydroxypropyl methylcellulose 2910 USP 4,000 cps, hydroxypropyl methylcellulose 2910 USP 10,000 cps, and mixtures thereof. More favorably, the HPMC is hydroxypropyl methylcellulose 2208 USP 4,000 cps. In the pharmaceutical dosage formulations of the invention, the water- insoluble, hydrophilic excipient is selected from the group consisting of microcrystalline cellulose (MCC), silicified microcrystalline cellulose, methyl cellulose, cellulose, starch, pregelatinized starch, direct compressible starch and mixtures thereof. In particular embodiments, the water-insoluble, hydrophilic excipient is microcrystalline cellulose (MCC).

In certain embodiments of the invention, the dosage formulation is a tablet, and has an instant release film coating. The instant-release film coating comprises hypromellose (HPMC), a plasticizer, titanium dioxide and optionally pharmaceutically acceptable colorants.

In other embodiments, the invention provides a controlled release tablet for oral ingestion which comprises: (a) from about 0.1% w/w to about 10% w/w varenicline, or a pharmaceutically acceptable salt thereof; (b) from about 35% w/w to about 70% w/w of a water-insoluble, hydrophilic excipient; and, (c) from about 30% to about 65% w/w of a high molecular weight water soluble gel forming polymer. Preferably, the pharmaceutically acceptable salt of the controlled release tablet is varenicline tartrate; the water-insoluble, hydrophilic excipient is pregelatinized starch or direct compressible starch; and, the high molecular weight water soluble gel forming polymer is hydroxypropyl methylcellulose. More preferably, the pharmaceutically acceptable salt of the controlled release tablet is varenicline tartrate; the water-insoluble, hydrophilic excipient is microcrystalline cellulose; and, the high molecular weight water soluble gel forming polymer is hydroxypropyl methylcellulose. In certain embodiments, the pharmaceutical dosage formulation of the invention exhibits a 40 to 70% reduction in the C_max compared to an immediate release tablet of the same dose when both formulations are given as a single dose after a standardized non-high fat breakfast.

In certain embodiments, the present invention provides such a pharmaceutical dosage formulation, wherein said varenicline is present in an amount from about 0.4 mgA to about 6 mgA per tablet; and, wherein said formulation further comprises a lubricant selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, and sodium fumarate. In particular embodiments, said varenicliπe is present in an amount of about 0.5 to 4.0 mgA, more preferably about 0.5 to 3.5 mgA, and most preferably about 0.5 to 2.5 mgA per tablet; and, the lubricant is magnesium stearate present in an amount of from about 0.2 % w/w to about 2.0% w/w. In other particular embodiments, the magnesium stearate is present in an amount of from about 0.4% w/w to about 1.0% w/w. In certain other embodiments, the formulation further comprises a glidant selected from colloidal silicon dioxide and talc. In particular embodiments, the glidant is colloidal silicon dioxide present in an amount of from about 0.2% w/w to about 1.0% w/w. In certain particular embodiments, the formulation when in the form of a tablet has a tablet core of about 100, 200 or 400 mg in total weight.

The present invention further relates to a pharmaceutical dosage formulation as described above, having the following dissolution profile when tested in 900 ml of 0.01 N HCI, using a USP Type I apparatus at 100 rpm at 37° C with sinkers: (a) from about 15 % to about 60% of said varenicline is released after 2.0 hour; (b) from about 35 to about 85% thereof is released after 5.0 hours; (c) from about 45% to about 95% thereof is released after 8.0 hours; (d) not less than about 50% thereof is released after 12.0 hours; and, (f) not less than about 70% thereof is released after 24.0 hours.

The present invention further relates to a pharmaceutical dosage formulation as described above, having the following dissolution profile when tested in 900 ml of 0.01 N HCI, using a USP Type I apparatus at 100 rpm at 37° C with sinkers: (a) from about 25% to about 55% of said varenicline is released after 2.0 hour; (b) from about 45% to about 80% thereof is released after 5.0 hours; (c) from about 60 to about 95% thereof is released after 8.0 hours; (d) not less than about 65% thereof is released after 12.0 hours; and, (f) not less than about 85% thereof is released after 24.0 hours In particular embodiments, the following blood level concentrations of varenicline are present when administered as a single dose of two 200mg weight tablets comprising 1.OmgA, wherein said tablets are administered after a standardized non-high fat breakfast: (a) from about 0 ng/ml to about 4 ng/ml of varenicline after 1.5 hours; (b) from about 2 ng/ml to about 8ng/ml thereof from 4.0 to 12.0 hours; (c) from about 1.5 ng/ml to about 6.5 ng/ml thereof after 16.0 hours; and, (d) from about 0.5 ng/ml to about 4.5 ng/ml thereof after 24.0 hours. In other particular embodiments, the following blood level concentrations of varenicline are present when administered as a single dose of two 400mg weight tablets comprising 1.0 mgA of varenicline, wherein said tablets are administered after a standardized non-high fat breakfast: (a) from about 0 ng/ml to about 3 ng/ml of varenicline after 1.5 hours; (b) from about 1.5 ng/nl to about 6.5 ng/ml of varenicline from about 4.0 to about 14.0 hours; and, (c) from about 0.5 ng/ml to about 4.5 ng/ml of varenicline after 24.0 hours.

The present invention also provides a controlled release tablet comprising an admixture of varenicline, or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose and microcrystalline cellulose, varenicline being present at a strength of about 0.5 mgA to about 5 mgA, in a 200 mg tablet made from 5/16" standard round concave (SRC) tooling having a surface to volume ratio of about 0.9 mm^"1 to about 1.1 mm^"1. In certain embodiments, the controlled release tablet according to the invention comprises an admixture of varenicline, or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose and microcrystalline cellulose, varenicline being present at a strength of about 0.5 mgA to about 5 mgA, in a 400 mg tablet made from 13/32" standard round concave (SRC) tooling having a surface to volume ratio of about 0.65 mm^"1 to about 0.85 mm^"1. In certain particular embodiments, the invention provides a controlled controlled release tablet comprising an admixture of varenicline, or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose and microcrystalline cellulose, varenicline being present at a strength of 0.5 to 5 mgA, in a 100 mg tablet made from 1/4" standard round concave (SRC) tooling having a surface to volume ratio of about 1.1 mm^"1 to about 1.3 mm^"1. The present invention also further provides a combination IR/CR tablet of varenicline or its pharmaceutically acceptable salts. A multilayered IR/CR tablet that includes a matrix layer is well known in the art as exemplified by US 5,681,583. The present invention further provides a method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a subject, comprising administering to said subject an amount of any of the pharmaceutical dosage formulations described herein that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use. Preferably, the method is practiced wherein said pharmaceutical dosage formulation comprises an L- tartrate salt.

Also provided is a method for treating a disorder or condition selected from inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, Crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions; dependencies on, or addictions to, nicotine, tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine; headache, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age related cognitive decline, epilepsy, petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD)₁ attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a subject in need of such treatment, comprising administering to the subject an amount of any of the pharmaceutical dosage formulations described herein that is effective in treating such disorder or condition. Preferably, the method is practiced wherein said pharmaceutical dosage formulation comprises an L- tartrate salt. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "varenicline" means the drug that binds to neuronal nicotinic acetylcholine specific receptor sites, and is useful in modulating cholinergic function. Varenicline has the general formula 1. Varenicline includes the parent drug and all pharmaceutically acceptable salts and prodrugs thereof. The parent drug varenicline is described in International Patent Publication WO 99/35131 , published July 15, 1999, the contents of which are incorporated herein by reference in their entirety. Varenicline or any of its pharmaceutically acceptable salts, solvates and/or hydrates can be used. Procedures for making varenicline are described in U.S. Patent No. 6,410,550, the contents of which are incorporated herein by reference in their entirety.

As used herein, the term "controlled-release" (CR) refers to dosage forms which when taken orally slowly release or deliver the drug to the gastrointestinal (Gl) system at a rate such that at least some of the drug is unavailable in the first hour in the fed or fasted state. A CR system can provide the drug at a constant rate (zero order), at a steadily decreasing rate (first order) or an uneven or pulsatile rate. The drug delivery can also involve a lag time in initial drug release. In many cases it is convenient to measure an in vitro dissolution curve for a dosage form. Measuring such dissolution characteristics are well-known in the art and in many cases will correlate with the in vivo behavior.

An "immediate-release" (IR) dosage form refers to a dosage form which when taken orally substantially provides the drug in a form available to be absorbed within about one hour. An example of this is Chantix™ (varenicline) tablets.

A "matrix" system refers to a particular CR dosage form where the drug is admixed with excipients, often in compressed or extruded form, such that the release of the drug from the dosage form is controlled by a combination of erosion and diffusion. Erosional control of drug delivery involves the slow removal of the matrix material by the Gl fluids to gradually expose and release the drug from the matrix. Diffusional control of drug delivery involves diffusion of soluble drug through the network of matrix excipients in a controlled fashion. In practice, many matrix dosage forms involve some degree of combination of the two mechanisms. An IR/CR dosage form is one wherein a portion of the active is released within one hour and the rest of the active is released in a controlled fashion. There are several methods known in the art that can accomplish this. One such method is a bi layer tablet wherein one layer consists of a controlled release formulation and the other layer consists of an immediate release formulation.

The term "mgA" refers to the number of milligrams of active drug based on the free base form of the drug.

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

The term "pharmaceutically acceptable salt" means non-toxic acid addition salts derived from inorganic and organic acids. Suitable salt derivatives include, but are not limited to, halides, thiocyanates, sulfates, bisulfates, sulfites, bisulfites, arylsulfonates, alkylsulfates, phosphonates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphonates, alkanoates, cycloalkylalkanoates, arylalkonates, adipates, alginates, aspartates, benzoates, fumarates, glucoheptanoates, glycerophosphates, lactates, maleates, nicotinates, oxalates, palmitates, pectinates, picrates, pivalates, succinates, tartarates, citrates, camphorates, camphorsulfonates, digluconates, trifluoroacetates, and the like.

The term "active ingredient" means the therapeutically active compound, varenicline, as well as any prodrugs thereof and pharmaceutically acceptable salts, hydrates, and solvates of the compound and the prodrugs. The term "ingredients" means any excipients, diluents, solvents, permeation enhancer, preservatives, buffers, gel forming agents, lubricants, glidants, carriers, stabilizers, gels, dyes, pigments, surfactants, inert fillers, tackifiers, texturizers, softeners, emulsifiers, and mixtures thereof that are formulated with varenicline or any pharmaceutically acceptable salts, hydrates, and solvates of this drug. The term "appropriate period of time" or "suitable period of time" means the period of time necessary to achieve a desired effect or result. For example, a mixture can be blended until a potency distribution is reached that is within an acceptable range for a given application or use of the blended mixture. The term "unit dose," "unit dosage," or "unit dosage form" means a physically discrete unit that contains a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect.

The term "effective amount," as used herein means the amount determined by such considerations as are known in the art of reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in an individual, wherein it must be effective to provide measurable relief in treated individuals such as exhibiting improvements including, but not limited to, more rapid recovery, improvement or elimination of symptoms or reduction of complications, lack of dependency upon nicotine-containing compounds, lack of desire towards nicotine-containing compounds, or other measurements as appropriate and known to those skilled in the medical arts.

Procedures for making compound 1 are described in U.S. Patent No. 6,410,550, the contents of which are hereby incorporated herein by reference. In accordance with the present invention, the CR pharmaceutical compositions of compound 1 can be desirably administered in doses ranging from about 0.1 mgA up to about 6 mgA per day, more preferably from about 0.5 to about 4 mgA/day, and most preferably from about 0.5 to about 3 mgA per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated. Depending on individual responses, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects.

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

A number of means have been found to produce such a varenicline CR system to achieve a sustained rate of drug administration. Examples of such means are set forth in US Patent Application US 2003/0180360A1 , which is hereby incorporated by reference. However, the novel hydrophilic matrix controlled release formulations of varenicline and its pharmaceutically acceptable salts that are disclosed in this invention differ from US 2003/0180360A1 in that the matrix composition is comprised of a high-molecular weight water soluble gel forming polymer; and a water-insoluble, hydrophilic excipient. The incorporation of the water-insoluble, hydrophilic excipient surprisingly and unexpectedly produces a more preferred, varenicline release profile in humans. In particular, a matrix tablet or matrix multiparticulates of compound 1 can be prepared in accordance with this invention. In the case of multiparticulates, the final presentation of the dosage form can be made by adding the particulates to a capsule or providing a sachet or other such presentation. These matrix dosage forms can be formed using traditional techniques such as by compression with a tablet press or by such processes as extrusion/spheronization, roto-granulation or melt congealing. The type of matrix dosage form that is the subject of the present invention and appropriate for compound 1 is hydrophilic.

Formulations useful for the present invention can be prepared using a wide range of materials and processes known in the art. The inventors have found, however, that the presence of reducing carbohydrates is detrimental to the drug stability on storage. In particular, CR formulations with less than 20 % w/w of reducing carbohydrates are preferred; still more preferred are CR formulations with less than 10% w/w reducing carbohydrates; and most prefenred are CR formulations with less than 5% w/w reducing carbohydrates. A particular reducing carbohydrate that is preferably avoided is lactose.

For preparation of the controlled release dosage forms, the active ingredient may be used per se or in the form of its pharmaceutically acceptable salt, solvate and/or hydrate. The active ingredient may be used per se or in the form of its pharmaceutically acceptable salt, solvate and/or hydrate.

The invention provides a CR tablet for oral ingestion which comprises from about 0.1% w/w to about 10% w/w varenicline or a pharmaceutically acceptable salt thereof. Preferred dosage forms contain from about 0.1% w/w to about 7.5% w/w varenicline tartrate. Most preferred dosage forms contain from about 0.1% w/w to about 5% w/w varenicline tartrate.

Mixtures of water soluble, gel forming polymers make up a portion of the matrix in the present invention. These water soluble, gel forming polymers comprise from about 30% to about 65% w/w of the CR tablet for oral ingestion. Preferred percentages contain from about 35% to about 60% w/w of the CR tablet. Most preferred percentages contain from about 40% to about 55% w/w of the CR tablet.

A hydrophilic matrix formulation found to be most suitable for compound 1 in this invention consists of mixtures of high molecular weight water-soluble, gel-forming cellulosic polymers and a water-insoluble, hydrophilic excipient. The high molecular weight water soluble gel forming polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC)₁ carboxymethylcellulose sodium (carmellose sodium), carbomer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene oxide, hydroxypropyl cellulose (HPC), sodium alginate, and hydroxyethyl cellulose (HEC). As used herein, carbomer is classified as a water soluble polymer. As a crosslinked polymer carbomer does not dissolve in water, but swells as described in the Carbomer monograph in Handbook of Pharmaceutical Excipients, fourth edition, R.C. Rowe, P. J. Sheskey and PJ. Weller, eds.; American Pharmaceutical Association 2003, page 90. Wherein the high molecular weight water-soluble, gel-forming polymer consists of hydroxypropyl methylcellulose (HPMC). Preferred HPMC polymers are hydroxypropyl methylcellulose 2208 USP 100 cps, hydroxypropyl methylcellulose 2208 USP 4,000 cps, hydroxypropyl methylcellulose 2208 USP 15,000 cps, hydroxypropyl methylcellulose 2208 USP 100,000 cps, hydroxypropyl methylcellulose 2910 USP 4,000 cps, hydroxypropyl methylcellulose 2910 USP 10,000 cps, and mixtures thereof. A particularly preferred HPMC is hydroxypropyl methylcellulose 2208 USP 4,000 cps. High molecular weight is meant to include those polymers having molecular weights greater than 10,000 daltons.

The water-insoluble, hydrophilic excipient component of the CR matrix comprise from about 35% w/w to about 70% w/w of the CR tablet dosage form. Preferred percentages contain from about 35% to about 60% w/w of the CR tablet. Most preferred percentages contain from about 40% to about 60% w/w of the CR tablet.

The water-insoluble, hydrophilic excipients consist of materials that are not soluble in water, but are hygroscopic. The water-insoluble, hydrophilic excipient is selected from the group consisting of microcrystalline cellulose (MCC), silicified microcrystalline cellulose, methyl cellulose, cellulose, starch, pregelatinized starch, direct compressible starch (Starch DC) and mixtures thereof. A particularly preferred water-insoluble, hydrophilic excipient is MCC.

The varenicline matrix tablet formulations prepared in accordance with the invention used a variety of drug loadings, polymers and diluents. Typically, a lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, and sodium fumarate. Preferably, formulations were formulated using magnesium stearate (animal and vegetable grade from Mallinkrodt Baker, Inc., Phillipsburg, NJ) as the lubricant. When the matrix tablets were made by dry granulation, the magnesium stearate was added both intragranular (IG) and extragranular (EG). Diluents used in the matrix tablet formulation of the invention include insoluble microcrystalline cellulose (Avicel® PH-102, PH-200 FMC Biopolymer, Philadelphia, PA), anhydrous dibasic calcium phosphate and direct compressiblie starch (C^PharmGel DC 93000, Cargill Inc., Hammond, IN). Preferably, formulations were formulated using Avicel PH 102 or PH 200 and most preferably Avicel PH 102. Among the polymers which may be used in the matrix tablets of the invention, favored polymers are selected from the group consisting of hydroxypropyl methylcellulose (hypromellose 2208 USP 4,000 cps as Methocel® K4M Premium CR and hypromellose 2208 USP 100,000 cps as Methocel® K100MP Premium CR, Dow Chemical Company, Midland, Ml), polyethylene oxide (Polyox® Coagulant) and methacrylic polymers (Eudragit® RS and RL). A glidant is typically selected from the group consisting of colloidal silicon dioxide and talc. In preferred embodiments, the glidant is colloidal silicon dioxide (Cab-O-Sil® M-5, Cabot). Formulation compositions made in accordance with the invention are provided in the specific worked examples set forth hereinafter. CR systems for the present invention can involve a delay or lag period between when the dose is administered and when drug is available for absorption. Such delays can be temporal or related to the position in the gastrointestinal tract. These systems will be effective for the purposes of the present invention as long as once they begin providing drug for absorption, the rate falls within the limits described above. A particularly preferred delayed release system is an enteric-coated tablet or multiparticulate. Preferred enteric systems can be prepared by coating tablets or multiparticulates with such materials as cellulose acetate phthalate or enteric polyacrylics such as those marketed under the Eudragit™ brand name (available from Rohm Pharmaceuticals).

A blending process that used a low shear blender such as a bin blender or V-blender followed by a sieving process provided uniform drug distribution even at low doses of O.δmgA per tablet. One preferred sieving process performed after the initial blending step, uses a conical mill (Comil 197, Quadro Engineering, Inc., Waterloo, Ontario, Canada) fitted with a 0.8 mm screen to sieve the active blend. The lubricant is then added to the active blend and blended for about 3 minutes in the twin shell "V" or bin blender prior to dry granulation.

For scales smaller than about 9 kg, it was found that precoating surfaces that would contact the blend with excipients was beneficial to ensure blend uniformity of the drug at low doses, less than about 6 mgA per tablet. This included precoating the blender and the polyethylene bags used to contain the blend or granulation between blending, milling and dry granulation steps.

The pharmaceutical composition can be used to produce unit dosage forms containing about 0.5 mgA to about 6.0 mgA per unit dosage, preferably, about 0.5 mgA to about 3.5 mgA per unit dosage. The tablet size (i.e., unit dosage form) is typically between about 100 mg and 400 mg.

The tablets are generally prepared by compression in a rotary press. However, the particular method used for tablet formation is non-limiting and is well known to those skilled in the art. After formation of the tablets, the tablets can optionally be coated with one or more coatings. The tablet may be coated with a coating to mask flavor, to provide color for identification, for ease of swallowing, to improve further processing such as packaging, to act as a sealant and/or to act as a receptor for printing a logo or trademark on the tablet surface. Suitable film-forming coating agents include celluloses (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose), polyvinyl pyrrolidone, and ethyl acrylate-methyl methacrylate copolymers. The coating formulations may also include additives such as plasticizers (e.g., polyethylene glycol or triacetin), preservatives, antioxidants, sweeteners, flavoring agents, opacifiers, coloring agents and other known additives to provide an elegant presentation of the drug. A preferred coating formulation contains 40-70 wt% cellulosic polymer(s). Preferably, the aqueous coating of the immediate release dosage form of the present invention comprises Opadry® white or colored and Opadry® Clear manufactured by Colorcon, West Point, Pennsylvania. Opadry®, useful as an opacifying coat, contains hydroxypropyl methylcellulose, titanium dioxide, and polyethylene glycol or triacetin and optional colorants. Opadry® Clear, useful as a polish coat, contains hydroxypropyl methylcellulose and placticizer.

Alternatively, the tablet may be coated with a film-forming protecting agent(s) to modify the dissolution properties of the tablet. For example, the tablet may be coated with a film-forming coating that resists dissolution for a predictable period of time thus resulting in a delayed or prolonged release of the active ingredient.

The inventors have found that preferred formulations consist of cores made from the L-tartrate salt of the drug, HPMC, microcrystalline cellulose, Cab-O-Sil and magnesium stearate. More preferred formulations consist of cores made from the L-tartrate salt of the drug, microcrystalline cellulose [Avicel® PH 102], HPMC [hypromellose 2208 USP 4,000 cps as Methocel® K4M Premium CR], silicon dioxide [Cab-O-Sil] and magnesium stearate. These cores can be prepared by direct compression or dry granulation. Roller compaction is especially preferred due to its ability to prevent drug segregation, while maintaining drug stability (in contrast to aqueous wet granulations which can lead to drug hydrate formation). The tablets can be prepared on standard rotary tablet presses. The tablet cores are then coated using a pan coater. The preferred color coating consists of a mixture of hydroxypropyl methylcellulose, titanium dioxide triacetin, and optionally a colorant as well as an optional gloss coat consisting of hydroxypropyl methylcellulose and triacetin.

Alternatively, the active pharmaceutical matrix microparticulates may be filled into hard shell capsules, also referred to as the dry-filled capsule (DFC). The capsule formulation and manufacturing process is similar to the reported tablet core formulation and manufacturing process. A hard shell capsule could consist of gelatin and water or hydroxypropyl methylcellulose, water and a gelling agent (gelan gum or carageenan). In the present invention, a suitable CR dosage form of compound 1 can be identified by measuring the in vitro behavior of the drug in the dosage form by sampling and analyzing its release profile in a suitable dissolution test. One particular test is the USP I method at 100 RPM in simulated gastric (0.1 N HCI) media at 37⁰C in which the dosage forms are kept from sticking to surfaces or floating by using suitable sinkers (such as three prong or metal baskets). Dissolution can also be determined in a reduced phosphate SIN media described in Table 15 in the Examples. A preferred dissolution profile of the present invention is about 10% to about 60% of said varenicline is released after 2.0 hours; about 35 to about 85% is released after 5.0 hours; about 45% to about 95% is released after 8.0 hours; not less than about 50% is released after 12.0 hours; and, not less than about 65% is released after 24.0 hours. A more preferred dissolution profile of the present invention is about 20% to about 55% of said varenicline is released after 2.0 hours; from about 40% to about 75% is released after 5.0 hours; from about 55 to about 95 % is released after 8.0 hours; not less than about 60% is released after 12.0 hours; and, not less than about 75% is released after 24.0 hours

In the present invention, a suitable CR dosage form of compound 1 can be identified by measuring the in vivo behavior of the drug in the dosage form by sampling and analyzing blood after initial administration of the drug to a subject (generating a pharmacokinetic profile). Initial administration refers to drug administered to a subject either for the first time, or with at least four days since a previous dosing of any form of compound 1. It has been found that of particular importance in reducing nausea with compound 1 is the maximum blood level of 1 reached after initial administration of the drug (Cmax). In measuring Cmax, it will be recognized by those skilled in the art that there is significant variability between dosings and between subjects. To achieve an adequate comparison in C_max and thereby to determine if a given dosage form will achieve the desired reduction in nausea, it is necessary to measure these parameters for at least 6 subjects in a cross-over experiment (i.e., each subject receives both dosage forms, IR and CR) with at least 4-5 days between experimental legs. In particular, it is preferred that the average initial C_maχ be reduced to achieve a value of 20 to 80% of that achieved with an immediate release tablet of the same dose when both formulations are given as a single dose after a standardized non-high fat breakfast; more preferred is between 35 and 70%.

The pharmaceutical composition (or formulation) may be packaged in a variety of ways. Generally, an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, blister packs, and the like. The container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions. The pharmaceutical compositions of the invention containing varenicline described herein are useful in the treatment or prevention of inter alia inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome.

Accordingly, the pharmaceutical formulations containing compound 1 and processes described herein may be used in the manufacture of a medicament for the therapeutic applications described above.

A therapeutically effective amount of the manufactured medicament may be administered to a human in need of such treatment or prevention. As used herein, the term "therapeutically effective amount" refers to an amount of active ingredient which is capable of inhibiting or preventing the various pathological conditions or symptoms thereof and sequelae, referred to above. The terms "inhibif or "inhibiting" refers to prohibiting, treating, alleviating, ameliorating, halting, restraining, slowing or reversing the progression, or reducing the severity of a pathological condition or symptom related to or resultant from the respective condition being treated. As such, the pharmaceutical formulations may be used for both medical therapeutic (acute or chronic) and/or prophylactic (prevention) administration as appropriate. The dose, frequency and duration will vary depending on such factors as the nature and severity of the condition being treated, the age and general health of the host and the tolerance of the host to the active ingredient. The pharmaceutical composition or medicament may be given in a single daily dose, in multiple doses during the day or even in a weekly dose. The regimen may last from about 2-3 days to several weeks or longer. Typically, the composition is administered to a human patient once or twice a day with a unit dosage of about 0.25 mg to about 10.0 mg, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration.

Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope. Examples Dissolution Test Method

Unless otherwise stated in the specific example or data table, the dissolution of varenicline matrix tablets was carried out with a USP Apparatus I at 100 rpm with three prong sinkers in 900 ml_ of 0.01 N HCI at 37⁰C. Samples were assayed by HPLC to determine the % Released at the dissolution timepoint.

Example 1

Matrix Tablets made with Avicel PH 102 and 0.5% magnesium stearate at Large Scale M 00 kg)

Table 1. Placebo and 0.5 and 2.5 mgA Varenicline Matrix Tablet Compositions for Example 1

^•Based on varenicline theoretical potency of 58.5%

Process for manufacturing Varenicline Matrix Tablets at Large Scale MOO kg)

All the MCC, HPMC, silicon dioxide and drug were added to a 400L bin blender and mixed for 15 minutes at 12 rpm. The blend was passed through a Comil (Model U10) fitted with a 0.8mm screen at 1500 rpm into a 400 L bin blender. The intragranular magnesium stearate was added and it was mixed for 5 minutes at 12 rpm. The lubed blend was compacted using a Gerteis 3W Polygran roller compacter with diamond knurled rollers with side rims. The following roller compactor settings were used: roll speed was 5 rpm, roll pressure was ~7kN, gap was -2.6 mm, and the tamp/feed auger ratio was 170%. The ribbons were milled through the rotary granulator that was part of the Gerteis roller compactor using a deep die pocket rotor into a 400 L bin blender. The following milling parameters were used: screen size was 0.8mm, angle of rotation was 230° clockwise/260⁰ counterclockwise at a speed of 25 rpm. The granulation was blended for 10 minutes at 12 rpm. The extragranular magnesium stearate was added and it was blended for an additional 5 minutes at 12 rpm. The lubed granulation was tabletted at 250,000 tablets/h on an IMA Comprima 250 rotary tablet press using 5/16" standard round concave (SRC) tooling to a target tablet weight of about 200 mg. The precompression force was set at ~2 kN. Tablets were compressed to provide tablet hardness values in the range of about 7 - 12 kp. A portion of the 2.5mgA tablets, designated as Lot Ex. 1B, were compressed at a tablet press speed of 150,000 tablets/hr. The dissolution data for these lots are provided in Table 2.

Table 2. Dissolution Data for Uncoated 0.5 and 2.5mqA Tablets (Average Values are given as percent released (n=6 tablets))

Example 2.

Matrix Tablets made with Avicel PH 102 and 0.5% magnesium stearate at Medium Scale (~9 kg)

Table 3. 0.5 mgA and 5.0 mgA Varenicline Matrix Tablet Compositions for

Example 2

*Based on varenicline theoretical potency of 58.5% Process for manufacturing Varenicline Matrix Tablets at Medium Scale (1 cubic foot V-Blender ~9 kg)

All but approximately 50 g of the MCC was added to a 1 cubic foot V- blender and blend for 2 minutes to coat the metal surfaces. Drug was added to the blender and the drug container was rinsed with the remaining MCC and then added to the blender. The HPMC and silicon dioxide were added to the V-blender and it was mixed for 15 minutes. The blend was passed through a Comil (Model 197) fitted with a 0.032" screen (#2A032R02528) and impeller (#2A-1601-173) at 850 rpm. The milled blend was transferred to the 1 cubic foot V-blender and the intragranular magnesium stearate was added. The blend was lubed for 3 minutes. The lubed blend was compacted using a Gerteis minipactor roller compacter with diamond knurled roller with side rims. The following roller compactor settings were used: roll speed was 3 rpm, roll pressure was ~7kN, gap was ~2.6mm, agitator speed was 10 rpm and a tamp/feed auger ration of 160%. The ribbons were milled through the rotary granulation that was part of the Gerteis roller compactor with a die pocket rotor using the following parameters: screen size was 0.8mm (20 mesh), angle of rotation was 360° clockwise/360⁰ counterclockwise at a speed of 50 rpm. The granulation was transferred to the 1 cubic foot V-blender and blended for 10 minutes. The extragranular magnesium stearate was added and it was blended for an additional 3 minutes. The granulation was tabletted on a Kilian T-100 rotary tablet press using 5/16" standard round concave (SRC) tooling to a target tablet weight of about 200 mg. The precompression force was set at ~ 2 KN. Table 4. Dissolution Data for Uncoated 0.5 and 5.0 m A Varenicline Matrix

Example 3.

Matrix Tablets made with Avicel PH 200 and 0.75% magnesium stearate at Medium Scale

Table 5. 2.5 mαA and 3.5 mαA Varenicline Matrix Tablet Compositions for

Example 3

*Based on varenicline theoretical potency of 58.5%

Process for manufacturing Varenicline Matrix Tablets at Medium Scale

(9 k

Approximately 2.3 kg of MCC was added to a 1 cubic foot V-blender and blended for 2 minutes to coat the metal surfaces. Two portions of approximately 50Og of MCC were removed from the blender to coat 2 separate polyethylene bags. The MCC in the bags was emptied back into the

V-blender. A small amount of the MCC was set aside to rinse the drug container. Varenicline tartrate was added to the blender. The drug container was rinsed with approximately 10Og of MCC and it was added to the blender.

The HPMC₁ silicon dioxide and the remainder of the MCC were added to the

V-blender and it was mixed for 15 minutes and emptied into one of the precoated polyethylene bags. The blend was passed through a U10 Quadra

Comil fitted with a 0.032" screen at 850 rpm into the other precoated polyethylene bag. The milled blend was transferred to the V-blender and the intragranular magnesium stearate was added. The blend was Iu bed for 3 minutes and emptied into one of the polyethylene bags. The lubed blend was compacted using Gerteis minipactor roller compacter with diamond knurled rollers with side rims. The following roller compactor settings were used: roll speed was 3 rpm, roll pressure was ~7kN, gap was ~2.6mm, agitator speed was 10 rpm and a tamp/feed auger ratio of 160%. The ribbons were milled through the rotary granulation that was part of the Gerteis roller compactor with a star rotor using the following parameters: screen size was 0.8mm (20 mesh), angle of rotation was 400° clockwise/300⁰ counterclockwise at a speed of 50 rpm. The granulation was transferred to the V-blender and blended for 10 minutes. The extragranular magnesium stearate was added and it was blended for an additional 3 minutes. The granulation was tabletted on a Kikusui Virgo rotary tablet press using 5/16" standard round concave (SRC) tooling to a target tablet weight of about 200 mg using precompression to achieve the desired average tablet hardness of about 9kp. Table 6. Dissolution Data for Uncoated 2.5 and 3.5 m A Varenicline Matrix

Example 4.

Matrix Tablets made with Avicel PH 200 and 1.0% magnesium stearate at Medium Scale (5kq)

Table 7. 1.0 mαA Varenicline Matrix Tablet Compositions for Example 4

'Based on varenicline theoretical potency of 58.5%

Process for manufacturing Varenicline Matrix Tablets at Medium Scale (5 kg)

Approximately 1 kg of MCC was added to a 16 quart V-blender and blended for 2 minutes to coat the metal surfaces. Two portions of approximately 50Og of MCC was used to coat 2 separate polyethylene bags. The MCC in the bags was emptied into the V-blender. Varenicline tartrate was added to the blender. The drug container was rinsed with approximately 25 - 5O g of MCC and it was added to the blender. The HPMC, silicon dioxide and the remainder of the MCC were added to the V-blender and it was mixed for 15 minutes and emptied into one of the precoated polyethylene bags. The blend was passed through a Quadra Comil model 197 Ultra fitted with a 0.032" screen at 850 rpm into the other precoated polyethylene bag. The milled blend was transferred to the V-blender and the intragranular magnesium stearate was added. The blend was lubed for 3 minutes and emptied into one of the polyethylene bags. The lubed blend was compacted using Gerteis minipactor roller compacter with diamond knurled rollers with side rims. The following roller compactor settings were used: roll speed was 10 rpm, roll pressure was ~7kN/cm, gap was ~2.6mm, agitator speed was about 5 - 11 rpm and a tamp/feed auger ratio of 160%. The ribbons were milled through the rotary granulation that was part of the Gerteis roller compactor with a star rotor using the following parameters: screen size was 0.8mm (20 mesh), angle of rotation was 400° clockwise/300⁰ counterclockwise at a speed of about 48 - 50 rpm. The granulation was transferred to the V-blender and blended for 10 minutes. The extragranular magnesium stearate was added and it was blended for an additional 3 minutes. The granulation was tabletted on a Kilian LX-21 rotary tablet press using 5/16" standard round concave (SRC) tooling to achieve the selected target tablet weight of 200 mg or 13/32" SRC tooling to achieve the selected target tablet weight of 400 mg. A precompression setting of ~2 kN was used to obtain the desired average tablet hardness of about 6kp. Table 8. Dissolution Data for Uncoated 1 mqA Varenicline Matrix Tablets (200 and 400 mα Tablet Weight) (Average Values are given as percent released (n=6 tablets))

Example 5.

Matrix Tablets made with Avicel PH 200 and 1.0% magnesium stearate by Direct Compression

Table 9. 1.0 mαA Varenicline Matrix Tablet Compositions and Tablet

Properties for Example 5

Table 10. 0.5 mqA Varenicline Matrix Tablet Compositions for Example 5

Process for manufacturing Varenicline Matrix Tablets by Direct Compression at Small Scale Lots A, B, C, and E from Example 5 were made at a small scale of ~ 25 grams as follows. The MCC₁ drug and HPMC K4M were prescreened through a 30 mesh screen and blended in a 250cc amber glass bottle in a Turbula mixer for 2 minutes. The magnesium stearate was added and it was blended for an additional 30 seconds. The tablets were made on an F-press at the target tablet weight using the specified standard round concave (SRC) tooling turning the press over by hand.

Lot D from Example 5 was made at a small scale of -500 grams as follows. The MCC PH200, drug, HPMC K4M were prescreened through a 30 mesh screen and Cab-O-Sil through a 20 mesh screen and blended in a 4 quart V-blender for 15 minutes. The magnesium stearate was added and it was blended for an additional 3 minutes. The tablets were made under power on an F-press to obtain a target tablet weight of 400mg using 13/32" SRC tooling. Table 11. Dissolution Data for Uncoated 0.5 and 1 mqA Varenicline Matrix

Tablets

(Average Values are given as percent released for n=3 tablets except for Lot

Ex. 5D)

Notes: These data were normalized by setting the infinity point (dissolution test was run at high speed after the last 24 hour sample timepoint) to 100% released.

* No sinkers were used in these dissolution tests.

Example 6.

Matrix Tablets made with Starch by Direct Compression Table 12. 1.0 mqA Varenicline Matrix Tablet Compositions for Example 6

CO

Process for manufacturing Varenicline Matrix Tablets by Direct

Compression at Small Scale

Lots A, B, C₁ and D from Example 6 were made at a small scale of ~ 25 grams as follows. The starch, drug and HPMC were prescreened through a 30 mesh screen and blended in a 250cc amber glass bottle in a Turbula mixer for 2 minutes. The magnesium stearate was added and it was blended for an additional 30 seconds. The tablets were made on a F-press at the target tablet weight using the specified standard round concave (SRC) tooling turning the press over by hand.

Lot E from Example 6 was made at a small scale of -500 grams as follows. The starch, drug, HPMC K4M were prescreened through a 30 mesh screen and Cab-O-Sil through a 20 mesh screen and blended in a 4 quart V- blender for 15 minutes. The magnesium stearate was added and it was blended for an additional 3 minutes. The tablets were made under power on a F-press to obtain a target tablet weight of 400mg using 13/32" SRC tooling. Table 13.

Dissolution Data* for Uncoated 1 mqA Varenicline Matrix Tablets (Average Values are given as percent released)

Notes: These data for n=3 tablets were normalized by setting the infinity point (dissolution test was run at high speed after the last 24 hour sample timepoint) to 100% released. * No sinkers were used in these dissolution tests.

Example 7. Small scale Matrix tablets made with Different Polymers and Fillers by

Direct Compression

All the matrix tablet formulations shown in Table 14 were made by a dry blend direct compression process. All the individual ingredients except the magnesium stearate, were weighed, screened (#30 mesh) and blended for 2 minutes using a Turbula blender. The 1% magnesium stearate was added to the blend and mixed for an additional 30 seconds. The tablets were compressed on a F-Press using standard round concave tooling. Weight, hardness and thickness were determined for each formulation.

Dissolution profiles were obtained for each formulation in both simulated gastric (0.1 N HCI) and simulated intestinal fluid without enzymes (SIN) at 37°C using the USP Il method with a paddle speed of 50 RPM. Dissolution was also determined in a SIN media with a lower level of phosphate. Table 15 gives the composition of both the regular and the reduced phosphate SIN media that were used in these studies. Sinkers made from coiled wire were used with the SIN media to keep the tablets from sticking to the dissolution vessel.

S

*4mgA varenicline matrix tablet.

Table 15. Composition of the Regular and Reduced Phosphate SIN

Dissolution Media.

Example 8. Single Dose Pharmacokinetic Data

A single dose pharmacokinetic study in humans used the 1.0 mg tablets as set forth in Example 4, administered as two 1.0 mgA tablets after a standardized non-high fat breakfast. The pharmacokinetic (PK) data in Table 16 demonstrated the relative oral bioavailability of a 2-mg single dose of varenicline of the two CR matrix tablet formulations: Matrix-200, and Matrix- 400; compared with the IR tablet formulation in healthy adult smokers (Matrix- 200 and Matrix-400 refer to two different matrix tablet formulations based on tablet weight of 200 and 400 mg, respectively). The PK data also demonstrated the controlled release capability of the matrix tablet dosage forms based on an increased Tmax and a decrease in Cmax compared to the IR tablet.

Table 16. Oral Bioavailability of Matrix Tablet Formulations compared to an

IR Tablet

Open-label, randomized, single-dose, in adult smokers; IR and CR Dose = 2 mg (2x1 mg A) Data in parentheses is the standard deviation

Data for Tmax is the median with the range in parentheses.

Example 9.

Small Scale M kg) Qpadrv Color & Clear Coating of 0.5 and 5-OmgA Tablet Cores

Tablet cores (0.5 and 5.0mgA) from Example 2 were coated by an aqueous film coating process in a Vector LDCS-20 coating pan at small scale

(-1 kg) with an Opadry® HPMC polymeric film coating with titanium dioxide as the opacifier and either PEG or triacetin as the plasticizer and possibly a colorant. The color coating was optionally overcoated with a clear coating that did not contain the titanium dioxide or the colorant. The coating was applied at a coating level of 3 to 5% by weight and the clear coating was applied to an additional weight gain of 0.5 to 1.0%. Table 17. Varenicline 0.5 and 5.0 mqA tablets coated with a 4wt% white Qpadrv® coat and a 0.5wt% Qpadrv® clear coat

* Volatile, not in final dosage form

The Opadry® color coating suspension was prepared as a 15% (w/w) suspension. The Opadry® clear coating solution was prepared as a 5% (w/w) solution. The coating suspension and solution were applied to the tablet cores using a Vector LDCS-20 pan coater using the following parameters given in Table 18.

Table 18. Coating Parameters used in Small Scale Vector LDCS-20 Coating

Pan

Example 10.

Medium Scale (12kg) Qpadrv Color & Clear Coating of O.δmgA Tablet Cores A mixed bed made up of 200mg 5/16" SRC varenicline matrix tablet cores (O.δmgA) from Example 2 and embossed placebo tablets were coated by an aqueous film coating process in a Vector HCT-60 coating pan at medium scale (12 kg). The color coat was a white Opadry® HPMC polymeric film coating with titanium dioxide as the opacifier and PEG 400 as the plasticizer. The coated tablets were overcoated with a clear Opadry® HPMC polymeric film coating that did not contain titanium dioxide but had triacetin as the placticizer. The white coating was applied at a coating level of about 4% by weight (~8 mg) and the clear coating was applied to an additional weight gain of about 0.5% by weight (~1 mg). Table 19. Varenicline O.δmqA tablets coated with a 4wt% white Opadrv® coat and a 0.5wt% Qpadrv® clear coat

* Volatile, not in final dosage form

The Opadry® white coating suspension was prepared as a 15% (w/w) suspension. The Opadry® clear coating solution was prepared as a 5% (w/w) solution. The coating suspension and solution was applied to the tablet cores in a Vector HCT-60 pan coater using the following parameters shown in Table 20.

Table 20. Coating Parameters used in Medium Scale Vector HCT-60 Coating

Pan

Dissolution profiles were generated for both coated and uncoated O.δmgA varenicline matrix tablets. The dissolution data in Table 21 show that the polymeric HPMC coating does not affect the release profile.

Table 21. Dissolution Data for Coated and Uncoated O.δmgA Varenicline

Matrix Tablets

(200 mg Tablet Weight)

(Average Values are given as percent released (n=3 tablets))

Example 11.

Large Scale (~70 kg) Qpadrv Color & Clear Coating of Matrix Tablet Cores

The 2.5 mgA varenicline tablet cores from Example 1 were coated by an aqueous film coating process in a Glatt GCA 1000 100L coating pan at large scale (~70 kg) with an Opadry® HPMC polymeric film blue coating with titanium dioxide as the opacifier, PEG as the plasticizer and blue #1 as the colorant. The blue coated tablets were optionally overcoated with a clear Opadry® HPMC polymeric coating that did not contain the titanium dioxide or the colorant, but had triacetin as the placticizer. The blue coating was applied at a coating level of 3 to 5% by weight and the clear coating was applied to an additional weight gain of about 0.5%.

Table 22. Varenicline 2.5 mgA matrix tablets coated with a 4wt% blue Opadrv® coat and a 0.5wt% Qpadry® clear coat

* Volatile, not in final dosage form

Approximately 32.5 kg of the Opadry® blue coating suspension was prepared as a 12% (w/w) suspension. Approximately 19.5 kg of the Opadry® clear coating solution was prepared as a 5% (w/w) solution. The coating suspension and solution were applied to the placebo matrix tablet cores using a Glatt GCA 1000 100L pan coater using the parameters shown in Table 23. Table 23. Coating Parameters used in Large Scale Glatt GCA 1000 Coating

Pan

Claims

What is Claimed Is:

1. A pharmaceutical dosage formulation suitable for administration to a subject comprising (a) a therapeutic amount of varenicline or a pharmaceutically acceptable salt thereof, (b) at least 15% w/w of a high molecular weight water soluble polymer; and, (c) at least 15% w/w of a water- insoluble, hydrophilic excipient.

2. The pharmaceutical dosage formulation of claim 1 , comprising a matrix tablet.

3. The pharmaceutical dosage formulation of claim 1 , wherein said pharmaceutically acceptable salt is the tartrate salt.

4. The pharmaceutical dosage formulation of claim 1 , wherein the high molecular weight water soluble polymer is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethylcellulose sodium, carbomer, hydroxypropyl methylcellulose acetate succinate, polyethylene oxide, hydroxypropyl cellulose, sodium alginate, and hydroxyethyl cellulose.

5. The pharmaceutical dosage formulation of claim 1 , wherein the water-insoluble, hydrophilic excipient is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose methyl cellulose, cellulose, starch, pregelatinized starch, direct compressible starch, and mixtures thereof.

6. The pharmaceutical dosage formulation of claim 1 , wherein the dosage formulation is a tablet, and has a cosmetic film coating.

7. A controlled release tablet for oral ingestion which comprises: (a) from about 0.1% w/w to about 10% w/w varenicline, or a pharmaceutically acceptable salt thereof; (b) from about 35% w/w to about 70% w/w of a water- insoluble, hydrophilic excipient; and, (c) from about 30% to about 65% w/w of a high molecular weight water soluble polymer.

8. The controlled release tablet of claim 7, wherein the pharmaceutically acceptable salt is varenicline tartrate; the water-insoluble, hydrophilic excipient is microcrystalline cellulose; and, the high molecular weight water soluble polymer is hydroxypropyl methylcellulose.

9. The controlled release tablet of claim 7, wherein the pharmaceutically acceptable salt is varenicline tartrate; the water-insoluble, hydrophilic excipient is pregelatinized starch or direct compressible starch; and the high molecular weight water soluble polymer is hydroxypropyl methylcellulose.

10. The pharmaceutical dosage formulation of claim 7, wherein said varenicline, or pharmaceutically acceptable salt, is present in an amount from about 0.4 mgA to about 6 mgA per tablet; and wherein said formulation further comprises a lubricant selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, and sodium fumarate.

11. The pharmaceutical dosage formulation of claim 7, further comprising at least 0-10% w/w of a glidant.

12. The pharmaceutical dosage formulation of claim 11 , wherein the glidant is selected from colloidal silicon dioxide and talc.

13. The pharmaceutical dosage formulation of claim 11 , wherein the glidant is colloidal silicon dioxide present in an amount of from about 0.2% w/w to about 1.0% w/w.

14. The pharmaceutical dosage formulation of claim 7, having a tablet core between 50 and 500 mg in total weight.

15. A method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a subject, comprising administering to said subject an amount of the pharmaceutical dosage formulation of any of claims 1 to 14 that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use.

16. A method for treating a disorder or condition selected from inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, Crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions; dependencies on, or addictions to, nicotine, tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine; headache, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age related cognitive decline, epilepsy, petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD)₁ attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a subject in need of such treatment, comprising administering to the subject an amount of the pharmaceutical dosage formulation of any one of claims 1 to 14 that is effective in treating such disorder or condition.