PHARMACEUTICAL FORMULATIONS COMPRISING TOPIRAMATE AND PHENTERMINE

INTRODUCTION

Aspects of the present application provide fixed dose combination dosage formulations comprising phentermine or a salt thereof and topiramate, and methods of preparing such formulations. Further aspects of the present application provide fixed dose combination dosage forms, wherein such dosage forms comprise phentermine hydrochloride, topiramate and at least one drug release rate controlling material.

The drug having the adopted name "topiramate" has a chemical name 2,3:4,5-di-O-isopropylidene-0-D-fructopyranose sulfamate, and its structural formula is shown below.

Topiramate has the empirical formula Ci2H2iN08S and its molecular weight is 339.36. Topiramate is a white crystalline powder with a bitter taste. It is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3.

Topiramate, a fructose monosaccharide derivative with sulfamate functionality, was originally developed as an antidiabetes compound. However, topiramate received approval for the treatment of partial onset or primary generalized tonic-clonic seizures and prophylaxis of migraine headache.

Topiramate is the active ingredient in products sold as TOPAMAX® tablets for oral administration, containing 25 mg, 50 mg, 100 mg, or 200 mg of topiramate. Topiramate is also available in TOPAMAX® sprinkle capsules for oral administration as whole capsules and sprinkled onto soft foods, each capsule containing 15 mg or 25 mg of topiramate.

Inactive ingredients in TOPAMAX® 25 mg, 50 mg, 100 mg, or 200 mg tablets are lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hypromellose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80.

Inactive ingredients in TOPAMAX® sprinkle capsules, containing topiramate-coated beads in a hard gelatin capsule, are sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink.

U.S. Patent No. 4,513,006 discloses topiramate and the use thereof, especially as an anticonvulsant.

U.S. Patent Nos. 5,998,380, 6,503,884, 7,018,983, and 7,498,311 disclose migraine treatment using topiramate and related compounds. U.S. Patent No. 6,696,091 discloses a method of treating diabetes using a topiramate composition comprising a taste-masked coating. U.S. Patent No. 7,125,560 discloses a method of treating convulsions in a mammal using a topiramate composition comprising a taste-masked coating.

The drug having the adopted name "phentermine" has chemical names phenyl-te/t-butylamine, or 2-methyl-1-phenylpropan-2-amine, and the structural formula of its hydrochloride salt is shown below.
Phentermine hydrochloride has the empirical formula Ci0H15N-HCI and its molecular weight is 185.70. Phentermine hydrochloride is a white, odorless, hygroscopic, crystalline powder, which is soluble in water and lower alcohols, slightly soluble in chloroform and insoluble in ether. Phentermine hydrochloride is indicated as a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity.

The free base phentermine was approved as an appetite suppressant in 1959, whereas phentermine hydrochloride has been used as a weight loss agent since the 1970s in products sold as Adipex-P®, Fastin®, Zantril®, and others.

Phentermine hydrochloride is the active ingredient in products sold as ADIPEX-P® tablets and ADIPEX-P® capsules for oral administration, containing 37.5 mg of phentermine hydrochloride (equivalent to 30 mg of phentermine base). Phentermine hydrochloride is also available as SUPRENZA ® orally disintegrating tablets for oral administration containing 15 or 30 mg of phentermine hydrochloride (equivalent to 12 or 24 of phentermine base).

Inactive ingredients in ADIPEX-P® tablets are cornstarch, lactose (anhydrous), magnesium stearate, microcrystalline cellulose, pregelatinized starch, sucrose, and FD&C Blue #1.

Inactive ingredients in ADIPEX-P® capsules are cornstarch, gelatin, lactose monohydrate, magnesium stearate, titanium dioxide, black iron oxide, FD&C Blue #1, FD&C Red #40 and D&C Red #33.

Inactive ingredients in SUPRENZA® orally disintegrating tablets are mannitol powder, citric acid powder, povidone CL, povidone K 30, sucralose, magnesium stearate, peppermint flavor, talc, sodium lauryl sulfate, and mannitol pregranulated. Suprenza 15 mg ODT also contains FD&C Blue #1 lake and FD&C Yellow #5 lake. Suprenza 30 mg ODT also contains FD&C Yellow #5 lake.

Phentermine hydrochloride is approved in the U.S.A. only as a short-term monotherapy for the management of exogenous obesity, and coadministration of phentermine with other drugs for weight loss purposes is not recommended.

U.S. Patent No. 2,408,345 discloses phentermine, salts and process of preparation thereof.

A combination product named QNEXA® is currently under development for treating obesity and related conditions. The dosage forms have the following drug strengths (mg phentermine hydrochloride/mg topiramate): 3.75/23; 7.5/46; and 15/92. The phentermine component is in immediate release form and the topiramate component is in controlled release form.

International Application Publication No. WO 2000/76493 discloses a combination therapy for effecting weight loss which involves treating a subject with a sympathomimetic agent (e.g., phentermine or a phentermine-like drug) and an anticonvulsant sulfamate derivative (e.g., topiramate) such that the subject experiences weight loss.

International Application Publication No. WO 2009/152189 discloses a method for effecting weight loss by administering a combination low dose topiramate and phentermine compostion. This publication also discloses a combination dosage form providing topiramate sustained release and phentermine immediate release.

There remains a need to provide fixed dose combination dosage forms, wherein such combination dosage forms provide suppression of appetite throughout the day to offer effective weight loss, and mitigate potential side effects of the individual drug components.

SUMMARY

Aspects of the present application provide fixed dose combination dosage forms comprising phentermine hydrochloride and topiramate and methods of preparing such formulations. Further aspects of the present application provide fixed dose combination dosage forms, wherein such dosage forms comprise phentermine hydrochloride, topiramate and at least one release rate controlling material.

In embodiments, the application provides fixed dose combination dosage forms, wherein such dosage forms comprise phentermine hydrochloride, topiramate and at least one release rate controlling material.
In embodiments, the application provides fixed dose combination dosage forms, wherein such dosage forms comprise phentermine hydrochloride, topiramate and at least one release rate controlling material, wherein a release rate-controlling component is hydrophilic, hydrophobic, enteric, water-soluble or water-swellable material, or any combinations thereof.

In embodiments, the application provides fixed dose combination dosage forms, wherein such dosage forms provide immediate release of phentermine hydrochloride and controlled release of topiramate.
In embodiments, the application provides fixed dose combination dosage forms comprising phentermine hydrochloride and topiramate, wherein such dosage forms can withstand stresses while being transported and can easily be packaged using automated equipment.

In embodiments, the application includes fixed dose combination dosage forms comprising phentermine hydrochloride and topiramate, such that drug release characteristics of the formulations are maintained during storage for commercially relevant times.

In embodiments, the application includes processes to prepare fixed dose combination dosage forms comprising phentermine hydrochloride and topiramate.

The present application provides fixed dose combination dosage forms comprising phentermine hydrochloride and topiramate wherein such dosage forms are designed to produce Cmax of each drug separated by about four to about ten hours.

In embodiments, the present application provides fixed dose combination dosage forms comprising controlled release topiramate portion wherein such portion provides controlled release of topiramate by assuring reduced Cmax and delayed Tmax of topiramate.

In embodiments, the present application provides fixed dose combination dosage forms comprising immediate release phentermine portion and controlled release topiramate portion were designed to achieve a time to peak plasma concentration (Tmax) of 1 to 6 hours and 6 to12 hours, respectively.

DETAILED DESCRIPTION

Aspects of the present application provide fixed dose combination dosage forms comprising phentermine or a salt thereof and topiramate, and methods of preparing such formulations.

The term "active agent" or "drug" is meant to include solvates (including hydrates) of the free compound or its salts, as well as various polymorphic crystalline and non-crystalline forms. Unless otherwise specified, the term "active agent" is used herein to indicate topiramate, phentermine, and pharmaceutically acceptable salts thereof. For example, an active agent can include any optical isomers of the compound and any pharmaceutically acceptable salts thereof, either alone or in combination.
"Pharmaceutically acceptable" salts include derivatives of the disclosed compounds, wherein the parent compound is modified by forming acid or base addition salts thereof, and further refers to pharmaceutically acceptable solvates, including hynhStes, of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral and organic acid addition salts of basic residues such as amines, alkali or organic addition salts of acidic residues such as carboxylic acids, and the like, and combinations comprising one or more of the foregoing salts. The pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, non¬toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids, and the like. Other acceptable inorganic salts include metal salts such as a sodium salt, potassium salt, cesium salt, and the like, and alkaline earth metal salts, such as a calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.

As used herein the term "topiramate" includes the compound topiramate, pharmaceutically acceptable salts of topiramate, isomers, racemates, enantiomers, hydrates, solvates, metabolites, and polymorphs, and mixtures thereof. Formulations generally contain topiramate in the range of 1 to 500 mg, or 10 to 300 mg, or 20 to 100 mg, or 23 to 92 mg, per dosage unit.

As used, herein the term "phentermine" includes the compound phentermine, pharmaceutically acceptable salts of phentermine, isomers, racemates, enantiomers, hydrates, solvates, metabolites, and polymorphs, and mixtures thereof. Formulations generally contain phentermine in the range of 0.1 to 100 mg, or 1 to 50 mg, or 2 to 25 mg, or 3 to 15 mg, per dosage unit.

The term "pharmaceutical formulation" or "dosage form" for purposes of the present application includes solid pharmaceutical products such as tablets, capsules, sachets, pills, or granules, which may be matrix based formulations, reservoir based formulations, multi-particulate based formulations, multi-layer formulations, resin formulations, osmotic formulations, gastro-retentive formulations, etc.

As used herein the term "particulate" includes granules, spheroids, beads, pellets, and mini-tablets.
The term "immediate-release", as used herein, refers to a conventional or non-modified release dosage form which releases greater than or equal to about 75% of the active agent within about two hours after immersion into an aqueous fluid, or within about one hour after immersion.

The term "oontrolled-release", as used herein, refers to a dosage form in which the release t>f the active agent is controlled or modified over a period of time. Controlled can mean, for example, sustained, delayed, or pulsed-release at particular times following administration. Alternatively, it can mean that the release of the active agent is extended for longer times than it would be in an immediate-release dosage form, i.e., at least over several hours after administration.

The terms "sustained-release" or "extended-release", as used herein, refer to dosage forms that release the contained active agent at such a rate that steady state blood (e.g., plasma) levels are maintained within a therapeutic range, but below toxic levels, for at least about 4 hours, 6, hours, 8 hours, 12 hours, or longer times following administration. The term "steady-state" means that a plasma concentration
for a given active agent has been achieved and which is maintained with subsequent doses of the drug at levels at or above the minimum effective therapeutic level and below the minimum toxic plasma level for a given active agent.

The term "delayed-release", as used herein, refers to a dosage forms for which there is a time-delay after administration, before significant plasma levels of the active agent are achieved. A delayed-release formulation of the active agent can avoid an initial burst of the active agent, or can be formulated so that release of the active agent in the stomach is avoided and systemic absorption occurs in the small intestine.

Certain formulations described herein may be "coated." The coating can be a suitable coating, such as a functional or a non-functional coating, or multiple functional and/or non-functional coatings. "Functional coating" is meant to include a coating that modifies the release properties of the total formulation, for example, an enteric or sustained-release coating. "Non-functional coating" is meant to include a coating that is not a functional coating, for example, a cosmetic or protective coating. A non-functional coating can have some effect on the release of the active agent due to the initial dissolution, hydration, perforation of the coating, etc., but would not be considered to be a significant deviation from the non-coated composition.

The term "hydrophilic" for purposes of the present application relates to excipients that are soluble and/or swellable in water, or have affinity toward water.

The term "water soluble" for purposes of the present application relates to excipients that dissolve to the extent required, in aqueous fluids having pH values in the range of about 1 to about 8, and is not particularly limited.

The term "water swellable" for purposes of the present application relates to excipients that are relatively insoluble in water, but which can absorb at least two times their dry weight of water.

The term "enteric" for purposes of the present application relates to excipients that do not dissolve or decompose to a significant extent in aqueous fluids having pH values about 4 or less, in an in vitro test, but will dissolve or decompose in aqueous fluids having pH values about 5 or greater, such as in the range of about 5 to 7, in the range of about 5 to 6, or in the range of about 5 to 5.5. In general, enteric polymers are intended to remain intact while in the highly acidic environment of the stomach, but not in hiaher pH environments such as the intestines.

The term "hydrophobic material" for purposes of the present application relates to excipients that are insoluble in water, which are water repellent, or which lack affinity toward water.

The term "lipophilic material" for purposes of the present application relates to excipients that have strong affinity for oils and fats, or are soluble therein.

In embodiments, the application includes oral fixed unit dose formulations such as capsules filled with coated pellets or beads, controlled release matrix tablets, enteric-coated tablets, multilayered tablets, multiple unit tableted dosage forms, etc.

In embodiments, solid dosage forms may be multi-unit particulate systems comprising one portion having controlled release particles and another portion having immediate release, extended release or combinations of immediate and extended release particles, filled into capsules or sachets, or they may be tableted into finished dosage forms.

In embodiments, pharmaceutical combination products may comprise topiramate in a controlled release portion and phentermine hydrochloride in immediate release, extended release, or combination of immediate and extended release particles, and further these discrete portions with different actives may be filled into capsules or sachets. In embodiments, pharmaceutical combination products may comprise topiramate in an immediate release portion and phetermine hydrochloride as delayed release, extended release, or suitable combination of delayed and extended release particles, and further these discrete portions with different actives may be filled into capsules or sachets.

In embodiments, solid dosage forms may be multilayered tableted systems comprising a topiramate controlled release layer and a phentermine hydrochloride immediate release layer.
Pellets can be prepared using extrusion-spheronization processes. Extrusion can be defined as the process of forcing a material through an orifice or die under controlled conditions, thus forming cylinders or strands called extrudates. During spheronization, the extrudates are broken into small cylinders and rounded into spheres or pellets.

Pharmacologically inert pellets, beads, and cores that can be used as substrates for drugs include, but are not limited to: water-soluble particles such as sugar spheres, lactose, and the like; and water-insoluble particles such as celluloses, including microcrystalline cellulose, silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, and the like. Active substances may be layered onto inert particles to prepare drug-containing cores.

In embodiments, water-soluble core materials such as sugar spheres may be coated with an intermediate seal coating layer. The purpose of sealing is to offer an initial protection and to prevent some core ingredients from migrating into drug coatings. Sealing may be accomplished by the application of polymer based coating material on the surface of the core particles. Non-limiting examples of the polymers that can be used include shellac, zein, hydroxypropyl celluloses (HPC), hydroxyethyl celluloses (HEC), hydroxypropyl methylcelluloses (hypromellose or HPMC), polyvinyl acetate phthalates (PVAP), and cellulose acetate phthalates (CAP). This sealing agent may be dissolved in an appropriate aqueous or non-aqueous solvent for application.

In embodiments, controlled release portions of the present application have an active agent in intimate contact with at least one release rate-controlling material. The rate-controlling material is a material that permits release of the active agent in a desired controlled fashion into an aqueous medium. The release rate-controlling material can be associated with the formulation either in the form of a matrix or a coating.
In embodiments, a controlled release portion of the present application comprises an active agent in intimate contact with at least one release rate-controlling material wherein a rate-controlling component is hydrophilic, hydrophobic, lipophilic, or combinations thereof.

In embodiments, the application includes release rate-controlling materials providing a pH dependent or pH independent release of topiramate or its salts from a formulation.

"pH dependent" release rate-controlling materials for the purposes of this application include materials that permit release of the active agent into an aqueous medium depending upon the pH of the medium, such as enteric polymers.

"pH independent" release rate-controlling materials for the purposes of this application include materials that do not affect the release of the active agent into aqueous media having different pH values.

Suitable pH independent release rate-controlling materials include, for example, hydrophilic materials, hydrophobic materials, and combinations comprising one or more of the foregoing materials. The oral dosage forms can contain from about 1% to about 80% of rate-controlling material, by weight of the formulation.

Suitable hydrophilic materials comprise water soluble or water swellable materials. Examples of such materials include hydroxyalkyl celluloses, hydroxyalkyl alkylcelluloses, carboxyalkyl cellulose esters, for example, hydroxypropyl methylcelluloses, hydroxypropyl celluloses, hydroxyethyl celluloses, polyvinyl porollidones (povidone or PVP), for example, various grades like K25, K29, K30, K90, etc., and combinations comprising one or more of the foregoing materials. For the purposes of this application, the release-controlling agent may be present in a matrix, or in a coating covering a core containing atcive agent. For the purposes of this application, the concentration of hydrophilic material ranges from about 5% to about 50% by weight of the formulation.

In embodiments, pharmaceutical compositions comprise mixtures of water soluble materials of different viscosity grades, such as hydroxypropyl methylcelluloses and hydroxypropyl celluloses. These water soluble materials may be characterized by their viscosities in a 2% w/w aqueous solution as low viscosity (less than about 1 Pa*s, or less than about 1,000 cP), medium viscosity (about 1 Pa«s to about 10 Pa»s, or about 1,000 cP to about 10,000 cP), and high viscosity (greater than about 10 Pa»s, or greater than about 10,000 cP).

The hydroxypropyl cellulose polymers that may be used in the present application also include, for example, polymers available under the brand name Klucel™, availiafble from Nippon Soda Co. Hydroxypropyl cellulose polymers available as different grades, such as, Klucel EF, Klucel LF, Klucel JF and Klucel GF, whose 2% by weight aqueous solutions have viscosities less than 1000 cP, are examples of low viscosity hydrophilic polymers.

The hydroxyethyl cellulose polymers that may be used in the present application also include, for example, polymers available under the brand name Cellosize available from Amerchol Corp and Natrosol 250 available from Aqualon Inc. Hydroxyethyl cellulose polymers available under the brand name Natrosol 250 whose 1% by weight aqueous solution having a viscosity in the range from 800-5,000 cP are high viscosity hydrophilic polymers sold as grade MHR, HR, H4R or HHR.

Suitable substances that can be used as water swellable substances include, for example, low-substituted hydroxypropyl celluloses, e.g. L-HPC, cross-linked polyvinylpyrrolidones, e.g., PVP-XL, Kollidone™ CL and Polyplasdone™ XL, sodium carboxymethyl celluloses, cross-linked sodium carboxymethyl celluloses, e.g., Ac-di-sol™ and Primellose™, sodium starch glycolate, e.g., Primojel™, sodium carboxymethyl celluloses, e.g., Nymcel™ ZSB10, sodium carboxymethyl starches, e.g., Explotab™, ion-exchange resins, e.g., Dowex™ or Amberlite™ products, microcrystalline cellulose, e.g., Avicel™ products, starches and pregelatinized starches, e.g., Starch 1500™ and Sepistab ST200™, formalin-casein, e.g., Plas-Vita™, and combinations comprising one or more of the foregoing water swellable substances.

In embodiments, hydrophilic materials include polyalkylene oxides, polysaccharide gums, and crosslinked polyacrylic acids.

Polysaccharide gums, both natural and modified (semi-synthetic), can be used. Examples are dextran, xanthan gum, gellan gum, welan gum and rhamsan gum.

Crosslinked polyacrylic acids that can be used include those having properties similar to those described above for alkyl-substituted cellulose and polyalkylene oxide polymers. Useful crosslinked polyacrylic acids include those with viscosities about 4,000 to about 40,000 cP (for a 1% aqueous solution at 25°C). Three specific examples are CARBOPOL™ grades 971P, 974P, and 934P (sold by The Lubrizol Corporation, Cleveland, Ohio, USA). Further, polymers such as WATER LOCK™, which are starch/acrylate/acrylamide copolymers available from Grain Processing Corporation, Muscatine, Iowa, USA are also used.

Suitable "hydrophobic" materials include water-insoluble neutral or synthetic waxes, fatty alcohols such as lauryl, myristyl, stearyl, cetyl, and cetostearyl alcohols, fatty acids and derivatives thereof, including fatty acid esters such as such as glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, stearin, palmitin, laurin, myristin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, hydrogenated castor oils, cottonseed oils, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, calcium stearate, zinc stearate, stearyl alcohol, materials having hydrocarbon backbones, and combinations comprising one or more of the foregoing materials.

A wax formulation is a solid dosage form comprising a drug substance in a waxy matrix. The wax material can be, for example, an amorphous wax, an anionic wax, an anionic emulsifying wax, a bleached wax, a camauba wax, a cetyl esters wax, a beeswax, a castor wax, a cationic emulsifying wax, a cetrimide emulsifying wax, an emulsifying wax, glyceryl behenate, a microcrystalline wax, a nonionic wax, a nonionic emulsifying wax, a paraffin, a petroleum wax, a spermaceti wax, a white wax, a yellow wax, and combinations comprising one or more of the foregoing waxes.

In embodiments, formulations include a rate-controlling material that is an "enteric polymer," being insoluble in highly acidic environments such as the stomach, but being dissolved or decomposed in higher pH environments such as the intestines. Examples include polyvinylacetate phthalates (PVAP), alginic acid and its derivatives, hydroxypropyl methylcellulose acetate succinates (HPMCAS), cellulose acetate phthalates (CAP), methacrylic acid copolymers, hydroxypropyl methylcellulose succinates, cellulose acetate succinates, cellulose acetate hexahydrophthalates, hydroxypropyl methylcellulose hexahydrophthalates, hydroxypropyl methylcellulose phthalates (HPMCP), cellulose propionate phthalates, cellulose acetate maleates, cellulose acetate trimellitates, cellulose acetate butyrates, cellulose acetate propionates, methacrylic acid/methacrylate polymers (e.g., acid number 300 to 330 and also known as EUDRAGIT™ L from Evonik Industries, Germany, which is an anionic copolymer based on methacrylate, available as a powder, and also known as methacrylic acid copolymer, type A NF), methacrylic acid-methyl methacrylate copolymers, ethyl methacrylate-methylmethacrytete-chlorotrimethylammonium ethyl methacrylate copolymers, and the like, and combinations comprising one or more of the foregoing enteric polymers.

Polymethacrylate enteric polymers are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid and methacrylic acid esters in varying molar ratios. Several different types are commercially available and may be purchased as dry powders, or in aqueous mixtures.
EUDRAGIT polymers are products of Evonik Industries AG, Essen, Germany. Commercially available Eudragit products include, but are not limited to, EUDRAGIT RL, EUDRAGIT RS, EUDRAGIT RL PO, EUDRAGIT RS PO, EUDRAGIT RD, EUDRAGIT L, EUDRAGIT S, EUDRAGIT L 100-5, EUDRAGIT NE 30D, and EUDRAGIT E 100. GANTREZ™ polymers are products of International Specialty Products, Parsippany, New Jersey USA.

The polymers sold as EUDRAGIT have the general repeating unit:

where R is COOH for the EUDRAGIT L products, R is COOCH2N(CH3)2 for the EUDRAGIT E products, R is COOCH3 for the EUDRAGIT NE 30 D product, and R is COOCH2CH2N+(CH3)3Cr for the EUDRAGIT E and EUDRAGIT RS products. The alkyl groups vary between different products, and have 1-4 carbons.

In embodiments, pharmaceutically acceptable excipients for use in formulations include, but are not limited to, any one or more of diluents, disintegrants, binders, glidants, lubricants, colouring agents, coating materials, and the like.

Diluents include, but are not limited to, starches, lactose, mannitol (e.g., Pearlitol™ SD 200) and other sugar alcohols, celluloses, confectioners' sugar, and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tabletting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV), and others. Different grades of starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starches (commercially available as PCS PC10 from Signet CSWemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starches (commercially available as National 78-1551 from Essex Grain Products) and others. Different celluloses that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include, but are not limited to, CEOLUS™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose ("MCC") 114, and microcrystalline cellulose 112.

Disintegrants may be incorporated into intragranular or extragranular blends, or both. Various useful disintegrants include, but are not limited to, carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di-sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, KOLLIDON™ CL from BASF (Germany), POLYPLASDONE™ XL, XL10, and INF-10 from ISP Inc. (USA), and low-substituted hydroxypropylcelluloses ("L-HPC"). Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, starches, and any combinations thereof.

Binders include, but are not limited to, hydroxypropyl celluloses ("HPC") e.g., Klucel™ LF, Nisso HPC- L (Nippon Soda Co. Ltd.), HPC-EXF, hydroxypropyl methylcelluloses ("HPMC" or hypromelloses), e.g., Methocel™ products, polyvinylpyrrolidones ("PVP" or povidones), e.g., grades PVP-K25, PVP-K29, PVP-K30, PVP-K90, etc., copovidones (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, carbomers (e.g. Carbopol™ products), methylcelluloses, polymethacrylates, starches, and any combinations thereof.

Direct compression vehicles include, but are not limited to, lactose (spray-dried, Celutab™), lactose derivatives (e.g., a-lactose monohydrate), starch (StarX 1500), cellulose derivatives (e.g., Avicel™ PH101), sugar and sugar alcohols (e.g., Di-Pac,™), sucrose, dextrose, sorbitol, mannitol, maltodextrin, corn flour, dicalcium phosphate dihydrate (e.g., Encompress™), and any combinations thereof.
Solvents that are useful in processing include, but are not limited to, water, methanol, ethanol, isopropanol, butanols, acidified ethanol, acetone, diacetone, polyols, polyeWers, oils, esters, alkyl ketones, methylene chloride, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, and any combinations thereof.

Glidants or anti-sticking agents can be used, including but not limited to talc, silica derivatives, colloidal silicon dioxide, and the like, or any mixtures thereof, and lubricants that can be used include, but are not limited to, stearic acid and stearic acid derivatives such as magnesium stearate, calcium stearate, zinc stearate, sucrose esters of fatty acid, polyethylene glycol, talc, sodium stearyl fumarate, zinc stearate, castor oils, waxes, and any combinations thereof.

An effective amount of any pharmaceutical^ acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and any combinations thereof.

Various useful colourants include, but are not limited to, Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, and the like, food lake colorants, iron oxides, and any combinations thereof.

If desired, an outer continuous phase in the form of a film coating may be applied, optionally containing additional adjuvants for coating processing such as plasticizers, polishing agents, colorants, pigments, antifoam agents, opacifiers, antisticking agents, the like, including any combinations thereof.

Film-forming agents include, but are not limited to: soluble alkyl- or hydroalkyl-cellulose derivatives, for
example, methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethyethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc.; acidic cellulose derivatives, for example, cellulose acetate phthalates, cellulose acetate trimellitates, methyl hydroxypropylcellulose phthalates, polyvinyl acetate phthalates, etc.; insoluble cellulose derivatives, for example ethylcelluloses and the like; dextrins; starches and starch derivatives; polymers based on carbohydrates and derivatives thereof; natural gums, for example gum Arabic, xanthans, and alginates; polyacrylic acid; polyvinyl alcohols ("PVA"); polyvinyl acetate; polyvinylpyrrolidones; polymethacrylates and derivatives thereof (e.g., Eudragit™ products); chitosan and derivatives thereof; shellac and derivatives thereof; and waxes and fat substances.

Various useful plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycol, triacetin, triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent.

An opacifier like titianium dioxide may also be present, in amounts ranging from about 10% to about 20%, based on the total weight of the coating. When coloured tablets are desired then the colour is frequently applied in the coating. Consequently, colouring agents and pigments may be present in the film coating.

Anti-adhesives are frequently used in film coating processes to avoid sticking effects during film formation and drying. An example of an anti-adhesive for this purpose is talc.

Useful polishing agents include, but are not limited to, polyethylene glycols of differing molecular weights or mixtures thereof, talc and surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax).

As alternatives for combining individual coating ingredients, sometimes pre-formulated coating products such as those sold as OPADRY™ (supplied by Colorcon) will be used, for example Opadry Blue 13B50579 or Opadry White OY 59800 or Opadry AMB. The products sold in a solid form require only mixing with a liquid before use.

Suitable alkaline drug stabilizers include, but are not limited to, sodium, potassium, calcium, magnesium,
and aluminum salts of phosphoric acid, carbonic acid, citric acid and aluminum/magnesium compounds such as Al203*6 MgOC02»12H20, MgOAfeOa^SiCVnHaO, where n is an integer of 2 or higher. In addition, the alkaline material may be an antacid material such as aluminum hydroxides, calcium hydroxides, magnesium hydroxides, and magnesium oxide.

The foregoing lists of excipient substances are intended to be representative of materials in the various classes and are not exhaustive. Many other substances can be used, as is well known to those skilled in the art, and their use is specifically contemplated in this application.

Sustained Release Dosage Forms

In embodiments, the disclosure relates to sustained release compositions comprising topiramate or phentermine, providing formulations which, following dosing, can result in a reduced incidence of adverse effects and/or enhanced efficacy, when compared to an equivalent dose in an immediate release formulation.

In embodiments, solid dosage forms may be multi-unit particulate systems comprising one portion having delayed release particles and another portion having immediate release, extended release, or combinations of immediate and extended release particles, filled into capsules or sachets or tableted into finished dosage forms.

In embodiments, sustained release formulations of the present disclosure may be prepared by coating powders, granules, pellets, tablets, or cores with one or more functional coatings and then filling into capsules.

Targeted-Release Dosage Forms
"Targeted-release" refers to release of topiramate or phentermine in a particular segment of the gastrointestinal tract. A targeted-release formulation may, for example, have a coating such as an enteric coating, whereby release to a particular portion of the gastrointestinal tract is achieved. An enteric coating is a coating that prevents release of the active agent until the dosage form reaches regions of the digestive tract having pH values higher than those of the stomach.

Delaved-Release Dosage Forms
Delayed-release formulations may comprise a core, a first coating and optionally a second coating. The core may include topiramate or phentermine, and excipients, notably a lubricant, and a binder and/or filler, and optionally a glidant, as well as other excipients.

The coating may contain a water-insoluble polymer and/or a water-soluble polymer, and a plasticizer. The relative proportions of ingredients, notably the ratios of water-insoluble, film-forming polymer to water-soluble polymer, can be varied depending on the release profile to be obtained. The coating may comprise an enteric polymer of the methacrylic type and optionally a plasticizer.

Pulsed-Release Dosage Forms
An exemplary pulsed-release dosage form may provide at least a part of the dose with a pulsed delayed-release of topiramate or phentermine, and have another part of the formtrtation providing rapid or immediate release. The immediate and pulsed delayed-release of the drug can be achieved according to different principles, such as by single dose layered pellets or tablets, by multiple dose layered pellets or tablets, or by two or more different fractions of single or multiple dose layered pellets or tablets, optionally in combination with pellets or tablets having instant-release characteristics.

Dosage forms can be subjected to in vitro dissolution evaluations according to Test 711 "Dissolution" in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP") to determine the rate at which the active substance is released from the dosage forms, and content of active ingredient can conveniently be determined in solutions by techniques such as high performance liquid chromatography.

Pharmacokinetic properties of drug products can be studied by administering the products in a cross-over study with healthy volunteer subjects. Serum plasma samples are obtained at regular intervals following dosing and assayed for drug (or sometimes metabolite) concentrations.

In embodiments, the application provides fixed dose combination dosage forms comprising phentermine hydrochloride and topiramate, wherein a dosage form is designed in a way that Cmax of each drug is separated by a period of time, such as about four to about eight hours.

In embodiments, dosage forms of the application provide phentermine peak exposure from morning to about early afternoon and topiramate peak exposure from late afternoon to evening, thus providing complete coverage for appetite throughout the day.

In embodiments, dosage forms of the application provide optimal coverage to assure efficacy, mitigate potential side effects of individual drug components, and minimize drug-drug interactions between phentermine hydrochloride and topiramate.

In embodiments, the application provides fixed dose combination dosage forms comprising a controlled release topiramate portion, wherein such portion provides controlled release of topiramate by assuring reduced Cmax and delayed Tmax of topiramate.

In embodiments, the application provides fixed dose combination dosage forms comprising immediate release phentermine beads and controlled release topiramate prifcSts, designed to achieve a time to peak plasma concentration (Tmax) of 2 to 4 hours and 8 to10 hours, respectively.

In embodiments, the application provides fixed dose combination dosage forms comprising phentermine hydrochloride and topiramate, wherein once-daily administration of such dosage form suppresses appetite through complementary and distinct mechanisms (decreased appetite and increased satiety), leading to additive effects on weight loss and allowing for the use of lower doses of the constituent agents. Moreover, once-daily administration can improve overall compliance and tolerability, compared to individual drug therapy or individual immediate release drug therapy.

In embodiments, the application includes the use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and/or polypropylene and/or glass, and blisters or strips composed of aluminum, high-density polypropylene, polyvinylchloride, polyvinylidine dichloride, etc.

The following examples further describe certain specific aspects and embodiments of the application and demonstrate the practice and advantages thereof. It is to be understood that the examples are provided for purposes of illustration only and are not intended to limit the scope of the disclosure in any manner.

EXAMPLES 1-4: Topiramate pellets.
* Evaporates during processing. Manufacturing procedure:
1. Topiramate and microcrystalline cellulose are sifted through a 40 mesh sieve and blended.
2. Methylcellulose is dissolved in water.
3. The mixture of step 1 is granulated using solution of step 2.
4. The wet mass is extruded through a 0.8 mm screen in a roll extruder.
5. The extrudates obtained in step 4 are spheronized using a plate with 3 mm cross hatching.
6. Spheroids obtained in step 5 are dried at 60°C until loss on drying (LOD) is not more than 2% w/w.
7. Dried spheres are sifted through a 16-18 mesh seive.
8. A 5% w/w solution of ethyl cellulose and povidone in an isopropyl alcohol and water mixture (85:15) is sprayed on dried spheres using a Wurster coater to produce a weight gain of 8.5% after drying.
9. Coated spheroids are dried in the Wurster coater for 1 hour.
10. Dried coated spheroids are sifted through an 18-20 mesh seive.

EXAMPLES 5-8: Phentermine beads.
* Evaporates during processing. Manufacturing procedure:
1. Sugar spheres are coated in a Wurster coater by spraying with a 10% w/w solution of phentermine hydrochloride in water.
2. The drug-coated spheres are dried at 60°C until LOD is not more than 2% w/w.
3. Dried spheres are sifted through a 16-18 mesh sieve.
EXAMPLES 9-21: Topiramate pellets.

* Evaporates during processing. Manufacturing procedures: Examples 9-12:
1. Topiramate and microcrystalline cellulose (MCC) are sifted through a 40 mesh sieve and mixed in a rapid mixer granulator.
2. The mixture is granulated using a solution of hydroxyethyl cellulose (HEC) in water.
3. The wet mass is extruded through a 0.8 mm screen in a roll extruder.
4. The extrudates of step 3 are spheronized using a plate with 3 mm cross hatching.
5. The spheroids of step 4 are dried to achieve a LOD not more than 2% w/w.
6. Dried spheroids are sifted through a 20-25 mesh sieve.
7. A coating of a 5% w/w solution of ethylcellulose and povidone (PVP K30) in a mixture of isopropanol and water (85:15, respectively, by volume) is sprayed onto the spheroids using a Wurster coater to produce a weight gain of 8.5%, after drying.
8. The coated spheroids are dried in the Wurster coater for 1 hour.
9. The dried spheroids are sifted through an 18-20 mesh sieve. Example 13:
Procedure is similar to that of Example 12, except in step 2 where hydroxypropyl cellulose (HPC) is substituted for HEC.

Example 14:

1. Topiramate and MCC are sifted through a 40 mesh sieve and blended in a rapid mixer granulator.
2. The blend is granulated using water.
3. The wet mass of step 2 is extruded through a 0.8 mm screen in a roll extruder.
4. The extrudates of step 3 are spheronized using a plate with 3 mm cross hatching.
5. The spheroids of step 4 are dried to achieve a LOD not more than 2% w/w.
6. The dried spheroids are sifted through a 20-25 mesh sieve.
7. A coating solution of 5% w/w ethyl cellulose and PVP in an isopropyl alcohol and water mixture (85:15 by volume, respectively) is sprayed onto the spheroids in the Wurster coater to produce a weight gain of 8.5%, after drying.
8. Coated spheroids are dried in the Wurster coater for 1 hour.
9. The dried spheroids are sifted through an 18-20 mesh sieve.

Example 15:
1. Topiramate and MCC are sifted through a 40 mesh sieve and blended in a rapid mixer granulator.
2. Hydrogenated castor oil is melted at 90-100°C.
3. The mixure of step 1 is granulated using the melt of step 2.
4. The granulated mass is again granulated using water.
5. The wet mass of step 4 is extruded through a 0.8 mm screen in a roll extruder.
6. The extrudates of step 5 are spheronized using a plate with 3 mm cross hatching.
7. The spheroids of step 6 are dried to achieve a LOD not more than 2% w/w.
8. The dried spheroids are sifted through a 20-25 mesh sieve.
9. A coating solution of 5% w/w ethyl cellulose and PVP in an isopropyl alcohol and water mixture (85:15 by volume, respectively) is sprayed onto dried spheroids, using a Wurster coater, to produce a weight gain of 8.5%, after drying.
10. The coated spheroids are dried in the Wurster coater for 1 hour.
11. Dried spheroids are sifted through an 18-20 mesh sieve.

Example 16:

1. Topiramate and MCC are sifted through a 40 mesh sieve and blended in a rapid mixer granulator.
2. HEC is dissolved in water and used to granulate the blend.
3. The wet mass is extruded through a 0.8 mm screen in a roll extruder.
4. The extrudates are spheronized using a plate with 3 mm cross hatching.
5. The spheroids of step 4 are dried to achieve a LOD not more than 2% w/w.
6. Dried spheroids are sifted through a 20-25 mesh sieve.
7. A coating solution of 5% w/w Kollidon SR in an I PA and water mixture (85:15 by volume, respectively) is sprayed onto dried spheroids using a Wurster coater to produce a weight gain of 8.5%, after drying.
8. The coated spheroids are dried in the Wurster coater for 1 hour.
9. Dried spheroids are sifted through an 18-20 mesh sieve.

Example 17:
1. Topiramate and MCC are sifted through a 40 mesh sieve and blended in a rapid mixer granulator.
2. HPC is dissolved in water and the solution used to granulate the blend.
3. The wet mass is extruded through a 0.8 mm screen in a roll extruder.
4. The extrudates of step 4 are spheronized using a plate with 3 mm cross hatching.
5. The spheroids are dried to achieve a LOD not more than 2% w/w.
6. Dried spheroids are sifted through a 20-25 mesh seive.
7. A coating solution of 5% w/w Eudragit RL100 and lactose anhydrous in an isopropyl alcohol and water mixture (85:15 by volume, respectively) is sprayed onto the spheroids using a Wurster coater to produce a weight gain of 8.5% w/w, after drying.
8. The coated spheroids are dried in the Wurster coater for 1 hour.
9. Dried spheroids are sifted through an 18-20 mesh seive.

Example 18:
Procedure is similar to that of Example 17 except in step 7, where Eudragit RS100 is used instead of Eudragit RL100.

Example 19:
Procedure is similar to that of Example 17 except in step 7, where Eudragit L 100 is used instead of Eudragit RL100.

Example 20:
Procedure is similar to that of Example 17 except in step 7, where Eudragit S 100 is used instead of Eudragit RL100.

Example 21:
Procedure is similar to that of Example 17 except in step 7, where a mixture of Eudragit L-100 and Eudragit S-100 is used instead of a mixture of Eudragit RL100 and lactose anhydrous.
EXAMPLES 22-31: Topiramate pellets.

* Evaporates during processing. Manufacturing procedures:

Example 22:
1. MCC spheres are seal coated with a solution of HPC in water to produce a weight gain of 5%, after drying, using a Wurster coater granulator.
2. A solution of 5% w/w topiramate and HEC in water is sprayed onto seal coated pellets in the Wurster coater to obtain drug-loaded pellets.
3. Drug loaded pellets are dried at 60°C to a LOD not more than 2% w/w.
4. Dried pellets are sifted through a 20-25 mesh sieve.
5. A coating solution of 5% ethylcellulose and PVP K30 in a mixture of isopropyl alcohol and water (85:15 by volume, respectively) is sprayed onto the pellets using a Wurster coater to produce a weight gain of 8.5%, after drying.
6. Coated pellets are dried in the Wurster coater for 1 hour.
7. Dried pellets are sifted through an 18-20 mesh sieve.

Example 23:
Procedure is similar to that of Example 22 except in step 2, where HPC is used instead of HEC.

Example 24:
Procedure is similar to that of Example 22 except in step 2, where PVP K30 is used instead of HEC.

Example 25:

Procedure is similar to that of Example 22 except in step 2, where HMPC is used instead of HEC.

Example 26:
Procedure is similar to that of Example 22 except in step 2, where only topiramate is dissolved in water to make the solution, instead of topiramate and HEC.

Example 27:
Procedure is similar to that of Example 22 except in step 1, where sugar spheres are seal coated instead of MCC spheres, and in step 5, where a 5% w/w solution of lactose and Eudragit RL is prepared in the mixture of isopropyl alcohol and water.

Example 28:
Procedure is similar to that of Example 27 except in step 5, where a 5% w/w solution of lactose and Eudragit RS is prepared in the mixture of isopropyl alcohol and water.

Example 29:
Procedure is similar to that of Example 27 except in step 5, where a 5% w/w solution of lactose and Eudragit L is prepared in the mixture of isopropyl alcohol and water.

Example 30:
Procedure is similar to that of Example 27 except in step 5, where a 5% w/w solution of lactose and Eudragit S is prepared in the mixture of isopropyl alcohol and water.

Exampfe31:
Procedure is similar to that of Example 27 except in step 5, where a 5% w/w solution of Eudragit L and Eudragit S is prepared in the mixture of isopropyl alcohol and water.

EXAMPLE 32: Topiramate pellets, coated with a phentermine immediate release coating.

* Evaporates during processing. Manufacturing procedure:
1. Topiramate pellets are coated with a solution of HPC in water to produce a weight gain of 5%, after drying, using a Wurster coater.
2. Phentermine hydrochloride is dissolved in water and sprayed onto pellets from step 1 in the Wurster coater, and the pellets are dried.

EXAMPLE 33: Fixed dose drug combination capsules.
Manufacturing procedure: Appropriate quantities of topiramate pellets and phentermine beads are filled into hard gelatin capsules.

WE CLAIM:

1. A controlled release composition for oral administration comprising about 10 mg to 100 mg of topiramate and about 5 mg to about 15 mg of phentermine, wherein composition is devoid of microcrystalline cellulose and/or methylcellulose.

2. The composition of claim 1, wherein topiramate is present as matrix core of beads or pellets or granules and phentermine is present as a coating on the beads or pellets or granules.

3. The composition of claim 1, wherein beads or pellets or granules of topiramate or phentermine are further coated with ethylcellulose and polyvinylpyrrolidone.

4. The composition of claim 1, wherein the bead or pellets or granules of topiramate and phentermine are filled in a capsule or can be compressed in the form of tablet, which can be optionally filled in a capsule.

5. The composition of claim 1, wherein topiramate is in delayed or controlled release form and phentermine is in an immediate or controlled release form.

6. The composition of claim 1, wherein the composition may be in the form of a bi-layered tablet.

7. The composition of claim 1, wherein the composition is utilized for treating obesity, diabetes or a related condition.