Claims:We Claim:
1. A pharmaceutical composition comprising:
i) naltrexone or pharmaceutically acceptable salts thereof, and
ii) zonisamide or pharmaceutically acceptable salts thereof.
2. The composition of claim 1, wherein naltrexone and zonisamide or pharmaceutically acceptable salts thereof are present in the composition in a weight ratio of about 1: 2 to 1: 12.
3. The composition of claim 1, wherein naltrexone and zonisamide or pharmaceutically acceptable salts thereof are present in the composition in an amount of about16-48 mg and 50-400 mg respectively.
4. The composition of claim 1, wherein naltrexone and zonisamide or pharmaceutically acceptable salts thereof are present in the composition in an amount of 32 mg and 91-364 mg respectively.
5. The composition of claim 1, wherein the composition is used for obesity management.
6. The composition of claim 1, wherein the composition is administered once daily.
7. The composition of claim 1, wherein naltrexone and zonisamide are physically separated in the composition.
8. A pharmaceutical unit composition comprising:
i) sustained release formulation of naltrexone or pharmaceutically acceptable salts thereof, and
ii) sustained release formulation of zonisamide or pharmaceutically acceptable salts thereof, wherein the said composition is administered once daily.
9. The composition of claim 8, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus, exhibits a characteristic release profile of naltrexone or pharmaceutically acceptable salts thereof in the manner of:
i) releases no more than 50% in 1 hour,
ii) releases at least about 30% and no more than 70% in 2 hours, and
iii) releases at least about 75% in 8 hours.
10. The composition of claim 8, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus, exhibits a characteristic release profile of zonisamide or pharmaceutically acceptable salts thereof in the manner of:
i) releases no more than 45% in 1 hour,
ii) releases at least about 25% and no more than 70% in 4 hours. and
iii) releases at least about 75% in 12 hours.
11. The composition of claim 8, wherein the sustained release formulation of naltrexone and zonisamide comprising one or more release retarding polymer.
12. The composition of claim 11, wherein the release retarding polymer is selected from one or more of polyethylene glycols, hydroxymethyl celluloses, ethyl cellulose, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, methylcelluloses, carboxymethyl celluloses, sodium carboxymethyl celluloses, carboxyethyl celluloses, carboxy polymethylenes, hydroxypropyl methyl phthalates, polyvinylpyrrolidones, cellulose acetates, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methyl acrylates, sodium alginate, gums such as acacia gum, guar gum, tragacanth gum, and xanthan gum, methacrylic acid copolymers or mixtures thereof.
13. The composition of claim 8, wherein the said naltrexone and zonisamide formulations are physically separated.
14. The composition of claim 8, wherein the said pharmaceutical unit composition is selected from capsule, bilayer tablets or sachets.
15. The composition of claim 8, wherein naltrexone and zonisamide or pharmaceutically acceptable salts thereof are present in the composition in an amount of about 16-48 mg and 50-400 mg respectively.
16. A capsule composition comprising:
i) one or more sustained release tablet or mini-tablet formulation of naltrexone or pharmaceutically acceptable salt thereof, and
ii) one or more sustained release tablet or mini-tablet formulation of zonisamide or pharmaceutically acceptable salt thereof,
wherein naltrexone and zonisamide or their pharmaceutically acceptable salts are present in the composition in an amount of 32 mg and 91-364 mg respectively,
wherein the said composition is administered once daily.

17. The composition of claim 16, wherein naltrexone or pharmaceutically acceptable salt thereof is present in an amount of more than 20% based on the total weight of said naltrexone tablet or mini-tablet formulation.
18. The composition of claim 16, wherein zonisamide or pharmaceutically acceptable salt thereof is present in an amount of more than 50% based on the total weight of said zonisamide tablet or mini-tablet formulation.
, Description:The following specification describes the invention and the manner
in which it is to be performed

PHARMACEUTICAL COMPOSITIONS FOR OBESITY MANAGEMENT

TECHNICAL FIELD OF THE INVENTION
The present specification relates to pharmaceutical compositions for obesity management comprising naltrexone and zonisamide or pharmaceutically acceptable salt thereof. The specification also relates to once daily pharmaceutical unit composition comprising sustained release naltrexone and sustained release zonisamide formulations. Methods of preparing such compositions are also provided.

BACKGROUND OF THE INVENTION
Obesity is characterized by increased in body weight which is influenced by unbalance between energy intake and expenditure, a positive energy balance in which the absorption of energy surpasses its metabolism by the body that is, intake is higher than expenditure. A successful weight-loss drug should reduce energy intake and/or increase energy expenditure without adverse side effects.
There have been several methods to treat obesity, for example, diet therapy or exercise therapy, however, those methods often result in failure because of genetic factor such as personal differences in respect to appetite, favor to high-fat food and metabolism of fat formation. Therefore, there exists a need for therapy to promote reducing body weight other than classical approach methods.
The drugs for the obesity management include, not limiting examples, such as orlistat, lorcaserin, sibutramine, rimonabant, metformin, exenatide, pramlintide, combination of phentermine/topiramate, combination of naltrexone/bupropion, diethylpropion, liraglutide, methamphetamine, phendimetrazine, benzphetamine, fenfluramine, dexfenfluramine. One of the biggest challenge for the obesity management by using these anti-obesity drugs is the poor safety profile of these drugs. Historically, the limitations have been due to a variety of concerns. Some of these include valvulopathy associated with fenfluramine and dexfenfluramine, the abuse potential and psychiatric side effects associated with rimonabant, and, most recently, cardiac adverse events associated with sibutramine.
Naltrexone hydrochloride is an opioid antagonist, with no opioid agonist properties approved by US Food and Drug Administration (FDA) for the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. Commercially, naltrexone is marketed under the brand name as NODICT®, and it is available as 25 mg, 50 mg and 100 mg oral tablets. Chemically, naltrexone is 17- (cyclopropylmethyl)-4,5a-epoxy- 3,14-dihydroxymorphinan-6-one. The chemical structure of naltrexone is shown below:

Zonisamide is a sodium channel blocker useful in the treatment of epilepsy and is marketed as an anticonvulsant. It is chemically known as 1,2-benzisoxazole-3-methanesulfonamide. ZONEGRAN® (zonisamide) capsules, available commercially from Eisai, Inc., are immediate-release capsules designed for oral administration of one to four capsules once per day to provide a daily dose of 100 to 400 mg. The chemical structure of zonisamide is shown below:

As of our knowledge, the combination of naltrexone and zonisamide is not approved anywhere in the world for the treatment or management of obesity. The individual drugs are also not approved for obesity management. The inventors of the present specification have surprisingly found that novel pharmaceutical composition comprising of naltrexone and zonisamide, which can be administered once daily and suitable for obesity management.
The existing commercial products of naltrexone hydrochloride and zonisamide are available as oral immediate release formulation and exhibits high peak plasma concentration and hence have shown CNS and GIT adverse effects such as nausea, vomiting, anorexia, dizziness, headache etc. after administration. Thus, there exists a strong need to develop an effective fixed dose compositions comprising naltrexone and zonisamide combination to address the unmet clinical need and reducing the potential adverse effects. Also from the formulation perspective, it is difficult to prepare both the drugs in a single unit composition, as naltrexone hydrochloride belongs to class I of bio pharmaceutics classification system (BCS) with high solubility and high permeability and zonisamide belongs to BCS class II with low solubility and high permeability. Therefore, preparing a sustained release formulation of naltrexone and zonisamide in a single composition is also challenging. A single unit composition would generally reduce the pill burden and improves the patient compliance.
Accordingly, the present invention provides pharmaceutical unit compositions for once daily administration comprising sustained release naltrexone and sustained release zonisamide formulation, which are stable and could be effective for the treatment and/or management of obesity with better safety profile. The pharmaceutical unit compositions is expected to reduce peak plasma concentration and provide potentially lesser adverse effect in obese patient.
OBJECT OF THE INVENTION
The present specification relates to pharmaceutical compositions comprising naltrexone and zonisamide. The specification also relates to use of such compositions for obesity management. The specification also relates to once daily pharmaceutical unit composition comprising sustained release naltrexone and sustained release zonisamide formulation.
In one aspect, the present specification relates to a pharmaceutical composition for obesity management comprising:
i) naltrexone or pharmaceutically acceptable salts thereof, and
ii) zonisamide or pharmaceutically acceptable salts thereof, wherein the composition is administered once daily.
In another aspect, the present specification relates to a pharmaceutical composition for obesity management comprising:
i) naltrexone or pharmaceutically acceptable salts thereof, and
ii) zonisamide or pharmaceutically acceptable salts thereof, wherein naltrexone and zonisamide are present in the composition in a weight ratio of about 1: 2 to 1: 12.
In yet another aspect, the present specification relates to a pharmaceutical composition for obesity management comprising:
i) naltrexone or pharmaceutically acceptable salts thereof, and
ii) zonisamide or pharmaceutically acceptable salts thereof, wherein naltrexone and zonisamide or pharmaceutically acceptable salts thereof are present in the composition in an amount of about 16-48 mg and 50-400 mg respectively.
In another aspect, the present specification relates to a pharmaceutical composition for obesity management comprising:
i) naltrexone or pharmaceutically acceptable salts thereof, and
ii) zonisamide or pharmaceutically acceptable salts thereof, wherein naltrexone and zonisamide are physically separated in the composition.
In one aspect, the present specification relates to a pharmaceutical unit composition comprising:
i) sustained release formulation of naltrexone or pharmaceutically acceptable salts thereof, and
ii) sustained release formulation of zonisamide or pharmaceutically acceptable salts thereof, wherein the said composition is administered once daily.
In another aspect, the present specification relates to a pharmaceutical unit composition for once daily administration comprising:
i) sustained release formulation of naltrexone or pharmaceutically acceptable salts thereof, and
ii) sustained release formulation of zonisamide or pharmaceutically acceptable salts thereof, wherein the said naltrexone formulation releases at least about 75% of naltrexone in 8 hours and the said zonisamide formulation releases at least about 75% of zonisamide in 12 hours, when subjected to an in-vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.
In yet another aspect, the present specification relates to a pharmaceutical unit composition for once daily administration comprising:
i) sustained release formulation of naltrexone or pharmaceutically acceptable salts thereof, and
ii) sustained release formulation of zonisamide or pharmaceutically acceptable salts thereof, wherein the naltrexone and zonisamide formulations are physically separated.
In another aspect, the present specification relates to a capsule composition comprising:
i) one or more sustained release tablet or mini-tablet formulation of naltrexone or pharmaceutically acceptable salts thereof, and
ii) one or more sustained release tablet or mini-tablet formulation of zonisamide or pharmaceutically acceptable salts thereof, wherein naltrexone and zonisamide or their pharmaceutically acceptable salts are present in the composition in an amount of 32 mg and 91-364 mg respectively,
wherein the said composition is administered once daily.
The present specification also relates to use of pharmaceutical unit composition comprising naltrexone and zonisamide for the management of obesity.
BRIEF DESCRIPTION OF FIGURES
Figure 1: Dissolution profile of naltrexone HCl and zonisamide of the pharmaceutical unit composition at initial stage.

Figure 2: Dissolution profile of naltrexone HCl and zonisamide of the pharmaceutical unit composition after 6 month storage at accelerated stability condition (40 °C/75% RH).

DESCRIPTION OF INVENTION
The present specification relates to pharmaceutical compositions comprising naltrexone and zonisamide. The specification also relates to use of such compositions for obesity management. The specification also relates to once daily pharmaceutical unit composition comprising sustained release naltrexone and sustained release zonisamide formulations.
In one aspect, the present specification relates to a pharmaceutical composition for obesity management comprising:
i) naltrexone or pharmaceutically acceptable salts thereof, and
ii) zonisamide or pharmaceutically acceptable salts thereof, wherein the composition is administered once daily.
In another aspect, the present specification relates to a pharmaceutical composition for obesity management comprising:
i) naltrexone or pharmaceutically acceptable salts thereof, and
ii) zonisamide or pharmaceutically acceptable salts thereof, wherein naltrexone and zonisamide are present in the composition in a weight ratio of about 1: 2 to 1: 12.
In yet another aspect, the present specification relates to a pharmaceutical composition for obesity management comprising:
i) naltrexone or pharmaceutically acceptable salts thereof, and
ii) zonisamide or pharmaceutically acceptable salts thereof, wherein naltrexone and zonisamide or pharmaceutically acceptable salts thereof are present in the composition in an amount of about 16-48 mg and 50-400 mg respectively.
In another aspect, the present specification relates to a pharmaceutical composition for obesity management comprising:
i) naltrexone or pharmaceutically acceptable salts thereof, and
ii) zonisamide or pharmaceutically acceptable salts thereof, wherein naltrexone and zonisamide are physically separated in the composition.

In one aspect, the present specification relates to a once daily pharmaceutical unit composition comprising:
i) sustained release formulation of naltrexone or pharmaceutically acceptable salts thereof, and
ii) sustained release formulation of zonisamide or pharmaceutically acceptable salts thereof, wherein the composition is administered once daily.
In another aspect, the present specification relates to a pharmaceutical unit composition for once daily administration comprising:
i) sustained release formulation of naltrexone or pharmaceutically acceptable salts thereof, and
ii) sustained release formulation of zonisamide or pharmaceutically acceptable salts thereof,
wherein the said naltrexone formulation releases at least about 75% of naltrexone in 8 hours and the said zonisamide formulation releases at least about 75% of zonisamide in 12 hours, when subjected to an in-vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.
In yet another aspect, the present specification relates to a pharmaceutical unit composition for once daily administration comprising:
i) sustained release formulation of naltrexone or pharmaceutically acceptable salts thereof, and
ii) sustained release formulation of zonisamide or pharmaceutically acceptable salts thereof, wherein the naltrexone and zonisamide formulations are physically separated.
In another aspect, the present specification relates to a capsule composition comprising:
i) one or more sustained release tablet or mini-tablet formulation of naltrexone or pharmaceutically acceptable salts thereof, and
ii) one or more sustained release tablet or mini-tablet formulation of zonisamide or pharmaceutically acceptable salts thereof, wherein naltrexone and zonisamide or their pharmaceutically acceptable salts are present in the composition in an amount of 32 mg and 91-364 mg respectively, wherein the composition is administered once daily.
The term “once daily” as used herein refers to once in a day administration of the compositions to the subject in the need thereof. The once daily administration could be any time of the day, before or after meal.
The term “pharmaceutical composition” as used herein refers to oral dosage forms preferably in the form of tablets, capsules, sachets and the like. The dosage forms generally are prepared by using suitable pharmaceutically acceptable excipients. The unit composition refers to a single unit of such pharmaceutical compositions.
The term “sustained release” or “prolong release” or “extended release” are used herein interchangeably and it refers to release of drug from the composition for a prolonged period of time at a controlled rate to reduce dosing frequency or to a specific target in the body. The said release occurs some times after the administration. These terms are also used by the pharmacopoeias and the FDA. Whilst immediate-release dosage forms are designed to give a fast onset of drug action, modifications in drug release are often desirable to increase the stability, safety and efficacy of the drug, to improve the therapeutic outcome of the drug treatment and/or to increase patient compliance and convenience of administration.
The term “naltrexone” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. Preferably naltrexone is present in the pharmaceutically acceptable salt form, e.g. naltrexone hydrochloride (HCl). The amount of naltrexone or pharmaceutically acceptable salt thereof employed in the present composition is in the range of 16-48 mg, preferably in the range of 32-48 mg, e.g. 32 mg.
The term “zonisamide” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. The amount of zonisamide or pharmaceutically acceptable salt thereof employed in the present composition is in the range of 50-400 mg, e.g. 91 mg, 182, 364 mg.
The term “obesity management” or “management of obesity” as used herein, refers to treatment and/or management of obesity resulting in reduction of food intake and/or reduction in body weight, when used in conjunction with a reduced-calorie diet and increased physical activity.
The term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. As used herein, the term "about" means a slight variation of the value specified, within 10 percent of the value specified. Nevertheless, the term "about" can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present invention.
The term “release retarding polymers” as used in the context of the present specification relates to one or more pharmaceutically acceptable polymers which prolongs and controls the drug release from the formulation. The release retarding polymers helps to achieve extended release or delayed or sustained release profile.
Suitable “release retarding polymers” that can be used in the present application include, but are not limited to, water soluble, water swellable, water insoluble, pH dependent, pH independent, enteric polymers, melt extrusion polymers and the like. Examples of release retarding polymers in the context of the present specification include, but are not limited to, polyethylene glycols (e.g. molecular weight less than about 400), hydroxymethyl celluloses, ethyl cellulose, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, methylcelluloses, carboxymethylcelluloses (CMC), sodium CMC, carboxyethyl celluloses, carboxy polymethylenes, hydroxypropyl methyl phthalates, polyvinylpyrrolidones, cellulose acetates, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearyl alcohol, glyceryl behenate, glyceryl dibehenate, polyanhydrides, methyl acrylates, sodium alginate, gums such as acacia gum, guar gum, tragacanth gum, xanthan gum, methacrylic acid copolymers such as poly(butylmethacrylate), (2-dimethylaminoethyl)methacrylates, methylmethacrylates, Eudragit™ products designated as E100 or E12.5 or EPO, polyvinyl acetal diethylaminoacetate, chitosan, and the like, including any mixtures thereof.
Other release retarding polymers suitable for use in the invention include, but are not limited to, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrol idone, polyvinylphenol, Polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide-co-glycolide], polyanhydrides (e.g., poly(adipic anhydride)), polyorthoesters, blends and copolymers thereof and the like. Methacrylates can be but not limited to Eudragit® L; Eudragit® S; Eudragit® FS 30 D; Eudragit® L30D-55; and Eudragit® L100-55, Eudragit RL PO, Eudragit RL 100, Eudragit RL 30 D, Eudragit?® E, Eudragit?® NE and the like.
Suitable release retarding polymers may include one or more enteric coatings are usually formulated with synthetic polymers that contain ionisable functional groups that render the polymer water soluble at a pH value.
All enteric polymers that remain intact at pH value lower than about 4.0 and dissolve at pH values higher than 4.0, preferably higher than 5.0, most preferably about 6.0, are considered useful as rate controlling agents for this composition.
Suitable enteric polymers may include but not limited to one or more of methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, hydroxyethyl ethyl cellulose phthalate, cellulose acetate tetrahydrophtalate, acrylic resin and the like.
Suitable melt extrusion polymers can be, but not limited to derivatised cellulose, poly(methacrylate) derivative, poly(ethylene-co-vinyl acetate), poly(ethylene), poly(vinyl acetate-co-methacrylic acid), epoxy resins and caprolactones, poly(ethylene oxide), poly(ethylene glycol) and others including various waxes, fats, lipid-based excipients, including the Gelucire®, Witepsol®, Labrafil® and the like.
Pharmaceutically acceptable excipients
The compositions of the present inventions further comprises one or more pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipients” include, but not limited to, diluents, disintegrants, binders, lubricants, glidants, acidifying agent, alkalizing agent, stabilizers, surfactants, sweetener, film coating materials, plasticizers, pigments, opacifiers, coloring agents and the like.
Suitable diluents, may be selected from, but not limited to the group consisting of different grades of starches, such as maize starch, potato starch, rice starch, wheat starch, pregelatinised starch, fully pregelatinised starch; cellulose derivatives, such as microcrystalline cellulose or silicified microcrystalline cellulose; sugar alcohols such as mannitol, erythritol, sorbitol, xylitol; monosaccharides like glucose; oligosaccharides like sucrose and lactose such as lactose monohydrate, lactose anhydrous, spray dried lactose or anhydrous lactose; calcium salts, such as calcium hydrogenphosphate; particularly preferably the fillers are selected from the group consisting of, microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, spray dried lactose, and anhydrous lactose and the like.
Suitable disintegrants, if used, may be selected from, but not limited to the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, crosslinked), starch, modified starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate, crosslinked polyvinylpyrrolidone (crospovidone), and low-substituted hydroxypropylcellulose, and disintegrating aids such as magnesium alumino-metasilicate and ion exchange resins like polacrilin potassium; particularly preferably the disintegrants are selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone and the like.
Suitable binders may be selected from, but not limited to the group consisting of polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (Copovidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates, water, pregelatinized starch and the like.
Suitable lubricants may be selected from, but not limited to the group consisting of stearic acid, talc, glyceryl behenate, sodium stearyl fumarate and magnesium stearate; particularly preferably the lubricant is magnesium stearate and sodium stearyl fumarate and the like.
Suitable glidants, if used, may be selected from, but not limited to the group consisting of colloidal silica, hydrophobic colloidal silica and magnesium trisilicate, such as talc and the like.
Composition may contain acidifying and alkalinizing agent. Acidifying agents can be selected from, but not limited to citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid and mixtures thereof and the like. Alkalizing agent can be selected from, but not limited to magnesium oxide, aluminium oxide, ammonium hydroxide, magaldrate, an alkali metal salt or alkaline earth metal salt, such as sodium bicarbonate, calcium carbonate or sodium citrate, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide, with magnesium oxide or calcium carbonate and meglumine and the like.
Suitable sweeteners, if used, may be selected from, but not limited to the group consisting of aspartame, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, and the like.
Suitable film-forming agents and coating materials, if used, may include, but are not limited to hydroxypropyl methylcellulose (Hypromellose), hydroxypropyl cellulose, polyvinylalcohol, , methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, shellac, liquid glucose, hydroxyethyl cellulose, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate such as Kollidon® VA64 BASF, copolymers of acrylic and/or methacrylic acid esters with trimethylammoniummethylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid methylester and the like.
Suitable plasticizers, if used, may include, but are not limited to polyethylene glycol, diethyl phthalate and glycerol. Preference is given to polyethylene glycol and the like.
Suitable stabilizers, if used, may include, but are not limited sodium metabisulphite, ascorbic acid and its derivatives, malic acid, isoascorbic acid, citric acid, tartaric acid, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, calcium hydrogen phosphate, sulphur dioxide, sodium sulphite, sodium bisulphate, EDTA (ethylene diamine tetraacetic acid), tocopherol and the like.
Naltrexone formulations
The naltrexone formulations or compositions of the present specification are preferably in oral dosage forms, and having sustained release profile. Examples of said oral dosage form includes, are but not limited to tablets, mini-tablets, pellets or other multi-particulates compositions.
The sustained release naltrexone (or pharmaceutically acceptable salt thereof) formulations are prepared by using one or more release retarding polymers and one or more pharmaceutically acceptable excipients. The use of release retarding polymer aids to achieve sustained or extended release profile. The sustained release naltrexone formulation of the present specification typically provides release profile of about 6-8 hour. The sustained release naltrexone formulation contains naltrexone in an amount of more than 20%, preferably more than 25% (w/w) based on the total weight of said naltrexone formulation. The sustained release naltrexone formulations/portions can be prepared by one or more of various methods, but not limited direct compression, wet granulation, dry granulation (roller compaction), solvent evaporation, hot melt granulation, hot melt extrusion, fluid bed granulation, spray drying, extrusion-spheronization and the like. Such processes are well known in the art.
The sustained release naltrexone formulation of the present specifications when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus, exhibits a characteristic release profile of naltrexone or pharmaceutically acceptable salt thereof in the manner of:
i) releases no more than 50% in 1 hour,
ii) releases at least about 30% and no more than 70% in 2 hours, and
iii) releases at least about 75% in 8 hours.
Zonisamide formulations
The zonisamide compositions or formulations of the present specification are preferably in solid oral dosage forms, and having sustained release profile. Examples of said solid oral dosage form includes, are but not limited to tablets, mini-tablets, pellets or other multi-particulates compositions. The extended release zonisamide (or pharmaceutically acceptable salt thereof) formulation further comprise one or more release retarding polymers and one or more pharmaceutically acceptable excipients. The use of release retarding polymer aids to achieve extended release profile. The sustained release zonisamide formulation of the present specification typically provides release profile of about 10-12 hours. The sustained release zonisamide formulation contains zonisamide in an amount of more than 40%, preferably more than 50% (w/w) based on the total weight of said zonisamide formulation. The zonisamide formulation of the present invention can be prepared by one or more of various methods, but not limited direct compression, wet granulation, dry granulation (roller compaction), solvent evaporation, hot melt granulation, hot melt extrusion, fluid bed granulation, spray drying, extrusion-spheronization and the like. Such processes are well known in the art.
The sustained release zonisamide formulation of the present specifications when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus, exhibits a characteristic release profile of zonisamide or pharmaceutically acceptable salt thereof in the manner of:
i) releases no more than 45% in 1 hour,
ii) releases at least about 25% and no more than 70% in 4 hours, and
iii) releases at least about 75% in 12 hours.
Pharmaceutical unit composition
The pharmaceutical unit composition comprising combination of naltrexone and zonisamide (or pharmaceutically acceptable salt thereof) can be prepared by making the individual components or formulations of naltrexone or zonisamide separately which can then be formulated in to a suitable unit composition like tablets, capsules, sachets and the like. For example, the individual formulations can be filled in a capsule or a sachet. The size/dimensions of the individual formulations can be modified in such a way that it can be filled in the capsule of a suitable size. Alternatively, the individual components can be further processed to form a bilayer tablet or inlay tablet. Thus, the naltrexone and zonisamide formulations are present in physically separated form in the pharmaceutical unit composition. The individual components can be prepared by the one or more of various methods, as described above.
The pharmaceutical unit composition of the present specification comprising naltrexone and zonisamide may have different release profile. For example, naltrexone formulation with sustained release profile of about 6-8 hours and zonisamide formulation with sustained release profile of about 10-12 hours. The release profile are selected based on the need, and therapeutic effective dose of the naltrexone and zonisamide, so that the unit composition can be administered once daily and reduced the side effects of immediate release formulations of individual drugs. In order to achieve such release profile, the said compositions can be further coated with suitable film-forming agents and/or coating materials to form a subcoating or enteric coating. Such coating methods are well known in the art.
The pharmaceutical unit composition of the present specifications when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus, exhibits a characteristic release profile of naltrexone or pharmaceutically acceptable salts thereof in the manner of:
i) releases no more than 50% in 1 hour,
ii) releases at least about 30% and no more than 70% in 2 hours, and
iii) releases at least about 75% in 8 hours.
and/or exhibits a characteristic release profile zonisamide or pharmaceutically acceptable salts thereof in the manner of:
i) releases no more than 45% in 1 hour,
ii) releases at least about 25% and no more than 70% in 4 hours, and
iii) releases at least about 75% in 12 hours.
The pharmaceutical unit compositions of the present specification may be suitably packed in to any conventional pack like stick pack, blister pack, HDPE bottle or any other packaging well known in the art.
The composition or pharmaceutical unit composition comprising naltrexone and zonisamide of the present specification can be used for the treatment and/or management of obesity. The combination of naltrexone and zonisamide would provide synergistic activity against the inhibition of food intake and reduction of bodyweight when compared to their individual treatment.
The pharmaceutical unit compositions of the present specification would be stable throughout the shelf life which can be established by subjecting the compositions to accelerated and long term stability studies.
The following examples will further describe certain specific aspects and embodiments of the invention in greater details and are not intended to limit the scope of invention.
EXAMPLES
Example 1: Sustained release (SR) formulations of naltrexone.
Naltrexone SR Formulations
Ingredients Example 1a
(% w/w) Example 1b
(% w/w) Example 1c
(% w/w) Example 1d
(% w/w) Example 1e
(% w/w)
Intra-granular
Naltrexone hydrochloride 32 25 32 25 32
Microcrystalline cellulose 32 35 - 43 -
Mannitol - - 30 25 35
Hydroxypropyl methyl cellulose 35 34 37 -
Sodium carboxymethyl cellulose - 5.4 - 4.4
Ethyl cellulose - - 31.3 28
Disodium EDTA 0.40 - 0.2 - -
ascorbic acid - - 0.3 0.2 -
sodium metabisulphite - 0.10 - - 0.10
Binder solution
Water q.s. q.s. q.s. q.s. q.s.
Extra-granular
Magnesium stearate 0.60 0.50 - - 0.5
Talc - - 0.50 0.50 -
Total 100 100 100 100 100

Process:
1. Naltrexone along with other intra-granular excipients were granulated by using granulating fluid in fluidized bed process.
2. Granules obtained in step 1 were then dried, milled to a suitable sized.
3. The milled granules obtained in step 2 were lubricated with extra-granular material and compressed in to tablets of a suitable size.
Example 2: Sustained release (SR) formulations of zonisamide.
Ingredients Example 2a
(% w/w) Example 2b
(% w/w) Example 2c
(% w/w) Example 2d
(% w/w) Example 2e
(% w/w)
Intra-granular
Zonisamide 60.4 70.8 72.8 65.2 65.8
Microcrystalline cellulose 14.4 - 10.4 10.4 14.4
Hydroxypropyl methyl cellulose 10.2 - - 7.2
Sodium carboxymethyl cellulose - 13.3 - - 7.4
Binder Solution
Water q.s. q.s. q.s. q.s. q.s.
Hydroxypropyl methyl cellulose 2 - 1.6 - 1.2
Polyvinyl pyrrolidone - 1.6 - 2 -
Extra-granular
Magnesium stearate 0.4 0.4 0.48 0.48 0.4
Iron oxide 0.2 0.3 0.32 0.32 0.3
Hydroxypropyl methyl cellulose 8.8 - 14.4 14.4 10.5
Glyceryl dibehenate 3.6 13.6 - - -
Total 100 100 100 100 100

Process:
1. Zonisamide along with other intra-granular excipients were granulated using the binder solution in a rapid mix granulator.
2. Granules obtained in step 1, were then dried, milled to a suitable sized.
3. The milled granules obtained in step 2, were lubricated with extra-granular material and compressed in to tablets of a suitable size.

Example 3: Pharmaceutical unit compositions of naltrexone and zonisamide
Some pharmaceutical unit compositions comprising naltrexone and zonisamide formulations as per the present specification are described below:
Examples API* Dosage form Dose/Amount
Example 3a Naltrexone Sustained release tablet 16 mg
Zonisamide Sustained release tablet 91 mg

Example 3b Naltrexone Sustained release tablet 32 mg
Zonisamide Sustained release tablet 182 mg

Example 3c Naltrexone Sustained release tablet 32 mg
Zonisamide Sustained release tablet 364 mg

Example 3d Naltrexone Sustained release pellets 16 mg
Zonisamide Sustained release pellets 273 mg
*API or their pharmaceutically acceptable salts

Process:
1. Sustained release formulations of naltrexone were prepared according to example 1.
2. Sustained release formulations of zonisamide were prepared according to example 2.
3. The compositions prepared in Step 1&2 were filled in a capsule of suitable size.

Stability Study:
The stability of the pharmaceutical unit composition comprising naltrexone and zonisamide formulations as per the present specification were evaluated through accelerated stability studies. Two compositions were prepared according to the formula and process of example 3b and 3c, and the compositions were subjected to stability study at 40 °C/75% RH. The compositions were found to be stable at accelerated conditions. Table 1 represents the study result data.

Table 1: Stability study of unit composition comprising naltrexone and zonisamide.
Example- 3b Example- 3c
Stability condition 40 °C/75% RH 40 °C/75% RH
Time period Limit Initial 3M 6M Limit Initial 3M 6M
Naltrexone HCl
Assay (%) 90-110 97.4 97.3 96.0 90-110 97.4 97.4 99.3
Related Substance (%) NMT 2 0.58 0.82 0.69 NMT 2 0.39 0.66 0.81
Zonisamide
Assay (%) 90-110 99.8 99.0 101.6 90-110 99.6 98.9 98.4
Related Substance (%) NMT 2 ND ND ND NMT 2 ND ND ND

ND: Not detected, NMT: Not more than.

In-vitro dissolution study:

The release profile of the pharmaceutical unit composition comprising naltrexone and zonisamide formulations as per the present specification was evaluated through in-vitro dissolution studies. The unit composition was prepared according to the formula and process of example 3b, and was subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus (paddle). Table 2 represents the dissolution results data of naltrexone and zonisamide. The dissolution profile of the composition was also assessed after storage in accelerated stability condition (40 °C/75% RH) for 6 months. Figure 1 & 2 represent the dissolution profile of naltrexone hydrochloride and zonisamide at initial stage and after 6 month storage in accelerated stability condition (40 °C/75% RH) respectively.

Table 2: Dissolution study of unit composition comprising naltrexone and zonisamide.

Naltrexone HCl release profile Zonisamide release profile
Time point Time (hour) Initial
(% of release) 6M
(% of release) Time (hour) Initial
(% of release) 6M
(% of release)
Dissolution study of example 3b 1 hr. 30 25 1 hr. 20 11
2 hr. 48 41 4 hr. 49 42
8 hr. 93 87 8 hr. 78 78
10 hr. 97 92 10 hr. 93 89
12 hr. 99 94

Efficacy Study:

The efficacy of naltrexone and zonisamide combination for the treatment or management obesity was evaluated in animal model. The diet induced obese (DIO) mice were selected for the study. Animals were kept either on high fat diet (60% kcal) or Harlan diet (2918 Irradiated diet) for a period of 20 weeks. On the day of initiation of study, animals was randomized into different groups (four group) as indicated in the table 1 below based on bodyweight, such that there is less than 10% intergroup variation and 25% intragroup variation for bodyweight. Dosing were initiated once daily from day 1 to day 14. All the test compounds were administered intraperitoneally.

Feed Intake:
Feed consumption was observed daily from day 1 to day 13. At day 1 and day 13, a pre-weighed amount of food was kept (Immediate after the administration vehicle or test or reference compound) and same was reweighed at the end of the day. From this food consumption was calculated for individual animal. Results showed in Table 3.

Body weight:
Body weight was observed daily from day 0 to day 14. Results showed in Table 3.

Statistical Analysis:
Statistical analysis was performed using one way analysis of variance (ANOVA), followed by Dunnett’s multiple comparison test wherever applicable. p<0.05 was considered to be statistically significant.

Results:
Table 3: Food consumption and body weight measurement in different groups of diet induced obese (DIO) mice.
Food consumptions in different days
Body weights in Different days (gm)
Groups Day 1 Day 13 Day 0 Day 14
Vehicle, I.P (DIO Mice)
2.4 ± 0.4 3.2 ± 0.1 46.6 ± 1.0 45.2 ± 1
Zonisamide, 30 mg/kg, I.P, (DIO Mice) 2.0 ± 0.1 3.1 ± 0.1 46.6 ± 0.9 43.4 ± 1.1
Naltrexone HCl, 3 mg/kg, I.P, (DIO Mice)
2.2 ± 0.3 3.5 ± 0.1 46.8 ± 0.7 45.5 ± 0.6
Zonisamide + Naltrexone HCl, 30+3 mg/kg, I.P, (DIO Mice) 1.6 ± 0.3 2.4 ± 0.2 46.8 ± 0.6 42.4 ± 1.6
Vehicle for Zonisamide: PEG 400 (35%) + 2% HPMC (32.5%) + Water for injection
Vehicle for Naltrexone HCl: Sterile water for injection
Vehicle used for Zonisamide will be used as vehicle control in the current study

Feed intake from day 1 to 13 in DIO mice

Zonisamide at 30mg/kg, i.p. showed significant reduction (*p<0.05) in food intake as compared to vehicle group. The treatment with Naltrexone HCl at 3 mg/kg, i.p. did not show significant reduction in food intake when compared to vehicle group. Combination group showed significant reduction (*p<0.001) in food intake as compared to vehicle group (Table 3).

Body weight from day 0 to 14 in DIO mice

Zonisamide at 30mg/kg, i.p. showed significant reduction (*p<0.05) in bodyweight as compared to vehicle group. The treatment with Naltrexone HCl at 3 mg/kg, i.p. did not show significant reduction in bodyweight when compared to vehicle group. Combination group showed significant reduction (*p<0.001) in bodyweight as compared to vehicle group (Table 3).

Overall the combination of naltrexone and zonisamide showed synergistic activity against the inhibition of food intake in and very robust reduction of bodyweight diet induced obese mice when compared to their individual treatment groups.