WO2021053542A1 - Compositions pharmaceutiques pour la gestion de l'obésité - Google Patents

Compositions pharmaceutiques pour la gestion de l'obésité Download PDF

Info

Publication number
WO2021053542A1
WO2021053542A1 PCT/IB2020/058622 IB2020058622W WO2021053542A1 WO 2021053542 A1 WO2021053542 A1 WO 2021053542A1 IB 2020058622 W IB2020058622 W IB 2020058622W WO 2021053542 A1 WO2021053542 A1 WO 2021053542A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
naltrexone
zonisamide
pharmaceutically acceptable
acceptable salts
Prior art date
Application number
PCT/IB2020/058622
Other languages
English (en)
Inventor
Rajan Mittal
Syed Mujtaba Hussain Naqvi
Suyog Mehta
Sanjay Kumar Singh
Saurabh Srivastava
Anup Avijit Choudhury
Rajeev Raghuvanshi
Original Assignee
Dr. Reddy’S Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Reddy’S Laboratories Limited filed Critical Dr. Reddy’S Laboratories Limited
Publication of WO2021053542A1 publication Critical patent/WO2021053542A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • 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.
  • 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.
  • BMI body mass index
  • 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.
  • 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.
  • FDA US Food and Drug Administration
  • naltrexone is marketed under the brand name as NODICT®, and it is available as 25 mg, 50 mg and 100 mg oral tablets.
  • NODICT® naltrexone
  • 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 l,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:
  • naltrexone and zonisamide are not approved anywhere in the world for the treatment or management of obesity.
  • the individual drugs are also not approved for obesity management.
  • novel pharmaceutical composition comprising of naltrexone and zonisamide, which can be administered once daily and suitable for obesity management.
  • 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.
  • CNS and GIT adverse effects such as nausea, vomiting, anorexia, dizziness, headache etc. after administration.
  • naltrexone hydrochloride belongs to class I of bio pharmaceutics classification system (BCS) with high solubility and high permeability
  • 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.
  • 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 are expected to reduce peak plasma concentration and provide potentially lesser adverse effect in obese patient.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present specification relates to a pharmaceutical unit composition
  • 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.
  • 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 in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.
  • 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.
  • the present specification relates to a capsule composition
  • 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 as an adjunct to a reduced- calorie diet and increased physical activity in individuals with an initial body mass index (BMI) of: 30 kg/m2 or greater (obese) or 25 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity.
  • BMI body mass index
  • the present specification relates to a method of treating overweight or obesity as an adjunct to a reduced-calorie diet and increased physical activity in an individual as suffering from overweight or obesity with an initial body mass index of at least 30 kg/m2 or 25 kg/m2 in the presence of at least one weight- related comorbidity, said method comprising administering to the said individual to a pharmaceutical unit composition 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 32 mg and 91-364 mg respectively, wherein the said composition is administered once daily.
  • Figure 1 Dissolution profile of naltrexone HC1 and zonisamide of the pharmaceutical unit composition at initial stage.
  • Figure 2 Dissolution profile of naltrexone HC1 and zonisamide of the pharmaceutical unit composition after 6 month storage at accelerated stability condition (40°C/75% RH).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present specification relates to a capsule composition
  • 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 present specification relates to a method of treating overweight or obesity as an adjunct to a reduced-calorie diet and increased physical activity in an individual as suffering from overweight or obesity with an initial body mass index of at least 30 kg/m2 or 25 kg/m2 in the presence of at least one weight- related comorbidity, said method comprising administering to the said individual to a pharmaceutical unit composition 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 32 mg and 91-364 mg respectively, wherein the said composition is administered once daily
  • once daily 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.
  • composition 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.
  • 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.
  • 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.
  • naltrexone is present in the pharmaceutically acceptable salt form, e.g. naltrexone hydrochloride (HC1).
  • HC1 naltrexone hydrochloride
  • 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.
  • 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.
  • obesity management 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 in individuals with an initial body mass index (BMI) of 30 kg/m2 or greater (obese) or body mass index of 25 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity.
  • BMI body mass index
  • comorbidity includes hypertension, type 2 diabetes mellitus, or dyslipidemia or other cardio vascular diseases and the like.
  • 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.
  • release retarding polymers in the context of the present specification include, but are not limited to, polyethylene glycols (e.g.
  • 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- di
  • 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 idon
  • 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.
  • 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.
  • CAP cellulose acetate phthalate
  • PVAP polyvinyl a
  • 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.
  • compositions of the present inventions further comprises one or more pharmaceutically acceptable excipients.
  • 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.
  • starches such as maize starch, potato starch, rice starch, wheat
  • Suitable disintegrants may be selected from, but not limited to the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, crossbnked), 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.
  • ovidone polyvinyl pyrrolidone
  • Polyvinyl alcohol 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 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 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 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 may include, but are not limited to polyethylene glycol, diethyl phthalate and glycerol. Preference is given to polyethylene glycol and the like.
  • Suitable stabilizers 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 or compositions of the present specification are preferably in oral dosage forms, and having sustained release profile.
  • 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.
  • the zonisamide compositions or formulations of the present specification are preferably in solid oral dosage forms, and having sustained release profile.
  • 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.
  • the pharmaceutical unit composition comprising combination of naltrexone and zonisamide (or pharmaceutically acceptable salts 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.
  • a suitable unit composition like tablets, capsules, sachets and the like.
  • 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.
  • the individual components can be further processed to form a bilayer tablet or inlay tablet.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 1 Sustained release (SR) formulations of naltrexone.
  • Naltrexone along with other intra-granular excipients were granulated by using granulating fluid in fluidized bed process.
  • step 2 Granules obtained in step 1 were then dried, milled to a suitable sized.
  • Example 2 Sustained release (SR) formulations of zonisamide.
  • step 2 Granules obtained in step 1, were then dried, milled to a suitable sized.
  • Example 3 Pharmaceutical unit compositions of naltrexone and zonisamide
  • compositions comprising naltrexone and zonisamide formulations as per the present specification are described below:
  • compositions 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.
  • 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.
  • mice 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.
  • Table 3 Food consumption and body weight measurement in different groups of diet induced obese (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 HC1 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).
  • 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.
  • the pharmacokinetic parameters of the sustained release formulations of naltrexone and sustained release formulations of zonisamide according to the present invention were evaluated in-vivo through comparative bioavailability studies. The safety and tolerability of the formulations were also assessed.
  • test product Tl
  • reference product Rl
  • the pharmacokinetic parameters of the test and the reference product were assessed in an open label, randomized, three-way, crossover single dose comparative bioavailability study in healthy, adult, and male subjects under fasting conditions.
  • the measured pharmacokinetic parameters of naltrexone are summarized in table 4.
  • the test and reference products were well tolerated by the subjects. No adverse event were reported after administration of test products.
  • the 91 mg sustained release formulation of zonisamide was prepared according to the formula and process of example 2c and referred herein as test product (T2).
  • the reference product (R2) used herein was ZONEGRAN® (zonisamide) Capsules 100 mg of Concordia Pharmaceuticals.
  • the pharmacokinetic parameters of the test and the reference product were assessed in three-treatment randomized, single-dose, parallel design, comparative bioavailability study in healthy, adult, and male subjects under fasting conditions.
  • the measured pharmacokinetic parameters of zonisamide are summarized in table 5.
  • the test and reference products were well tolerated by the subjects. No adverse event were reported after administration of test products.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques comprenant de la naltrexone et du zonisamide ou un sel pharmaceutiquement acceptable de ceux-ci. L'invention concerne également une composition unitaire pharmaceutique de prise quotidienne comprenant de la naltrexone à libération prolongée et des formulations de zonisamide à libération prolongée. L'invention concerne en outre des procédés de préparation de telles compositions. L'invention concerne enfin l'utilisation de telles compositions pour le traitement et/ou la gestion de l'obésité.
PCT/IB2020/058622 2019-09-20 2020-09-16 Compositions pharmaceutiques pour la gestion de l'obésité WO2021053542A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201941038081 2019-09-20
IN201941038081 2019-09-20

Publications (1)

Publication Number Publication Date
WO2021053542A1 true WO2021053542A1 (fr) 2021-03-25

Family

ID=74883990

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2020/058622 WO2021053542A1 (fr) 2019-09-20 2020-09-16 Compositions pharmaceutiques pour la gestion de l'obésité

Country Status (1)

Country Link
WO (1) WO2021053542A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023146983A1 (fr) * 2022-01-26 2023-08-03 Aardvark Therapeutics, Inc. Formulation de naltrexone orale à libération prolongée de résine liquide pour le traitement de troubles liés à l'autisme

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007062228A1 (fr) * 2005-11-28 2007-05-31 Orexigen Therapeutics, Inc. Formulation de zonisamide a liberation prolongee
WO2008060964A2 (fr) * 2006-11-09 2008-05-22 Orexigen Therapeutics, Inc. Procédés d'administration de médications pour la perte de poids
WO2008060963A2 (fr) * 2006-11-09 2008-05-22 Orexigen Therapeutics, Inc. Formulations pharmaceutiques en couches
WO2009017755A2 (fr) * 2007-07-30 2009-02-05 Ampla Pharmaceuticals Inc. Agonistes de cb1 et agonistes inverses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007062228A1 (fr) * 2005-11-28 2007-05-31 Orexigen Therapeutics, Inc. Formulation de zonisamide a liberation prolongee
WO2008060964A2 (fr) * 2006-11-09 2008-05-22 Orexigen Therapeutics, Inc. Procédés d'administration de médications pour la perte de poids
WO2008060963A2 (fr) * 2006-11-09 2008-05-22 Orexigen Therapeutics, Inc. Formulations pharmaceutiques en couches
WO2009017755A2 (fr) * 2007-07-30 2009-02-05 Ampla Pharmaceuticals Inc. Agonistes de cb1 et agonistes inverses

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023146983A1 (fr) * 2022-01-26 2023-08-03 Aardvark Therapeutics, Inc. Formulation de naltrexone orale à libération prolongée de résine liquide pour le traitement de troubles liés à l'autisme

Similar Documents

Publication Publication Date Title
AU763309B2 (en) Bioenhanced formulations comprising eprosartan in oral solid dosage form
US6515010B1 (en) Carvedilol methanesulfonate
CA2592102C (fr) Preparation a liberation prolongee de type matrice contenant une drogue de base ou un sel de celle-ci, et methode pour la produire
US5807579A (en) Pseudoephedrine combination pharmaceutical compositions
JP5284967B2 (ja) 打錠障害を生じない錠剤製剤
AU2012357795B2 (en) New combination
CN110548149A (zh) 含葡萄糖激酶激活剂和α-葡萄糖苷酶抑制剂的药物组合及其制备方法和用途
US20060159753A1 (en) Matrix type sustained-release preparation containing basic drug or salt thereof
SK163998A3 (en) Pharmaceutical compositions
WO2010128525A2 (fr) Préparation d'ivabradine dans le traitement des maladies cardiovasculaires
NZ576987A (en) Pharmaceutical formulation comprising neurokinin antagonist
PL211062B1 (pl) Kompozycja farmaceutyczna do podawania doustnegozawierająca flibanserynę oraz zastosowanie kompozycji
WO2021053542A1 (fr) Compositions pharmaceutiques pour la gestion de l'obésité
US20050181055A1 (en) Pharmaceutical compositions of quinapril
US20120121722A1 (en) Atazanavir formulations
US20100010062A1 (en) Method of treatment using eprosartan
RU2453315C2 (ru) Фармацевтическая композиция для лечения аллергических заболеваний
WO2022070209A1 (fr) Formulations de combinaison de doses fixes à libération biphasique
WO2005030219A1 (fr) Procede de stabilisation d'un compose diarylvinylene
US20050118262A1 (en) Controlled release formulation
WO2022119542A1 (fr) Formulations pharmaceutiques solides de dapagliflozine amorphe
WO2020104955A1 (fr) Compositions pharmaceutiques d'acotiamide et d'inhibiteur de pompe à protons
NZ625506B2 (en) Compositions For Treatment of Heart Failure in Dogs.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20865903

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20865903

Country of ref document: EP

Kind code of ref document: A1