Classifications

• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
• • 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
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • 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
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • 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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

• the present invention relates to a stable pharmaceutical composition of fesoterodine hydrochloride and the process for its preparation. Background of the invention
• Fesoterodine is used in the treatment of overactive bladder, urinary incontinence and other dysfunctions of the urinary tract.
• European Patent number 1077912BI (assigned to M/s Schwarz Pharma AG and referred to herein as '912 patent) titled novel derivatives of 3, 3- diphenyl- propylamines discloses festoterodine hydrochloride.
• '912 patent does not disclose compositions of fesoterodine hydrochloride.
• European Patent number 1230209B1 (assigned to M/s Schwarz Pharma AG and referred to herein as '209 patent) discloses stable salts of novel derivatives of 3,3-diphenylpropylamines which includes Fesoterodine hydrogen fumarate.
• Fesoterodine is known in the art for its potency in treating urinary incontinence, it may exhibit substantial degradation under stress conditions, like humid environment and increased temperature. Hydrolyzation and oxidation are the probable mechanisms resulting in degradation. Hence, it is desirable to develop new pharmaceutical compositions comprising Fesoterodine that are more stable against degradation over an extended period of time even under stress conditions. It has now been surprisingly found that some pharmaceutical excipients are able to significantly slow down the degradation of Fesoterodine under stress conditions.
• United States Patent number 7807715 and United States Patent Publication number 20091117159 (both assigned to M/s UCB Pharma GmbH and referred to herein as '715 patent and '159 publication respectively) disclose a pharmaceutical granulate comprising fesoterodine or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable stabilizer, such as sorbitol, xylitol, polydextrose, isomalt, dextrose or combirrations thereof.
• sugar alcohols are very essential to prepare stable compositions of fesoterodine.
• the object of the present invention is to provide stable pharmaceutical composition comprising fesoterodine.bydrochloride.
• a stable pharmaceutical composition comprising fesoterodine hydrochloride, a rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selected from mannitol, maltitol and lactitol.
• a stable pharmaceutical extended release composition of fesoterodine hydrochloride comprising fesoterodine hydrochloride, a rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selectedfrom mannitol, maltitol and lactitol and total impurities are less than 1.00%w/w when stored in open vial at 40°C and 75% relative humidity for at least three months.
• a process for the preparation of a stable pharmaceutical composition of fesoterodine hydrochloride comprising admixing festoterodine hydrochloride, rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selected from mannitol, maltitol and lactitol and total impurities are less than 1.00%w/w when stored in open vial at 40°C and 75% relative humidity for at least three months; and optionally compressing.
• the present invention is directed to a stable pharmaceutical composition of fesoterodioe hydrochloride.
• Fesoterodine being an ester is susceptible to hydrolyzation during storage and after administration invivo. On hydrolyzation fesoterodine generates the metabolite (2- [(lR)-3-diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl) phenol along with other degradation products.
• a stable pharmaceutical composition of fesoterodine hydrochloride is provided.
• the stable pharmaceutical composition of fesoterodine hydrochloride of the present invention will comprise rate controlling, sugar alcohol and at least one pharmaceutical excipient.
• the % total impurities in the stable pharmaceutical composition of fesoterodine hydrochloride of the present invention is less than 1.00% w/w when stored in open vial at 40°C/75% RH for at least three months.
• Fesoterodine hydrochloride may be stabilized with sugar alcohol, polyethylene glycol, cyclodextrin, maltodextrin and the like.
• Sugar alcohols may be selected from mannitol, maltitol and lactitol.
• the ratio of fesoterodine hydrochloride to sugar alcohol may be selected from 1:25 to 25:1 parts by weight.
• the rate controlling polymers may be selected from one or more polymers/copolymers of cellulose or its derivatives such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, methylcellulose, carboxymethylcellulose and its salts; polyacrylates, methylacrylates, polyethylene oxides, polyethylene glycols, gums, chitosan, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or its derivatives, ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methylacrylates, polyamides, polycarbonates, polyalkylene, polyalkylene glycols, polyalkylene oxides, polyalky
• Natural polymers may also be added to the composition such as pectin, zein, casein, gluten, gelatin, serum albumin, collagen, oligosaccharides and polysaccharides such as cellulose, dextrans, gellan, carrageenan, xanthan gum, gum Arabic, alginic acid and the like.
• the amount of the rate controlling polymer in the pharmaceutical Composition ranges from about 10 to 80%w/w of the composition.
• the stable pharmaceutical composition of fesoterodine hydrochloride of the present invention may provide immediate or sustained or extended or controlled release of fesoterodine hydrochloride, preferably extended release.
• Pharmaceutical composition of fesoterodine hydrochloride of the present invention may be selected from tablets, capsules, pellets, granules, spheroids, beads, minitablets in capsules, pellets in capsule, granules in capsule and powders.
• the pharmaceutical composition of fesoterodine hydrochloride of the present invention may or may not be coated. Coating such as film, enteric coating may be used.
• the stable pharmaceutical composition of fesoterodine hydrochloride is an extended release composition comprising rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient.
• the % total impurities in the stable pharmaceutical composition of fesoterodine hydrochloride of the present invention is less than 1.00% w/w when stored in open vial at 40°C/75% RH for at least three months.
• Fesoterodine hydrochloride may be stabilized with sugar alcohol, polyethylene glycol, cyclodextrin, maltodextrin and the like.
• Sugar alcohols may be selected from mannitol, maltitol and lactitol.
• the ratio of fesoterodine hydrochloride to sugar alcohol may be selected from 1:25 to 25:1 parts by weight.
• the rate controlling polymers may be selected from one or more polymers/copolymers of cellulose or its derivatives such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, methylcellulose, carboxymethylcellulose and its salts; polyacrylates, methylacrylates, polyethylene oxides, polyethylene, glycols, gums, chitosan, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or its derivatives, ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methylacrylates, polyamides, polycarbonates, polyalkylene, polyalkylene glycols, polyalkylene oxides, polyal
• Natural polymers may also be added to the composition such as pectin, zein, casein, gluten, gelatin, serum albumin, collagen, oligosaccharides and polysaccharides such as cellulose, dextrans, gellan, carrageenan, xanthan gum, gum Arabic, alginic acid and the like.
• the amount of the rate controlling polymer in the pharmaceutical composition ranges from about 10 to 80%w/w of the composition.
• Pharmaceutical composition of fesoterodine hydrochloride of the present invention may be selected from tablets, capsules, pellets/ granules, spheroids, beads, minitablets in capsules, pellets in capsule, granules in capsule and powders.
• the pharmaceutical composition of fesoterodine hydrochloride of the present invention may or may not be coated. Coating such as film, enteric coating may be used.
• According to yet another embodiment of the present invention is the process for the preparation of stable pharmaceutical composition of fesoterodine hydrochloride is provided.
• Processes such as direct compression, wet granulation, dry granulation, slugging, roller compaction, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion spheronization, spray drying and the like may be used.
• Fesoterodine hydrochloride is admixed with rate controlling polymer, sugar alcohol and at least one pharmaceutically acceptable excipient; wherein sugar alcohol may be selected from mannitol, maltitol and lactitol, optionally granulated and optionally compressed.
• a process for the preparation of a stable pharmaceutical composition of fesoterodine hydrochloride comprising admixing or granulating festoterodine hydrochloride, rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selected from mannitol, maltitol and lactitol and total impurities are less than 1 %w/w when stored in open vial at 40°C and 75% relative humidity for at least three months; optionally compressing.
• the stable pharmaceutical composition of fesoterodine hydrochloride of the present invention may provide immediate or sustained or extended or controlled release of fesoterodine hydrochloride, preferably extended release.
• the pharmaceutically acceptable excipient used in the composition and process for preparation of the composition of the present invention must be compatible with fesoterodine hydrochloride.
• the pharmaceutical excipients may be selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, solubilizers, surfactants, glidants, plasticizers, preservatives and sweeteners.
• Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol. lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 5-98 weight % of the total weight of the composition.
• Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol. Binders may be in the range of 1- 40 weight % of the total weight of the composition.
• Suitable fillers are preferably selected from atleast one of starch derivatives, such as com starch, potato starch, maize starch maize or rice starch.
• starch derivatives such as com starch, potato starch, maize starch maize or rice starch.
• Polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol, sorbitol and the like.
• Disintegrants may be selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium , poloxamer, povidone, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and the like. Disintegrants may be in the range of 5 - 25 weight % of the total weight of the composition.
• Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and the like. Glidants may be in the range of 0.01-2 weight % of the total weight of the composition.
• Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, glyceryl behenate and the like. Lubricants may be in the range of 0.1-2 weight % of the total weight of the composition.
• Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; aspartame and the like.
• Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavor, peppermint flavor and the like.
• Solubilizers may be selected from complex forming agents such as cyclodextrins, ion exchange resins, crown ethers and the like.
• Surfactants may be selected from polyoxyethylene alcohol ethers, polysorbates, polyoxypropylene polyoxyethylene copolymers such as poloxamers and the like.
• the following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.
• Results Indicate a controlled release profile of fesoterodine hydrochloride releasing approximately 55% of fesoterodine hydrochloride in 6hrs; and the profile remained stable after tablet storage in open vial at accelerated conditions for 1 month.
• the tablets are also checked for their degradation products under the same stability conditions and the table below summarizes the % Diol i.e. R(+)-2-(3-diisopropylamino-1- phenylpropyl)-4-hydroxymethylphenol and % of Total impurities formed during storage.

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Citations (4)

• 2014
  • 2014-08-11 WO PCT/IN2014/000523 patent/WO2015022703A1/en not_active Ceased
  • 2014-08-11 IN IN2631MU2013 patent/IN2013MU02631A/en unknown

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