JP2013538807A - Pharmaceutical composition comprising metformin and pioglitazone - Google Patents

Pharmaceutical composition comprising metformin and pioglitazone Download PDF

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Publication number
JP2013538807A
JP2013538807A JP2013526558A JP2013526558A JP2013538807A JP 2013538807 A JP2013538807 A JP 2013538807A JP 2013526558 A JP2013526558 A JP 2013526558A JP 2013526558 A JP2013526558 A JP 2013526558A JP 2013538807 A JP2013538807 A JP 2013538807A
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sustained release
pioglitazone
metformin
wax
cellulose
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シリシュクマール・クルカルニ
サティッシュ・クマール・ダラル
ハーシャル・ジャハギルダール
ヴィシャル・パティル
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ルピン・リミテッドLupin Limited
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Priority to IN979/KOL/2010 priority Critical
Priority to IN979KO2010 priority
Application filed by ルピン・リミテッドLupin Limited filed Critical ルピン・リミテッドLupin Limited
Priority to PCT/IB2011/002001 priority patent/WO2012028934A1/en
Publication of JP2013538807A publication Critical patent/JP2013538807A/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/155Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Abstract

Sustained release form of metformin or pharmaceutically acceptable salt, ester, solvate, hydrate, metabolite, prodrug or isomer thereof, and immediate release form of pioglitazone or pharmaceutically acceptable thereof Provided are pharmaceutical compositions comprising a salt, an ester, a solvate, a hydrate, a metabolite, a prodrug or an isomer. More specifically, a sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable additives, pioglitazone, a high viscosity polymer, and other pharmaceutically acceptable additives And a pharmaceutical composition comprising an immediate release pioglitazone layer. In addition, a sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable additives, and a fast comprising pioglitazone, polyvinyl alcohol, surfactants and other pharmaceutically acceptable additives. A pharmaceutical composition comprising a release pioglitazone layer.

Description

  The present invention relates to a sustained release form of metformin or a pharmaceutically acceptable salt, ester, solvate, hydrate, metabolite, prodrug or isomer thereof, and a rapid release form of pioglitazone or a pharmaceutical thereof And a pharmaceutical composition comprising an acceptable salt, ester, solvate, hydrate, metabolite, prodrug or isomer thereof.

  Type 2 diabetes is a chronic, lifelong disease that occurs when the body's insulin does not work effectively. Insulin is a hormone released by the pancreas in response to elevated blood glucose (glucose) levels in the blood. Type 2 diabetes is associated with insulin resistance (lack of physical ability to respond appropriately to insulin) and is often accompanied by obesity and high cholesterol.

  The main component of type 2 diabetes is "insulin resistance". The insulin produced by the pancreas can not bind to adipocytes and muscle cells and can not send glucose internally to produce energy. This results in hyperglycemia (high blood glucose). At the expense of the pancreas, it produces more insulin. The cell senses this large amount of insulin and makes it more resistant, resulting in a vicious circle where glucose levels are high and in many cases insulin levels are high.

  If such people can not make blood glucose levels normal or nearly normal by eating and exercising, drug therapy may be applied to lower blood glucose levels. For drug therapy to treat type 2 diabetes, for example, oral sulfonylureas (such as glimepiride, glyburide and tolazamide) cause the pancreas to make more insulin, and biguanides (metformin) reduce glucose production, Alpha-glucosidase inhibitors (such as acarbose) reduce the absorption of carbohydrates from the digestive tract, which lowers postprandial glucose levels, and thiazolidinediones (such as rosiglitazone and pioglitazone) make insulin more effective at cell sites Including to help make it effective. Essentially, they increase the sensitivity (reactivity) of cells to insulin, and meglitinide (including repaglinide and nateglinide) causes the pancreas to make more insulin depending on the amount of glucose in the blood, and the insulin in the blood DPP-IV inhibitors (such as vildagliptin and sitagliptin) that lower blood glucose levels by blocking the enzyme known as dipeptidyl peptidase IV or DPP-IV, which normally inactivates the circulating protein (GLP-1) ) And their combinations.

  Pioglitazone, a member of the thiazolidinediones, reduces insulin resistance in the periphery and in the liver, resulting in increased insulin-dependent glucose disposal and reduced hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-γ (PPAR-γ). PPAR receptors are found in tissues important for insulin activity, such as adipose tissue, skeletal muscle and liver. Activation of the PPAR-γ nuclear receptor regulates transcription of many insulin responsive genes involved in the control of glucose and lipid metabolism.

  Metformin hydrochloride, biguanide improves glucose tolerance in patients with type 2 diabetes and reduces both basal and postprandial plasma glucose levels. Metformin improves hepatic insulin sensitivity by reducing hepatic glucose production, reducing intestinal glucose absorption, and increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not cause hypoglycemia in patients with type 2 diabetes or in healthy individuals. With metformin therapy, insulin secretion remains unchanged, but fasting insulin levels and all-day plasma insulin response may actually decrease.

  The chemical name of pioglitazone is (±) -5-[[4- [2- (5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl] -2,4-thiazolidinedione. Its molecular formula is C19H20N2O3S.HCl and its molecular weight is 392.90. The molecular formula of metformin (N, N-dimethylimidodicarbonimidic acid diamide) is C4 H11 N5.HCl, and the molecular weight is 165.62.

  The combination of pioglitazone hydrochloride and metformin hydrochloride is marketed in the United States as ACTOPLUS MET® and ACTOPLUS MET® XR and is already treated with pioglitazone and metformin, or pioglitazone alone or metformin It has been approved as a dietary and exercise supplement to improve glycemic control in adults with type 2 diabetes mellitus, who alone has poor glycemic control. ACTOPLUS MET® is available as a tablet for oral administration containing pioglitazone hydrochloride and metformin hydrochloride in an amount corresponding to 15 mg pioglitazone and 500 mg metformin hydrochloride or 850 mg metformin hydrochloride. ACTOPLUS MET® XR is a once-daily tablet for oral administration containing pioglitazone hydrochloride and metformin hydrochloride in an amount corresponding to 15 mg pioglitazone and 1000 mg metformin hydrochloride, or 30 mg pioglitazone and 1000 mg metformin hydrochloride It is available as

  US 4,687,777 in particular discloses pioglitazone. US 5,965,584 discloses a composition comprising a combination of pioglitazone and metformin. US 6,166,042 relates to the use of a combination of pioglitazone and metformin for the treatment of glucose metabolism disorders. US 6,166,043 relates to the use of a combination of pioglitazone and metformin to reduce the amount of active ingredient for diabetic patients. US 6,172,090 discloses the use of a combination of pioglitazone and metformin to reduce the side effects of the active ingredient for diabetic patients. US 6,099,859, US 6,166,042, US 6,495,162, US 6,790,459 and US 6,866,866 disclose controlled release compositions of metformin hydrochloride.

  Many proposals have been described in the prior art and disclose compositions comprising pioglitazone and metformin.

  US 6,780,432 discloses a combined preparation comprising pioglitazone hydrochloride and a biguanide such as metformin. Specifically, the product comprises a core of biguanide, such as metformin, at least a portion of which has a pioglitazone layer or coat.

  US 6,524,621 discloses a formulation comprising pioglitazone hydrochloride and a biguanide such as metformin. Specifically, the product comprises a core of a biguanide, eg metformin, at least a portion of which comprises a layer or coat of pioglitazone and a regulatory polymer comprising silate associated with at least one of said active ingredients. Have.

  US 6,403, 121 discloses a formulation comprising pioglitazone hydrochloride and a biguanide such as metformin. Specifically, the product comprises a core of a biguanide, eg metformin, at least a portion of which comprises a layer or coat of pioglitazone and a regulatory polymer comprising a polysaccharide associated with at least one of the active ingredients. Have.

  US 2006/0141128 discloses a process for preparing coated pioglitazone hydrochloride comprising pioglitazone hydrochloride and a core coating material having a low viscosity polymer.

  US 2006/0286168 is a step of coating a core containing an active ingredient with pioglitazone hydrochloride dispersed in an organic solvent, wherein the organic solvent contains polyvinylpyrrolidone as a coating base soluble in the organic solvent. Disclosed are methods of preparing coated pioglitazone hydrochloride, including:

  US 2004/0106 660 discloses a once-a-day oral pharmaceutical tablet consisting of a semipermeable coating surrounding the core and a core with an immediate release pioglitazone coating.

  US 2004/0161462 discloses a pharmaceutical dosage form comprising a controlled release metformin hydrochloride core, a sustained release coating surrounding the core, and an immediate release pioglitazone layer.

  WO 2004/026241 discloses a pharmaceutical dosage form comprising a biguanide (such as metformin) in combination with a thiazolidinedione derivative, wherein the metformin is formulated as a permeable tablet with or without a gelling or expandable polymer ing. The thiazolidinedione derivative may be part of the controlled release core, and preferably may be combined with the controlled release core to provide an immediate release of the thiazolidinedione derivative.

  US 2009/0246232 is a pharmaceutical composition comprising the steps of compressing a mixture comprising an insulin sensitivity enhancer (pioglitazone hydrochloride), a biguanide and an additive, and coating the compressed mixture to form an oral dosage form. Discloses a manufacturing method of

  US 2007/0166376 comprises (1) a layer containing an insulin sensitizer, and (2) (a) an active ingredient (excluding an insulin sensitizer), (b) microcrystalline cellulose having an average particle size of 5 to 25 μm, A solid formulation comprising (c) a layer containing microcrystalline cellulose having an average particle size of 30 to 100 μm and (d) polyvinyl pyrrolidone K-90 is disclosed.

  US2009 / 0028939 describes "a part containing coated particles, wherein particles containing an insulin sensitizer are coated with lactose or sugar alcohol" and "a part containing an active ingredient other than an insulin sensitizer" Disclosed is a solid preparation comprising.

  US 2006/0057202 discloses a composition comprising thiazolidinediones and biguanides for controlling hyperglycemia, manufactured as multilayer tablets.

  Pioglitazone hydrochloride is insoluble in water, and it is well known in the art that water insoluble drugs have a correspondingly low degree of bioavailability due to their low solubility in solid dosage forms.

U.S. Pat. No. 4,687,777 U.S. Pat. No. 5,965,584 U.S. Patent No. 6,166,042 U.S. Patent No. 6,166,043 U.S. Patent No. 6,172,090 U.S. Patent No. 6,099,859 U.S. Patent No. 6,166,042 U.S. Patent No. 6,495,162 U.S. Patent No. 6,790,459 U.S. Patent No. 6,866,866 U.S. Patent No. 6,780,432 U.S. Patent No. 6,524,621 U.S. Patent No. 6,403,121 US Patent Application Publication No. 2006/0141128 US Patent Application Publication No. 2006/0286168 US Patent Application Publication No. 2004/0106660 US Patent Application Publication No. 2004/0161462 WO 2004/026241 pamphlet U.S. Patent Application Publication No. 2009/0246232 U.S. Patent Application Publication No. 2007/0166376 US Patent Application Publication No. 2009/0028939 US Patent Application Publication No. 2006/0057202

  Thus, one embodiment discloses a pharmaceutical composition comprising sustained release metformin having a high viscosity polymer and a rapid release pioglitazone coating comprising a disintegrant.

  Another aspect discloses a pharmaceutical composition comprising sustained release metformin with an immediate release pioglitazone coating comprising a polymer and a surfactant.

  While there are many prior art disclosing compositions comprising sustained release metformin and immediate release pioglitazone in a coating, there is a need to provide improved compositions with good solubility.

One embodiment is
a) a sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable additives, and b) pioglitazone, a high viscosity polymer, a disintegrant and other pharmaceutically acceptable additives Disclosed is a pharmaceutical composition comprising an immediate release pioglitazone layer.

Other embodiments are
a) a sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable excipients, and b) pioglitazone, polyvinyl alcohol, surfactants and other pharmaceutically acceptable excipients Disclosed is a pharmaceutical composition comprising an immediate release pioglitazone layer.

Another embodiment is
a) A sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable additives,
Disclosed is a pharmaceutical composition comprising b) a sustained release membrane coat, and c) a rapid release pioglitazone layer comprising pioglitazone, a high viscosity polymer, a disintegrant and other pharmaceutically acceptable additives.

Another embodiment is
a) A sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable additives,
Disclosed is a pharmaceutical composition comprising b) a sustained release membrane coat, and c) a rapid release pioglitazone layer comprising pioglitazone, polyvinyl alcohol, surfactants and other pharmaceutically acceptable excipients.

Another embodiment is a method of preparing a pharmaceutical composition comprising sustained release metformin hydrochloride and immediate release pioglitazone hydrochloride,
a) preparing metformin granules using an aqueous binder solution comprising a pharmaceutically acceptable binder,
b) mixing the dried metformin granules with the sustained release polymer and other pharmaceutically acceptable excipients,
c) Lubricating and compressing the blend of step b) using a pharmaceutically acceptable additive into a core,
d) applying a sustained release membrane coat to the core of step c), and e) adding a high viscosity polymer, a disintegrant and other pharmaceutically acceptable to the sustained release membrane coated core of step d) Disclosed is a method comprising the step of applying a pioglitazone coating solution comprising an additive.

Another embodiment is a method of preparing a pharmaceutical composition comprising sustained release metformin hydrochloride and immediate release pioglitazone hydrochloride,
a) preparing metformin granules using an aqueous binder solution comprising a pharmaceutically acceptable binder,
b) mixing the dried metformin granules with the sustained release polymer and other pharmaceutically acceptable excipients,
c) Lubricating and compressing the blend of step b) using a pharmaceutically acceptable additive into a core,
d) applying a sustained release membrane coat to the core of step c), and e) polyvinyl alcohol, surfactant and other pharmaceutically acceptable to the slow release membrane coated core of step d) Disclosed is a method comprising the step of applying a pioglitazone coating solution comprising an additive.

  The present invention relates to metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, sustained release cores comprising prodrugs or isomers, and pioglitazone or pharmaceutically acceptable thereof The invention relates to a pharmaceutical composition comprising an immediate release layer comprising a salt, an ester, a solvate, a hydrate, a metabolite, a prodrug or isomer and a high viscosity polymer.

  As used herein, the term pioglitazone is intended to include all forms of pioglitazone or a pharmaceutically acceptable salt, ester, solvate, hydrate, metabolite, prodrug or isomer thereof. Become. The most preferred form is pioglitazone hydrochloride.

  As used herein, the term metformin includes all forms of metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof. Become. The most preferred form is metformin hydrochloride.

  A sustained release formulation will either release the drug at a near constant rate over time, or a near constant amount of drug will be released incrementally over time.

  The term sustained release formulations refers to extended release formulations, programmed release formulations, timed release formulations, controlled release formulations, site specific release formulations, sustained release formulations, controlled release formulations, slow release formulations, delayed release formulations, permeation It can also be used interchangeably with sexual dosage forms, bioadhesive formulations, buccal disintegration controlled release formulations, gastric retention formulations and other such dosage forms.

  As used herein, the term "rapid release" assumes the widely recognized definition in the pharmaceutical art. The immediate release form releases the drug immediately after administration.

  The term "core" is defined to mean a solid vehicle in which at least one active drug is uniformly or heterogeneously dispersed with pharmaceutically acceptable additives, powders, beads, granules It can be in the form of granules, microcapsules, granules, tablets, minitablets, compacts, long spheres, particles and the like.

  The terms "layer", "coat" or "coating" as used herein are used interchangeably and are defined to mean a process in which the entire surface of the core is coated with the coating composition.

  The term "sustained release membrane coat" is defined to mean a functional coat comprising at least one sustained release polymer. The controlled release membrane coat is permeable to both metformin and water.

  As used herein, the term "high viscosity polymer" is defined to mean a 5% aqueous solution having a viscosity of 35 mPas or greater when measured at 25 ° C.

  As used herein, the term "pharmaceutically acceptable excipient" is physiologically compatible with the physical and chemical properties of the particular metformin and rosiglitazone which are the active ingredients selected for use. Inert, pharmacologically inactive, including any material known to those skilled in the art.

  The pharmaceutical composition is a tablet (single-layer tablet, multilayer tablet, mini-tablet, bioadhesive tablet, caplet, matrix tablet, tablet in tablet, mucoadhesive tablet, controlled release tablet, pulse release tablet, sustained release tablet, etc. In the form of granules, beads, granules, long spheres, particles, powders, capsules, microcapsules, tablets in capsules, microspheres, matrix preparations, microencapsulating agents.

One embodiment is
a) a sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable additives, and b) pioglitazone, a high viscosity polymer, a disintegrant and other pharmaceutically acceptable additives Disclosed is a pharmaceutical composition comprising an immediate release pioglitazone layer.

Other embodiments are
a) a sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable excipients, and b) pioglitazone, polyvinyl alcohol, surfactants and other pharmaceutically acceptable excipients Disclosed is a pharmaceutical composition comprising an immediate release pioglitazone layer.

  The sustained release polymer may be selected from water soluble polymers, water insoluble polymers, waxy materials or combinations thereof.

  The water soluble polymer can be selected from: Methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; sodium or calcium carboxymethylcellulose, methylethylcellulose, ethylhydroxyethylcellulose, carboxy Alkyl celluloses such as alkyl cellulose esters; carbomer, glycerin fatty acid ester, sorbitan ester, lecithin; galactomannan, tragacanth gum, agarten, guar gum, gum arabic, pectin, acacia, karaya gum, locust bean gum, xanthan Ngum, pullulan, collagen, casein, carrageenan, algin, polycarbophil, ammonium alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, scleroglucan and polyfructan, other natural, semi-synthetic, such as maltodextrin, or Synthetic disaccharides, oligosaccharides and polysaccharides; methacrylate copolymers, polyvinyl alcohol, polyvinyl pyrrolidone, copolymers of polyvinyl pyrrolidone and vinyl acetate, combinations of polyvinyl alcohol and polyvinyl pyrrolidone; and polyethylene oxide and polypropylene oxide and ethylene oxide Polyalkylene oxides such as copolymers with propylene oxide; carboxyvinyl poly Sodium alginate, sodium hyaluronate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, gelatin, starch, cross-linked starch, microcrystalline cellulose, ceratonia, chitin, poly (hydroxyalkyl methacrylate), Polyvinyl alcohol low in acetate residues, expandable mixtures of agar and carboxymethylcellulose, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, and mixtures and blends thereof.

  The water insoluble polymer can be selected from: Cellulose acylate, Cellulose ethyl ether, Cellulose diacylate, Cellulose trisylate, Cellulose acetate, Cellulose diacetate, Cellulose triacetate, Mono-, di- and tri-cellulose alkanes, mono-, di- and tri-cellulose Aroyl, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, glycerin monooleate, glycerin monostearate, glycerin palmitostearate, polyvinyl acetate phthalate, Hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate; poly (alkyl methacrylate), poly (vinyl acetate) V) polyvinyl alcohol, polyacrylamide derivative, ammonio methacrylate copolymer, copolymer of polyacrylic acid and polyacrylate and methacrylate, aminoacryl-methacrylate copolymer, polyvinyl acetal diethylaminoacetate, maleic anhydride and styrene, ethylene, Copolymers with propylene or isobutylene, polyacrylamide, Polyox (polyethylene oxide), diesters of polyglucan, cellulose butyrate, cellulose propionate, shellac, chitosan, oleyl alcohol, zein, hydrogenated castor oil and the like.

  The waxy material can be selected from the following. Carnauba wax, beeswax, Chinese wax, persimmon wax, lanolin, white loam, white wax, yellow wax, candelilla wax, microcrystalline wax, castor oil, espartaw wax, wood wax, jojoba oil, cotton seed oil, corn oil, hydrogenation Cottonseed oil, auricula wax, spermaceti wax, ceresin wax, montan wax, ozokerite, peat wax, paraffin wax, polyethylene wax, and polyglycerin fatty acid ester.

  In one embodiment, the sustained release polymer may be bioadhesive.

  The bioadhesive polymer can be selected from the group consisting of: Proteins (eg hydrophilic proteins) such as carbohydrates, pectin, zein, modified zein, casein, gelatin, gluten, serum albumin and collagen; chitosan, oligosaccharides, polysaccharides such as cellulose, dextran, tamarind seed polysaccharides, gellan, carrageenan Gum, gum arabic, hyaluronic acid, polyhyaluronic acid, alginic acid and sodium alginate; glycerin monooleate, polyamide, polycarbonate, polyalkylene, polyalkylene glycol, polyalkylene oxide, polyalkylene terephthalate, polyvinyl alcohol, polyvinyl ether, polyvinyl alcohol Ester, polyvinyl halide, polyvinyl pyrrolidone, polyglycolide, polysiloxane, polyurethane, poly Polymers of styrene, acrylic and methacrylic acid esters, polylactic acid, poly (butyric acid), poly (valeric acid), poly (lactide-co-glycolide), polyanhydrides, polyorthoesters, poly (fumaric acid), poly ( Maleic acid), poly (methyl vinyl ether / maleic anhydride), polycarbophil and blends or copolymers or mixtures thereof.

  High viscosity polymers used for immediate release pioglitazone layers can include, but are not limited to: Methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; sodium or calcium carboxymethylcellulose, methylethylcellulose, ethylhydroxyethylcellulose, carboxy Alkyl celluloses such as alkyl cellulose esters; polyvinyl alcohol, crosslinked polyvinyl alcohol, polyvinyl pyrrolidone, copolymer of polyvinyl pyrrolidone and vinyl acetate, combination of polyvinyl alcohol and polyvinyl pyrrolidone; and polyethylene Kishido and polypropylene oxide and polyalkylene oxide, such as copolymers of ethylene oxide and propylene oxide.

  In a preferred embodiment, the high viscosity polymer used in the immediate release pioglitazone layer is hydroxypropyl cellulose (grade: Klucel LF, Aqualon (USA)), as measured at 25 ° C. using a Brookfield LVF viscometer: Its 5% aqueous solution with a viscosity of 75-150 mPas, hydroxypropyl cellulose (grade: Nisso HPC-L, Nisso America Inc.), 2% with a viscosity of 6.0-10.0 mPas when measured at 20 ° C. An aqueous solution, or a combination thereof.

  Disintegrants used for immediate release pioglitazone layers can include, but are not limited to: Povidone, low substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone (crospovidone), cross-linked sodium carboxymethyl cellulose, hydroxypropyl starch, sodium starch glycolate, sodium starch glucolate, sodium carboxymethyl cellulose, Carboxymethylcellulose calcium, sodium carboxymethyl starch; Ion exchange resins such as polacrilin potassium; microcrystalline cellulose, starch and pregelatinized starch, formalin-casein; clay such as bentonite or veegum; guar gum; cellulose or cellulose derivatives; sodium alginate, algin Calcium, alginate, chitosan, magnesium aluminum silicate and colloidal silicon dioxide.

  The surfactant used in the immediate release pioglitazone layer can be selected from hydrophilic surfactants, lipophilic surfactants or combinations thereof.

One embodiment is
a) a sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable excipients, and b) pioglitazone, a high viscosity polymer, surfactants and other pharmaceutically acceptable excipients Disclosed are pharmaceutical compositions comprising an immediate release pioglitazone layer comprising:

  The hydrophilic surfactant may be ionic or non-ionic.

  Suitable hydrophilic ionic surfactants include, but are not limited to: Alkyl ammonium salts, fusidates, amino acids, fatty acid derivatives of oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; And derivatives thereof; carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, sodium doxate, acyl lactylate; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides Citric acid esters of mono- and di-glycerides, and mixtures thereof. The preferred hydrophilic ionic surfactant is lecithin.

  Suitable hydrophilic nonionic surfactants include the following. Alkylglucosides, alkylmaltosides, alkylthioglucosides, lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkyl phenols such as polyethylene glycol alkyl phenols; poly such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters Oxyalkylene alkyl phenol fatty acid ester; polyethylene glycol glycerin fatty acid ester, polyglycerin fatty acid ester; polyoxyalkylene sorbitan fatty acid ester such as polyethylene glycol sorbitan fatty acid ester; group comprising polyol, glyceride, vegetable oil, hydrogenated vegetable oil, fatty acid and sterol Hydrophilic transesterification products of at least one element; polyoxyethylene sterol, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof, polyoxyethylene - polyoxypropylene block copolymers, and mixtures thereof.

  Suitable lipophilic surfactants include, but are not limited to: Fatty alcohol, glycerine fatty acid ester, acetylated glycerine fatty acid ester, lower alcohol fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyethylene glycol sorbitan fatty acid ester; sterol and sterol derivative; polyoxyethylated sterol and sterol derivative; Ethers, sugar esters, sugar ethers, lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols Oil-soluble vitamins / vitamin derivatives, as well as mixtures thereof. Within this group, preferred lipophilic surfactants comprise glycerin fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or at least one member of the group consisting of polyols and vegetable oils, hydrogenated vegetable oils, and triglycerides And hydrophobic transesterification products.

  The pharmaceutical composition of the invention further comprises one or more pharmaceutically acceptable additives such as binders, diluents, lubricants, disintegrants, glidants, stabilizers and penetrants. be able to.

  The binder can include the following. Potato starch, pregelatinized starch, modified starch, gelatin, wheat starch, corn starch; methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose and cellulose such as sodium carboxymethylcellulose; hydroxypropyl starch, polymethacrylate, carbomer; Natural gums such as acacia, alginic acid and guar gum; lactose (anhydrous, monohydrate, spray-dried), liquid glucose, dextrin, sodium alginate, kaolin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, poly-N- Vinylamide, polyethylene glycol, sucrose, polydextro , Gelatin, polypropylene glycol, tragacanth gum, ceratonia, glycerin behenate, hydrogenated vegetable oil, zein, castor oil, paraffin, higher aliphatic alcohol, higher aliphatic acid, long chain fatty acid, fatty acid ester, agarten, chitosan, maltodextrin, Magnesium aluminum silicate, inulin, and waxy materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hardened fats, hydrocarbons, stearic acid, copovidone, dextrates, sunflower oil and stearyl alcohol.

  The diluent can include the following. Microcrystalline cellulose, lactose, powdered cellulose, cellulose silicified, cellulose acetate, methyl cellulose, microcrystalline lactose, secondary or tertiary calcium phosphate, sugar, powdered sugar, compressible sugar, Powdered sugar, spherical sugar (sugar sphere), dextrate, dextrin, dextrose, fructose, maltose, sodium chloride, lactitol, maltodextrin, mannitol, sucrose, fructose, glycerin palmitostearate, simethicone, magnesium aluminum silicate, starch, Pregelatinized starch, maltitol, xylitol, erythritol, Maltodextrin, sorbitol, sulfobutylether b- cyclodextrin, polymethacrylates, talc, trehalose, ammonium alginate, calcium carbonate, cellulose, magnesium carbonate, magnesium oxide and calcium sulfate.

  The lubricant can include the following. Mg stearate, Al stearate or Ca stearate or Zn stearate; polyethylene glycol, polyvinyl alcohol, glycerin behenate, glycerin monostearate, glycerin palmitostearate, potassium benzoate, sodium benzoate, mineral oil, stearyl fumarate Sodium, palmitic acid, myristic acid, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, hydrogenated soybean oil, stearyl alcohol, leucine, sodium lauryl sulfate, ethylene oxide polymer, poloxamer, octyl dodecanol, sodium stearyl fumarate and Colloidal silica.

  Suitable stabilizers can include, but are not limited to: Natural and synthetic phospholipids, their hydrogenated derivatives and mixtures thereof; Organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, lactic acid and mixtures thereof; sphingolipids and glycosphingolipids; sodium cholate, dehydro Physiological bile salts such as sodium cholate, sodium deoxycholate, sodium glycocholate and sodium taurocholate; saturated and unsaturated fatty acids or fatty alcohols; ethoxylated fatty acids or fatty alcohols and their esters and ethers; such as tyloxapol Alkylaryl-polyether alcohols; fatty acids or esters of sugars or sugar alcohols with fatty alcohols; acetylated or ethoxylated mono- and diglycerides; Ethoxylated sorbitan esters or sorbitan ethers; or a combination thereof; amino acids, proteins such as polypeptides and gelatin and albumin - a block copolymer of polyoxypropylene oxide synthetic biodegradable polymers such as polymers.

  Glidants can include the following. Magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, magnesium trisilicate, colloidal silicon dioxide and silicone hydrogels.

  Penetration agents include the following. Sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, lithium sulfate, urea, inositol, sucrose, lactose (anhydrous, monohydrate, spray drying), glucose, sorbitol, fructose, mannitol, dextrose, magnesium succinate And dipotassium phosphate, sulfobutyl ether b-cyclodextrin. A penetrant can also be added into the sustained release coating.

  The sustained release core is dry granulation, slugging, roller compression, wet granulation (using aqueous / non-aqueous solvent), melt granulation, solid dispersion, direct compression, double compression, extrusion-spheronization, layering High shear mixing granulation, fluid bed granulation, spray drying, steam granulation, water activated dry granulation, wet granulation, heat bonding granulation, foam granulation, etc. by various methods known in the art It can be manufactured. Compressing the blend into a coprimate can be performed using slugging techniques or roller compaction. The milling of the granules can be carried out by conventional milling methods.

  The solvents that can be used to produce the formulation may be aqueous solvents, non-aqueous solvents or combinations thereof.

Another embodiment is
a) A sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable additives,
Disclosed is a pharmaceutical composition comprising b) a sustained release membrane coat, and c) a rapid release pioglitazone layer comprising pioglitazone, a high viscosity polymer, a disintegrant and other pharmaceutically acceptable additives.

Other embodiments are
a) A sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable additives,
Disclosed is a pharmaceutical composition comprising b) a sustained release membrane coat, and c) a rapid release pioglitazone layer comprising pioglitazone, polyvinyl alcohol, surfactants and other pharmaceutically acceptable excipients.

  The sustained release membrane coat comprises a sustained release polymer and other pharmaceutically acceptable excipients. Sustained release polymers include the hydrophilic polymers, hydrophobic polymers or waxes disclosed above.

  Sustained release membrane coats using water and / or conventional organic solvents for the coating solution in a suitable coating pan or fluid bed apparatus in a conventional coating procedure, in a sustained release metformin core , Can be applied.

  Other pharmaceutically acceptable additives that can be added to the coating composition may include pore formers, lubricants, plasticizers and colorants.

  The porosity of the controlled release coating can be adjusted using a pore forming agent. The pore former may in fact be polymeric or non-polymeric. Any water soluble material present in the coating that dissolves to form pores in the coating layer can act as a pore forming agent. Pore forming agents are potassium salts such as potassium chloride, sodium salts such as sodium chloride; calcium salts, magnesium salts, amino acids, weak acids; sucrose, mannitol, sorbitol, lactose (anhydrous, monohydrate, spray drying), etc. It can be selected from carbohydrates; polymers with amino and / or acidic functional groups or polyvinyl pyrrolidine. Examples are aspargin, glutamine, leucine, norleucine, meglumine, isoleucine, magnesium citrate, magnesium phosphate, magnesium carbonate, magnesium hydroxide, magnesium oxide.

  The plasticizer can include, for example: Acetylated monoglyceride, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycollate, glycerin, propylene glycol, triacetin, citric acid, tripropioin, diacetin, dibutyl phthalate, acetyl Monoglyceride, polyethylene glycol, castor oil, triethyl citrate, polyhydric alcohol, glycerin, acetate, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, phthalate Butyl octyl, dioctyl azelate, epoxidised tallate, triisooctyl trimellitate, phthalate Hexyl, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, Di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate.

  The lubricant used in the coating can include the following. Mg stearate, Al stearate or Ca stearate or Zn stearate; polyethylene glycol, polyvinyl alcohol, glycerin behenate, glycerin monostearate, glycerin palmitostearate, potassium benzoate, sodium benzoate, mineral oil, stearyl fumarate Sodium, palmitic acid, myristic acid, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, hydrogenated soybean oil, stearyl alcohol, leucine, sodium lauryl sulfate, ethylene oxide polymer, poloxamer, octyl dodecanol, sodium stearyl fumarate and Colloidal silica.

Another embodiment is a method of preparing a pharmaceutical composition comprising sustained release metformin hydrochloride and immediate release pioglitazone hydrochloride,
a) preparing metformin hydrochloride granules using an aqueous binder solution comprising a pharmaceutically acceptable binder,
b) mixing the dried metformin hydrochloride granules with the sustained release polymer and other pharmaceutically acceptable additives,
c) Lubricating and compressing the blend of step b) using a pharmaceutically acceptable additive into a core,
d) applying a sustained release membrane coat to the core of step c), and e) adding a high viscosity polymer, a disintegrant and other pharmaceutically acceptable to the sustained release membrane coated core of step d) Disclosed is a method comprising the step of applying a pioglitazone hydrochloride coating solution comprising an additive.

Another embodiment is a method of preparing a pharmaceutical composition comprising sustained release metformin hydrochloride and immediate release pioglitazone hydrochloride,
a) preparing metformin granules using an aqueous binder solution comprising a pharmaceutically acceptable binder,
b) mixing the dried metformin granules with the sustained release polymer and other pharmaceutically acceptable excipients,
c) Lubricating and compressing the blend of step b) using a pharmaceutically acceptable additive into a core,
d) applying a sustained release membrane coat to the core of step c), and e) polyvinyl alcohol, surfactant and other pharmaceutically acceptable to the slow release membrane coated core of step d) Disclosed is a method comprising the step of applying a pioglitazone coating solution comprising an additive.

  An immediate release pioglitazone hydrochloride layer is applied to the sustained release membrane coated coated sustained release metformin hydrochloride in a conventional coating procedure, in a suitable coating pan or fluid bed apparatus, for a coating solution It can be applied using water and / or conventional organic solvents.

  Other pharmaceutically acceptable additives that can be added to the coating composition may include the pore forming agents, lubricants, plasticizers and colorants disclosed above.

  The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Procedure Sustained Release Core Metformin hydrochloride was sieved and granulated using a povidone solution dissolved in water. The granules were dried. Hypromellose, crospovidone and microcrystalline cellulose were sieved and mixed with the prepared metformin hydrochloride granules, then lubricated and compressed.

Sustained Release Membrane Coat The compressed sustained release core was coated with a coating solution containing amino methacrylate copolymer type A and type B.

Fast Release Layer Hydroxypropyl cellulose, polyethylene glycol and lactose were dissolved in purified water. Pioglitazone hydrochloride and titanium dioxide were added into it, the solution was homogenized and applied to the slow release film coated core.

Procedure Sustained Release Core Metformin hydrochloride was sieved and granulated using a povidone solution dissolved in water. The granules were dried. Hypromellose, crospovidone and microcrystalline cellulose were sieved and mixed with the prepared metformin hydrochloride granules, then lubricated and compressed.

Sustained Release Membrane Coat The compressed sustained release core was coated with a coating solution containing amino methacrylate copolymer type A and type B.

Fast Release Layer Hydroxypropyl cellulose, polyethylene glycol and lactose were dissolved in purified water. Pioglitazone hydrochloride and titanium dioxide were added into it, the solution was homogenized and applied to the slow release film coated core.

Procedure Sustained Release Core Metformin hydrochloride was sieved and granulated using a povidone solution dissolved in water. The granules were dried. Hypromellose, crospovidone and microcrystalline cellulose were sieved and mixed with the prepared metformin hydrochloride granules, then lubricated and compressed.

Sustained Release Membrane Coat The compressed sustained release core was coated with a coating solution containing amino methacrylate copolymer type A and type B.

Fast Release Layer Hypromellose, polyethylene glycol and talc were dissolved in purified water. Pioglitazone hydrochloride and titanium dioxide were added into it, the solution was homogenized and applied to the slow release film coated core.

Procedure Sustained Release Core Metformin hydrochloride was sieved and granulated using a povidone solution dissolved in water. The granules were dried. Hypromellose, crospovidone and microcrystalline cellulose were sieved and mixed with the prepared metformin hydrochloride granules, then lubricated and compressed.

Sustained Release Membrane Coat The compressed sustained release core was coated with a coating solution containing amino methacrylate copolymer type A and type B.

Immediate Release Layer Lecithin, polyvinyl alcohol, talc and polyethylene glycol were dissolved in purified water. Pioglitazone hydrochloride and titanium dioxide were added into it, the solution was homogenized and applied to the slow release film coated core.

Dissolution Test of Metformin and Pioglitazone from Tablets of Example 1 Release Test of Pioglitazone The dissolution was carried out in a USP Type II dissolution tester at 75 rpm, at a temperature of about 37 ± 0.5 ° C., 900 ml 0. Conducted in 3 M KCl pH2. It releases about 75% or more of pioglitazone within one hour.

Release of Metformin Elution was carried out in 1000 ml of pH 6.8 phosphate buffer at 100 rpm, temperature of about 37 ± 0.5 ° C. in a USP Type I dissolution tester. Less than 25% of metformin is released within one hour, about 45% to about 75% of metformin is released within 6 hours, and about 80% or more of metformin is released within 12 hours.

The results of the in vitro elution profile are shown in Table 01.

Claims (13)

  1. a) a sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable excipients, and b) a fast release comprising pioglitazone, a high viscosity polymer and other pharmaceutically acceptable excipients Pharmaceutical Composition Comprising a Pioglitazone Layer.
  2.   The pharmaceutical composition according to claim 1, wherein the sustained release polymer is selected from a water soluble polymer, a water insoluble polymer, a waxy material or a combination thereof.
  3.   Water-soluble polymers are methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose; sodium or calcium carboxymethylcellulose; methylethylcellulose, ethylhydroxyethylcellulose, carboxyalkylcellulose ester, carbomer, glycerin Fatty acid ester, sorbitan ester, lecithin; galactomannan, tragacanth gum, agar, guar gum, gum arabic, pectin, acacia, karaya gum, locust bean gum, xanthan gum, pullulan, collagen, casein, carrageenan, algin, polycarbophil, alginate Other natural, semi-synthetic or synthetic disaccharides, oligosaccharides, and polysaccharides selected from monya, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, scleroglucan and polyfructan, maltodextrin; methacrylates; methacrylates Copolymers, polyvinyl alcohol, polyvinyl pyrrolidone, copolymers of polyvinyl pyrrolidone and vinyl acetate, combinations of polyvinyl alcohol and polyvinyl pyrrolidone; and polyalkylene oxides selected from polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide; Carboxy vinyl polymer, sodium alginate, sodium hyaluronate, carboxymethyl starch starch Sodium, gelatin, starch, crosslinked starch, microcrystalline cellulose, ceratonia, chitin, poly (hydroxyalkyl methacrylate), polyvinyl alcohol with low acetate residues, expandable mixtures of agarten and carboxymethylcellulose, crosslinked polyvinyl alcohol and poly N The pharmaceutical composition according to claim 2, selected from -vinyl-2-pyrrolidone, and mixtures and blends thereof.
  4.   Water-insoluble polymers such as cellulose acylate, cellulose ethyl ether, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkanes, mono-, Di- and tricellulose aroyl, ethylcellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, glycerin monooleate, glycerin monostearate, glycerin palmitostearate, polyvinyl Acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; poly (alkyl methacrylate) Poly (vinyl acetate), polyvinyl alcohol, polyacrylamide derivative, ammonio methacrylate copolymer, polyacrylic acid and copolymer of polyacrylate and methacrylate, aminoacryl-methacrylate copolymer, polyvinyl acetal diethylaminoacetate, maleic anhydride and the like Choose from styrene, copolymers with ethylene, propylene or isobutylene, polyacrylamide, Polyox (polyethylene oxide), diesters of polyglucan, cellulose butyrate, cellulose propionate, shellac, chitosan, oleyl alcohol, zein, hydrogenated castor oil, etc. The pharmaceutical composition according to claim 2, which is
  5.   The waxy material is carnauba wax, beeswax, Chinese wax, spermaceti wax, lanolin, white loam, white wax, yellow wax, candelilla wax, microcrystalline wax, castor oil, esparto wax, wood wax, jojoba oil, cotton seed oil The pharmaceutical composition according to claim 2, wherein the composition is selected from corn oil, hydrogenated cottonseed oil, auricule wax, spermaceti wax, ceresine wax, montan wax, ozokerite, peat wax, paraffin wax, polyethylene wax and polyglycerin fatty acid ester.
  6.   High viscosity polymers are selected from methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, sodium or calcium carboxymethylcellulose, methylethylcellulose, ethylhydroxyethylcellulose, carboxyalkylcellulose esters Alkyl cellulose; polyvinyl alcohol, cross-linked polyvinyl alcohol, polyvinyl pyrrolidone, copolymer of polyvinyl pyrrolidone and vinyl acetate, combination of polyvinyl alcohol and polyvinyl pyrrolidone; and polyethylene oxide and polypropylene oxide and ethylene oxide Including de polyalkylene oxide selected from copolymers of propylene oxide, the pharmaceutical composition according to claim 1.
  7.   The pharmaceutical composition according to claim 1, wherein the immediate release pioglitazone layer further comprises at least one disintegrant.
  8.   The pharmaceutical composition according to claim 1, wherein the immediate release pioglitazone layer further comprises at least one surfactant.
  9.   The pharmaceutical composition according to claim 1, wherein the sustained release metformin core is further coated with a sustained release coating.
  10. (A) a sustained release metformin core comprising metformin, a sustained release polymer and other pharmaceutically acceptable excipients, and (b) pioglitazone, polyvinyl alcohol, surfactants and other pharmaceutically acceptable additions Pharmaceutical composition comprising an immediate release pioglitazone layer comprising an agent.
  11.   11. The pharmaceutical composition according to claim 10, wherein the surfactant is selected from hydrophilic surfactants, lipophilic surfactants or combinations thereof.
  12.   11. The pharmaceutical composition according to claim 10, wherein the hydrophilic surfactant is ionic or non-ionic.
  13.   11. The pharmaceutical composition of claim 10, wherein the sustained release metformin core is further coated with a sustained release coating.
JP2013526558A 2010-09-01 2011-08-31 Pharmaceutical composition comprising metformin and pioglitazone Withdrawn JP2013538807A (en)

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