EP2611434A1 - Pharmaceutical composition comprising metformin and pioglitazone - Google Patents

Pharmaceutical composition comprising metformin and pioglitazone

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Publication number
EP2611434A1
EP2611434A1 EP11776517.2A EP11776517A EP2611434A1 EP 2611434 A1 EP2611434 A1 EP 2611434A1 EP 11776517 A EP11776517 A EP 11776517A EP 2611434 A1 EP2611434 A1 EP 2611434A1
Authority
EP
European Patent Office
Prior art keywords
cellulose
metformin
pioglitazone
extended release
pharmaceutical composition
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP11776517.2A
Other languages
German (de)
French (fr)
Inventor
Shirishkumar Kulkarni
Satish Kumar Dalal
Harshal Jahagirdar
Vishal Patil
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lupin Ltd
Original Assignee
Lupin Ltd
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 Lupin Ltd filed Critical Lupin Ltd
Publication of EP2611434A1 publication Critical patent/EP2611434A1/en
Withdrawn legal-status Critical Current

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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
    • A61K31/33—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non 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
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • 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
    • A61K9/2072—Pills, 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to pharmaceutical composition
  • pharmaceutical composition comprising metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof in extended release form and pioglitazone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof in immediate release form.
  • Type 2 diabetes is a chronic, life-long disease that results when the body's insulin does not work effectively.
  • Insulin is a hormone released by the pancreas in response to increased levels of blood sugar (glucose) in the blood. It is related to insulin resistance (lack of the ability of the body to respond to insulin appropriately) and is often accompanied by obesity and high cholesterol
  • a main component of type 2 diabetes is "insulin resistance".
  • the insulin produced by pancreas cannot connect with fat and muscle cells to let glucose inside and produce energy. This causes hyperglycemia (high blood glucose).To compensate, the pancreas produces more insulin. The cells sense this flood of insulin and become even more resistant, resulting in a vicious cycle of high glucose levels and often high insulin levels.
  • medication may be used to lower blood glucose levels.
  • the medication for the treatment of type 2 diabetes include, for example oral sulfonylureas (like glimepiride, glyburide, and tolazamide) trigger the pancreas to make more insulin, biguanides (metformin) decrease the production of glucose, alpha-glucosidase inhibitors (such as acarbose) decrease the absorption of carbohydrates from the digestive tract, thereby lowering the after-meal glucose levels, thiazolidinediones (such as rosiglitazone, and pioglitazone) help insulin work better at the cell site.
  • oral sulfonylureas like glimepiride, glyburide, and tolazamide
  • biguanides such as acarbose
  • alpha-glucosidase inhibitors such as acarbose
  • thiazolidinediones such as rosiglitazone, and
  • meglitinides including repaglinide and nateglinide
  • DPP-IV inhibitors like vildagliptin and sitagliptin
  • GLP-1 a protein
  • Pioglitazone belonging to thiazolidinedione decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.
  • Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPAR- ⁇ ).
  • PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR- ⁇ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
  • Metformin hydrochloride a biguanide improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
  • pioglitazone ( ⁇ )-5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione. It has a molecular formula of C19H20N2O3S'HCI and a molecular weight of 392.90.
  • Metformin N,N- dimethylimidodicarbonimidic diamide
  • C4H1 1 N5 » HCI and a molecular weight of 165.62.
  • ACTOPLUS MET® The combination of pioglitazone hydrochloride and metformin hydrochloride is marketed in United States as ACTOPLUS MET® and ACTOPLUS MET ® XR which is approved as adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with pioglitazone and metformin or who have inadequate glycemic control on pioglitazone alone or metformin alone.
  • ACTOPLUS MET ® is available as a tablet for oral administration containing pioglitazone hydrochloride and metformin hydrochloride equivalent to 15 mg pioglitazone and 500 mg metformin hydrochloride or 850 mg metformin hydrochloride.
  • ACTOPLUS MET® XR is available as a tablet for once-a-day oral administration containing pioglitazone hydrochloride and metformin hydrochloride equivalent to 15 mg pioglitazone and 1000 mg metformin hydrochloride or 30 mg pioglitazone and 1000 mg metformin hydrochloride.
  • US 4,687,777 disclose pioglitazone specifically.
  • US 5,965,584 disclose composition comprising combination of pioglitazone and metformin.
  • US 6,166,042 relate to use of combination of pioglitazone and metformin for the treatment of glycometabolism disorders.
  • US 6,166,043 relate to use of combination of pioglitazone and metformin for reducing the amount of active components to a diabetic patient.
  • US 6,172,090 disclose the use of combination of pioglitazone and metformin for reducing the side effects of active components to a diabetic patient.
  • US 6,099,859; US 6,166,042; US 6,495,162; US 6,790,459 & US 6,866,866 disclose the controlled release composition of metformin hydrochloride.
  • composition comprising pioglitazone and metformin.
  • US 6,780,432 disclose a combination drug product comprising pioglitazone hydrochloride and a biguanide, e.g. metformin.
  • the product comprises a core of the biguanide, e.g. metformin; at least a portion thereof has a layer or coat thereon of pioglitazone.
  • US 6,524,621 disclose a formulation comprising pioglitazone hydrochloride and a biguanide, e.g. metformin.
  • the product comprises a core of the biguanide, e.g. metformin; at least a portion thereof has a layer or coat thereon of pioglitazone and a modulating polymer comprising a silicate which is associated with at least one of said active ingredients.
  • US 6,403,121 disclose a formulation comprising pioglitazone hydrochloride and a biguanide, e.g. metformin.
  • the product comprises a core of the biguanide, e.g. metformin; at least a portion thereof has a layer or coat thereon of pioglitazone and a modulating polymer comprising a polysaccharide which is associated with at least one of said active ingredients.
  • US 2006/0141 128 disclose method of a preparation of coated pioglitazone hydrochloride comprising pioglitazone hydrochloride and a core coating material having a low viscosity polymer.
  • US 2006/0286168 disclose method of a preparation of coated pioglitazone hydrochloride comprises coating a core containing an active ingredient with a dispersion of pioglitazone hydrochloride in an organic solvent, which organic solvent contains polyvinylpyrrolidone as a coating base soluble in organic solvents.
  • US 2004/0106660 disclose a once a day oral pharmaceutical tablet consisting of a core having a semipermeable coating surrounding the core; and immediate release pioglitazone coating.
  • US 2004/0161462 disclose a pharmaceutical dosage form comprising a controlled release metformin hydrochloride core, a sustained release coating surrounding the core, and immediate release pioglitazone layer.
  • WO 2004/026241 discloses a pharmaceutical dosage form comprising biguanide (such as metformin) in combination with thiazolidinedione derivative, wherein the metformin is formulated as an osmotic tablet, with or without a gelling or expanding polymer.
  • biguanide such as metformin
  • thiazolidinedione derivative may be part of the controlled release core or it may preferably be combined with the controlled release core in a manner that provides for immediate release of the thiazolidinedione derivative.
  • US 2009/0246232 disclose a method of manufacturing pharmaceutical composition comprising compressing the admixture comprising the insulin sensitivity enhancer (pioglitazone hydrochloride), biguanide and an excipient and coating the compressed admixture to form an oral dosage form.
  • the insulin sensitivity enhancer prioglitazone hydrochloride
  • biguanide biguanide
  • US 2007/0166376 disclose a solid preparation containing (1) a layer containing an insulin sensitizer, and (2) a layer containing (a) an active ingredient (except insulin sensitizers), (b) microcrystalline cellulose having a mean particle size of 5-25 pm, (c) microcrystalline cellulose having a mean particle size of 30-100 pm and (d) polyvinylpyrrolidone K-90.
  • US 2009/0028939 disclose a solid preparation comprises "a part containing coated particles in which the particles containing an insulin sensitizer are coated with lactose or a sugar alcohol" and "a part containing an active ingredient other than an insulin sensitizer".
  • US2006/0057202 discloses a composition comprising of thiazolidinediones and biguanide for controlling hyperglycemia manufactured as multilayer tablet.
  • Pioglitazone hydrochloride is insoluble in water and it is well known in the art that in solid dosage form due to low solubility, water insoluble drug show correspondingly low degree of bioavailability.
  • composition comprising extended release metformin having a immediate release pioglitazone coating comprising high viscosity polymer and disintegrant.
  • Another aspect discloses a pharmaceutical composition
  • a pharmaceutical composition comprising extended release metformin with immediate release pioglitazone coating comprising a polymer and surfactant.
  • Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients
  • Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients
  • Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients
  • Extended release membrane coat and c) Immediate release pioglitazone layer comprising pioglitazone, high viscosity polymer, disintegrant and other pharmaceutically acceptable excipients
  • Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients
  • step b) Lubricating the blend of step b) using pharmaceutical acceptable excipients and compressing in to a core;
  • step d) Applying to the core of step c) a extended release membrane coat; and e) Applying to the core coated with a extended release membrane coat of step d) a pioglitazone coating solution comprising high viscosity polymer, disintegrant and other pharmaceutical acceptable excipients
  • step b) Mixing the dried metformin granules with extended release polymer and other pharmaceutical acceptable excipients; c) Lubricating the blend of step b) using pharmaceutical acceptable excipients and compressing in to a core;
  • step d) Applying to the core of step c) a extended release membrane coat; and e) Applying to the core coated with a extended release membrane coat of step d) a pioglitazone coating solution comprising polyvinylalcohol, surfactant and other pharmaceutical acceptable excipients
  • the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising extended release core comprising metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof and immediate release layer comprising pioglitazone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof and high viscosity polymer.
  • pioglitazone would include all forms of pioglitazone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof. The most preferred form is pioglitazone hydrochloride.
  • metformin would include all forms of metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof. The most preferred form is metformin hydrochloride.
  • the extended release formulation would release drug at substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrementally over an extended period of time.
  • extended release formulation may also used synonymously with prolonged release formulation, programmed release formulation, timed release formulation, modified release formulation, site specific release formulation, sustained release formulation, controlled release formulation, slow release formulation, delayed release formulation, osmotic dosage form, bioadhesive formulation, orally disintegrating modified release formulation, gastroretentive formulation and other such dosage forms.
  • immediate release assumes the definition as widely recognized in the art of pharmaceutical sciences. An immediate release form releases drug immediately after administration
  • core defined to mean a solid vehicle in which at least one active drug is uniformly or non-uniformly dispersed with pharmaceutically acceptable excipients which can be in the form of powder, beads, pellets, granules, microcapsules, microgranules, tablet, minitablet, compact, spheroid, particles and the like.
  • layer as used herein are used interchangeably and are defined to mean a process in which the whole surface of a core is covered with a coating composition.
  • extended release membrane coat defined to mean a functional coat which comprises at least one extended release polymer.
  • the extended release membrane coat is permeable to both metformin and water.
  • high viscosity polymer as used herein defined to mean a 5% aqueous solution of which polymer has a viscosity not less than 35 mPas when determined at 25°C.
  • pharmaceutically acceptable excipients includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular metformin and rosiglitazone the active ingredient selected for use.
  • the pharmaceutical composition may be in the form of tablets (such as single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets and timed release tablets), pellets, beads, granules, spheroids, particles, powders, capsules microcapsules, tablets in capsules, microspheres, matrix formulations, microencapsulation.
  • tablets such as single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets and timed release tablets
  • pellets such as single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets and timed release tablets
  • pellets such as single layered tablets, multilayered tablets
  • Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients
  • Immediate release pioglitazone layer comprising pioglitazone, high viscosity polymer, disintegrant and other pharmaceutically acceptable excipients
  • Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients
  • the extended release polymer may be selected from water soluble polymer, water insoluble polymer, waxy material or combination thereof.
  • the water soluble polymer may be selected from alkyl celluloses such as methyl cellulose; hydroxyalkyl celluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; sodium or calcium carboxymethyl cellulose, methyl ethyl cellulose, ethylhydroxy ethylcellulose, carboxyalkyl cellulose esters; carbomers ; glycerol fatty acid esters, sorbitan esters, lecithins, other natural, semi-synthetic, or synthetic di-, oligo-, and polysaccharides such as galactomannans, tragacanth, agar, guar gum, gum arabic, pectin, acacia, karaya, locust bean gum, xanthan gum, pullul
  • Water insoluble polymer may be selected from cellulose acylate; cellulose ethyl ether; cellulose diacylate; cellulose triacylate; cellulose acetate; cellulose diacetate; cellulose triacetate; mono-, di- and tricellulose alkan, mono-, di- and tricellulose aroyl; ethyl cellulose; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; Glyceryl monooleate; glyceryl monostearate; Glyceryl palmitostearate; polyvinyl acetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate); poly (vinyl acetate); poly vinyl alcohols; polyacrylamide derivatives ammonio methacrylate copolymers, poly acrylic acid and poly acrylate and methacrylate copolymers, aminoacryl-methacrylate copolymer
  • Waxy material may be selected from carnauba wax; beeswax; Chinese wax; spermaceti; lanolin; bayberry wax; white wax; yellow wax; candelilla wax; microcrystalline wax; castor wax; esparto wax; Japan wax; jojoba oil; cotton seed oil, corn oil, hydrogenated cotton seed oil, ouricury wax; rice bran wax; ceresin waxes; montan wax; ozokerite; peat waxes; paraffin wax; polyethylene waxes; and polyglycerol fatty acid esters.
  • the extended release polymer may be bioadhesive.
  • the bioadhesive polymers may be selected from the group consisting of proteins
  • hydrophilic proteins such as carbomers, pectin, zein, modified zein, casein, gelatin, gluten, serum albumin and collagen; chitosan; oligosaccharides; polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum arabic, hyaluronic acid, polyhyaluronic acid, alginic acid and sodium alginate; Glyceryl monooleate; polyamides;, polycarbonates; polyalkylenes; polyalkylene glycols; polyalkylene oxides; polyalkylene terephthalates; polyvinyl alcohols; polyvinyl ethers; polyvinyl esters; polyvinyl halides; polyvinylpyrrolidone; polyglycolides; polysiloxanes; polyurethanes; polystyrene; polymers of acrylic and methacrylic esters;
  • hydrophilic proteins
  • the high viscosity polymer used in the immediate release pioglitazone layer may include but not limited to alkyl celluloses such as methyl cellulose; hydroxyalkyl celluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; sodium or calcium carboxymethyl cellulose, methyl ethyl cellulose, ethylhydroxy ethylcellulose, carboxyalkyl cellulose esters; polyvinyl alcohol; crosslinked polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide
  • the high viscosity polymer used in the immediate release pioglitazone layer is hydroxypropyl cellulose (Grade: Klucel LF, Aqualon (USA)), a 5% aqueous solution of which has a viscosity of 75-150 mPas when determined at 25 ° C, using a Brookfield LVF viscometer, hydroxypropyl cellulose (Grade: Nisso HPC - L, Nisso America Inc.), a 2% aqueous solution of which has a viscosity of 6.0 - 10.0 mPas when determined at 20 ° C or combination thereof.
  • the disintegrant used in the immediate release pioglitazone layer may include but not limited to, povidone; low-substituted hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone (crosspovidone); cross-linked sodium carboxymethylcellulose; hydroxypropyl starch; sodium starch glycolate; sodium starch glucolate; sodium carboxymethylcellulose; carboxymethyl cellulose calcium; sodium carboxymethyl starch; ion-exchange resins such as polacrillin potassium; microcrystalline cellulose; starches and pregelatinized starch; formalin-casein; clays such as bentonite or veegum; guar gum; celluloses or cellulose derivatives; sodium alginate; calcium alginate; alginic acid; chitosan; magnesium aluminum silicate; and colloidal silicon dioxide.
  • povidone low-substituted hydroxypropyl cellulose
  • cross-linked polyvinyl pyrrolidone crosspovidone
  • the surfactant used in the immediate release pioglitazone layer may be selected from hydrophilic surfactant, lipophilic surfactant or combination thereof.
  • Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients
  • Immediate release pioglitazone layer comprising pioglitazone, high viscosity polymer, surfactant and other pharmaceutically acceptable excipients
  • Hydrophilic surfactants may be either ionic or non-ionic.
  • Suitable hydrophilc ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; 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.
  • Suitable hydrophilic non-ionic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and ana
  • Suitable lipophilic surfactants include, but are not limited to fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol 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; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable excipients such as binders; diluents; lubricants; disintegrants; glidants; stabilizers; and osmotic agents.
  • pharmaceutically acceptable excipients such as binders; diluents; lubricants; disintegrants; glidants; stabilizers; and osmotic agents.
  • the binders may include, potato starch; pregelatinized starch; modified starch; gelatin; wheat starch; corn starch; celluloses such as methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose and sodium carboxy methyl cellulose; hydroxypropyl Starch, polymethacrylates; carbomers; natural gums such as acacia, alginic acid and guar gum; lactose (anhydrous, monohydrate, spraydried); liquid glucose; dextrin; sodium alginate; kaolin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; poly vinyl alcohol; poly-N-vinyl amide; polyethylene glycol; sucrose; polydextrose; gelatin; poly propylene glycol; tragacanth; ceratonia; glyceryl behenate; hydrogenated vegetable oil; zein; castor oil; paraffin; higher alipha
  • the diluents may include, microcrystalline cellulose; lactose, cellulose powdered, cellulose silicified, cellulose acetate, methyl cellulose, microcrystalline lactose; dibasic or tribasic calcium phosphate; saccharides; confectioner's sugar; compressible sugar; confectioner's sugar; sugar spheres; dextrates; dextrin; dextrose; fructose; maltose; sodium chloride; lactitol; maltodextrin; mannitol; sucrose; fructose; glyceryl palmitostearate; semithicone; Magnesium aluminum silicate; starch; pregelatinized starch; maltitol; xylitol; erythritol; isomalt; sorbitol; sulfobutylether b-cyclodextrin, polymethacrylates; talc; trehalose; ammonium alginate; calcium carbonate;
  • the lubricants may include Mg, Al or Ca or Zn stearate; polyethylene glycol; polyvinyl alcohol; glyceryl behenate; glyceryl monostearate; Glyceryl palmitostearate; potassium benzoate; sodium benzoate; mineral oil; sodium stearyl fumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable oil; hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; sodium lauryl sulfate; ethylene oxide polymers; poloxamer; Octyldodecanol; Sodium stearyl fumarate and colloidal silica.
  • Suitable stabilizers may include but are not limited to naturally occurring as well as synthetic phospholipids, their hydrogenated derivatives and mixtures thereof; organic acids like acetic acid, tartaric acid, citric acid, fumaric acid, lactic acid, and mixtures thereof sphingolipids and glycosphingolipids; physiological bile salts such as sodium cholate, sodium dehydrocholate, 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; alkylaryl-polyether alcohols such as tyloxapol; esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols; acetylated or ethoxylated mono- and diglycerides; synthetic biodegradable polymers like block copolymers of polyoxyethylene and polyoxypropyleneoxide; ethoxylated sorbitanesters or
  • the glidants may include magnesium trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; magnesium trisilicate; colloidal silicon dioxide; and silicon hydrogel.
  • the osmotic agents include sodium chloride; potassium chloride; magnesium sulfate; magnesium chloride; sodium sulfate; lithium sulfate; urea; inositol; sucrose; lactose (anhydrous, monohydrate, spraydried); glucose; sorbitol; fructose; mannitol; dextrose; magnesium succinate; and potassium acid phosphate, sulfobutylether b-cyclodextrin.
  • the osmotic agents may also be added in the extended release coating.
  • the extended release core may be manufactured by various methods known in the art such as by dry granulation, slugging, roller compaction, wet granulation (using aqueous / nonaqueous solvents), melt granulation, solid dispersion, direct compression, double compression, extrusion spheronization, layering, High shear mixture granulation, Fluid bed granulation, spray drying, steam granulation, moisture activated dry granulation, moist granulation, thermal adhesion granulation, foam granulation and the like.
  • Compaction of the blend into coprimate may be carried out using a slugging technique or roller compaction.
  • the milling of the granules may be carried out according to conventional milling methods.
  • the solvent which may be used for manufacturing the formulation may be aqueous, non aqueous or combination thereof.
  • Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients
  • Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients
  • the extended release membrane coat comprises extended release polymer and other pharmaceutically acceptable excipients.
  • the extended release polymers includes hydrophilic polymers, hydrophobic polymers or waxes as disclosed above.
  • the extended release membrane coat can be applied to the extended release metformin core by conventional coating procedures in a suitable coating pan or in fluidized bed apparatus using water and/or conventional organic solvents for the coating solution.
  • the other pharmaceutically acceptable excipients which may be added to coating composition may include pore forming agents, lubricants, plasticizers and colorants.
  • the porosity of the controlled release coating may be modified by using pore forming agents.
  • the pore forming agents may be polymeric or non polymeric in nature. Any water soluble material present in the coating which dissolves and forms pores in the coating layer may act as pore forming agents.
  • Pore forming agents may be selected form of potassium salts such as potassium chloride, sodium salts as sodium chloride, calcium salts, magnesium salts, amino acids, weak acids, carbohydrates such as sucrose; mannitol; sorbitol, lactose (anhydrous, monohydrate, spray dried), polymers with amino and/or acid functions or polyvinyl pyrrolidine. Examples are aspargine, glutamine, leucin, neroleucine, meglumine, isoleucine, magnesium citrate, magnesium phosphate, magnesium carbonate, magnesium hydroxide, magnesium oxide.
  • the plasticizers may include, for example acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, tri
  • the lubricants used in coating may include, Mg, Al or Ca or Zn stearate; polyethylene glycol; polyvinyl alcohol; glyceryl behenate; glyceryl monostearate; glyceryl palmitostearate; potassium benzoate; sodium benzoate; mineral oil; sodium stearyl fumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable oil; hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; sodium lauryl sulfate; ethylene oxide polymers; poloxamer; octyldodecanol; sodium stearyl fumarate and colloidal silica.
  • step b) Mixing the dried metformin hydrochloride granules with extended release polymer and other pharmaceutical acceptable excipients; c) Lubricating the blend of step b) using pharmaceutical acceptable excipients and compressing in to a core;
  • step d) Applying to the core of step c) an extended release membrane coat; and e) Applying to the core coated with an extended release membrane coat of step d) a pioglitazone hydrochloride coating solution comprising high viscosity polymer, disintegrant and other pharmaceutical acceptable excipients
  • step b) Lubricating the blend of step b) using pharmaceutical acceptable excipients and compressing in to a core;
  • step d) Applying to the core of step c) a extended release membrane coat; and e) Applying to the core coated with a extended release membrane coat of step d) a pioglitazone coating solution comprising polyvinylalcohol, surfactant and other pharmaceutical acceptable excipients.
  • the immediate release pioglitazone hydrochloride layer can be applied to the extended release metformin hydrochloride coated with an extended release membrane coat, by conventional coating procedures in a suitable coating pan or in fluidized bed apparatus using water and/or conventional organic solvents for the coating solution.
  • the other pharmaceutically acceptable excipients which may be added to coating composition may include pore forming agents, lubricants, plasticizers and colorants as disclosed above.
  • Metformin hydrochloride was sifted and granulated using povidone solution in water. The granules were dried. Hypromellose, crosspovidone and microcrystalline cellulose were sifted and mixed with the prepared metformin hydrochloride granules, which were then lubricated and compressed.
  • he compressed extended release core was coated with coating solution containing aminomethacrylate co-polymer type A and type B.
  • Hydroxypropyl cellulose, polyethylene glycol and lactose were dissolved in purified water. Pioglitazone hydrochloride and titanium di-oxide were added in it, homogenize the solution and applied the core coated with extended release membrane coat.
  • Metformin hydrochloride was sifted and granulated using povidone solution in water. The granules were dried. Hypromellose, crosspovidone and microcrystalline cellulose were sifted and mixed with the prepared metformin hydrochloride granules, which were then lubricated and compressed.
  • the compressed extended release core was coated with coating solution containing aminomethacrylate co-polymer type A and type B.
  • Hydroxypropyl cellulose, polyethylene glycol and lactose were dissolved in purified water. Pioglitazone hydrochloride and titanium di-oxide were added in it, homogenize the solution and applied the core coated with extended release membrane coat.
  • Metformin hydrochloride was sifted and granulated using povidone solution in water. The granules were dried. Hypromellose, crosspovidone and microcrystalline cellulose were sifted and mixed with the prepared metformin hydrochloride granules, which were then lubricated and compressed.
  • the compressed extended release core was coated with coating solution containing aminomethacrylate co-polymer type A and type B.
  • Hypromellose, polyethylene glycol and talc were dissolved in purified water. Piogiitazone hydrochloride and titanium di-oxide were added in it, homogenize the solution and applied the core coated with extended release membrane coat.
  • Example 04
  • Metformin hydrochloride was sifted and granulated using povidone solution in water. The granules were dried. Hypromellose, crosspovidone and microcrystalline cellulose were sifted and mixed with the prepared metformin hydrochloride granules, which were then lubricated and compressed.
  • the compressed extended releae core was coated with coating solution containing aminomethacrylate co-polymer type A and type B.
  • the dissolution was carried out in USP type II dissolution apparatus, at 75 rpm, at a temperature of about 37 ⁇ 0.5"C, in 900 ml of 0.3M KCI pH 2 with HCI and releases not less than about 75% of pioglitazone within 1 hour.
  • the dissolution was carried out in USP type I dissolution apparatus, at 100 rpm, at a temperature of about 37 ⁇ 0.5°C, in 1000 ml of pH 6.8 phosphate buffer and releases not more than 25 % of metformin within 1 hour, from about 45% to about 75% of metformin is released within 6 hour and not less than about 80% of metformin is released within 12 hours.

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Abstract

A pharmaceutical composition comprising metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof in extended release form and pioglitazone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof in immediate release form is provided. More particularly a pharmaceutical composition comprising extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients; and immediate release pioglitazone layer comprising pioglitazone, high viscosity polymer, and other pharmaceutically acceptable excipients. Further a pharmaceutical composition comprising extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients; and immediate release pioglitazone layer comprising pioglitazone, polyvinyl alcohol, surfactant and other pharmaceutically acceptable excipients

Description

PHARMACEUTICAL COMPOSITION COMPRISING
METFORMIN AND PIOGLITAZONE
Field of the Invention:
The invention relates to pharmaceutical composition comprising metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof in extended release form and pioglitazone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof in immediate release form.
Background of the Invention:
Type 2 diabetes is a chronic, life-long disease that results when the body's insulin does not work effectively. Insulin is a hormone released by the pancreas in response to increased levels of blood sugar (glucose) in the blood. It is related to insulin resistance (lack of the ability of the body to respond to insulin appropriately) and is often accompanied by obesity and high cholesterol
A main component of type 2 diabetes is "insulin resistance". The insulin produced by pancreas cannot connect with fat and muscle cells to let glucose inside and produce energy. This causes hyperglycemia (high blood glucose).To compensate, the pancreas produces more insulin. The cells sense this flood of insulin and become even more resistant, resulting in a vicious cycle of high glucose levels and often high insulin levels.
When the person cannot achieve normal or near-normal blood glucose levels with diet and exercise, medication may be used to lower blood glucose levels. The medication for the treatment of type 2 diabetes include, for example oral sulfonylureas (like glimepiride, glyburide, and tolazamide) trigger the pancreas to make more insulin, biguanides (metformin) decrease the production of glucose, alpha-glucosidase inhibitors (such as acarbose) decrease the absorption of carbohydrates from the digestive tract, thereby lowering the after-meal glucose levels, thiazolidinediones (such as rosiglitazone, and pioglitazone) help insulin work better at the cell site. In essence, they increase the cell's sensitivity (responsiveness) to insulin, meglitinides (including repaglinide and nateglinide) trigger the pancreas to make more insulin in response to how much glucose is in the blood, DPP-IV inhibitors (like vildagliptin and sitagliptin) which lower blood sugar levels by blocking an enzyme known as dipeptidyl peptidase IV or DPP-IV that normally deactivates a protein (GLP-1 ) that keeps insulin circulating in the blood or combinations thereof.
Pioglitazone belonging to thiazolidinedione decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPAR-γ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-γ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
Metformin hydrochloride, a biguanide improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long 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. It has a molecular formula of C19H20N2O3S'HCI and a molecular weight of 392.90. Metformin (N,N- dimethylimidodicarbonimidic diamide) has a molecular formula of C4H1 1 N5»HCI and a molecular weight of 165.62.
The combination of pioglitazone hydrochloride and metformin hydrochloride is marketed in United States as ACTOPLUS MET® and ACTOPLUS MET® XR which is approved as adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with pioglitazone and metformin or who have inadequate glycemic control on pioglitazone alone or metformin alone. ACTOPLUS MET® is available as a tablet for oral administration containing pioglitazone hydrochloride and metformin hydrochloride equivalent to 15 mg pioglitazone and 500 mg metformin hydrochloride or 850 mg metformin hydrochloride. ACTOPLUS MET® XR is available as a tablet for once-a-day oral administration containing pioglitazone hydrochloride and metformin hydrochloride equivalent to 15 mg pioglitazone and 1000 mg metformin hydrochloride or 30 mg pioglitazone and 1000 mg metformin hydrochloride.
US 4,687,777 disclose pioglitazone specifically. US 5,965,584 disclose composition comprising combination of pioglitazone and metformin. US 6,166,042 relate to use of combination of pioglitazone and metformin for the treatment of glycometabolism disorders. US 6,166,043 relate to use of combination of pioglitazone and metformin for reducing the amount of active components to a diabetic patient. US 6,172,090 disclose the use of combination of pioglitazone and metformin for reducing the side effects of active components to a diabetic patient. US 6,099,859; US 6,166,042; US 6,495,162; US 6,790,459 & US 6,866,866 disclose the controlled release composition of metformin hydrochloride.
There are number of approaches described in prior arts which disclose composition comprising pioglitazone and metformin.
US 6,780,432 disclose a combination drug product comprising pioglitazone hydrochloride and a biguanide, e.g. metformin. In particular, the product comprises a core of the biguanide, e.g. metformin; at least a portion thereof has a layer or coat thereon of pioglitazone.
US 6,524,621 disclose a formulation comprising pioglitazone hydrochloride and a biguanide, e.g. metformin. In particular, the product comprises a core of the biguanide, e.g. metformin; at least a portion thereof has a layer or coat thereon of pioglitazone and a modulating polymer comprising a silicate which is associated with at least one of said active ingredients.
US 6,403,121 disclose a formulation comprising pioglitazone hydrochloride and a biguanide, e.g. metformin. In particular, the product comprises a core of the biguanide, e.g. metformin; at least a portion thereof has a layer or coat thereon of pioglitazone and a modulating polymer comprising a polysaccharide which is associated with at least one of said active ingredients.
US 2006/0141 128 disclose method of a preparation of coated pioglitazone hydrochloride comprising pioglitazone hydrochloride and a core coating material having a low viscosity polymer. US 2006/0286168 disclose method of a preparation of coated pioglitazone hydrochloride comprises coating a core containing an active ingredient with a dispersion of pioglitazone hydrochloride in an organic solvent, which organic solvent contains polyvinylpyrrolidone as a coating base soluble in organic solvents.
US 2004/0106660 disclose a once a day oral pharmaceutical tablet consisting of a core having a semipermeable coating surrounding the core; and immediate release pioglitazone coating.
US 2004/0161462 disclose a pharmaceutical dosage form comprising a controlled release metformin hydrochloride core, a sustained release coating surrounding the core, and immediate release pioglitazone layer.
WO 2004/026241 discloses a pharmaceutical dosage form comprising biguanide (such as metformin) in combination with thiazolidinedione derivative, wherein the metformin is formulated as an osmotic tablet, with or without a gelling or expanding polymer. The thiazolidinedione derivative may be part of the controlled release core or it may preferably be combined with the controlled release core in a manner that provides for immediate release of the thiazolidinedione derivative.
US 2009/0246232 disclose a method of manufacturing pharmaceutical composition comprising compressing the admixture comprising the insulin sensitivity enhancer (pioglitazone hydrochloride), biguanide and an excipient and coating the compressed admixture to form an oral dosage form.
US 2007/0166376 disclose a solid preparation containing (1) a layer containing an insulin sensitizer, and (2) a layer containing (a) an active ingredient (except insulin sensitizers), (b) microcrystalline cellulose having a mean particle size of 5-25 pm, (c) microcrystalline cellulose having a mean particle size of 30-100 pm and (d) polyvinylpyrrolidone K-90.
US 2009/0028939 disclose a solid preparation comprises "a part containing coated particles in which the particles containing an insulin sensitizer are coated with lactose or a sugar alcohol" and "a part containing an active ingredient other than an insulin sensitizer".
US2006/0057202 discloses a composition comprising of thiazolidinediones and biguanide for controlling hyperglycemia manufactured as multilayer tablet. Pioglitazone hydrochloride is insoluble in water and it is well known in the art that in solid dosage form due to low solubility, water insoluble drug show correspondingly low degree of bioavailability.
Thus one aspect discloses a pharmaceutical composition comprising extended release metformin having a immediate release pioglitazone coating comprising high viscosity polymer and disintegrant.
Another aspect discloses a pharmaceutical composition comprising extended release metformin with immediate release pioglitazone coating comprising a polymer and surfactant.
Although number of prior arts exists which disclose the composition comprising extended release metformin and immediate release pioglitazone in coating, there exists a need to provide an improved composition with good dissolution property.
Summary of the Invention:
One embodiment discloses a pharmaceutical composition comprising
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients; and
b) Immediate release pioglitazone layer comprising pioglitazone, high
polymer, disintegrant and other pharmaceutically acceptable excipients
Other embodiment discloses a pharmaceutical composition comprising
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients; and
b) Immediate release pioglitazone layer comprising pioglitazone, polyvinyl alcohol, surfactant and other pharmaceutically acceptable excipients
Another embodiment discloses a pharmaceutical composition comprising
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients;
Extended release membrane coat; and c) Immediate release pioglitazone layer comprising pioglitazone, high viscosity polymer, disintegrant and other pharmaceutically acceptable excipients
Another embodiment discloses a pharmaceutical composition comprising
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients;
b) Extended release membrane coat; and
c) Immediate release pioglitazone layer comprising pioglitazone, polyvinyl alcohol, surfactant and other pharmaceutically acceptable excipients
Another embodiment discloses a method of preparing pharmaceutical composition comprising extended release metformin hydrochloride and immediate release pioglitazone hydrochloride comprising
a) Preparing metformin granules using aqueous binder solution comprising pharmaceutically acceptable binder;
b) Mixing the dried metformin granules with extended release polymer and other pharmaceutical acceptable excipients;
c) Lubricating the blend of step b) using pharmaceutical acceptable excipients and compressing in to a core;
d) Applying to the core of step c) a extended release membrane coat; and e) Applying to the core coated with a extended release membrane coat of step d) a pioglitazone coating solution comprising high viscosity polymer, disintegrant and other pharmaceutical acceptable excipients
Another embodiment discloses a method of preparing pharmaceutical composition comprising extended release metformin hydrochloride and immediate release pioglitazone hydrochloride comprising
a) Preparing metformin granules using aqueous binder solution comprising pharmaceutically acceptable binder;
b) Mixing the dried metformin granules with extended release polymer and other pharmaceutical acceptable excipients; c) Lubricating the blend of step b) using pharmaceutical acceptable excipients and compressing in to a core;
d) Applying to the core of step c) a extended release membrane coat; and e) Applying to the core coated with a extended release membrane coat of step d) a pioglitazone coating solution comprising polyvinylalcohol, surfactant and other pharmaceutical acceptable excipients
Detailed Description of the Invention:
The present invention relates to pharmaceutical composition comprising extended release core comprising metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof and immediate release layer comprising pioglitazone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof and high viscosity polymer.
As used herein the term pioglitazone would include all forms of pioglitazone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof. The most preferred form is pioglitazone hydrochloride.
As used herein the term metformin would include all forms of metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof. The most preferred form is metformin hydrochloride.
The extended release formulation would release drug at substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrementally over an extended period of time.
The term extended release formulation may also used synonymously with prolonged release formulation, programmed release formulation, timed release formulation, modified release formulation, site specific release formulation, sustained release formulation, controlled release formulation, slow release formulation, delayed release formulation, osmotic dosage form, bioadhesive formulation, orally disintegrating modified release formulation, gastroretentive formulation and other such dosage forms. As used herein, the term "immediate release" assumes the definition as widely recognized in the art of pharmaceutical sciences. An immediate release form releases drug immediately after administration
The term "core" defined to mean a solid vehicle in which at least one active drug is uniformly or non-uniformly dispersed with pharmaceutically acceptable excipients which can be in the form of powder, beads, pellets, granules, microcapsules, microgranules, tablet, minitablet, compact, spheroid, particles and the like.
The term "layer", "coat" or "coating" as used herein are used interchangeably and are defined to mean a process in which the whole surface of a core is covered with a coating composition.
The term "extended release membrane coat" defined to mean a functional coat which comprises at least one extended release polymer. The extended release membrane coat is permeable to both metformin and water.
The term "high viscosity polymer" as used herein defined to mean a 5% aqueous solution of which polymer has a viscosity not less than 35 mPas when determined at 25°C.
The term "pharmaceutically acceptable excipients" as used herein includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular metformin and rosiglitazone the active ingredient selected for use.
The pharmaceutical composition may be in the form of tablets (such as single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets and timed release tablets), pellets, beads, granules, spheroids, particles, powders, capsules microcapsules, tablets in capsules, microspheres, matrix formulations, microencapsulation.
One embodiment discloses a pharmaceutical composition comprising
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients; and b) Immediate release pioglitazone layer comprising pioglitazone, high viscosity polymer, disintegrant and other pharmaceutically acceptable excipients
Other embodiment discloses a pharmaceutical composition comprising
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients; and
b) Immediate release pioglitazone layer comprising pioglitazone, poiyvinylalcohol, surfactant and other pharmaceutically acceptable excipients
The extended release polymer may be selected from water soluble polymer, water insoluble polymer, waxy material or combination thereof.
The water soluble polymer may be selected from alkyl celluloses such as methyl cellulose; hydroxyalkyl celluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; sodium or calcium carboxymethyl cellulose, methyl ethyl cellulose, ethylhydroxy ethylcellulose, carboxyalkyl cellulose esters; carbomers ; glycerol fatty acid esters, sorbitan esters, lecithins, other natural, semi-synthetic, or synthetic di-, oligo-, and polysaccharides such as galactomannans, tragacanth, agar, guar gum, gum arabic, pectin, acacia, karaya, locust bean gum, xanthan gum, pullulan, collagen, casein, carrageenan, aligns, polycarbophil, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, scleroglucan and polyfructans, maltodextrin; methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, carboxyvinyl polymers, sodium alginate, sodium hyluronate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, gelatin, starch, crosslinked starch, microcrystalline cellulose, ceratonia, chitin, poly(hydroxyalkyl methacrylate), polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone and mixtures and blends thereof.. Water insoluble polymer may be selected from cellulose acylate; cellulose ethyl ether; cellulose diacylate; cellulose triacylate; cellulose acetate; cellulose diacetate; cellulose triacetate; mono-, di- and tricellulose alkan, mono-, di- and tricellulose aroyl; ethyl cellulose; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; Glyceryl monooleate; glyceryl monostearate; Glyceryl palmitostearate; polyvinyl acetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate); poly (vinyl acetate); poly vinyl alcohols; polyacrylamide derivatives ammonio methacrylate copolymers, poly acrylic acid and poly acrylate and methacrylate copolymers, aminoacryl-methacrylate copolymer, polyvinyl acetaldiethylamino acetate, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, polyacrylamides, Polyox( polyethylene oxides), diesters of polyglucan, cellulose butyrate, cellulose propionate, shellac, chitosan, Oleyl alcohol, zein, hydrogenated castor oil and the like.
Waxy material may be selected from carnauba wax; beeswax; Chinese wax; spermaceti; lanolin; bayberry wax; white wax; yellow wax; candelilla wax; microcrystalline wax; castor wax; esparto wax; Japan wax; jojoba oil; cotton seed oil, corn oil, hydrogenated cotton seed oil, ouricury wax; rice bran wax; ceresin waxes; montan wax; ozokerite; peat waxes; paraffin wax; polyethylene waxes; and polyglycerol fatty acid esters.
In one of the embodiment the extended release polymer may be bioadhesive.
The bioadhesive polymers may be selected from the group consisting of proteins
(e.g., hydrophilic proteins) such as carbomers, pectin, zein, modified zein, casein, gelatin, gluten, serum albumin and collagen; chitosan; oligosaccharides; polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum arabic, hyaluronic acid, polyhyaluronic acid, alginic acid and sodium alginate; Glyceryl monooleate; polyamides;, polycarbonates; polyalkylenes; polyalkylene glycols; polyalkylene oxides; polyalkylene terephthalates; polyvinyl alcohols; polyvinyl ethers; polyvinyl esters; polyvinyl halides; polyvinylpyrrolidone; polyglycolides; polysiloxanes; polyurethanes; polystyrene; polymers of acrylic and methacrylic esters; polylactides; 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. The high viscosity polymer used in the immediate release pioglitazone layer may include but not limited to alkyl celluloses such as methyl cellulose; hydroxyalkyl celluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; sodium or calcium carboxymethyl cellulose, methyl ethyl cellulose, ethylhydroxy ethylcellulose, carboxyalkyl cellulose esters; polyvinyl alcohol; crosslinked polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide
In preferred embodiment, the high viscosity polymer used in the immediate release pioglitazone layer is hydroxypropyl cellulose (Grade: Klucel LF, Aqualon (USA)), a 5% aqueous solution of which has a viscosity of 75-150 mPas when determined at 25°C, using a Brookfield LVF viscometer, hydroxypropyl cellulose (Grade: Nisso HPC - L, Nisso America Inc.), a 2% aqueous solution of which has a viscosity of 6.0 - 10.0 mPas when determined at 20°C or combination thereof.
The disintegrant used in the immediate release pioglitazone layer may include but not limited to, povidone; low-substituted hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone (crosspovidone); cross-linked sodium carboxymethylcellulose; hydroxypropyl starch; sodium starch glycolate; sodium starch glucolate; sodium carboxymethylcellulose; carboxymethyl cellulose calcium; sodium carboxymethyl starch; ion-exchange resins such as polacrillin potassium; microcrystalline cellulose; starches and pregelatinized starch; formalin-casein; clays such as bentonite or veegum; guar gum; celluloses or cellulose derivatives; sodium alginate; calcium alginate; alginic acid; chitosan; magnesium aluminum silicate; and colloidal silicon dioxide.
The surfactant used in the immediate release pioglitazone layer may be selected from hydrophilic surfactant, lipophilic surfactant or combination thereof.
One embodiment discloses a pharmaceutical composition comprising
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients; and b) Immediate release pioglitazone layer comprising pioglitazone, high viscosity polymer, surfactant and other pharmaceutically acceptable excipients
Hydrophilic surfactants may be either ionic or non-ionic.
Suitable hydrophilc ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; 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. Preferred hydrophilic ionic surfactant is lecithin.
Suitable hydrophilic non-ionic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene- polyoxypropylene block copolymers; and mixtures thereof.
Suitable lipophilic surfactants include, but are not limited to fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol 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; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
The pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable excipients such as binders; diluents; lubricants; disintegrants; glidants; stabilizers; and osmotic agents.
The binders may include, potato starch; pregelatinized starch; modified starch; gelatin; wheat starch; corn starch; celluloses such as methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose and sodium carboxy methyl cellulose; hydroxypropyl Starch, polymethacrylates; carbomers; natural gums such as acacia, alginic acid and guar gum; lactose (anhydrous, monohydrate, spraydried); liquid glucose; dextrin; sodium alginate; kaolin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; poly vinyl alcohol; poly-N-vinyl amide; polyethylene glycol; sucrose; polydextrose; gelatin; poly propylene glycol; tragacanth; ceratonia; glyceryl behenate; hydrogenated vegetable oil; zein; castor oil; paraffin; higher aliphatic alcohols; higher aliphatic acids; long chain fatty acids; fatty acid esters; agar; chitosan; maltodextrin; magnesium aluminum silicate; inulin and wax-like materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, stearic acid; copovidone; dextrates, sunflower oil and stearyl alcohol.
The diluents may include, microcrystalline cellulose; lactose, cellulose powdered, cellulose silicified, cellulose acetate, methyl cellulose, microcrystalline lactose; dibasic or tribasic calcium phosphate; saccharides; confectioner's sugar; compressible sugar; confectioner's sugar; sugar spheres; dextrates; dextrin; dextrose; fructose; maltose; sodium chloride; lactitol; maltodextrin; mannitol; sucrose; fructose; glyceryl palmitostearate; semithicone; Magnesium aluminum silicate; starch; pregelatinized starch; maltitol; xylitol; erythritol; isomalt; sorbitol; sulfobutylether b-cyclodextrin, polymethacrylates; talc; trehalose; ammonium alginate; calcium carbonate; ethyl cellulose; magnesium carbonate; magnesium oxide and calcium sulphate.
The lubricants may include Mg, Al or Ca or Zn stearate; polyethylene glycol; polyvinyl alcohol; glyceryl behenate; glyceryl monostearate; Glyceryl palmitostearate; potassium benzoate; sodium benzoate; mineral oil; sodium stearyl fumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable oil; hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; sodium lauryl sulfate; ethylene oxide polymers; poloxamer; Octyldodecanol; Sodium stearyl fumarate and colloidal silica.
Suitable stabilizers may include but are not limited to naturally occurring as well as synthetic phospholipids, their hydrogenated derivatives and mixtures thereof; organic acids like acetic acid, tartaric acid, citric acid, fumaric acid, lactic acid, and mixtures thereof sphingolipids and glycosphingolipids; physiological bile salts such as sodium cholate, sodium dehydrocholate, 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; alkylaryl-polyether alcohols such as tyloxapol; esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols; acetylated or ethoxylated mono- and diglycerides; synthetic biodegradable polymers like block copolymers of polyoxyethylene and polyoxypropyleneoxide; ethoxylated sorbitanesters or sorbitanethers; amino acids, polypeptides and proteins such as gelatine and albumin; or combination thereof.
The glidants may include magnesium trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; magnesium trisilicate; colloidal silicon dioxide; and silicon hydrogel.
The osmotic agents include sodium chloride; potassium chloride; magnesium sulfate; magnesium chloride; sodium sulfate; lithium sulfate; urea; inositol; sucrose; lactose (anhydrous, monohydrate, spraydried); glucose; sorbitol; fructose; mannitol; dextrose; magnesium succinate; and potassium acid phosphate, sulfobutylether b-cyclodextrin. The osmotic agents may also be added in the extended release coating.
The extended release core may be manufactured by various methods known in the art such as by dry granulation, slugging, roller compaction, wet granulation (using aqueous / nonaqueous solvents), melt granulation, solid dispersion, direct compression, double compression, extrusion spheronization, layering, High shear mixture granulation, Fluid bed granulation, spray drying, steam granulation, moisture activated dry granulation, moist granulation, thermal adhesion granulation, foam granulation and the like. Compaction of the blend into coprimate may be carried out using a slugging technique or roller compaction. The milling of the granules may be carried out according to conventional milling methods.
The solvent which may be used for manufacturing the formulation may be aqueous, non aqueous or combination thereof.
Another embodiment discloses a pharmaceutical composition comprising
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients;
b) Extended release membrane coat; and
c) Immediate release pioglitazone layer comprising pioglitazone, high viscosity polymer, disintegrant and other pharmaceutically acceptable excipients;
Other embodiment discloses a pharmaceutical composition comprising
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients;
b) Extended release membrane coat; and
c) Immediate release pioglitazone layer comprising pioglitazone, polyvinylalcohol, surfactant and other pharmaceutically acceptable excipients;
The extended release membrane coat comprises extended release polymer and other pharmaceutically acceptable excipients. The extended release polymers includes hydrophilic polymers, hydrophobic polymers or waxes as disclosed above.
The extended release membrane coat can be applied to the extended release metformin core by conventional coating procedures in a suitable coating pan or in fluidized bed apparatus using water and/or conventional organic solvents for the coating solution.
The other pharmaceutically acceptable excipients which may be added to coating composition may include pore forming agents, lubricants, plasticizers and colorants.
The porosity of the controlled release coating may be modified by using pore forming agents. The pore forming agents may be polymeric or non polymeric in nature. Any water soluble material present in the coating which dissolves and forms pores in the coating layer may act as pore forming agents. Pore forming agents may be selected form of potassium salts such as potassium chloride, sodium salts as sodium chloride, calcium salts, magnesium salts, amino acids, weak acids, carbohydrates such as sucrose; mannitol; sorbitol, lactose (anhydrous, monohydrate, spray dried), polymers with amino and/or acid functions or polyvinyl pyrrolidine. Examples are aspargine, glutamine, leucin, neroleucine, meglumine, isoleucine, magnesium citrate, magnesium phosphate, magnesium carbonate, magnesium hydroxide, magnesium oxide.
The plasticizers may include, for example acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate, 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 lubricants used in coating may include, Mg, Al or Ca or Zn stearate; polyethylene glycol; polyvinyl alcohol; glyceryl behenate; glyceryl monostearate; glyceryl palmitostearate; potassium benzoate; sodium benzoate; mineral oil; sodium stearyl fumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable oil; hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; sodium lauryl sulfate; ethylene oxide polymers; poloxamer; octyldodecanol; sodium stearyl fumarate and colloidal silica.
Another embodiment discloses a method of preparing pharmaceutical composition comprising extended release metformin hydrochloride and immediate release pioglitazone hydrochloride comprising
a) Preparing metformin hydrochloride granules using aqueous binder solution comprising pharmaceutically acceptable binder;
b) Mixing the dried metformin hydrochloride granules with extended release polymer and other pharmaceutical acceptable excipients; c) Lubricating the blend of step b) using pharmaceutical acceptable excipients and compressing in to a core;
d) Applying to the core of step c) an extended release membrane coat; and e) Applying to the core coated with an extended release membrane coat of step d) a pioglitazone hydrochloride coating solution comprising high viscosity polymer, disintegrant and other pharmaceutical acceptable excipients
Another embodiment discloses a method of preparing pharmaceutical composition comprising extended release metformin hydrochloride and immediate release pioglitazone hydrochloride comprising
a) Preparing metformin granules using aqueous binder solution comprising pharmaceutically acceptable binder;
b) Mixing the dried metformin granules with extended release polymer and other pharmaceutical acceptable excipients;
c) Lubricating the blend of step b) using pharmaceutical acceptable excipients and compressing in to a core;
d) Applying to the core of step c) a extended release membrane coat; and e) Applying to the core coated with a extended release membrane coat of step d) a pioglitazone coating solution comprising polyvinylalcohol, surfactant and other pharmaceutical acceptable excipients.
The immediate release pioglitazone hydrochloride layer can be applied to the extended release metformin hydrochloride coated with an extended release membrane coat, by conventional coating procedures in a suitable coating pan or in fluidized bed apparatus using water and/or conventional organic solvents for the coating solution.
The other pharmaceutically acceptable excipients which may be added to coating composition may include pore forming agents, lubricants, plasticizers and colorants as disclosed above.
The 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 become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.
Example 01:
Sr. No. Ingredients mg/tab
Extended Release Core:
1 Metformin hydrochloride 1000
2 Povidone 45
3 Crospovidone 65
4 Hypromellose 230
5 Microcrystalline Cellulose 55
6 Colloidal Sillicon di-oxide 12.5
7 Mg-stearate 12.5
Average tablet weight of core 1 20 mg/tab
Extended Release Membrane Coat:
8 Amminomethacrylate co-polymer type A 19.23
9 Amminomethacrylate co-polymer type B 19.23
10 Dibutyl sebacate 8.69
11 Isopropyl Alcohol Q.S.
12 Acetone Q.S.
Average tablet weight after functional coat 1467.15 mg/tab
Immediate Release Layer:
13 Pioglitazone hydrochloride 33.07
14 Hydroxy propyl cellulose 8
15 Crospovidone 25
16 Lactose Monohydrate 16
17 Polyethylene glycol 12
18 Titanium di-oxide 3
19 Purified water Q.S.
Average tablet weight after drug loading 1564.22 mg/tab Procedure:
Extended Release Core:
Metformin hydrochloride was sifted and granulated using povidone solution in water. The granules were dried. Hypromellose, crosspovidone and microcrystalline cellulose were sifted and mixed with the prepared metformin hydrochloride granules, which were then lubricated and compressed.
Extended Release Membrane Coat:
he compressed extended release core was coated with coating solution containing aminomethacrylate co-polymer type A and type B.
Immediate Release Layer:
Hydroxypropyl cellulose, polyethylene glycol and lactose were dissolved in purified water. Pioglitazone hydrochloride and titanium di-oxide were added in it, homogenize the solution and applied the core coated with extended release membrane coat.
Example 02:
Sr. No. Ingredients mg/tab
Extended Release Core:
1 Metformin hydrochloride 1000
2 Povidone 20
3 Crospovidone 90
4 Hypromellose 100
5 Microcrystalline Cellulose 190
6 Colloidal Sillicon di-oxide 10
7 Mg-stearate 10
Average tablet weight of core 1420 mg/tab
Extended Release Membrane Coat:
8 Amminomethacrylate co-polymer type A 49.23
9 Amminomethacrylate co-polymer type B 29.23
10 Dibutyl sebacate 14.69
11 Isopropyl Alcohol Q.S.
12 Acetone Q.S.
Average tablet weight after functional coat 1513.15 mg/tab
Immediate Release Layer:
13 Pioglitazone hydrochloride 33.07
14 Hydroxy propyl cellulose 30
15 Crospovidone 10
16 Lactose Monohydrate 14
17 Polyethylene glycol 18
18 Titanium di-oxide 2
19 Purified water Q.S.
Average tablet weight after drug loading 1620.22 mg/tab Procedure:
Extended Release Core:
Metformin hydrochloride was sifted and granulated using povidone solution in water. The granules were dried. Hypromellose, crosspovidone and microcrystalline cellulose were sifted and mixed with the prepared metformin hydrochloride granules, which were then lubricated and compressed.
Extended Release Membrane Coat:
The compressed extended release core was coated with coating solution containing aminomethacrylate co-polymer type A and type B.
Immediate Release Layer:
Hydroxypropyl cellulose, polyethylene glycol and lactose were dissolved in purified water. Pioglitazone hydrochloride and titanium di-oxide were added in it, homogenize the solution and applied the core coated with extended release membrane coat.
Example 03:
Sr. No. Ingredients mg/tab
Extended Release Core:
1 Metformin hydrochloride 1000
2 Povidone 50
3 Crospovidone 60
4 Hypromellose 200
5 Microcrystalline Cellulose 90
6 Colloidal Sillicon di-oxide 10
7 Mg-stearate 10
Average tablet weight of core 1420 mg/tab
Extended Release Membrane Coat:
8 Amminomethacrylate co-polymer type A 19.23
9 Amminomethacrylate co-polymer type B 19.23
10 Dibutyl sebacate 7.69
11 Isopropyl Alcohol Q.S.
12 Acetone Q.S.
Average tablet weight after functional coat 1466.15 mg/tab
Immediate Release Layer:
13 Pioglitazone hydrochloride 33.07
14
Crospovidone 30
15 Hypromellose 30
16 Talc 1
17 Polyethylene glycol 18
18 Titanium di-oxide 1
19 Purified water Q.S.
Average tablet weight after drug loading 1579.22 mg/tab Procedure:
Extended Release Core:
Metformin hydrochloride was sifted and granulated using povidone solution in water. The granules were dried. Hypromellose, crosspovidone and microcrystalline cellulose were sifted and mixed with the prepared metformin hydrochloride granules, which were then lubricated and compressed.
Extended Release Membrane Coat:
The compressed extended release core was coated with coating solution containing aminomethacrylate co-polymer type A and type B.
Immediate Release Layer:
Hypromellose, polyethylene glycol and talc were dissolved in purified water. Piogiitazone hydrochloride and titanium di-oxide were added in it, homogenize the solution and applied the core coated with extended release membrane coat. Example 04:
Sr. No. Ingredients mg/tab
Extended Release Core:
1 Metformin hydrochloride 1000
2 Povidone 30
3 Crospovidone 70
4 Hypromellose 150
5 Microcrystalline Cellulose 130
6 Colloidal Sillicon di-oxide 15
7 Mg-stearate 15
Average tablet weight of core 1410 mg/tab
Extended Release Membrane Coat:
8 Amminomethacrylate co-polymer type A 9.23
9 Amminomethacrylate co-polymer type B 29.23
10 Dibutyl sebacate 7.69
11 Isopropyl Alcohol Q.S.
12 Acetone Q.S.
Average tablet weight after functional coat 1456.15 mg/tab
Immediate Release Layer:
13 Pioglitazone hydrochloride 33.07
14 Lecithin 20
15 Polyvinyl Alcohol 40
16 Talc 2
17 Polyethylene glycol 17
18 Titanium di-oxide 1
19 Purified water Q.S.
Average tablet weight after drug loading 1569.22 mg/tab Procedure:
Extended Release Core:
Metformin hydrochloride was sifted and granulated using povidone solution in water. The granules were dried. Hypromellose, crosspovidone and microcrystalline cellulose were sifted and mixed with the prepared metformin hydrochloride granules, which were then lubricated and compressed.
Extended Release Membrane Coat:
The compressed extended releae core was coated with coating solution containing aminomethacrylate co-polymer type A and type B.
Immediate Release Layer:
Lecithin, polyvinyl alcohol, talc and polyethylene glycol were dissolved in purified water. Pioglitazone hydrochloride and titanium di-oxide were added in it, homogenize the solution and applied the core coated with extended release membrane coat. Example 05:
Dissolution study for metformin and pioglitazone from tablets of Example 01 :
Pioglitazone release study:
The dissolution was carried out in USP type II dissolution apparatus, at 75 rpm, at a temperature of about 37±0.5"C, in 900 ml of 0.3M KCI pH 2 with HCI and releases not less than about 75% of pioglitazone within 1 hour.
Metformin release study:
The dissolution was carried out in USP type I dissolution apparatus, at 100 rpm, at a temperature of about 37±0.5°C, in 1000 ml of pH 6.8 phosphate buffer and releases not more than 25 % of metformin within 1 hour, from about 45% to about 75% of metformin is released within 6 hour and not less than about 80% of metformin is released within 12 hours.
The results of the in vitro dissolution profile are set forth in Table: 01. Table 01
Dissolution profile for metformin and pioglitazone tablets of Example 01
Pioglitazone Release Profile:
Time (Min) Avg. % Pioglitazone Release
5 34.6
10 51.6
15 65.8
30 84.4
45 91.2
60 96.5
120 103.9
Metformin Release Profile:
Time (Hrs) Avg. % Metformin Release
1 3.8
2 12.6
4 45.3
6 68.2
8 83.8
10 93.8
12 100.4

Claims

1. A pharmaceutical composition comprising:
a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients; and
b) Immediate release pioglitazone layer comprising pioglitazone, high viscosity polymer, and other pharmaceutically acceptable excipients.
2. The pharmaceutical composition of claim 1 , wherein the extended release polymer is selected from water soluble polymer, water insoluble polymer, waxy material or combination thereof
3. The pharmaceutical composition of claim 2, wherein the water soluble polymer is selected from methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose; sodium or calcium carboxymethyl cellulose, methyl ethyl cellulose, ethylhydroxy ethylcellulose, carboxyalkyl cellulose esters, carbomers ; glycerol fatty acid esters, sorbitan esters, lecithins; other natural, semi-synthetic, or synthetic di-, oligo-, and polysaccharides selected from galactomannans, tragacanth, agar, guar gum, gum arabic, pectin, acacia, karaya, locust bean gum, xanthan gum, pullulan, collagen, casein, carrageenan, aligns, polycarbophil, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, scleroglucan and polyfructans, maltodextrin; methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides selected from polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, carboxyvinyl polymers, sodium alginate, sodium hyluronate, sodium carboxymethyl starch, gelatin, starch, crosslinked starch, microcrystalline cellulose, ceratonia, chitin, poly(hydroxyalkyl methacrylate), polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone and mixtures and blends thereof.
4. The pharmaceutical composition of claim 2, wherein the water insoluble polymer is selected from cellulose acylate; cellulose ethyl ether; cellulose diacylate; cellulose triacylate; cellulose acetate; cellulose diacetate; cellulose triacetate; mono-, di- and tricellulose alkan, mono-, di- and tricellulose aroyl; ethyl cellulose; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; Glyceryl monooleate; glyceryl monostearate; Glyceryl palmitostearate; polyvinyl acetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate); poly (vinyl acetate); poly vinyl alcohols; polyacrylamide derivatives ammonio methacrylate copolymers, poly acrylic acid and poly acrylate and methacrylate copolymers, aminoacryl-methacrylate copolymer, polyvinyl acetaldiethylamino acetate, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, polyacrylamides, Polyox( polyethylene oxides), diesters of polyglucan, cellulose butyrate, cellulose propionate, shellac, chitosan, Oleyl alcohol, zein, hydrogenated castor oil and the like.
5. The pharmaceutical composition of claim 2, wherein the waxy material is selected from carnauba wax; beeswax; Chinese wax; spermaceti; lanolin; bayberry wax; white wax; yellow wax; candelilla wax; microcrystalline wax; castor wax; esparto wax; Japan wax; jojoba oil; cotton seed oil, corn oil, hydrogenated cotton seed oil, ouricury wax; rice bran wax; ceresin waxes; montan wax; ozokerite; peat waxes; paraffin wax; polyethylene waxes; and polyglycerol fatty acid esters.
6. The pharmaceutical composition of claim 1 , wherein the high viscosity polymer comprising of alkyl celluloses selected from methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; sodium or calcium carboxymethyl cellulose, methyl ethyl cellulose, ethylhydroxy ethylcellulose, carboxyalkyl cellulose esters; polyvinyl alcohol; crosslinked polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides selected from polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide
7. The pharmaceutical composition of claim 1 , wherein the immediate release pioglitazone layer further comprises at least one disintegrant.
8. The pharmaceutical composition of claim 1 , wherein the immediate release pioglitazone layer further comprises at least one surfactant.
9. The pharmaceutical composition of claim 1 wherein said extended release metformin core is further coated with extended release coating.
10. A pharmaceutical composition comprising
(a) Extended release metformin core comprising metformin, extended release polymer and other pharmaceutically acceptable excipients; and
(b) Immediate release pioglitazone layer comprising pioglitazone, polyvinyl alcohol, surfactant and other pharmaceutically acceptable excipients
11. The pharmaceutical composition of claim 10, wherein said surfactant is selected from hydrophilic surfactant, lipophilic surfactant or combination thereof.
12. The pharmaceutical composition of claim 10, wherein said hydrophilic surfactant is either ionic or non-ionic.
13. The pharmaceutical composition of claim 10 wherein said extended release metformin core is further coated with extended release coating.
EP11776517.2A 2010-09-01 2011-08-31 Pharmaceutical composition comprising metformin and pioglitazone Withdrawn EP2611434A1 (en)

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