WO2013077825A1 - Procédé de fabrication d'une préparation comprenant de la metformine - Google Patents

Procédé de fabrication d'une préparation comprenant de la metformine Download PDF

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Publication number
WO2013077825A1
WO2013077825A1 PCT/TR2012/000180 TR2012000180W WO2013077825A1 WO 2013077825 A1 WO2013077825 A1 WO 2013077825A1 TR 2012000180 W TR2012000180 W TR 2012000180W WO 2013077825 A1 WO2013077825 A1 WO 2013077825A1
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WO
WIPO (PCT)
Prior art keywords
formulation
process according
range
tablet
group
Prior art date
Application number
PCT/TR2012/000180
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English (en)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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 Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2013077825A1 publication Critical patent/WO2013077825A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2022—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
    • A61K9/2009—Inorganic compounds
    • 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

Definitions

  • the present invention relates to a preparation process for pharmaceutical formulations comprising metformin that shall be used in the treatment of diabetes.
  • Metformin was first disclosed in the application numbered US3174901 (A). In said document, it was disclosed that metformin is effective in the treatment of diabetes.
  • Metformin is available in 500, 850, 1000 mg film tablet forms on the market.
  • Metformin is a molecule which has low binding capacity. Therefore, the pharmaceutical compositions comprising this active agent have low compressibility. Therefore, problems arise when the formulations comprising metformin hydrochloride are prepared in tablet dosage forms. Generally, obtaining the tablet form having desired physical characteristics is difficult and in the case that the dosage forms having the desired physical characteristics are obtained, sizes of the dosage forms appear to be so large that they are not suitable for swallowing.
  • solutions for the abovementioned problems of metformin have been developed in various documents. For instance, the document numbered EP 1653936 relates to a formulation comprising metformin having a particle size less than 710 ⁇ . An excipient combination comprising metformin having a particle size less than 710 ⁇ and excipients having specific sizes has been suggested as a solution for the difficulties in obtaining the dosage form. Dry granulation and direct compression methods are used as the method.
  • dry granulation and direct compression methods have disadvantages that can significantly affect the quality of the end product such as problems in dose uniformity, disintegration in the formulation.
  • metformin formulations wherein compressibility problem of metformin has been prevented and dose uniformity of the end product can be adjusted properly by using wet granulation method.
  • the inventors have surprisingly seen that compressibility problem is not observed in metformin formulations which are produced by a method wherein the mixture comprising metformin and at least one excipient is granulated with a granulation solution comprising the binder in the range of 1 to 5% in proportion to weight of unit formulation and the dosage forms having desired physical characteristics can be obtained.
  • the present invention is a process in order to prepare formulations comprising metformin hydrochloride characterized in that said process relates to use of a granulation solution comprising the binder in the range of 1 to 5% in proportion to weight of unit formulation in granulation of the mixture comprising metformin hydrochloride and at least one pharmaceutically acceptable excipient.
  • the granulation solution comprises the binder in the range of 1 to 5%, preferably in the range of 2 to 4% in proportion to weight of unit formulation.
  • the binder can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
  • non-cellulosic polymeric binders more preferably polyvinylpyrrolidone is used. The inventors have obtained quite successful results by use of polyvinylpyrrolidone.
  • the present invention is a process for preparation of the formulations comprising metformin hydrochloride, characterized in that said process relates to use of a granulation solution comprising polyvinylpyrrolidone in the range of 1-5% in proportion to weight of unit formulation in granulation of the mixture comprising metformin hydrochloride and at least one pharmaceutically acceptable excipient.
  • the inventors have performed tests with polyvinylpyrrolidone having different molecular weights. In the tests performed, it has been observed that the best results are obtained in the case that molecular weight of polyvinylpyrrolidone used in metformin formulations is in the range of 55000 to 65000 daltons, preferably 60000 daltons. Furthermore, it is preferred that polyvinylpyrrolidone to be used has bulk density in the range of 0.2 to 0.8.
  • the production method of the present invention comprises the following steps:
  • At least one pharmaceutically acceptable excipient that shall be used can be selected from a group comprising diluent, disintegrant, lubricant, flavouring agent, effervescent acid, effervescent base, glidant.
  • the mixture in the II nd step comprises effervescent acid and effervescent base in addition to metformin.
  • the granules obtained are dried such that they have moisture content less than 1%, preferably in the range of 0.1 to 0.5%. It has been observed that more stable formulations are obtained in this manner.
  • the granules are preferably dried at a temperature in the range of 20 to 80 °C.
  • the granules obtained are passed through sieves with mesh sizes in the range of 10 -150 ⁇ , preferably in the range of 20-130 ⁇ . It has been seen that this has a positive effect on improving dissolution profile of the formulation obtained.
  • the inventors have observed that the lubricant also has an important role on improving tableting and compressibility properties of metformin formulations.
  • the inventors have found that using particularly a polymeric lubricant in the V th step of the process provides advantage in compressibility and tableting properties of the dosage forms prepared with the formulations obtained.
  • the lubricant can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
  • a lubricant from polyethylene glycols for instance polyethylene glycol (PEG) having a molecular weight in the range of 400 to 10000, more preferably PEG 6000 is used.
  • PEG 6000 in the range of 0.1-1 %, more preferably in the range of 0.3 to 0.8% is used.
  • the production method of the present invention comprises the following steps: I. Preparing the granulation solution with the granulation solvent comprising polyvinylpyrrolidone in the range of 1-5% in proportion to weight of unit formulation
  • the formulations prepared according to the present invention can be in various dosage forms which are suitable for oral use, for instance in the form of tablet, film tablet, prolonged release tablet, modified release tablet, capsule, dry powder to form suspension, effervescent tablet, orodispersible tablet, chewable tablet, sachet.
  • the formulations of the present invention are preferably in tablet or film coated tablet, more preferably in effervescent tablet form.
  • the present invention relates to use of the binder in the range of 1 to 5 % in proportion to weight of unit formulation in granulation of the mixture comprising metformin hydrochloride and at least one pharmaceutically acceptable excipient in a process that shall be used in preparation of the effervescent formulations comprising metformin hydrochloride.
  • the formulation obtained is compressed in tablet form, the tablets obtained can optionally be coated with film coating agents, for instance sugar based coating agents, water soluble film coating agents, enteric coating or modified release coating agents.
  • Saccharose can be used singly or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof as the sugar based coating agent.
  • agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof as the sugar based coating agent.
  • the water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.
  • cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose
  • synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.
  • the enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.
  • cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate
  • acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.
  • the delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, emulsion copolymer of ethyl acrylate-methyl methacrylate or combinations thereof.
  • the present invention relates to formulations comprising metformin hydrochloride prepared by the production method of the present invention.
  • Said metformin hydrochloride formulations comprise at least one pharmaceutically acceptable excipient along with metformin hydrochloride.
  • At least one pharmaceutically acceptable excipient that can be used in said metformin hydrochloride formulations can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavouring agent, diluent, effervescent acid, effervescent base, glidant.
  • At least one pharmaceutically acceptable binder that can be used in said metformin hydrochloride formulations is selected from a group comprising non-cellulosic polymeric binders, carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
  • At least one pharmaceutically acceptable lubricant that can be used in said metformin hydrochloride formulations is selected from a group calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
  • At least one pharmaceutically acceptable diluent that can be used in said metformin hydrochloride formulations is selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
  • At least one pharmaceutically acceptable flavouring agent that can be used in said metformin hydrochloride formulations is selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
  • At least one pharmaceutically acceptable glidant that can be used in said metformin hydrochloride formulations is selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
  • At least one pharmaceutically acceptable effervescent acid that can be used in said metformin hydrochloride formulations is selected from a group comprising organic acids such as agent malic acid, citric acid, tartaric acid, fumaric acid.
  • At least one pharmaceutically acceptable effervescent base that can be used in said metformin hydrochloride formulations is selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
  • At least one pharmaceutically acceptable disintegrant that can be used in said metformin hydrochloride formulations is selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
  • the formulations of the present invention comprise metformin hydrochloride in the range of 5 to 45%, preferably in the range of 10 to 40%, more preferably in the range of 15 to 35% in proportion to total weight of unit dosage amount.
  • Metformin hydrochloride comprised in the formulations of the present invention can be in crystalline or amorphous forms and/or in the form of its hydrates, solvates or a combination thereof.
  • compositions comprising metformin hydrochloride of the present invention can comprise a second active agent in addition to metformin hydrochloride.
  • Said second active agent can be selected from a group comprising meglinitides, alpha glucosidase inhibitors, sulfonylureas, tiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors.
  • said second active agent can be selected from a group comprising agents such as repaglinide, nateglinide belonging to meglitinide group; alpha-glucosidase inhibitor acarbose; acetohexamide, glibenclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, tolbutamide belonging to sulfonylurea group; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to thiazolidinedione group; phenformin belonging to biguanide group; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate
  • the second active agent can be used in the same formulation with metformin hydrochloride formulations of the present invention, though it can also be combined with metformin hydrochloride formulation of the present invention after being used in a different formulation.
  • Said formulations can be in a single dosage form or in a treatment package form of different dosage forms.
  • formulations can be used in the treatment of type 2 diabetes that cannot be controlled by diet or exercise.
  • Example 1 Formulation and Production Method for Preparation of Tablets Comprising Metformin Hydrochloride
  • Deionized water and organic solvent, polyvinylpyrrolidone are mixed in order to prepare the granulation solution.
  • Metformin hydrochloride, effervescent couple and other excipients are mixed in a container mixer.
  • the mixture obtained is granulated with the granulation solution.
  • the granules are dried and sieved.
  • the granules sieved are mixed again after adding PEG 6000.
  • the granules are formed into tablets after tablet compression and packed in the last phase.
  • Example 2 The Formulation for Preparation of Tablets Comprising Metformin Hydrochloride and Nateglinide
  • Deionized water and ethyl alcohol are mixed with polyvinylpyrrolidone in order to prepare the granulation solution.
  • Metformin hydrochloride and at least one other excipient are mixed.
  • the mixture obtained is granulated with the granulation solution.
  • the granules are dried at a temperature in the range of 20 to 80 °C until they have moisture content less than 1% and sieved.
  • the granules sieved are mixed again after adding nateglinide, PEG 6000 and at least one excipient.
  • the granules are formed into tablets as a result of tablet compression and packed in the last phase.
  • Example 3 The Formulation for Preparation of the Treatment Package Comprising Metformin Hydrochloride and Nateglinide
  • the formulation comprising nateglinide given above is prepared by dry granulation method.
  • the other excipients except for the lubricant comprised in the formulation are subjected to precompression process after being mixed with an appropriate method.
  • the tablets obtained after precompression are granulated in granulator.
  • the lubricant is added into these granules, mixed and the mixture obtained is compressed in tablet form.
  • Deionized water and ethyl alcohol are mixed with polyvinylpyrrolidone in order to prepare the granulation solution.
  • Metformin hydrochloride, effervescent couple and at least one other excipient are mixed in a container mixer.
  • the mixture obtained is granulated with the granulation solution.
  • the granules are dried at a specific temperature until the desired moisture content is obtained and they are sieved.
  • the granules sieved are mixed again after adding PEG 6000 and at least one excipient. In the last phase, the granules are formed into tablets as a result of tablet compression and they are packed.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention concerne un procédé de fabrication de préparations pharmaceutiques comprenant de la metformine qui sont utilisées pour le traitement du diabète.
PCT/TR2012/000180 2011-11-23 2012-10-31 Procédé de fabrication d'une préparation comprenant de la metformine WO2013077825A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR201111590 2011-11-23
TR2011/11590 2011-11-23
TR201201872 2012-02-21
TR2012/01872 2012-02-21

Publications (1)

Publication Number Publication Date
WO2013077825A1 true WO2013077825A1 (fr) 2013-05-30

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104434840A (zh) * 2014-12-10 2015-03-25 哈药集团技术中心 一种瑞格列奈片及其制备方法
US11096890B2 (en) * 2017-09-29 2021-08-24 Merck Sharp & Dohme Corp. Chewable dosage forms containing sitagliptin and metformin
EP4125824A4 (fr) * 2020-03-27 2023-12-27 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation en sachet comprenant de la metformine et de la dapagliflozine

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3174901A (en) 1963-01-31 1965-03-23 Jan Marcel Didier Aron Samuel Process for the oral treatment of diabetes
US20030064101A1 (en) * 2001-09-25 2003-04-03 J.B. Chemicals & Pharmaceuticals Limited Floating osmotic device for controlled release drug delivery
WO2003026637A2 (fr) * 2001-09-28 2003-04-03 Sun Pharmaceutical Industries Limited Forme posologique pour traiter le diabete sucre
WO2003051293A2 (fr) * 2001-12-17 2003-06-26 Bristol-Myers Squibb Company Formulation anti-diabete et procede
WO2006017541A2 (fr) * 2004-08-03 2006-02-16 Emisphere Technologies, Inc. Association d'insuline et d'un biguanide pour administration orale contre le diabète
EP1653936A2 (fr) 2003-08-06 2006-05-10 SARL Galenix Innovations Composition pharmaceutique solide dispersible et/ou orodispersible non pelliculee contenant au moins le principe actif metformine, et procede de preparation
WO2007131930A1 (fr) * 2006-05-13 2007-11-22 Novo Nordisk A/S Formulation de comprimé comprenant du répaglinide et de la metformine
WO2008037807A1 (fr) * 2006-09-29 2008-04-03 Novo Nordisk A/S Formulation pharmaceutique contenant de la metformine et du répaglinide
WO2009011451A1 (fr) * 2007-07-19 2009-01-22 Takeda Pharmaceutical Company Limited Preparation solide

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3174901A (en) 1963-01-31 1965-03-23 Jan Marcel Didier Aron Samuel Process for the oral treatment of diabetes
US20030064101A1 (en) * 2001-09-25 2003-04-03 J.B. Chemicals & Pharmaceuticals Limited Floating osmotic device for controlled release drug delivery
WO2003026637A2 (fr) * 2001-09-28 2003-04-03 Sun Pharmaceutical Industries Limited Forme posologique pour traiter le diabete sucre
WO2003051293A2 (fr) * 2001-12-17 2003-06-26 Bristol-Myers Squibb Company Formulation anti-diabete et procede
EP1653936A2 (fr) 2003-08-06 2006-05-10 SARL Galenix Innovations Composition pharmaceutique solide dispersible et/ou orodispersible non pelliculee contenant au moins le principe actif metformine, et procede de preparation
WO2006017541A2 (fr) * 2004-08-03 2006-02-16 Emisphere Technologies, Inc. Association d'insuline et d'un biguanide pour administration orale contre le diabète
WO2007131930A1 (fr) * 2006-05-13 2007-11-22 Novo Nordisk A/S Formulation de comprimé comprenant du répaglinide et de la metformine
WO2008037807A1 (fr) * 2006-09-29 2008-04-03 Novo Nordisk A/S Formulation pharmaceutique contenant de la metformine et du répaglinide
WO2009011451A1 (fr) * 2007-07-19 2009-01-22 Takeda Pharmaceutical Company Limited Preparation solide

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104434840A (zh) * 2014-12-10 2015-03-25 哈药集团技术中心 一种瑞格列奈片及其制备方法
US11096890B2 (en) * 2017-09-29 2021-08-24 Merck Sharp & Dohme Corp. Chewable dosage forms containing sitagliptin and metformin
EP4125824A4 (fr) * 2020-03-27 2023-12-27 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation en sachet comprenant de la metformine et de la dapagliflozine

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