WO2013077824A1 - 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
WO2013077824A1
WO2013077824A1 PCT/TR2012/000176 TR2012000176W WO2013077824A1 WO 2013077824 A1 WO2013077824 A1 WO 2013077824A1 TR 2012000176 W TR2012000176 W TR 2012000176W WO 2013077824 A1 WO2013077824 A1 WO 2013077824A1
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WO
WIPO (PCT)
Prior art keywords
formulation
metformin hydrochloride
process according
range
tablet
Prior art date
Application number
PCT/TR2012/000176
Other languages
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 WO2013077824A1 publication Critical patent/WO2013077824A1/fr

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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
    • A61K31/13—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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 so as to be used in the treatment of diabetes.
  • Metformin was first disclosed in the US patent application numbered 3174901 (A). In said document, metformin was indicated to be effective in the treatment of diabetes.
  • Metformin is available in the form of 500, 850, 1000 mg film tablets on the market.
  • Dose uniformity is highly important in terms of providing a successful treatment. Dose uniformity is generally depends on obtaining homogenous formulations. When formulations are not homogeneous, obtained dosage forms comprise different amounts of active agent and this poses problems both in terms of quality standards and problems of overdose or deficient dose intake in the treatment to be applied with said product.
  • ingredients of a granulation solution used in a process for the preparation of formulations comprising metformin hydrochloride play an important role in terms of homogeneity of the obtained granules and thus dose uniformity of the final product.
  • the inventors have observed that granules obtained through a process where the granulation solution used comprise water in the range of 1% and 5%, organic solvent in the range of 1% and 20% in proportion to the weight of metformin hydrochloride; and the formulations prepared with these granules are homogeneous and that dose uniformity is obtained in the final product.
  • the present invention relates to a process so as to be used in the preparation of formulations comprising metformin hydrochloride, wherein said process is characterized in that the granulation of the mixture comprising metformin hydrochloride and at least one pharmaceutically acceptable excipient comprises water in the range of 1% and 5%, organic solvent in the range of 10% and 20% in proportion to the weight of metformin hydrochloride in the formulation.
  • the present invention relates to a process where a granulation solution comprising water in the range of 1% and 5%, organic solvent in the range of 10% and 20% in proportion to the weight of metformin hydrochloride in the formulation is used for the granulation of the mixture comprising metformin hydrochloride and at least one pharmaceutically acceptable excipient in preparation of formulations comprising metformin hydrochloride.
  • granulation solution of the present invention preferably water in the range of 2% and 4% and organic solvent in the range of 12% and 17% are used.
  • the ratio of water and organic solvent in the granulation solution is in the range of 1 :2 and 1 :20, preferably in the range of 1 :4 and 1 :8.
  • Said organic solvent can be selected from primary, secondary or tertiary alcohols, amines or ketones, esters, ether derivatives, hydrocarbons.
  • Said organic solvent is selected from a group comprising ethanol, methanol, tetrahydrofuran, hexane, heptane, ethyl acetate, acetone, methyl ethyl ketone, n-butyl acetate, isopropyl alcohol, n-butanol, 1-propanol, tert-butyl alcohol.
  • one of the derivatives of alcohol more preferably ethyl alcohol is used as an organic solvent in the process of the invention.
  • the present invention relates to the use of a granulation solution comprising water in the range of 1% and 5%, ethanol in the range of 10% and 20% in proportion to the weight of metformin hydrochloride in the formulation for the granulation of the mixture comprising metformin hydrochloride and at least one pharmaceutically acceptable excipient in a process to be utilized for preparation of formulations comprising metformin hydrochloride.
  • the production method of the invention comprises the steps below;
  • step II Granulating the mixture comprising metformin and at least one pharmaceutically acceptable excipient with the granulation solution obtained in step I, III. Drying the obtained granules,
  • At least one pharmaceutically acceptable excipient to be used in steps I, II and V can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavoring agent, effervescent acid, effervescent base, glidant or combinations thereof.
  • the granules obtained in step III are dried such that the moisture rate of the granules is lower than 1%, preferably in the range of 0.1% and 0.5%. It was observed that more stable formulations are obtained in this way.
  • the granules are dried at a temperature between 20 and 80°C.
  • step III the obtained granules are sieved through sieves with mesh sizes in the range of 10- 150 ⁇ , preferably in the range of 20-130 ⁇ . It was seen that this has a positive effect on improving the dissolution profile of the obtained formulation.
  • the production method of the invention comprises the steps of;
  • the formulations prepared in accordance with the invention can be in various dosage forms appropriate for oral intake, e.g. in one of the forms such as tablet, film tablet, extended-release tablet, modified-release tablet, capsule, dry powder for suspension preparation, effervescent tablet, orodispersible tablet, chewable tablet, sachet.
  • the formulations of the invention are preferably in the form of tablet or film-coated tablet, more preferably in the form of effervescent tablet.
  • the present invention relates to the use of a granulation solution comprising water in the range of 1% and 5%, organic solvent in the range of 10% and 20% in proportion to the total weight of metformin hydrochloride in the formulation, for the granulation of the mixture comprising metformin hydrochloride and at least one pharmaceutically acceptable excipient in a process for preparation of effervescent formulations comprising metformin hydrochloride.
  • the mixture comprising metformin hydrochloride, effervescent acid and effervescent base is granulated with the granulation solution of the present invention.
  • the present invention relates to the use of a granulation solution comprising water in the range of 1% and 5%, organic solvent in the range of 10% and 20% in proportion to the total weight of metformin hydrochloride in the formulation, for the granulation of the mixture comprising metformin hydrochloride, effervescent acid and effervescent base in the preparation process of effervescent formulations comprising metformin hydrochloride.
  • said formulation can optionally be coated with film-coating agents; e.g. sugar-based coating agents, water-soluble film-coating agent, enteric coating agents and modified-release coating agents.
  • film-coating agents e.g. sugar-based coating agents, water-soluble film-coating agent, enteric coating agents and modified-release coating agents.
  • saccharose can be used on its own or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or with any combinations thereof.
  • agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or with any combinations thereof.
  • Water-soluble film-coating agents 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
  • polysaccharides such as pullulan; or combinations thereof.
  • 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
  • natural substances such as shellac; or combinations thereof.
  • Delayed-release coating agents can be selected from cellulose derivatives such as ethyl cellulose, aminoalkyl methacrylate copolymer RS; acrylic acid derivatives such as ethyl acrylate-methyl methacrylate copolymer emulsion; or combinations thereof.
  • the present invention relates to formulations comprising metformin hydrochloride prepared in accordance with the production method of the present invention.
  • Said metformin hydrochloride formulations comprise at least one pharmaceutically acceptable excipient in addition to metformin hydrochloride.
  • At least one pharmaceutically acceptable excipient that can be used in said formulations comprising metformin hydrochloride can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavoring 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 carboxymethyl cellulose sodium, ethyl cellulose, gelatin, 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 comprising 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 flavoring agent that can be used in said metformin hydrochloride formulations is selected from flavors such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and the like.
  • 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 silicon 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 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 invention comprise metformin hydrochloride in the range of 5% and 45%, preferably in the range of 10% and 40%, more preferably in the range of 15% and 35% in proportion to the total weight of the dosage amount.
  • Metformin hydrochloride comprised in the formulations of the invention can be in crystalline or amorphous forms and/or in the forms of its hydrates, solvates or combinations thereof.
  • compositions of the present invention comprising metformin hydrochloride can comprise a second active agent in addition to metformin hydrochloride.
  • Said second active agent can be selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulphonylureas, thiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors.
  • said second active agent can be selected from repaglinide, nateglinide from the group meglitinide; alphaglucosidase inhibitor acarbose; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, tolbutamide from the group sulfonylurea; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone from the group tiazolidinedione; phenformin from the group biguanide; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate, si
  • the second active agent can be used in the same formulation with metformin formulations of the invention, it can also be used in a different formulation and then combined with the metformin formulation of the invention.
  • Said formulations can be in a single dosage form or as a treatment package in different dosage forms.
  • formulations can be used in the treatment of type 2 diabetes that cannot be controlled with diet or exercise.
  • Example 1 Formulation and Production Method for the Preparation of Tablets Comprising Metformin Hydrochloride
  • granulation solution deionized water (2% in proportion to the weight of metformin) and ethyl alcohol (18% in proportion to the weight of metformin) are mixed with at least another excipient. Metformin hydrochloride and at least another excipient are mixed. The obtained mixture is granulated with the granulation solution. The granules are dried at a temperature between 20 and 80°C such that the moisture rate is lower than 1% and they are sieved. The sieved granules are mixed again after adding nateglinide, lubricant and at least one excipient. In the last step, granules are compressed into tablets and packaged.
  • Example 3 Formulation for the Preparation of the Treatment Package Comprising Metformin Hydrochloride and Nateglinide
  • the formulation above comprising nateglinide is prepared with dry granulation method.
  • other substances in the formulation except the lubricants are mixed with an appropriate method and pre-compressed. Tablets obtained through pre-compression are granulated with a granulator. Lubricant is added to these granules, they are mixed and the obtained mixture is compressed into tablets.
  • granulation solution deionized water (in an amount of 2.8% in proportion to the weight of metformin) and ethyl alcohol (in an amount of 14% in proportion to the weight of metformin) are mixed with at least one excipient.
  • Metformin hydrochloride is mixed with an effervescent couple and at least another excipient.
  • the obtained mixture is granulated with the granulation solution.
  • Granules are dried at a certain temperature until a desired moisture rate is obtained. The sieved granules are mixed again after adding additional excipients. In the last step, granules are brought into tablet form via tablet compression and then the tablets are packaged.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

Cette invention concerne un procédé de fabrication de préparations pharmaceutiques comprenant de la metformine qui sont utilisées pour le traitement du diabète.
PCT/TR2012/000176 2011-11-23 2012-10-19 Procédé de fabrication d'une préparation comprenant de la metformine WO2013077824A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR201111590 2011-11-23
TR2011/11590 2011-11-23
TR201112199 2011-12-09
TR2011/12199 2011-12-09

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WO2013077824A1 true WO2013077824A1 (fr) 2013-05-30

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2848242A1 (fr) * 2013-09-12 2015-03-18 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations orodispersibles de Linagliptin
EP2848241A1 (fr) * 2013-09-12 2015-03-18 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations effervescentes de linagliptin
WO2018185669A1 (fr) * 2017-04-07 2018-10-11 Zenvision Pharma Llp Compositions effervescentes comprenant de la saxagliptine ou un sel de celle-ci
CN109985014A (zh) * 2019-05-17 2019-07-09 贵州天安药业股份有限公司 一种2型糖尿病治疗用盐酸吡格列酮分散片

Citations (7)

* 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
WO2003105809A1 (fr) * 2002-06-17 2003-12-24 Themis Laboratories Private Limited Comprimes multicouche contenant des thiazolidinediones et des biguanides et procedes de production desdits comprimes
WO2005123134A2 (fr) * 2004-05-14 2005-12-29 Cadila Healthcare Limited Systeme d'administration a liberation controlee pour metformine
CZ297247B6 (cs) * 2005-03-15 2006-10-11 Lunaria, Spol. S R. O. Farmaceutický prípravek obsahující metformin
WO2007041053A2 (fr) * 2005-09-29 2007-04-12 Novartis Ag Nouvelle formulation
WO2007038979A1 (fr) * 2005-09-22 2007-04-12 Swissco Development Ag Composition effervescente de metformine et comprimés et granules fabriqués à partir de cette composition
WO2009111200A1 (fr) * 2008-03-04 2009-09-11 Merck & Co., Inc. Compositions pharmaceutiques d'une combinaison de metformine et d'un inhibiteur de dipeptidyl peptidase-iv

Patent Citations (7)

* 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
WO2003105809A1 (fr) * 2002-06-17 2003-12-24 Themis Laboratories Private Limited Comprimes multicouche contenant des thiazolidinediones et des biguanides et procedes de production desdits comprimes
WO2005123134A2 (fr) * 2004-05-14 2005-12-29 Cadila Healthcare Limited Systeme d'administration a liberation controlee pour metformine
CZ297247B6 (cs) * 2005-03-15 2006-10-11 Lunaria, Spol. S R. O. Farmaceutický prípravek obsahující metformin
WO2007038979A1 (fr) * 2005-09-22 2007-04-12 Swissco Development Ag Composition effervescente de metformine et comprimés et granules fabriqués à partir de cette composition
WO2007041053A2 (fr) * 2005-09-29 2007-04-12 Novartis Ag Nouvelle formulation
WO2009111200A1 (fr) * 2008-03-04 2009-09-11 Merck & Co., Inc. Compositions pharmaceutiques d'une combinaison de metformine et d'un inhibiteur de dipeptidyl peptidase-iv

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2848242A1 (fr) * 2013-09-12 2015-03-18 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations orodispersibles de Linagliptin
EP2848241A1 (fr) * 2013-09-12 2015-03-18 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations effervescentes de linagliptin
WO2018185669A1 (fr) * 2017-04-07 2018-10-11 Zenvision Pharma Llp Compositions effervescentes comprenant de la saxagliptine ou un sel de celle-ci
CN109985014A (zh) * 2019-05-17 2019-07-09 贵州天安药业股份有限公司 一种2型糖尿病治疗用盐酸吡格列酮分散片

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