WO2013074049A1 - Metformine micronisée - Google Patents

Metformine micronisée Download PDF

Info

Publication number
WO2013074049A1
WO2013074049A1 PCT/TR2012/000153 TR2012000153W WO2013074049A1 WO 2013074049 A1 WO2013074049 A1 WO 2013074049A1 TR 2012000153 W TR2012000153 W TR 2012000153W WO 2013074049 A1 WO2013074049 A1 WO 2013074049A1
Authority
WO
WIPO (PCT)
Prior art keywords
metformin
pharmaceutical composition
active agent
less
particle size
Prior art date
Application number
PCT/TR2012/000153
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 WO2013074049A1 publication Critical patent/WO2013074049A1/fr

Links

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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to pharmaceutical compositions comprising metformin that shall be used in the treatment of type 2 diabetes.
  • Metformin (Formula 1), chemical name of which is N,N-dimethylimidodicarbonimidic diamide, is a molecule belonging to biguanide class. Metformin was firstly disclosed in the application numbered US3174901. It is known that metformin is effective in the treatment of especially overweight and obese patients with type 2 diabetes who have healthy kidney functions. In different sources, it has been disclosed that said active agent can also be used in the treatment of polycystic ovary syndrome or different diseases caused by insulin resistance.
  • Metformin is available in metformin hydrochloride salt form as 500 mg, 750 mg and 1000 mg film coated tablet and prolonged release tablet forms on the market.
  • Bioavailability characteristics of products taken by the oral route are closely associated with dissolutions of the products.
  • the active agent cannot reach therapeutically sufficient amounts in body resulting from insufficient dissolution of the active agent in body and this affects the treatment process negatively.
  • compositions when the pharmaceutical compositions are formed into various dosage forms they are required to have content uniformity, in other words to comprise equal amount of active agent in unit dosage form. This depends on flow characteristics of the formulations prepared. Each unit dose of the formulations having desired flow characteristics comprises equal amount of the active agent.
  • the inventors have found that the pharmaceutical formulations wherein metformin having an average particle size (d 50 ) equal to or less than 15 ⁇ is used have better dissolution and content uniformity of the pharmaceutical compositions comprising metformin having an average particle size (d 5 o) equal to or less than 15 ⁇ is ensured easily during preparation of the dosage forms.
  • the present invention relates to pharmaceutical compositions comprising metformin having an average particle size (d 5 o) equal to or less than 15 ⁇ .
  • the formulations of the present invention comprise metformin having an average particle size (d 50 ) preferably in the range of 1 ⁇ to 15 ⁇ , more preferably in the range of 3 ⁇ ⁇ 12 ⁇ .
  • average particle size refers to average particle size by volume and it is also shown with d 50 in short.
  • d 50 signifies that half of the said substance by volume has a particle size over the value stated with d 50 and the other half of the substance by volume has a particle size below the value stated with d 50 .
  • Metformin comprised in the pharmaceutical compositions of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof. Metformin is preferably in the form of its salts, more preferably its hydrochloride salt.
  • D 5 o value can be measured with one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
  • Metformin of the present invention having a d 50 value equal to or less than 15 ⁇ can be bought and used as a product commercially provided in this manner.
  • metformin having a d 50 value equal to or less than 15 ⁇ can also be obtained by pulverizing a product having coarser particle size singly or with an excipient (for instance microcrystalline cellulose etc.).
  • pulverization can be performed by using the methods such as impact mill, jet mill, blade mill etc. Pulverization can be performed before preparation of the pharmaceutical composition comprising metformin as well as during preparation of the pharmaceutical composition of the present invention or before post-production storage of the pharmaceutical composition prepared.
  • pulverization is performed by the effect of rotating blades in the device.
  • pulverization is performed by the effect of rotating hammers in the device.
  • compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can be prepared in any dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enteric- coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.
  • the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ are preferably in tablet, prolonged release tablet, film coated tablet or effervescent tablet forms, more preferably in effervescent tablet form.
  • the pharmaceutical composition obtained can be formed into any dosage form stated above.
  • the compositions are in tablet forms
  • the tablets obtained can be treated with film coating agents, for instance sugar based coating agents, water soluble film coating agents, enteric-coating agents, delayed release coating agents or coating compositions comprising any combination thereof.
  • 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 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 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.
  • 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 pharmaceutical compositions in effervescent tablet form comprising metformin having an average particle size (d 0 ) equal to or less than 15 ⁇ .
  • compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can comprise various excipients in addition to the active agent metformin.
  • the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ comprise at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent in addition to the active agent metformin.
  • the disintegrant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can be 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 diluent that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can be 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.
  • the lubricant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ 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.
  • the glidant that can be used in the pharmaceutical compositions of the present invention comprising metformin having d 50 value equal to or less than 15 ⁇ can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
  • the binder that can be used in the pharmaceutical compositions of the present invention comprising metformin having d 50 value equal to or less than 15 ⁇ 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.
  • the acidic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇
  • the acidic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇
  • the basic agent can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
  • the pH regulating agent that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 0 value equal to or less than 15 ⁇ can be selected from citrate, phosphate, carbonate, tartarate, fumarate, acetate and amino acid salts.
  • the surfactant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
  • the stabilizing agent that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
  • the sweetener and/or taste regulating agent that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
  • the flavouring agent that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can be selected from a group comprising menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
  • the pharmaceutical compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can comprise metformin in the range of 0.1 to 100% by weight, preferably in the range of 1 to 99% by weight, preferably in the range of 5 to 95% by weight and more preferably in the range of 10 to 50% by weight
  • the present invention relates to pharmaceutical compositions comprising metformin having a d 90 value equal to or less than 50 ⁇ .
  • the inventors have observed that the active agent and the excipients are mixed homogeneously during preparation of the pharmaceutical compositions comprising metformin having a d 90 value equal to or less than 50 ⁇ and as a result of this, each unit dosage form prepared with the formulation comprises equal amount of active agent.
  • the present invention relates to pharmaceutical compositions comprising metformin having a d 90 value equal to or less than 50 ⁇ .
  • D 9 o value of metformin comprised in the pharmaceutical compositions of the present invention is equal to or less than 50 ⁇ , preferably in the range of 1 to 50 ⁇ , more preferably in the range of 5 to 45 ⁇ .
  • the present invention relates to pharmaceutical compositions comprising metformin having a d 50 value equal to or less than 15 ⁇ and a d 90 value equal to or less than 50 ⁇ .
  • compositions of the present invention comprising metformin having a d 5 o value equal to or less than 15 ⁇ can optionally comprise a second active agent in addition to metformin.
  • the second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid
  • compositions of the present invention comprising metformine having a d 50 value equal to or less than 15 ⁇ can optionally comprise a second active agent in addition to metformine.
  • the second active agent can be selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulfonylureas, thiazolidinediones, 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, glindeklamid, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, glibenclamide, chlorpropamide, tolbutamide belonging to sulfonylurea group; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to thiazolidinedione group; phenformin or a pharmaceutically acceptable salt thereof belonging to biguanide group; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxaglip
  • compositions of the present invention comprising metformin having a d 50 value equal to or less than 15 ⁇ can preferably comprise a second active agent belonging to meglitinide group, more preferably comprise nateglinide or rapeglinide as a second active agent in addition to metformin.
  • the pharmaceutical composition of the present invention can be obtained by:
  • the pharmaceutical composition of the present invention can be used in prevention and treatment of type 2 diabetes.
  • EXAMPLE 1 Tablet formulation comprising metformin
  • Metformin hydrochloride, organic base, organic acid are mixed and granulated.
  • the granules obtained are mixed with the excipients after dried.
  • the glidant is added into the mixture obtained and mixed.
  • the lubricant is added into the final mixture and the pharmaceutical composition obtained is compressed in tablet compression machine.
  • EXAMPLE 2 Tablet formulation comprising metformin
  • Metformin hydrochloride, organic base, organic acid are mixed.
  • the excipients and the glidant are added into the mixture obtained.
  • the lubricant is added into the final mixture and the pharmaceutical composition obtained is compressed in tablet compression machine.

Landscapes

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

Abstract

La présente invention porte sur des compositions pharmaceutiques comprenant de la metformine, destinées à être utilisées dans le traitement de diabètes de type 2.
PCT/TR2012/000153 2011-11-03 2012-09-24 Metformine micronisée WO2013074049A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR2011/10979 2011-11-03
TR201110979 2011-11-03
TR201111588 2011-11-23
TR2011/11588 2011-11-23

Publications (1)

Publication Number Publication Date
WO2013074049A1 true WO2013074049A1 (fr) 2013-05-23

Family

ID=47678976

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2012/000153 WO2013074049A1 (fr) 2011-11-03 2012-09-24 Metformine micronisée

Country Status (1)

Country Link
WO (1) WO2013074049A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103417971A (zh) * 2013-08-13 2013-12-04 深圳奥萨医药有限公司 二肽基肽酶抑制剂和b族维生素的药物组合物及用途
EP3342402A1 (fr) * 2016-12-30 2018-07-04 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions pharmaceutiques comprenant de metformine hydrochloride et pioglitazone hydrochloride

Citations (4)

* 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
EP1738754A1 (fr) * 2004-04-14 2007-01-03 Takeda Pharmaceutical Company Limited Preparation pharmaceutique solide
WO2007131930A1 (fr) * 2006-05-13 2007-11-22 Novo Nordisk A/S Formulation de comprimé comprenant du répaglinide et de la metformine
WO2008101943A1 (fr) * 2007-02-21 2008-08-28 Laboratori Guidotti S.P.A. Formulation pharmaceutique d'hydrochlorure de metformine et comprimé renfermant ladite formulation

Patent Citations (4)

* 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
EP1738754A1 (fr) * 2004-04-14 2007-01-03 Takeda Pharmaceutical Company Limited Preparation pharmaceutique solide
WO2007131930A1 (fr) * 2006-05-13 2007-11-22 Novo Nordisk A/S Formulation de comprimé comprenant du répaglinide et de la metformine
WO2008101943A1 (fr) * 2007-02-21 2008-08-28 Laboratori Guidotti S.P.A. Formulation pharmaceutique d'hydrochlorure de metformine et comprimé renfermant ladite formulation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103417971A (zh) * 2013-08-13 2013-12-04 深圳奥萨医药有限公司 二肽基肽酶抑制剂和b族维生素的药物组合物及用途
EP3342402A1 (fr) * 2016-12-30 2018-07-04 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions pharmaceutiques comprenant de metformine hydrochloride et pioglitazone hydrochloride
WO2018122385A1 (fr) * 2016-12-30 2018-07-05 Sanovel Ilac Sanayi Ve Ticaret A.S. Compositions pharmaceutiques de chlorhydrate de metformine et de chlorhydrate de pioglitazone

Similar Documents

Publication Publication Date Title
EP2698145B1 (fr) Formulations pharmaceutiques comprenant de la dapoxétine et un inhibiteur de la PDE-5.
TWI522100B (zh) 含有納布啡（ｎａｌｂｕｐｈｉｎｅ）之藥學組成物及其用途
EP3287438A1 (fr) Sel de choline d'un composé cyclobutène-dione substitué anti-inflammatoire
EP2550957B1 (fr) Formulations effervescentes de vildagliptine
WO2013115742A1 (fr) Composition pharmaceutique contenant un inhibiteur de l'alpha-glucosidase
WO2013115744A1 (fr) Procédé de préparation de compositions pharmaceutiques (effervescentes) contenant un inhibiteur de l'apha-glucosidase (p. ex. voglibose et metformine)
TW202237145A (zh) 莫奈皮拉韋的醫藥組成物
WO2013115738A1 (fr) Acarbose micronisée
WO2013109227A1 (fr) Compositions pharmaceutiques contenant du ceftibutène
WO2013074049A1 (fr) Metformine micronisée
EP2809316A1 (fr) Combinaison synergique contenant un dérivé de méglitinide et de l'acide lipoïque
WO2013077824A1 (fr) Procédé de fabrication d'une préparation comprenant de la metformine
WO2014104989A1 (fr) Compositions pharmaceutiques comprenant de l'aripiprazole
WO2013095316A1 (fr) Combinaison synergique comprenant un agent anti-diabétique
WO2013077819A1 (fr) Préparations pharmaceutiques comprenant du natéglinide
WO2018185669A1 (fr) Compositions effervescentes comprenant de la saxagliptine ou un sel de celle-ci
WO2013077822A1 (fr) Nouvelles préparations pour le traitement du diabète
WO2013115741A1 (fr) Compositions pharmaceutiques contenant un inhibiteur de l'alpha-glucosidase
WO2014007775A1 (fr) Nouvelle formulation à dissolution rapide
WO2013100879A1 (fr) Compositions pharmaceutiques contenant de la quétiapine
WO2013100873A1 (fr) Formulation pharmaceutique de prégabaline (taille de particules 300-2500 micromètres)
WO2013077821A1 (fr) Composition homogène contenant un biguanide
ES2435966T3 (es) Combinaciones de vildagliptina y glimepirida
ES2654331T3 (es) Comprimidos de ibuprofeno de sodio y procedimientos de fabricación de composiciones farmacéuticas que incluyen ibuprofeno de sodio
WO2013109230A1 (fr) Compositions pharmaceutiques contenant du tadalafil

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12823054

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12823054

Country of ref document: EP

Kind code of ref document: A1