WO2008062273A2 - Forme posologique solide administration orale contenant une combinaison de médicaments antidiabétiques - Google Patents

Forme posologique solide administration orale contenant une combinaison de médicaments antidiabétiques Download PDF

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Publication number
WO2008062273A2
WO2008062273A2 PCT/IB2007/003513 IB2007003513W WO2008062273A2 WO 2008062273 A2 WO2008062273 A2 WO 2008062273A2 IB 2007003513 W IB2007003513 W IB 2007003513W WO 2008062273 A2 WO2008062273 A2 WO 2008062273A2
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
amount
glibenclamide
cellulose
composition according
Prior art date
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PCT/IB2007/003513
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English (en)
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WO2008062273A8 (fr
WO2008062273A3 (fr
Inventor
Indravadan Ambalal Modi
Ashok Omray
Kartik Y. Shah
Bakuleh Mafatlal Khamar
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Cadila Pharmaceuticals Limited
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Publication date
Application filed by Cadila Pharmaceuticals Limited filed Critical Cadila Pharmaceuticals Limited
Publication of WO2008062273A2 publication Critical patent/WO2008062273A2/fr
Publication of WO2008062273A8 publication Critical patent/WO2008062273A8/fr
Publication of WO2008062273A3 publication Critical patent/WO2008062273A3/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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to solid oral dosage form for the treatment of non-insulin dependant type diabetes (diabetes of type II) using a combination of oral hypoglycemic agents.
  • Non-insulin dependant diabetes is a metabolic disorder characterized by hyperglycemia, which occurs due to insulin deficiency, insulin resistance and reduced glucose tolerance.
  • the biguanides such as Metformin (expressed as the hydrochloride salt of Metformin), act by decreasing gluconeogenesis thereby increasing peripheral utilization of glucose, and as they require endogenous insulin they are only effective with some residual pancreatic islet cell activity.
  • the use of sulphonylureas and biguanides in monotherapy in most cases, allows obtaining an effective glycometabolic control for some years if an appropriate diet and behavioral regimen are kept. Nevertheless, the efficacy of the therapy with oral hypoglycemic agents can decrease with time.
  • the co-therapy plays a significant role in therapeutic, since it allows obtaining an effective metabolic control in the patients of diabetes of type II, where the therapy using either sulphonylureas or biguanides becomes ineffective.
  • Combined antidiabetic therapy with sulphonylureas and biguanides, having complementary mode of action, is now an acceptable form of the treatment for diabetes of type II with solid oral dosage form like tablets that ensures enhanced patient compliance.
  • Such a combination of Metformin hydrochloride with Glibenclamide has been disclosed in PCT publication WO 97/17975 and Australian patent AU 199954179 B2 for the treatment of diabetes of type II with a defined ratio of the twc its, which is a requirement in order to obtain an optimum therapeutic effect.
  • the Australian patent AUl 99954179B2 discloses that the solid oral form such as tablet contains a combination of Metformin hydrochloride and Glibenclamide in which the size of the Glibenclamide at most 10% of the particles are less than 2 ⁇ m and at most 10% of the particles are greater than 60 ⁇ m so that the Glibenclamide bioavailability is comparable to the Glibenclamide bioavailability obtained with a separate administration of Metformin hydrochloride and Glibenclamide.
  • a solid oral dosage form comprising of the combination of Metformin hydrochloride and Glibenclamide in which the size of Glibenclamide wherein at most 25% of the particles are less than l l ⁇ m and at most 25% of the particles are greater than 46 ⁇ m so that the Glibenclamide bioavailability is comparable to the Glibenclamide bioavailability obtained with a separate administration of Metformin hydrochloride and Glibenclamide.
  • the present invention provides a pharmaceutical composition of Metformin hydrochloride and Glibenclamide pharmaceutically with acceptable surfactant provides the same dissolution profile and bioavailability obtained with a separate administration of Metformin hydrochloride and Glibenclamide.
  • composition of a solid oral dosage form comprising Metformin hydrochloride and Glibenclamide demonstrates bioequivalence with reference product (Glucovance).
  • the present invention provides pharmaceutical composition of a solid oral dosage form containing oral hypoglycemic agents, Metformin hydrochloride and Glibenclamide, in diverse therapeutically recommended strengths.
  • Metformin hydrochloride dose is 500mg
  • Glibenclamide dose is 5mg.
  • doses are respectively: 500mg of Metformin hydrochloride and 2.5mg of Glibenclamide, 250mg of Metformin hydrochloride and 1.25mg of Glibenclamide.
  • the novel pharmaceutical composition of Metformin hydrochloride and Glibenclamide with surfactant is giving the desired dissolution profile and its bioavailability.
  • the excipient is used here are such agents as diluents, earners, binders, disintegrants, surfactants, glidants, lubricants and coating agents. Such materials are employed which do not adversely effect the processing set forth herein and which do not interfere with the stability of the resulting products.
  • the known diluents are the family of modified celluloses such as hydroxyethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl cellulose and other cellulose derivatives such as starch and sodium starch glycolate, pregelatinised starch may also be employed.
  • the diluents disclosed herein are not limited to illustrate as above.
  • diluents of the present invention are preferably, lactose, saccharose, fructose, Sorbitol, Mannitol, calcium phosphate and calcium hydrogen phosphate.
  • microcrystalline cellulose wherein an amount of microcrystalline cellulose ranges from about 1.0 to 50.0%w/w per unit dose, preferably 3.0 to 20.0%w/w, and in particular from about 4.0 to 14.0%w/w. Any of the members of this family may be used in connection with the practice of one or more embodiments of the present invention. Other cellulose products those are similar in nature to microcrystalline cellulose may find utility herein, such a parenchymal cell cellulose.
  • the binder holds the components of the formulation together.
  • the preferred binders include gelatin, alginates (sodium alginate), starch grades (pregelatinized or plain), hydroxypropylcellulose, and carboxymethylcellulose and their salts, lactose, and microcrystalline cellulose (Avicel).
  • the illustrated binders are not limited to present invention.
  • the binder used herein is hydroxypropyl methylcellulose, wherein an amount ranges from about 0.5 to about 20.0%w/w, preferably about 1.0 to about 10.0%w/w, and more preferably ranges from about 1.37 to about 5.0% w/w. It may in addition also be advantageous to add other conventional pharmaceutical auxiliary substances and carriers as binders.
  • the disintegrating agent enhances the conversion of a compact material into fine primary particles during dissolution.
  • the preferred disintegrating agents are not limited to, starch (com starch), pectins, carboxymethyl cellulose, ultramyl pectin, bentonite, polyvinyl pyrrolidone (in the case of polyvinyl Pyrrolidone the filamentory macromolecules are crosslinked; it has a porous structure and a great swelling capacity).
  • the disintegrant is sodium starch glycolate and/or crosspovidone.
  • the preferred disintegrant ranges in amount from about 0.5 to about 20.0 %w/w, preferably about 1.0 to about 10.0 %w/w and more preferably from about 3.0 %w/w to about 9.0 %w/w.
  • Cellulose products such as microcrystalline cellulose (plain or coarse) may also find utility herein as most preferable disintegrant.
  • the surfactant enhances the wettability of poorly soluble drug at the diffusion layer, thereby improving the solubility.
  • Different types of surfactants i.e. cationic, anionic and non- ionic forms the basis to improvement of solubility of poorly soluble drugs.
  • Surfactants include in the present invention, but are not limited to, sodium lauryl sulphate, sodium lauryl sulfoacetate, sodium cocomonoglyceride sulphate, sodium sulphated monoglyceride, sodium N-lauroyl sarcosinate.
  • poloxamer(s) finds utility as well.
  • the surfactant is sodium lauryl sulphate.
  • Sodium lauryl sulphate an anionic surfactant, finds herein utility to show linear increase in solubility with increasing concentration. It has found to be an efficient solubiliser in a preferred embodiment of the present study and is characterized in amount from 0.1 to 2.0 %w/w, preferably 0.2 to 1.8 %w/w and in particular from about 0.3 % to 1.5 %w/w.
  • the lubricant acts as an additive to prevent the sticking of the formulation to tooling during the tabletting process.
  • Lubricants illustrated herein are not limited to stearates, hydrogenated vegetable oils, and talc.
  • the preferred lubricant is a stearate.
  • lubricant is magnesium stearate or glycerol monostearate which ranges in an amount from about 0.01 to about 10.0 %w/w per unit dose.
  • the preferred range of lubricant is magnesium stearate and in an amount from about 0.2 to about 1.0 %w/w per unit dose.
  • Microcrystalline cellulose of this example formulation serves as a diluent.
  • Sodium starch glycolate and crosspovidone are internally crosslmked polymer and serves as a disintegrant.
  • Binder is hydroxypropyl methylcellulose while sodium lauryl sulphate is a wetting agent.
  • Magnesium stearate serves as a lubricant.
  • the granulation solvent is purified water.
  • Table 1 shows the typical composition range of different excipients used in the present invention: TABLE 1
  • the tablet according to the present invention may be obtained by a process comprising:
  • a tablet of Metformin hydrochloride and Glibenclamide has been prepared as follows:
  • Granulating binder is prepared by mixing hydroxypropyl methylcellulose with purified water. The binder solution is added to the granulator and the wet mass is granulated. The granulated mass is emptied into a preheated fluidized bed dryer and the granules are dried until the moisture content is 2.5-3.5%w/w. Dried granulated mass is sifted through 16# sieve, while retention over milled through 2.0mm screen.
  • Sized granules thus obtained are blended with extragranular ingredients like sodium starch glycolate, colloidal silicon dioxide, Avicel PH 200 and purified talc, followed by lubrication with magnesium stearate.
  • the lubricated blend is compressed using a suitable tablet press.
  • the tablets are film coated using suitable aqueous coat in a coating machine.
  • Example 1 Preparation of Metformin Hydrochloride and Glibenclamide stable pharmaceutical solid dosage form (Batch Size: 100000 Units) using the Glibenclamide in which the size of the Glibenclamide between about 0.2 micron to about 10 micron.
  • Granulating binder is prepared by mixing hydroxypropyl methylcellulose 1.8 Kg with purified water. The binder solution is added to the granulator and the wet mass is granulated. The granulated mass is emptied into a preheated fluidized bed dryer and the granules are dried until the moisture content is 2.5-3.5%w/w.
  • Dried granulated mass is sifted through 16# sieve, while retention over milled through 2.0mm screen. Sized granules thus obtained are blended with extragranular ingredients like sodium starch glycolate 1.25 Kg, colloidal silicon dioxide 1.0 Kg, Avicel PH 200 0.70 Kg and purified talc 0.30 Kg, followed by lubrication with magnesium stearate 0.20 Kg.
  • the lubricated blend is compressed using a suitable tablet press.
  • the tablets are film coated using suitable aqueous coat in a coating machine.
  • Example 2 Preparation of Metformin Hydrochloride and Glibenclamide stable pharmaceutical solid dosage form (Batch Size: 100000 Units) using the Glibenclamide in which the size of the Glibenclamide is between about 60 micron to about 100 micron.
  • Granulating binder is prepared by mixing hydroxypropyl methylcellulose 1.8 Kg with purified water. The binder solution is added to the granulator and the wet mass is granulated. The granulated mass is emptied into a preheated fluidized bed dryer and the granules are dried until the moisture content is 2.5-3.5%w/w.
  • Dried granulated mass is sifted through 16# sieve, while retention over milled through 2.0mm screen. Sized granules thus obtained are blended with extragranular ingredients like sodium starch glycolate 1.25 Kg, colloidal silicon dioxide 1.0 Kg, Avicel PH 200 0.70 Kg and purified talc 0.30 Kg, followed by lubrication with magnesium stearate 0.20 Kg.
  • the lubricated blend is compressed using a suitable tablet press.
  • the tablets are film coated using suitable aqueous coat in a coating machine.
  • Figure Ia Comparative Dissolution Profiling of Metformin 500 from Lot No.: 52151 and Batch No.: B165E6001
  • Figure Ib Comparative Dissolution Profiling of Glibenclamide 5 from Lot No.: 52151 and Batch No.: B165E6001
  • Figure 2a Comparative Dissolution Profiling of Metformin 500 from Lot No.: 52151 and Batch No.: 08/038/13
  • Figure 2b Comparative Dissolution Profiling of Glibenclamide 5 from Lot No.: 52151 and Batch No.: 08/038/13
  • Figure 3 a Plasma concentration curves (mean ⁇ SEM) on log scale of Metformin hydrochloride in fixed dose formulation of Metformin hydrochloride 500 mg and Glibenclamide 5 mg Tablets of Cadila
  • Bioavailability refers to the degree to which the therapeutically active medicament becomes available in the body after administration. Typically, bioavailability is measured in patients who fasted overnight before being dosed with the test preparation. Plasma samples are then taken and analyzed for the plasma concentration of the parent compound and/ or its active metabolite. The data may be expressed as Cmax, the maximum amount of active ingredient found in the plasma, or as AUC, the area under the plasma concentration time curve. In-vivo bioavailability studies were performed, in particular, with tablets prepared using defined micronized particle size distrbution of Glibenclamide.
  • Table 6a represents descriptive statistical analysis of pharmacokinetic parameters (C max , AUC 0- t and AUC 0- ⁇ ) for test and reference products of Metfonnin hydrochlorides 00 mg and Glibenclamide 5 mg Tablets for Metformin hydrochloride.
  • Table 6b represents descriptive statistical analysis of pharmacokinetic parameters (C raax , AUC 0-t and AUC 0-00 ) for test and reference products of Metformin hydrochlorides 00 mg and Glibenclamide 5 mg Tablets for Glibenclamide.
  • the mean plasma concentration-time curve of Glibenclamide after administration of Metformin hydrochlorides 00 mg and Glibenclamide 5 mg Tablets, Cadila Pharmaceuticals Limited, India and Glucovance (Metformin hydrochloride 500 mg and Glibenclamide 5 mg) Tablets, Alphapharm, Australia formulations has been shown in Figure 3b.
  • TABLE 4 SUMMARY TABLE OF PHARMACOKINETIC PARAMETERS
  • Metformin hydrochloride 500 mg and Glibenclamide 5 mg Tablets of Cadila Pharmaceuticals Limited India has been bioequivalent in comparison with Glucovance of Alphapharm, Australia in terms of both rate and extent of absorption after single dose administration in healthy human subjects.

Abstract

La présente invention se rapporte à une forme posologique solide à administration orale pour le traitement du diabète de type non insulinodépendant (diabète de type II), comprenant une combinaison d'un sel pharmaceutiquement acceptable de Métformine et de Glibenclamide et contenant principalement un tensioactif et/ou d'autres excipients additionnels.
PCT/IB2007/003513 2006-11-20 2007-11-16 Forme posologique solide administration orale contenant une combinaison de médicaments antidiabétiques WO2008062273A2 (fr)

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100209506A1 (en) * 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US8551957B2 (en) 2007-08-16 2013-10-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
US8802842B2 (en) 2009-09-30 2014-08-12 Boehringer Ingelheim International Gmbh Method for the preparation of a crystalline form
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9873714B2 (en) 2009-09-30 2018-01-23 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20180185291A1 (en) 2011-03-07 2018-07-05 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US10406172B2 (en) 2009-02-13 2019-09-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof

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US6303146B1 (en) * 1998-07-15 2001-10-16 Lipha Solid oral dosage form comprising a combination of metformin and glibenclamide

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* Cited by examiner, † Cited by third party
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US8551957B2 (en) 2007-08-16 2013-10-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
US10406172B2 (en) 2009-02-13 2019-09-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20100209506A1 (en) * 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
US9873714B2 (en) 2009-09-30 2018-01-23 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US8802842B2 (en) 2009-09-30 2014-08-12 Boehringer Ingelheim International Gmbh Method for the preparation of a crystalline form
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
US10596120B2 (en) 2011-03-07 2020-03-24 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US11564886B2 (en) 2011-03-07 2023-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US20180185291A1 (en) 2011-03-07 2018-07-05 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10258637B2 (en) 2013-04-05 2019-04-16 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11090323B2 (en) 2013-04-05 2021-08-17 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11833166B2 (en) 2013-04-05 2023-12-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11918596B2 (en) 2013-04-05 2024-03-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof

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WO2008062273A3 (fr) 2009-04-23

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