EP1231917A2 - Composition pharmaceutique a base d'hydrochloride de thiazolidinedione-metformine - Google Patents

Composition pharmaceutique a base d'hydrochloride de thiazolidinedione-metformine

Info

Publication number
EP1231917A2
EP1231917A2 EP00976151A EP00976151A EP1231917A2 EP 1231917 A2 EP1231917 A2 EP 1231917A2 EP 00976151 A EP00976151 A EP 00976151A EP 00976151 A EP00976151 A EP 00976151A EP 1231917 A2 EP1231917 A2 EP 1231917A2
Authority
EP
European Patent Office
Prior art keywords
thiazolidinedione
metformin hydrochloride
composition according
composition
metformin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00976151A
Other languages
German (de)
English (en)
Inventor
Karen SmithKline Beecham Pharmaceuticals LEWIS
Nicola Jayne SmithKline Beecham Pharm. LILLOTT
Donald Colin SmithKline Beecham Pharm. MACKENZIE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9927121.5A external-priority patent/GB9927121D0/en
Priority claimed from GB0013238A external-priority patent/GB0013238D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1231917A2 publication Critical patent/EP1231917A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • This invention relates to novel compositions, in particular to compositions containing more than one active ingredient and their use in medicine, especially its use for the treatment of diabetes mellitus, preferably Type 2 diabetes, and conditions associated with diabetes mellitus.
  • Biguanide antihyperglycaemic agents are commonly used in the treatment of non-insulin dependent diabetes mellitus (NIDDM, or Type II diabetes).
  • NIDDM non-insulin dependent diabetes mellitus
  • 1,1- Dimethylbiguanidine or metformin
  • biguanide antihyperglycaemic agent is an example of a biguanide antihyperglycaemic agent.
  • European Patent Application Publication Number 0 306 228 relates to certain thiazolidinedione derivatives disclosed as having antihyperglycaemic and hypolipidaemic activity.
  • One particular thiazolidinedione disclosed in EP 0 306 228 is 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter referred to as "Compound (I)").
  • European Patent 0 658 161 discloses certain salts of Compound (I) including the maleate salt at Example 1 thereof.
  • Compound (I) is an example of a class of anti-hyperglycaemic agents known as "insulin sensitisers".
  • Compound (I) is a thiazolidinedione insulin sensitiser.
  • the above mentioned publications are incorporated herein by reference.
  • An important consideration in the preparation of formulations containing a combination of active agents is the stability of the active agents given that mutual interaction of the agents themselves or the agents with excipients can lead to instability of the agents.
  • Metformin is most commonly administered in the form of its hydrochloride salt (or metformin HCl). It is indicated that in certain formulations Compound (I) is prone to decomposition, both during preparation and storage, due to the presence of metformin hydrochloride
  • a pharmaceutical composition comprising a thiazolidinedione, such as Compound (I), metformin hydrochloride, and a pharmaceutically acceptable carrier, wherein the thiazolidinedione is formulated upon the surface of the metformin hydrochloride.
  • the thiazolidinedione is formulated as a thin layer upon the surface of the metformin hydrochloride
  • the metformin hydrochloride is in a compacted form, such as a tablet form.
  • the composition also comprises an inert barrier layer between the layer containing thiazolidinedione and the metformin hydrochloride.
  • the compositions so produced are multilayer compositions, generally bilayer compositions (wherein one active agent is applied, generally in a liquid form and usually directly, to the surface of the solid form of the other active agent), however the compositions may also comprise trilayer or tetralayer compositions (or indeed higher multilayers) wherein repeated layers of each active are formed, preferably separated by an inert barrier layer.
  • Suitable dosages, preferably unit dosages, of the thiazolidinedione, such as Compound (I,) and metformin hydrochloride include the known permissible doses for these compounds as described or referred to in reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) or the above mentioned publications.
  • the dosages of each particular active agent in any given composition can as required vary within a range of doses known to be required in respect of accepted dosage regimens for that compound.
  • the composition comprises 2 to 12 mg of Compound (I).
  • the composition comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I).
  • the composition comprises 2 to 4 , 4 to 8, or 8 to 12 mg of Compound (I).
  • the composition comprises 2 to 4mg of Compound (I).
  • the composition comprises 4 to 8mg of Compound (I).
  • the composition comprises 8 to 12 mg of Compound (I).
  • the composition comprises 2 mg of Compound (I).
  • the composition comprises 4 mg of Compound (I).
  • the composition comprises 8 mg of Compound (I).
  • the unit doses of metformin include those found in the reference texts mentioned herein and include the doses set out below.
  • a suitable dosage of metformin hydrochloride is between 100 to 3000mg, for example 250, 500mg, 850mg, or lOOOmg.
  • a suitable dosage of metformin hydrochloride is between 100 to 3000mg, for example 250, 500mg, 850mg, or lOOOmg.
  • Particular compositions of the invention comprise doses of Compound (I) in the range of from 2-12mg and metformin hydrochloride in the range of from 100 to 3000mg, for example 4mg of Compound (I) and 500mg of metformin hydrochloride.
  • Other formulations comprise 2mg of Compound (I) and 500mg or 850mg of metformin hydrochloride or 4mg of Compound (I) and 850mg of metformin hydrochloride.
  • thiazolidinediones include (+) -5-[[4-[(3,4-dihydro-6-hydroxy-2, 5,7,8- tetramethyl-2H- 1 -benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-[(l-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioghtazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone).
  • the compounds mentioned herein, in particular the thiazolidinediones such as Compound (I), may exist in one of several tautomeric forms, all of which are encompassed by the invention as individual tautomeric forms or as mixtures thereof.
  • the compounds mentioned herein may contain one or more chiral carbon atoms and hence can exist in two or more stereoisomeric forms, all of which are encompassed by the invention either as individual isomers or as mixtures of isomers, including racemates.
  • the thiazolidinedione, such as Compound (I) and metformin are in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate to the relevant pharmaceutically active agent chosen.
  • the names used for the antidiabetic agent may relate to a particular pharmaceutical form of the relevant active agent. It will be understood that all pharmaceutically acceptable forms of the active agents per se are encompassed by this invention.
  • Suitable pharmaceutically acceptable forms of the thiazolidinedione, such as Compound (I), and metformin include known pharmaceutically acceptable forms. Such derivatives are found or are referred to in standard reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) and the above mentioned publications. For example, a particular form of metformin is metformin hydrochloride.
  • Suitable pharmaceutically acceptable forms of Compound (I) include those described in EP 0 306 228 and WO 94/05659, especially pharmaceutically acceptable salted or solvated forms.
  • a preferred pharmaceutically acceptable salt form of Compound (I) is a maleate.
  • a preferred pharmaceutically acceptable solvated form of Compound (I) is a hydrate.
  • a preferred form of pioghtazone is as the hydrochloride salt.
  • Metformin is prepared according to known methods, such methods are found or are referred to in standard reference texts, such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st Edition page 341 and pages cited therein) or as described in the above mentioned publications.
  • Compound (I) or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof may be prepared using known methods, for example those disclosed in EP 0 306 228 and WO 94/05659. The disclosures of EP 0 306 228 and WO 94/05659 are incorporated herein by reference.
  • condition associated with diabetes includes those conditions associated with the pre-diabetic state, conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus.
  • condition associated with the pre-diabetic state includes conditions such as insulin resistance, impaired glucose tolerance, impaired fasting glucose and hyperinsulinaemia.
  • Constants associated with diabetes mellitus itself include hyperglycaemia, insulin resistance and obesity. Further conditions associated with diabetes mellitus itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome, steroid induced insulin resistance and gestational diabetes.
  • Complications associated with diabetes mellitus includes renal disease, especially renal disease associated with Type 2 diabetes, neuropathy and retinopathy. Renal diseases associated with Type 2 diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.
  • the term "pharmaceutically acceptable” embraces both human and veterinary use.
  • the term “pharmaceutically acceptable” embraces a veterinarily acceptable compound.
  • liquid form includes solutions and suspensions.
  • the scalar amount referred to is made in respect of the active compound per se.
  • 2 mg of Compound (I) in the form of the maleate salt is that amount of maleate salt that provides 2 mg of Compound (I).
  • Diabetes mellitus is preferably Type 2 diabetes.
  • Glycaemic control may be characterised using conventional methods, for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or glycosylated haemoglobin (Hb Ale). Such indices are determined using standard methodology, for example those described in Tuescher A, Richterich, P., Sau. med. Wschr. 101 (1971), 345 and 390, and Frank P., "Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements", Clinical Products 1988.
  • the compositions may be in the form of tablets, lozenges, suppositories, or capsules. Usually the compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example sublingual or transdermal administration.
  • the invention also provides a process for preparing a pharmaceutical composition comprising a thiazolidinedione, such as Compound (I), metformin hydrochloride and a pharmaceutically acceptable carrier, wherein the thiazolidinedione is formulated onto the surface of the metformin hydrochloride, which process comprises:
  • Suitable carriers for the metformin hydrochloride comprises one or more components selected from: a binding agent, preferably PVP, a filler, a lubricants, a glidant, a disintegrant and a wetting agent.
  • the carrier for the metformin hydrochloride is as indicated preferably PVP but optionally at least one additional binder, for example hydroxypropylmethyl cellulose (or HPMC) is also used.
  • additional binder for example hydroxypropylmethyl cellulose (or HPMC)
  • HPMC hydroxypropylmethyl cellulose
  • the amount of PVP is the minimum required providing the required compressibility for metformin.
  • the thiazolidinedione is dissolved or dispersed in a liquid and then applied to the surface of the metformin HCl.
  • the liquid may be water or a suitable organic solvent, such as ethanol.
  • a film-coating agent such as Opadry, is admixed with the thiazolidinedione solution or dispersion and this is applied to the surface of the metformin HCl.
  • the thiazolidinedione solution or dispersion is applied to the metformin HCl and then the solution or dispersion of film coating agent is applied.
  • the compositions are in unit dosage form.
  • Unit dosage presentation forms for oral administration may as necessary contain conventional excipients such as binding agents, fillers, lubricants, glidants, disintegrants and wetting agents.
  • binding agents include acacia, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate, sorbitol, starch, syrup, and tragacanth.
  • fillers include calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, and xylitol.
  • lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl umarate, talc, and zinc stearate.
  • glidants examples include colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, and talc.
  • disintegrants examples include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, and sodium starch glycollate.
  • An example of a pharmaceutically acceptable wetting agent is sodium lauryl sulphate.
  • compositions may be prepared by conventional methods of blending, tabletting, or encapsulation. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • compositions are formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) and Harry's Cosmeticology (Leonard Hill Books).
  • compositions for use in a method for the treatment of diabetes mellitus, preferably Type 2 diabetes, and conditions associated with diabetes mellitus.
  • Compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • Compound I is added to an Opadry coating suspension and applied to the surface of a preformed metformin tablet.
  • the Opadry I barrier and sealing coat are of identical formulation and are prepared as 15% w/w solid suspension.
  • the Opadry I plus Compound (I) suspension is prepared as a 15% w/w solid suspension with a 2:1 ratio of Opadry to Compound (I).
  • Metformin HCl tablet (equivalent to 500mg metformin HCl)
  • Metformin HCl tablet (equivalent to 500mg metformin HCl) 520 Opadry Barrier Coat ( 1 % of tablet core) 5.20 Opadry plus Compound (I) (equivalent to 4mg Compound (I)) 15.90 Opadry I Sealing Coat (2% of tablet core) 10.80

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention se rapporte à une composition pharmaceutique comprenant un hydrochlorure de méthformine de thiazolidinedione, ainsi qu'un excipient acceptable sur le plan pharmaceutique, la thiazolidinedione étant formulée à la surface de l'hydrochlorure de méthformine, ainsi qu'à l'utilisation de cette composition en médecine.
EP00976151A 1999-11-16 2000-11-16 Composition pharmaceutique a base d'hydrochloride de thiazolidinedione-metformine Withdrawn EP1231917A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9927121 1999-11-16
GBGB9927121.5A GB9927121D0 (en) 1999-11-16 1999-11-16 Novel composition and use
GB0013238 2000-05-31
GB0013238A GB0013238D0 (en) 2000-05-31 2000-05-31 Novel composition and use
PCT/GB2000/004363 WO2001035940A2 (fr) 1999-11-16 2000-11-16 Nouvelle composition et utilisation

Publications (1)

Publication Number Publication Date
EP1231917A2 true EP1231917A2 (fr) 2002-08-21

Family

ID=26244395

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00976151A Withdrawn EP1231917A2 (fr) 1999-11-16 2000-11-16 Composition pharmaceutique a base d'hydrochloride de thiazolidinedione-metformine

Country Status (4)

Country Link
EP (1) EP1231917A2 (fr)
JP (1) JP2003514011A (fr)
AU (1) AU1403501A (fr)
WO (1) WO2001035940A2 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR030920A1 (es) 1999-11-16 2003-09-03 Smithkline Beecham Plc Composiciones farmaceuticas para el tratamiento de la diabetes mellitus y condiciones asociadas con la diabetes mellitus, y procedimientos para preparar dichas composiciones
ATE367151T1 (de) * 2000-05-01 2007-08-15 Aeropharm Technology Llc Kernformulierung
AU2001273290B2 (en) * 2001-07-10 2004-10-07 Kos Life Sciences, Inc. Core formulation comprising troglitazone and a biguanide
EP1429732A4 (fr) * 2001-07-10 2005-01-26 Kos Life Sciences Inc Formulation de noyau
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
WO2004006921A1 (fr) * 2002-07-11 2004-01-22 Takeda Pharmaceutical Company Limited Procede de production d'une preparation recouverte
US7785627B2 (en) 2002-09-20 2010-08-31 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US8084058B2 (en) 2002-09-20 2011-12-27 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US9060941B2 (en) 2002-09-20 2015-06-23 Actavis, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US7959946B2 (en) 2002-09-20 2011-06-14 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
CN100544717C (zh) * 2002-09-20 2009-09-30 华生制药公司 含有双胍和噻唑烷二酮衍生物的药物剂型
UA80991C2 (en) 2002-10-07 2007-11-26 Solid preparation containing an insulin resistance improving drug and an active ingredient useful as a remedy for diabetes
UA86015C2 (ru) * 2003-01-29 2009-03-25 Такеда Фармасьютикал Компани Лимитед Способ получения твердой лекарственной формы с покрытием
PL377403A1 (pl) 2003-01-29 2006-02-06 Takeda Pharmaceutical Company Limited Sposób wytwarzania preparatu powlekanego
JP4567340B2 (ja) * 2003-01-29 2010-10-20 武田薬品工業株式会社 被覆製剤の製造方法
GB0318824D0 (en) * 2003-08-11 2003-09-10 Glaxo Group Ltd Novel composition
US8263121B2 (en) 2004-04-14 2012-09-11 Takeda Pharmaceutical Company Limited Solid pharmaceutical preparation
TR201202048T2 (tr) * 2009-05-26 2012-04-24 Abdi̇ İbrahi̇m İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇@ Pioglitazon çözeltisi ile kaplanmış metformin.

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL195136B1 (pl) * 1997-06-18 2007-08-31 Smithkline Beecham Plc Kombinacja zawierająca 5-[4-[2-(N-metylo-N-(2-pirydylo)amino)etoksy]-benzylo] tiazolidyno-2,4-dion i jej zastosowanie
GB9715295D0 (en) * 1997-07-18 1997-09-24 Smithkline Beecham Plc Novel method of treatment
KR100620935B1 (ko) * 1998-03-19 2006-09-13 브리스톨-마이어스스퀴브컴파니 용해도가 높은 약물에 대한 2상 서방성 전달 시스템과 방법

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0135940A2 *

Also Published As

Publication number Publication date
JP2003514011A (ja) 2003-04-15
WO2001035940A3 (fr) 2002-03-21
WO2001035940A2 (fr) 2001-05-25
AU1403501A (en) 2001-05-30

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