EP1231917A2 - Pharmazeutische zusammensetzung enthaltend ein thiazolidinedion-metformin hydrochlorid - Google Patents
Pharmazeutische zusammensetzung enthaltend ein thiazolidinedion-metformin hydrochloridInfo
- 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- Withdrawn
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
- A61K9/20—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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered 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
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic 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
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs 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
Landscapes
- 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)
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 |
GB0013238A GB0013238D0 (en) | 2000-05-31 | 2000-05-31 | Novel composition and use |
GB0013238 | 2000-05-31 | ||
PCT/GB2000/004363 WO2001035940A2 (en) | 1999-11-16 | 2000-11-16 | Pharmaceutical composition comprising a thiazolidinedione-metformin hydrochloride |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1231917A2 true EP1231917A2 (de) | 2002-08-21 |
Family
ID=26244395
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00976151A Withdrawn EP1231917A2 (de) | 1999-11-16 | 2000-11-16 | Pharmazeutische zusammensetzung enthaltend ein thiazolidinedion-metformin hydrochlorid |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1231917A2 (de) |
JP (1) | JP2003514011A (de) |
AU (1) | AU1403501A (de) |
WO (1) | WO2001035940A2 (de) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MY125516A (en) | 1999-11-16 | 2006-08-30 | Smithkline Beecham Plc | Novel composition based on thiazolidinedione and metformin and use |
DE60129425T2 (de) * | 2000-05-01 | 2008-04-17 | Aeropharm Technology LLC, Dover | Kernformulierung |
CA2453784A1 (en) * | 2001-07-10 | 2003-01-23 | Kos Life Sciences, Inc. | A core formulation |
EP1429740A4 (de) * | 2001-07-10 | 2005-01-26 | Kos Life Sciences Inc | Kernformulierung mit troglitazon und einem biguanid |
EP1515701B1 (de) | 2002-06-17 | 2014-09-17 | Inventia Healthcare Private Limited | Verfahren zur herstellung von mehrschichtigen tabletten die thiazolidinedione und biguanide enthalten |
EP1552832A1 (de) * | 2002-07-11 | 2005-07-13 | Takeda Pharmaceutical Company Limited | Verfahren zur herstellung einer beschichteten zubereitung |
US7785627B2 (en) * | 2002-09-20 | 2010-08-31 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
KR20120034211A (ko) * | 2002-09-20 | 2012-04-10 | 안드렉스 랩스 엘엘씨 | 약제학적 정제 |
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 |
US8084058B2 (en) | 2002-09-20 | 2011-12-27 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
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 |
NZ541749A (en) | 2003-01-29 | 2009-06-26 | Takeda Pharmaceutical | Process for producing coated preparation comprising pioglitazone hydrochloride and a coating material |
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ298469B6 (cs) * | 1997-06-18 | 2007-10-10 | Smithkline Beecham Plc | Farmaceutický prostredek obsahující 5-[4-/2-(N-methyl-N-(2-pyridyl)amino)ethoxy/benzyl]thiazolidin-2,4-dion a metformin, a lécivo pro lécení diabetesmellitus |
GB9715295D0 (en) * | 1997-07-18 | 1997-09-24 | Smithkline Beecham Plc | Novel method of treatment |
EA003101B1 (ru) * | 1998-03-19 | 2002-12-26 | Бристол-Майерз Сквибб Компани | Двухфазная система доставки с регулируемым высвобождением для фармацевтических средств с высокой растворимостью и способ лечения диабета с помощью этой системы |
-
2000
- 2000-11-16 WO PCT/GB2000/004363 patent/WO2001035940A2/en not_active Application Discontinuation
- 2000-11-16 EP EP00976151A patent/EP1231917A2/de not_active Withdrawn
- 2000-11-16 JP JP2001537933A patent/JP2003514011A/ja active Pending
- 2000-11-16 AU AU14035/01A patent/AU1403501A/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO0135940A2 * |
Also Published As
Publication number | Publication date |
---|---|
AU1403501A (en) | 2001-05-30 |
WO2001035940A2 (en) | 2001-05-25 |
JP2003514011A (ja) | 2003-04-15 |
WO2001035940A3 (en) | 2002-03-21 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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