OA11312A - Treatment of diabetes with thiazolidinedione, insulin secretagogue and alpha glucocidase inhibitor. - Google Patents

Treatment of diabetes with thiazolidinedione, insulin secretagogue and alpha glucocidase inhibitor. Download PDF

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Publication number
OA11312A
OA11312A OA1200000013A OA1200000013A OA11312A OA 11312 A OA11312 A OA 11312A OA 1200000013 A OA1200000013 A OA 1200000013A OA 1200000013 A OA1200000013 A OA 1200000013A OA 11312 A OA11312 A OA 11312A
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composition according
compound
daims
insulin
theadministration
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OA1200000013A
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Robin Edwin Buckingham
Stephen Alistair Smith
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Smithkline Beecham Plc
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • 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

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

Abstract

A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent, to amammal in need thereof; and composition for use in such method.

Description

P31854 011312
NOVEL METHOD OF TREATMENT
This invention relates to a method of treatment, in particular to a method forthe treatment of diabètes mellitus, especially non-insulin dépendent diabètes(NIDDM) or Type 2 diabètes and conditions associated with diabètes mellitus.
Insulin secretagogues are compounds which promote increased sécrétion ofinsulin by the pancreatic beta cells.
The sulphonylureas are well known examples of insulin secretagogues. Thesulphonylureas act as antihyperglycaemic agents and are used in the treatment of Type2 diabètes. Examples of sulphonylureas include glibenclamide, glipizide, gliclazide,glimepiride, tolazamide and tolbutamide.
Alpha glucosidase inhibitor antihyperglycaemic agents, such as acarbose,emiglitate and miglitol, are commonly used in the treatment of Type 2 diabètes.
European Patent Application, Publication Number 0,306,228 relates to certainthiazolidinedione dérivatives disclosed as having antihyperglycaemic andantihyperlipidaemic activity. One particdlar thiazolidinedione disclosed in EP0306228 is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter ’Compound (I)7). WO94/05659 discloses certain salts of Compound(I) including the maleate sait.
Compound (I) is an example of a class of anti-hyperglycaemic agents knownas 'insulin sensitisers’. In particular Compound (I) is a thiazolidinedione insulinsensitiser.
European Patent Applications, Publication Numbers: 0008203, 0139421,0032128,0428312,0489663,0155845, 0257781, 0208420, 0177353, 0319189,0332331, 0332332, 0528734,0508740; International Patent Application, PublicationNumbers 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888and 5478852, also disclose certain thiazolidinedione insulin sensitisers.
Another sériés of compounds generally recognised as having insulin sensitiseractivity are those typified by the compounds disclosed in International PatentApplications, Publication Numbers WO93/21166 and W094/01420. Thesecompounds are herein referred to as ’acyclic insulin sensitisers’. Other examples ofacyclic insulin sensitisers are those disclosed in United States Patent Number 5232945and International Patent Applications, Publication Numbers WO92/03425 andWO91/19702.
Examples of other insulin sensitisers are those disclosed in European Patent
Application, Publication Number 0533933, Japanese Patent Application Publication
Number 05271204 and United States Patent Number 5264451.
The above mentioned publications are incorporated herein by reference. P31854 -2- 011312
It is now surprisingly indicated that Compound (I) in combination with aninsulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agentprovides a particularly bénéficiai effect on glycaemic control, such combination istherefore particularly useful for the treatment of diabètes mellitus, especially Type 2diabètes, and conditions associated with diabètes mellitus. The treatment is alsoindicated to proceed with minimum side effects.
Accordingly, the invention provides a method for the treatment of diabètesmellitus, especially Type 2 diabètes, and conditions associated with diabètes mellitus,in a mammal such as a human, which method comprises administering an effectivenon-toxic and pharmaceutically acceptable amount of an insulin sensitiser, an insulinsecretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent, to amammal in need thereof.
The method comprises either co-administration of the insulin sensitiser, aninsulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent orsequential administration thereof.
Co-administration includes administration of a formulation which includes aninsulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitorantihyperglycaemic agent or the essentially simultaneous administration of separateformulations of each agent.
In another aspect the invention provides the use of an insulin sensitiser, suchas Compound (I), an insulin secretagogue and an alpha glucosidase inhibitorantihyperglycaemic agent, in the manufacture of a composition for the treatment ofdiabètes mellitus, especially Type 2 diabètes and conditions associated with diabètesmellitus. A suitable insulin sensitiser is a thiazolidinedione insulin sensitiser. A suitable thiazolidinedione insulin sensitiser is Compound (I).
Other suitable thiazolidinedione insulin sensitisers include (+) -5-[[4-[(3,4-dihydro-6-hydroxy-2, 5, 7, 8-tetramethyl-2H-l-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 pioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone)
Suitable insulin secretagogues include sulphonylureas.
Suitable sulphonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.
Further sulphonylureas include acetohexamide, carbutamide, chlorpropamide, glibomuride, gliquidone, glisentide, glisolamide, glisoxepide,glyclopyamide and glycylamide. P31854 -3- 011312
Further suïtable insulin secretagogues include repaglinide. A suitable alpha glucosidase inhibitor antihypérglycaemic agent is acarbose.
Other suitable alpha glucosidase inhibitor antihypérglycaemic agents areemiglitate and miglitol.
In one particular aspect, the method comprises the administration of 2 to 12mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 2 to 4,4 to 8 or 8 to12 mg of Compound (I) per day.
Particularly, the method comprises the administration of 2 to 4mg ofCompound (I), especially when administered per day.
Particularly, the method comprises the administration of 4 to 8mg ofCompound (I), especially when administered per day.
Particularly, the method comprises the administration of 8 to 12 mg ofCompound (I), especially when administered per day.
Preferably, the method comprises the administration of 2 mg of Compound(I), especially when administered per day?
Preferably, the method comprises the administration of 4 mg of Compound(I), especially when administered per day.
Preferably, the method comprises the administration of 8 mg of Compound(I), especially when administered per day.
It will be understood that the insulin sensitiser, such as compound (I), theinsulin secretagogue and the alpha glucosidase inhibitor antihypérglycaemic agent areeach administered in a pharmaceutically acceptable form, including pharmaceuticallyacceptable dérivatives such as pharmaceutically acceptable salts, esters and solvatésthereof, as appropriate. In certain instances herein the names used for the relevantinsulin secretagogues and the alpha glucosidase inhibitor antihypérglycaemic agentsmay relate to a particular pharmaceutical form of the relevant active agent: It will beunderstood that ail pharmaceutically acceptable forms of the active agents per se areencompassed by this invention.
Suitable pharmaceutically acceptable salted forms of the insulin sensitisers,such as Compound (I), include those described in the above mentioned patents andpatent applications such as in EP 0306228 and WO94/05659 for Compound (I). Apreferred pharmaceutically acceptable sait for Compound (I) is a maleate.
Suitable pharmaceutically acceptable solvated forms of the insulin sensitisers, such as Compound (I), include those described in the above mentioned patents and patent applications, such as in EP 0306228 and WO94/05659 for Compound (I), in particular hydrates. P31854 -4- 011312
Suitable pharmaceutically acceptable forms of the insulin secretagogue andthe alpha glucosidase inhibitor antihyperglycaemic agent dépend upon the particularcompound used but include known pharmaceutically acceptable forms of theparticular compound chosen. Such dérivatives are found or are referred to in standardreference texts such as the British and US Pharmacopoeias, Remington’sPharmaceutical Sciences (Mack Publishing Co.), Martindale The ExtraPharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st Editionpage 341 and pages cited therein).
The insulin sensitisers, such as Compound (I) or, a pharmaceuticallyacceptable sait thereof, or a pharmaceutically acceptable solvaté thereof, may beprepared using known methods, for example those disclosed in the above mentionedpatents and patent applications, such as EP 0306228 and WO94/05659 for Compound(I). The disclosures of the above mentioned patents and patent applications, such asEP 0306228 and WO94/05659, are incorporated herein by reference.
Compound (I) may exist in one of several tautomeric forms, ail of which areencompassed by the term Compound (I) âs individual tautomeric forms or as mixturesthereof. Compound (I) contains a chiral carbon atom, and hence can exist in up to twostereoisomeric forms, the term Compound (I) encompasses ail of these isomeric formswhether as individual isomers or as mixtures of isomers, including racemates.
The insulin secretagogue and alpha glucosidase inhibitor antihyperglycaemicagent of choice is prepared according to known methods, such methods are found orare referred to in standard reference texts, such as the British and US Pharmacopoeias,Remington’s Pharmaceutical Sciences (Mack Publishing Co.), Martindale The ExtraPharmacopoeia (London, The Pharmaceutical Press) (for example see the 3 lst Editionpage 341 and pages cited therein).
When used herein the term 'conditions associated with diabètes’ includesconditions associated with diabètes mellitus itself and complications associated withdiabètes mellitus. Also included in 'conditions associated with diabètes’ are thoseconditions associated with the pre-diabetic State.
When used herein the term 'conditions associated with the pre-diabetic State’includes conditions such as insulin résistance, including hereditary insulin résistance,impaired glucose tolérance and hyperinsulinaemia. 'Conditions associated with diabètes mellitus itself include hyperglycaemia,insulin résistance, including acquired insulin résistance. Further conditions associatedwith diabètes mellitus itself include hypertension and cardiovascular disease,especially atherosclerosis and conditions associated with insulin résistance.
Conditions associated with insulin résistance include polycystic ovarian syndrome and steroid induced insulin résistance and gestational diabètes. P31854 -5- 011312 'Complications associated with diabètes mellitus’ includes rénal disease,especially rénal disease associated with Type 2 diabètes, neuropathy and retinopathy. Rénal diseases associated with Type 2 diabètes include nephropathy,glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis and end stagerénal disease. Additional rénal diseases associated with Type 2 diabètes includenephrotic syndrome.
For the avoidance of doubt, when reference is made herein to scalar amounts,including mg amounts, of Compound (I) in a pharmaceutically acceptable form, thescalar amount referred to is made in respect of Compound (I) per se\ For example 2mg of Compound (I) in the form of the maleate sait is that amount of maleate saitwhich contains 2 mg of Compound (I).
Diabètes mellitus is preferably Type 2 diabètes.
The particularly bénéficiai effect on glycaemic control provided by thetreatment of the invention is indicated to be a synergistic effect relative to the controlexpected for the sum of the effects of the individual active agents.
Glycaemic control may be characferised using conventional methods, forexample by measurement of a typically used index of glycaemic control such asfasting plasma glucose or glycosylated haemoglobin (HbAlc). Such indices aredetermined using standard methodology, for example those described in: Tuescher A,Richterich, P., Schweiz. med. Wschr. 101 (1971), 345 and 390 and Frank P.,Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements’,Clinical Products 1988
In a preferred aspect, the dosage level of each of the active agents when usedin accordance with the treatment of the invention will be less than would hâve beenrequired from a purely additive effect upon glycaemic control.
Suitably, the insulin sensitiser is the agent of first administration.
Suitably the insulin secretagogue is the agent of second administration.
Suitably the alpha glucosidase inhibitor is the agent of third administration.
There is also an indication that the treatment of the invention willeffect an improvement, relative to the individual agents, in the levels ofadvanced glycosylation end products (AGEs), leptin and sérum lipidsincluding total cholestérol, HDL-cholesterol, LDL-cholesterol includingimprovements in the ratios thereof, in particular an improvement insérum lipids including total cholestérol, HDL-cholesterol, LDL-cholesterolincluding improvements in the ratios thereof.
As used herein the term 'pharmaceutically acceptable’ embraces both human and veterinary use: for example the term 'pharmaceutically acceptable’ embraces a veterinarily acceptable compound. P31854 -6- 011312
In the method of the invention, the active médicaments are preferably administered in pharmaceutical composition form. As indicated above, such compositions can include ail médicaments or one only of the médicaments.
Accordingly, in one aspect the présent invention also provides apharmaceutical composition comprising an insulin sensitiser, such as Compound (I)and especially 2 to 12 mg thereof, an insulin secretagogue and an alpha glucosidaseinhibitor antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor.
Such compositions may be prepared by admixing an insulin sensitiser, suchas Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and analpha glucosidase inhibitor antihyperglycaemic agent and a pharmaceuticallyacceptable carrier therefor.
Usually the compositions are adapted for oral administration. However, theymay be adapted for other modes of administration, for example parentéraladministration, sublingual or transdermal administration.
The compositions may be in the form of tablets, capsules, powders, granules,lozenges, suppositories, reconstitutable powders, or liquid préparations, such as oralor stérile parentéral solutions or suspensions.
In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose.
Unit dose présentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents, for examplesyrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, forexample lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine;tabletting lubricants, for example magnésium stéarate; disintegrants, for examplestarch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; orpharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The compositions are preferably in a unit dosage form in an amountappropriate for the relevant daily dosage.
Suitable dosages for the insulin sensitisers include those disclosed in theabovementioned patents and patent applications.
Suitable dosages, including unit dosages, of Compound (I) comprise 1, 2, 3,4, 5, 6, 7, 8, 9,10, 11 or 12 mg of Compound (I).
In the treatment the médicaments may be administered from 1 to 6 times aday, but most preferably 1 or 2 times per day.
Particular dosages of Compound (I) are 2mg/day, 4mg/day, including 2mg twice per day, and 8 mg/day, including 4mg twice per day.
Suitable dosages including unit dosages of the insulin secretagogue, such as the sulphonylurea^ or the alpha glucosidase inhibitor antihyperglycaemic agent, P31854 -7- 011312 include the known dosages including unit doses for these compounds as described or referred to in reference text 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).
Thus for the sulphonylureas, a typical daily dosage of glibenclamide is in therange of from 2.5 to 20 mg, for example lOmg twice per day or 20mg once per day; atypical daily dosage of glipizide is in the range of from 2.5 to 40 mg; a typical dailydosage of gliclazide is in the range of from 40 to 320 mg; a typical daily dosage oftolazamide is in the range of from 100 to 1000 mg; a typical daily dosage oftolbutamide is in the range of from 1000 to 3000 mg; a typical daily dosage ofchlorpropamide is in the range of from 100 to 500 mg; and a typical daily dosage ofgliquidone is in the range of from 15 to 180 mg.
Repaglinide may be taken in amounts, usually in the range of from 0.5mg to4mg and usually with meals, up to a typical maximum daily dosage of 16mg per day.
With regard to the alpha glucosidase inhibitor antihyperglycaemic agents, atypical daily dosage of acarbose is in the range of from 50 to 600 mg, an examplelOOmg or 200mg per day.
The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may be used to distributethe active agent throughout those compositions employing large quantities of fillers.Such operations are of course conventional in the art. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice, in particularwith an enteric coating.
Oral liquid préparations may be in the form of, for example, émulsions,syrups, or élixirs, or may be presented as a dry product for reconstitution with water orother suitable vehicle before use. Such liquid préparations may contain conventionaladditives such as suspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stéarate gel,hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitanmonooleate, or acacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such as esters of glycérine,propylene glycol, or ethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouringagents.
For parentéral administration, fluid unit dosage forms are prepared utilizing the compound and a stérile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can P31854 -8- 011312 be dissolved in water for injection and filter sterilized before filling into a suitable vialor ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, apreservative and buffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial and the waterremoved under vacuum. Parentéral suspensions are prepared in substantially the samemanner, except that the Compound (I) is suspended in the vehicle instead of beingdissolved, and sterilization cannot be accomplished by filtration. The compound canbe sterilized by exposure to ethylene oxide before suspending in the stérile vehicle.Advantageously, a surfactant or wetting agent is included in the composition tofacilitate uniform distribution of the compound.
Compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending upon the method ofadministration.
Composition may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.
The compositions are prepared aîid formulated according to conventionalmethods, such as those disclosed in standard reference texts, for example the Britishand US Pharmacopoeias, ’s Pharmaceutical Sciences (Mack Publishing Co.),Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry’sCosmeticology (Leonard Hill Books) (for example see the 3 lst Edition page 341 andpages cited therein).
The présent invention also provides a pharmaceutical compositioncomprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mgthereof, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemicagent and a pharmaceutically acceptable carrier therefor, for use as an activetherapeutic substance.
The invention also provides the use of an insulin sensitiser, such asCompound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an alphaglucosidase inhibitor antihyperglycaemic agent for the manufacture of a médicamentfor the treatment of diabètes mellitus and conditions associated with diabètes mellitus.
In particular, the présent invention provides a pharmaceutical compositioncomprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mgthereof, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemicagent and a pharmaceutically acceptable carrier therefor, for use in the treatment ofdiabètes mellitus and conditions associated with diabètes mellitus. A range of 2 to 4mg includes a range of 2.1 to 4, 2.2 to 4, 2.3 to 4, 2.4 to 4, 2.5 to 4, 2.6 to 4, 2.7 to 4, 2.8 to 4, 2.9 to 4 or 3 to 4mg. A range of 4 to 8mg includes a range of 4.1 to 8,4.2 to 8, 4.3 to 8,4.4 to 8, 4.5 to 8,4.6 to 8, 4.7 to 8,4.8 to 8,4.9 to 8, 5 to 8, 6 to 8 or 7 to 8mg. P31854 -9- 011312 A range of 8 to 12 mg includes a range of 8.1 to 12, 8.2 to 12, 8.3 to 12, 8.4to 12, 8.5 to 12, 8.6 to 12, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12, 10 to 12 or 11 to12mg.
No adverse toxicological effects are expected for the compositions or methods5 of the invention in the abovementioned dosage ranges. 011 312 Ο ι—Ι U3 00 τ-Η οο pu Ό
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Claims (15)

  1. P31854/A -1- Claims 011312
    1. A pharmaceutical composition comprising an insulin sensitiser, an insulinsecretagogue, an alpha glucosidase inhibitor antihyperglycaemic agent and apharmaceutically acceptable carrier therefor.
  2. 2. A composition according to claim 1, wherein the insulin secretagogue is asulphonylurea.
  3. 3. A composition according to claim 1 or claim 2, wherein the insulin secretagogueis glibenclamide, glipizide, gliclazide, glimepiride, tolazamide or tolbutamide,acetohexamide, carbutamide, chlorpropamide, glibomuride, gliquidone, glisentide,glisolamide, glisoxepide, glyclopyamide, glycylamide or repaglinide.
  4. 4. A composition according to claim 1, wherein the alpha glucosidase inhibitorantihyperglycaemic agent is acarbose; emiglitate and miglitol.
  5. 5. A composition according to claim 1, wherein the insulin sensitiser is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound I)or a tautomeric form thereof and/or a pharmaceutically acceptable dérivativethereof.
  6. 6. A composition according to any one of daims 1 to 5, which comprises 2 to 12 mgof Compound (I).
  7. 7. A composition according to any one of daims 1 to 6, which comprises theadministration of 2 to 4,4 to 8 or 8 to 12 mg of Compound (I).
  8. 8. A composition according to any one of daims 1 to 7, which comprises theadministration of 2 to 4mg of Compound (I).
  9. 9. A composition according to any one of daims 1 to 7, which comprises theadministration of 4 to 8mg of Compound (I).
  10. 10. A composition according to any one of daims 1 to 7, which comprises theadministration of 8 to 12 mg of Compound (I). P31854/A -2- 011312
  11. 11. A composition according to any one of daims 1 to 8, which comprises theadministration of 2 mg of Compound (I).
  12. 12. A composition according to any one of daims 1 to 8, which comprises the 5 administration of 4 mg of Compound (I).
  13. 13. A composition according to any one of daims 1 to 7, which comprises theadministration of 8 mg of Compound (I). 10 14. A composition according to daim 1, wherein the insulin sensitiser is (+) -5-[[4- [(3,4-dihydro-6-hydroxy-2, 5, 7, 8-tetramethyl-2H-l-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-[( 1-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone) or 15 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (orenglitazone); or a pharmaceutically acceptable form thereof.
  14. 15. A pharmaceutical composition according to any of daims 1 to 14, for use as anactive therapeutic substance. 20
  15. 16. A pharmaceutical composition according to any of daims 1 to 15, for use in thetreatment of diabètes mellitus and conditions associated with diabètes mellitus.
OA1200000013A 1997-07-18 2000-01-18 Treatment of diabetes with thiazolidinedione, insulin secretagogue and alpha glucocidase inhibitor. OA11312A (en)

Applications Claiming Priority (1)

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GB9715298A GB9715298D0 (en) 1997-07-18 1997-07-18 Novel method of treatment

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OA11312A true OA11312A (en) 2003-10-24

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JP (1) JP2001510160A (en)
KR (1) KR20010021952A (en)
CN (1) CN1263467A (en)
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AR (2) AR016350A1 (en)
AU (1) AU8449098A (en)
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CA (1) CA2297133A1 (en)
CO (1) CO4940489A1 (en)
DZ (1) DZ2563A1 (en)
EA (1) EA200000140A1 (en)
GB (1) GB9715298D0 (en)
HU (1) HUP0003626A3 (en)
ID (1) ID23804A (en)
IL (1) IL133907A0 (en)
MA (1) MA24608A1 (en)
NO (1) NO20000230D0 (en)
OA (1) OA11312A (en)
PE (1) PE99499A1 (en)
PL (1) PL338140A1 (en)
SK (1) SK612000A3 (en)
TR (1) TR200000133T2 (en)
UY (1) UY25101A1 (en)
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TWI238064B (en) * 1995-06-20 2005-08-21 Takeda Chemical Industries Ltd A pharmaceutical composition for prophylaxis and treatment of diabetes
ATE372782T1 (en) 1999-06-21 2007-09-15 Lilly Co Eli SYNERGITIC USE OF THIAZOLIDINEDIONES AND GLUCAGONE-LIKE PEPTIDE-1 AND THEIR AGONISTS FOR THE TREATMENT OF NON-INSULIN DEPENDENT DIABETES
JP2003520226A (en) * 2000-01-21 2003-07-02 ノバルティス アクチエンゲゼルシャフト Combination comprising a dipeptidyl peptidase-IV inhibitor and an antidiabetic agent
WO2001062295A1 (en) * 2000-02-24 2001-08-30 Takeda Chemical Industries, Ltd. Drugs containing combined active ingredients
JP4917712B2 (en) * 2000-02-24 2012-04-18 武田薬品工業株式会社 Concomitant medication
EP1738751B1 (en) 2001-01-12 2011-05-11 Sun Pharma Advanced Research Company Ltd Spaced drug delivery system
FR2832930A1 (en) * 2001-12-03 2003-06-06 Lipha PHARMACEUTICAL COMPOSITION COMPRISING AN ALPHA-GLUCOSIDASE INHIBITOR AND A THIAZOLIDINEDIONE DERIVATIVE AND USE THEREOF FOR THE PREPARATION OF MEDICINES FOR TREATING DIABETES
CA2540225C (en) 2003-10-31 2012-03-06 Takeda Pharmaceutical Company Limited Solid preparation of pioglitazone, glimepiride and a polyoxyethylene sorbitan fatty acid ester
CN101103993B (en) * 2006-07-14 2011-03-30 北京华安佛医药研究中心有限公司 Hypoglycemic medicine composition

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ES2101866T3 (en) * 1991-08-26 1997-07-16 Upjohn Co LIQUID FOOD PRODUCT CONTAINING 3-GUANIDINOPROPIONIC ACID.
US5917052A (en) * 1994-09-28 1999-06-29 Shaman Pharmaceuticals, Inc. Hypoglycemic agent from cryptolepis
TWI238064B (en) * 1995-06-20 2005-08-21 Takeda Chemical Industries Ltd A pharmaceutical composition for prophylaxis and treatment of diabetes

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EA200000140A1 (en) 2000-06-26
CN1263467A (en) 2000-08-16
TR200000133T2 (en) 2000-09-21
SK612000A3 (en) 2000-07-11
IL133907A0 (en) 2001-04-30
JP2001510160A (en) 2001-07-31
AP2000001735A0 (en) 2000-01-16
DZ2563A1 (en) 2003-02-15
UY25101A1 (en) 2000-12-29
KR20010021952A (en) 2001-03-15
ZA986364B (en) 2000-01-17
CO4940489A1 (en) 2000-07-24
WO1999003478A1 (en) 1999-01-28
CA2297133A1 (en) 1999-01-28
NO20000230L (en) 2000-01-17
EP1001784A1 (en) 2000-05-24
NO20000230D0 (en) 2000-01-17
HUP0003626A2 (en) 2001-05-28
AR019724A2 (en) 2002-03-13
PL338140A1 (en) 2000-09-25
PE99499A1 (en) 1999-12-18
AU8449098A (en) 1999-02-10
BG104062A (en) 2000-11-30
MA24608A1 (en) 1999-04-01
BR9810292A (en) 2000-09-19
ID23804A (en) 2000-05-11
HUP0003626A3 (en) 2001-12-28
AR016350A1 (en) 2001-07-04
GB9715298D0 (en) 1997-09-24

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