AU782419B2 - Treatment of diabetes with thiazolidinedione, insulin secretagogue and diguanide - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: SmithKline Beecham p.l.c.

ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Treatment of diabetes with thiazolidinedione, insulin secretagogue and diguanide" The following statement is a full description of this invention, including the best method of performing it known to us: TREATMENT OF DIABETES WITH THIAZOLIDINEDIONE, INSULIN SECRETAGOGUE AND DIGUANIDE This application is a divisional of Australian Patent Application No. 84488/98, the entire contents of which are incorporated herein by reference.

This invention relates to a method of treatment, in particular to a method for the treatment of diabetes mellitus, especially non-insulin dependent diabetes (NIDDM) (or Type 2 diabetes) and conditions associated with diabetes mellitus.

Insulin secretagogues are compounds which promote increased secretion of insulin by the pancreatic beta cells.

The sulphonylureas are well known examples of insulin secretagogues. The sulphonylureas act as antihyperglycaemic agents and are used in the treatment of Type 2 diabetes). Examples of sulphonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.

Biguanide antihyperglycaemic agents are commonly used in the treatment of Type 2 diabetes). 1,1 Dimethylbiguanidine (or Metformin) is an example of a biguanide antihyperglycaemic agent.

15 European Patent Application, Publication Number 0,306,228 relates to certain S* 0 thiazolidinedione derivatives disclosed as having antihyperglycaemic and antihyperlipidaemic activity. One particular thiazolidinedione disclosed in EP 0306228 is 5-[ 4 2 -(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2 4dione (hereinafter 'Compound W094/05659 discloses certain salts of Compound 20 including the maleate salt.

Compound is an example of a class ofanti-hyperglycaemic agents known as 'insulin sensitisers'. In particular Compound is a thiazolidinedione insulin sensitiser.

European Patent Applications, Publication Numbers: 0008203. 0139421, 25 0032128. 0428312, 0489663, 0155845, 02577810208420, 0177353,0319189, .i 0332331, 0332332, 0528734, 0508740; International Patent Application, Publication Numbers 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852, also disclose certain thiazolidinedione insulin sensitisers.

Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in International Patent Applications, Publication Numbers W093/21166 and W094/01420. These compounds are herein referred to as 'acyclic insulin sensitisers'. Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number 5232945 and International Patent Applications, Publication Numbers W092/03425 and W091/19702.

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.

01-06-'05 09:42 FROM- T-487 F015/035 F-341 .2- The above mentioned publications are incorporated herein by reference.

It is now surprisingly indicated that 2-12 mg of Compound in combination with an, insulin secretagogue and a biguanide anttyperglycaenmic agent provides a particularly beneficial effect on glycaeznic conirol. Such a combination Is thaerefore particularly useful for the treatMent of diabetes mollitus, especially Typo 2 diabetes aad conditions associated with diabetes mellitus. The teatment is also indicated to proceed with minimum side effects.

Accordingly, the invention provides a method for the ftratment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering 5-[4-[2-(N-znethyl-N-(2pyridyl)amino)ethoxylbenzyl]thiazoidine-2,4-dione (Compound 1) or a pharmaceutically acceptable form thereof in an amount of 2 to 12 mg an insulin secretagogue and a biguavide autibypeaglyceenic agent, to a mammal in need thereof. In a preferred embodiment the invertion. provided a method for the :15 treatment of diabetes mell itus and conditions asociated -with diabetes mellitus in a *mammal which method comprises administering thereto 5-[4-[2-(N-metbyl-N-(2pyidl)aino)ethoxy~benzyljthiazolidine-2,4-dione (Compound glimepiride; and one of metformin, buforin and phenformin.

The method comprises, either co-admixtisatioz of compound (or a phannaceuticafly acceptable form thereof), an insulin secretagogue and a biguaxtide antihypelrglycaemic agent or sequential administration thereof.

Co-administration includes administration of a formulation wbicb includes compound (or a pbarmaccutically acceptable form thereof), an insulin secretagoguo and a biguandd antibyperglycaemic; agent or the essentially simultaneous adininisiration of separate formulations of each agent.

In another aspect the invention provides the use, in the manufacture of a maedicament for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a marmal, of 5-[4-[2-(N-methyl-N--(2pyridyl)amino)ethoxy~benzyl]tbiazolidine-2,4-dione (Compound 1) or a pharmaceutically acceptable form thereof; in an amount of 2 to 12 mg; an insulin COMS ID No: SBMI-01276352 Received by IP Australia: Time 09:52 Date 2005-06-01 01-06-'05 09:42 FROM- T-487 POI17/035 F-341* secretagogue; and a bigum~ide an hyperglycacmio agent.

In a yet futher aspect the invenion provides a combination which comprises 2-12 mg of 5.4-[2-(N-mehy-N-(2pyridy)mino)ethioylbenzylthiawo~dine-2,4dione, (Compound I) or a pharmaccutically acceptable form thereon an insulin secretagoguc and a biguanide antihyperglycaemic agent.

Inu a preferred embodiment the invention provides a combination which comprises 2-12 mg of 5-[4-(2-(N-metbyI-N-(2pyidyl)amino)etboybnzy]thazolidiine-2,4-dione (Compound 1) or d pl~amacetial1y acceptable form thereof;, glimepiride; and one of metorinin, bufonnin and phenformin.

In a preferred embodiment the invention provides the use of mehlN(-yiy)Ln~fixlmy~baoii,-.4n (Compound 1) or a pharmaceutically acceptable form thereof in an amount 2 to 12 mg-, glimepiride; and on of metfonnin, butforimiu and 1 pheftflfiI Suitable mulin secretagogue inludo suiphonylureas.

Suitable suiphonylureas include glibenclaxmde, glipizide, gliclazide, glimepinide, tolaza:ide and tolbutamide.

Further suiphanylureas include acetohexamide, carbutamide, chlorproparnide, OLbornuride, gliquidone, glisentide, glisolamide, glisoxepide, glycl~pyamide and 20 glycylamido.

Further suitable insulin secretagogues inriude, rcpaglinide.

COMS ID No: SBMI-01276352 Received by IP Australia: Time 09:52 Date 2005-06-01 A suitable biguanide antihyperglycaemic agent is metformin, buformin or phenformin, especially metformin.

In one particular aspect, the method comprises the administration of 2 to 12 mg of Compound especially when administered per day.

Particularly, the method comprises the administration of 2 to 4, 4 to 8 or 8 to 12 mg of Compound per day.

Particularly, the method comprises the administration of 2 to 4mg of Compound especially when administered per day.

Particularly, the method comprises the administration of 4 to 8mg of Compound especially when administered per day.

Particularly, the method comprises the administration of 8 to 12 mg of Compound especially when administered per day.

Preferably, the method comprises the administration of 2 mg of Compound especially when administered per day.

15 Preferably, the method comprises the administration of 4 mg of Compound S. especially when administered per day.

Preferably, the method comprises the administration of 8 mg of Compound especially when administered per day.

It will be understood that the insulin sensitiser, such as compound the 20 insulin secretagogue and the biguanide antihyperglycaemic agent are each S. administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate. In certain instances herein the names used for the relevant insulin secretagogues and the biguanide antihyperglycaemic agents may relate to a 25 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 salted forms of the insulin sensitisers, such as Compound include those described in the above mentioned patents and patent applications such as in EP 0306228 and W094/05659 for Compound

A

preferred pharmaceutically acceptable salt for Compound is a maleate.

Suitable pharmaceutically acceptable solvated forms of the insulin sensitisers, such as Compound include those described in the above mentioned patents and patent applications, such as in EP 0306228 and W094/05659 for Compound in particular hydrates.

Suitable pharmaceutically acceptable forms of the insulin secretagogue and the biguanide antihyperglycaemic agent depend upon the particular compound used but include known pharmaceutically acceptable forms of the particular compound chosen. 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 Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein).

The insulin sensitisers, such as Compound or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared using known methods, for example those disclosed in the above mentioned patents and patent applications, such as EP 0306228 and W094/05659 for Compound The disclosures of the above mentioned patents and patent applications, such as EP 0306228 and W094/05659, are incorporated herein by reference.

Compound may exist in one of several tautomeric forms, all of which are encompassed by the term Compound as individual tautomeric forms or as mixtures thereof. Compound contains a chiral carbon atom, and hence can exist in up to two stereoisomeric forms, the term Compound encompasses all of these isomeric forms 15 whether as individual isomers or as mixtures of isomers, including racemates.

The insulin secretagogue and biguanide antihyperglycaemic agent of choice 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 Martindale The Extra 20 Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein).

When used herein the term 'conditions associated with diabetes' includes conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus. Also included in 'conditions associated with diabetes' are those 25 conditions associated with the pre-diabetic state.

When used herein the term 'conditions associated with the pre-diabetic state' includes conditions such as insulin resistance, including hereditary insulin resistance, impaired glucose tolerance and hyperinsulinaemia.

'Conditions associated with diabetes mellitus itself include hyperglycaemia, insulin resistance, including acquired insulin resistance. 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 and 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, hypertensive nephrosclerosis and end stage 01-06-'05 09:42 FROM---87P1,03 T-487 P018/035 F-342 rerZa disease. Addj~onal renal diseases associated wih Type 2 diabetes include nephrotic syndrom.

For the avoidance of doubt, when reference is made herein to scalar a~ouns, including mg atnounts, of Compo=nd i a pharnaceuxically acceptable form, the soslAr armOUZZ referred to Is made in respect of Compound (D)perse: For ex~ca 2 jug of Comnpound in the form of the nmale salt i5 that amount of maleate salt which contains 2 mg of Compound Diabetes mnellitus is Preferably Type 2 diabetes.

The parlicularly beneficial effect on glyclemic conatol provided by the treatment Of the inventon is indicatiod to be a synergishic effect relative to the conlrol expected for the sum of the cft of tbe individual active agents- Suitably the inndin sensitiser is the asent of AMrs administration, Glycaemic control may be clavctrised using conventional methods, for oxample by rneasuremen of a typically used iudex of glyeaernic cntrol suchb as hasing plaulm glucose or glyco~sylated haemoglobin (EbA Jc). Such indies are determined using standard metho3dology, for example those described in; Tuescher A, Richterich, P., Schweiz Mad. Wschr. 10 (1971), 345 and 3 90 and Frank 'Monitoring the Diabetic F&t. With Grlycosolattd Hiemoglobin M~um~aClinical Products

IOU

In a Preferred aspect, the dosage level of earb of the active agents when used it accrdanc* vith the ument of the invention will be less ?Jia would have been required from a purely additive effect upon glycaeenic controL 'Mhere is also an indication that the weatment of the invention wil effect an imPe~o~'mnt, relative t the individual agents, it the levels of advanccd _Wycosylaiion :25 end products (AGEs). leptitt and serum lipids ivclurding total choIostwl, HDLcholestewil, LDL-holesterol including inuproventents in the ratios thereof, itn Paxtcu.lar an irnprOveent In seum lipids including total cholesterol, HiDLcholesterol, LDL-c oiestcroi including ireprovcets in the ratios thcrebf.

~As used herein the tenn 'phamincetically accaptble' embrsees both bumnan :30) aud vete~dzary use: for example the term phwrmacutircaly acceptable'cembraces a vetcelarilY AcePhble compound.

In the method orthe invetioz, the active medi ects ame preferably adminisrer'ed In pharmaccurcal -composition form.' As indicated above, such compositions caix include all medicawments or one only of the zncdicaments.

Accordingly, in one aspect the present invoention also provides a phanaccutical composition comprising 2 to 12 mg of Compound an insulin secrotagogue and a biguanide antUhyergycaemjc a~gent and a pharmaceutically aoceptable carier therefor.

COMS ID No: SBMI-01276352 Received by IP Australia: Time 09:52 Date 2005-06-01 01-06-'05 09:43 FROM- T-487 P019/035 F-341 Such co ositioms my be prepared by adxnixing an ijsulin Sensimiser, Such as Com~pound and especialy 2to 12 mq themef, an instilin sectcxgog= alad a biguanide antihyperlycexrij agent and a pharmaccutically acccptable carrier therefor.

TiuaflY the comp oios ame adapted for oral adminisaaton. H~owever, they may be adapted for other modes of admihtistrain for example pa~renteral adsanton, tublingoal or asderinel administaion, The comnpositions may be in the forva of tablet*, capsules, powders, g=Wnes, lozenges, Suppositorims recnstitlatable powders, or liquid pnepamcions, such as oral or SMOO arentraJ solutions or suspetisions.

In order to obtain consistency of admnisuajon it is preferred that a composition of 1&e invention is hn the form of a unit dose.

Unit doxc preseutaxion forms for oral $dministaton may be tablets 2nd capsules and may coatain conventional cxcipleam sueb as binding agents-, for example syrp, acacia, gelatin. soibitol, tagacanth, or polyvinypyrrolidane; fffl=r, for examnple lactose, sugar, maze-sarch, clci phosphxte, sorbitol or glycizie: tablating lubricants. for example rnagneasium stearte; diuintegrants for exampole starch, poly-vinylpyn-orsdone, sodium starch glycojllate or micracrystalline cellulose; or phannacetically acceptable wetting agents such as slacium lauryl sulpbaxe- U U20 The conpositious are prvf~mbly in a unit dosage fbzm in an amotunt appropriate: for the relevant daily dosage.

:~al dosage for the 1rL=uin sensitis=r include Those disclosed in the tuitable dosages, inicluding unit dosages, of Compound comprise 2,3 In the trcauent the medicaments inay be administered from I to 6 times a U. day, but most preferably I or 2 times per day.

Paicuar~ dosages ofe Cmpounct are 2mg/day, 4mgfday, including 2 mg twice Pctr day, an o 9mg/day, including 4mg twice pr day..

Suitable dosages icuagunit dsgsof the iul ertggr uha the sulphouylurea, or the biguanide aritlype glycaeic agent, inlue he ko U dosages including unit doses for theso coumulads as described or referred to in refeence text such as the Britih and tJS Pharmaropoias, Remington's Phatmaeitical Sciences (Mack Publishing MfartindAle The Exta Pharmacopoeia (London, The Pharm~aceutia Press) (fbr example see the 3 Isi Edition page 341. and pages cited therein).

Thus for the sulphonylures, a tyical daily dosage of glibenclamide is in the ranlge of from 2.5 to 20 mg, for example 1 Omg Cwice per day or 20mg once per day; a -6- COMS ID No: SBMI-01276352 Received by IP Australia: Time 09:52 Date 2005-06-01 typical daily dosage of glipizide is in the range of from 2.5 to 40 mg; a typical daily dosage of gliclazide is in the range of from 40 to 320 mg; a typical daily dosage of tolazamide is in the range of from 100 to 1000 mg; a typical daily dosage of tolbutamide is in the range of from 1000 to 3000 mg; a typical daily dosage of chlorpropamide is in the range of from 100 to 500 mg; and a typical daily dosage of gliquidone is in the range of from 15 to 180 mg.

Repaglinide may be taken in amounts, usually in the range of from 0.5mg to 4mg and usually with meals, up to a typical maximum daily dosage of 16mg per day.

With regard to the biguanide antihyperglycaemic agents, suitable dosages of metformin include up to 3000mg per day, in unit doses of 500mg (for example two or three times per day) or 850mg (for example two times per day), one example of a dosage for metformin is 500mg once building to five times per day.

The solid oral compositions may be prepared by conventional methods of .blending, filling or tabletting. Repeated blending operations may be used to distribute 15 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, in particular :with an enteric coating.

Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin. sorbitan monooleate, or acacia: non-aqueous vehicles (which may include edible oils), for example almond oil. fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the Compound is suspended in the vehicle instead of being 01-06-'05 09:43 FROM- T-487 P020/035 F-341 diwslved, and stesilization Cannot be zccmplished by Mtraion. The cokaPound can be srrrilized by cxposue to etyleme oxide before suspending in The sterile vehlicle.

Advagc~Ously, A =ufvetnt Or wettW9 8 iag included in~ tbe ccomposition to filitate unifrm d-iuttion of The compound.

Co=POsit!Os MaY conain fMM 0.1% to 99% by weight, preferably from 10-60%1 by weightof the active material, depending upon the method of Couposition maty, If desred1, be in the form of a pack accompanied by wrimen or printed imsaructions for use_ The compositions are prepared and fomulated according to convernional =420ds% Suoh Its those diszlosed in standard referencc texts, for examnple the Brifti and UiS PbarM=uco1u, Pla=&MdutC-9 Sciences (Mack Publisb~ng Co.), Martindale The Exfra Pharacopoeia (London, The pharmaceutical Press) and Harry's cosinencology (Leonard RMI Books) (for example see The 3 1st Edition page 341 and pages cited therein).

The present inventiotl also provides a pharmnaceutical composition comprising 2 to 12 mg of Compound an insulin secretagogue and a biguaide antil)YPerglYcaenmir agent and a pharmnaceutically acceptable canier 'therefor, for use :as an active therapeutic substance.

The invention also provides the use of 2-12 mg of Compound an insulin ~secretagoswi and a biguanide antelyperglycaernic agent for the mnanufacture of a inedicainet for the trntnent of diabetes melitus and conditions associated with diabetes *.la particular, tbhe present invention provides a pharmaceutical composition ~comprises 2 to 12 mog of Compound Qt), an insulin secretagogue and a biguanide antibyerglycaetmc agent and a pharmaceutically acceptable carrier therefor, for use in the treatment of diabetes mellitus and conditions associated with diabetes mellitu.

:A range of 2 Tc;4m&gincludes a range of 7.l to 4, 2.2 to 4. 2.3 to 4, 2.4 to 4, to 4, 2 6 to 4 2 .7 to4, 2.9to4, 2.9to 4or 3 to 4mg.

A range of 4 to 8mg includes a range of 4. to 8, 4.2 to 8; 4.3 to 8, 4.4 to 8, 3, 4.6 to S.4.7 to 8, 4.8 to 8, 4.9 IQ 8, 5to 8, 6 to 8or 7to Smg.

A rang of 8 to 12 ig includes a range of 8. 1 to I2 Z8.2 to 12, 8.3 to 12, 8.4 1'2, 8-3 to 12, 8.6 to 12 8.7 to 12. 8.8 To 12, 19 to 12, 9 to 12,1 Dto 17 or I11 to NO adv'erse~ toxicological effects are expected efr the compositions or methods ofthbe invention in the zbovemntioned dosagc ranges, COMS ID No: SBMI-01276352 Received by IP Australia: Time (Hm) 09:52 Date 2005-06-01 Cor position for compound (1) Pre )aration of Concentrate: Tabletting concentrate was prepared using the following mat rials lugr dient Quantity(% Mill -d Compound as maleate 13.25 (pure salt maleate salt) Sodium Starch Glycollate 5.00 Hydbxypropyl Methylcellulose 5.00 291( Miciocrystalline Cellulose 20.0 (Avi el PH 102) Lact se Monohydrate, regular to 100 grad Puri ied water* Removed during processing.

The concentrate was then formulated into tablets using the following: Quantity (mg per Tablet) Tablet Strength 1.0mg 2.0mg 4.0mg Activ Ingredient: Compound maleate Concentrate granules 10.00 20.00 40.00 80.00 Othel Ingredients: Sodium Starch Glycollate 6.96 6.46 5.46 10.92 Micr crystalline Cellulose (Avicel PHI 02) 27.85 25.85 21.85 43.70 Lactose monohydrate, (Pharmatose DCL15), 104.44 96.94 81.94 163.88 Magnesium Stearate 0.75 0.75 0.75 1.50 Total Weight of Tablet Core 150.0 150.0 150.0 300.0 Opadry 4.5 4.5 4.5 Total Weight of Film Coated Tablet 154.5 154.5 154.5 309.0 Com positions for other active agents are as described in the above mentioned publications.

r therw nders xclus Throughout this specification and the claims which follow, unless the context requires ise, the word "comprise", and variations such as "comprises" and "comprising", will be :ood to imply the inclusion of a stated integer or step or group of integers or steps but not the on of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an ledgment or any form of suggestion that that prior art forms part of the common general :dge in Australia.

ackno nowl

Claims (19)

1. 01-06-'05 09:43 FROM- T-487 P021/035 F-341 THE CLAIMS DEFINTNG THE INVENTION ARE AS FOLLOWS: I. A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal. which metod comprises admiinistering [2- (N-methyl-N-(2-pyridy)amno)etoyenzy1tiazoidine-2,4-dione (Compound 1) or a pharmaceutically accptable form thereof in an amount of 2 to 12 mg, an hnsuin secretagogue and a biguanide antihyperglycaemic agent to a mammal in need thereof.
2. 2. A method according to claim 1 wheren the insulin socretagogue is a suiphonylureL
3. 3. A method according to claim Ilor 2, wherein the insulin secretagogue is glibenclamide, glipizide, gliclazid;. glixneplxide, tolazamide, tolbutantide, :15 acetohexamide, carbutamide, chiorpropamide, glibornuride, gliquidonc, glisentidc, glisolaniide, glisoxcpide, gi viopyamide, glycylamide or repaglinide. A metod ording to claim 1, 2 or 3 wherein the biguanide is uietformin, butbrmin or phenforu. A method according to any one of claims I to 4 wherein Comnpound is admiiswd in an amnount of 2 to 4, 4 to 8 or 8 to 12 mag.
4. 6. A method according to any one of claims 1 to 5, wherein Compound is admii~itered in aamount of 2to 4mg.
5. 7- A method according tv any one of Qlaims I to 5 wherein Compound is e~dmixisteed in an amotuit of 4 to 8 mg.
6. 8. A methiod according to any one of claims 1Ito S wherein Compound is COMS ID No: SBMI-01276352 Received by IP Australia: ime 09:52 Date 2005-06-01 01-06-'05 09:44 FROM- T-487 POZ2/035 F-341 -12- administered in an amount of 8 to 12 mg.
7. 9. A method according to any one of clams Ito 5, wherein Compound is administred in an amount of 2 mg. A method according to any one of claims I to 5, wherein Compound is administered in an amount of 4 mg.
8. 11. A method according to any one of claims 1 to 5, wherein Compound is adwinistered in an amount of 8 mg.
9. 12. A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering thereto 54[4-(2-(N-mehyl-N-(2-pidyl)nino)ethoxylbzyllthiazolidine-2,4-dione (Compound glinepiride; and one of metfomin, buformin and phenformin.
10. 13. Use, in the manufacture of a medicament for the treatment of diabetes mellitus and conditions associated with diabetes mdllitus in a mammal, of 5-[4-12- (N-xnethyl-N-(-pyridyl)amino)ethoxy]benzyljtaialdil-2,4-diofe (Compound 1) or a pharmaceutically acceptable farm thereof in an amount of 2 to 12 mg- an insulin secretagogue; and a biguanide antihyperglycamic agent.
11. 14. Use according to claim 13 wherein the insulin secretagogue is a suiphonylurca. Use according to claim 13 or 14 wherein the insulin secretagogue is glibenclaiide, glipizide, gliclazide, glinepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chiorpropamide, glibomuride, gliquidone, gliseatide. glisolamide, glisoxepide, glyclopyamide, glycylamide or repaglinide. COMS ID Na: SBMI-01276352 Received by IP Australia: Time 09:52 Date 2005-06-01 01-06-'05 09:44 FROM- T-487 P023/035 F-341 -13-
12. 16. Use according to any one of laims 13 to 15 wherein the biguanide antibyperglycaemic agent is mctfomin, buformin or phenformn.
13. 17. Use, in the manufacture of a medicament for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, of (N-methyl-N-(2-pyridyl)amino)etoxybenzyl]thiazolidine-2,4-dion (Compound 1) or a pharmaceutically acceptable form thereof in an amount of 2 to 12 mg; glimepiride; and one of metformin, buformin and phenformin.
14. 18. Use according to any one of claims 13 to 17 wherein the medicament comprises 2 to 4, 4 to 8 or 8 to 12 mg of Compound
15. 19. Use according to any one of claims 13 to 17 wherein the medicament comprises 2 to 4 mg of Compound 04
16. 20. Use according to any one of claims 13 to 17 wherein the medicament comprises 4 to 8 mg of Compound 9e 9 .9
17. 21. Use according to any one of claims 13 to 16 wherein the medicament 20 comprises 8 to 12 mg of Compound
18. 22. Use according to any one of claims 13 to 16 wherein the medicament comprises 2 mg of Compound
19. 23. Use according to any one of claims 13 to 16 wherein the medicament comprises 4 mg of Compound 24, Use according to any one of claims 13 to 16 wherein the medicament comprises 8 mg of Compound COMS ID No: SBMI-01276352 Received by IP Australia: Time 09:52 Date 2005-06-01 10-06-'05 09:34 FROMI- T-674 P004/006 F-522 -14- A pharmaceutical composition comprising 2-12 rug of 5-[4-[2-(N-methyl-N-(2- pyridyl)amnino)ethoxyjbenzyl]thiazolidine-2,4-dione (Compound 1) or a pharmaceutically acceptable form thereof, an insulin secretagogue and a biguanide antihyperglycaemic agent. DATED this 10 th day of June, 2005 SmithKline Beech am pJ.c. By DAVIES COLLISON CAVE Patent Attorneys for the Applicants COMS ID No: SBMI-01293529 Received by IP Australia: Time 09:39 Date 2005-06-10