AU778947B2 - Treatment of diabetes with thiazolidinedione and metformin - Google Patents

Treatment of diabetes with thiazolidinedione and metformin Download PDF

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AU778947B2
AU778947B2 AU10119/02A AU1011902A AU778947B2 AU 778947 B2 AU778947 B2 AU 778947B2 AU 10119/02 A AU10119/02 A AU 10119/02A AU 1011902 A AU1011902 A AU 1011902A AU 778947 B2 AU778947 B2 AU 778947B2
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mg
compound
pharmaceutically acceptable
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Stephen Alistair Smith
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority to AU85393/98A priority patent/AU8539398A/en
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AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: oo° SmithKline Beecham plc ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Treatment of diabetes with thiazolidinedione and metformin" The following statement is a full description of this invention, including the best method of performing it known to us: P OPER MKR SPECI S393-9q-di 10 01 02 -1- TREATMENT OF DIABETES WITH THIAZOLIDINEDIONE AND METFORMIN This is a divisional of application 85393/98, the disclosure of which is included herein in its entirety by way of 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 II diabetes and conditions associated with diabetes mellitus.

Biguanide antihyperglycaemic agents are commonly used in the treatment of NIDDM (or Type II diabetes). 1,1-Dimethylbiguanidine (or Metformin) is an example of a 10 biguanides 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 0306228 is 5-[4-[2-(N-methyl- N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter 'Compound(I)').

WO 94/05659 discloses certain salts of Compound including the maleate salt at example 1 thereof.

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

European Patent Applications, Publication Numbers: 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 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 WO93/21166 and WO94/01420. 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 WO92/03425 and WO91/19702.

08-11-'04 15:23 FROM- T-607 P006/025 F-595 -1A- Examples of other insulin sensitisers are those disclosed in European Patent Application, Publication No. 0533933, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.

The abovementioned publications are incorporated herein by reference.

It is now surprisingly indicated that from 2 to 8 mg of Compound or a pharmaceutically acceptable form thereof in combination with up to 3000 mg metformin or metformin hydrochloride provides a particularly beneficial effect on glycaemic control with no observed adverse effects, such combination is therefore particularly useful for the treatment of diabetes mellitus, especially Type II diabetes and conditions associated with diabetes mellitus.

Accordingly the present invention provides a pharmaceutical composition which comprises from 2 to 8 mg of 5-[4-[2-(N-methyl-(N-(2-pyridyl)amino)cthoxy]benzyl) thiazolidine-2,4-dione (Compound or a pharmaceutically acceptable form thereof, up to 3000 mg of metformin or metformin hydrochloride and a pharmaceutically acceptable carrier therefor.

In one aspect, the composition comprises from 2 to 4 or 4 to 8 mg of Compound (I) or a pharmaceutically acceptable form thereof.

Typically, the composition comprises from 2 to 4 mg of Compound or a pharmaceutically acceptable form thereof Typically, the composition comprises from 4 to 8 mg of Compound or a pharmaceutically acceptable form thereof.

Preferably, the composition comprises 2 mg of Compound or a pharmaceutically acceptable form thereof.

Preferably, the compositions of the present invention comprise 4 mg of Compound 25 or a pharmaceutically acceptable form thereof.

Preferably, the composition comprises 8 mg of Compound or a pharmaceutically acceptable form thereof.

:Preferably, the composition of the present invention comprises 500 mg or 850 mg of metformin or metformin hydrochloride.

oooo COMS ID No: SBMI-00987863 Received by IP Australia: Time 15:31 Date 2004-11-08 08-11-'04 15:23 FROM- T-607 P007/025 F-595 P.0a1r 20D6U412WasdI 2oo4SiI1K -2- Preferably, the composition of the present invention comprises the maleate salt of Compound The present invention further provides a method for the treatment of diabetes mellitus, especially Type II diabetes and conditions associated with diabetes mellitus in a mammal, such as a human, which method comprises administering from 2 to 8 mg of 5-[4- [2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound or a pharmaceutically acceptable form thereof, and up to 3000 mg of metformin or metformin hydrochloride per day, to a mammal in need thereof.

The method comprises either co-administration, of an insulin sensitiser, such as Compound and a biguanide antihyperglycaemic agent or the sequential administration thereof.

Co-administration includes administration of a formulation which includes both, an insulin sensitiser, such as Compound and a biguanide antihyperglycaemic agent or the essentially simultaneous administration of separate formulations of each agent.

In another aspect the present invention provides use of from 2 to 8 mg of (N-methyl-N (2-pyridyl)amino)ethoxy)benzyl]thiazolidine-2,4-dione (Compound or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride in the manufacture of a medicament for use in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

In one particular aspect, the method of the present invention, comprises the administration of 2 to 4 or 4 to 8 mg of Compound per day.

Particularly, the method comprises the administration of 2 to 4 mg of Compound or a pharmaceutically acceptable form thereof, per day.

Particularly, the method comprises the administration of 4 to 8 mg of Compound 25 or a pharmaceutically acceptable form thereof, per day.

Preferably, the method comprises the administration of 2 mg of Compound or a pharmaceutically acceptable form thereof, per day.

Preferably, the method comprises the administration of 4 mg of Compound or a pharmaceutically acceptable form thereof, per day.

Preferably, the method comprises the administration of 8 mg of Compound or a pharmaceutically acceptable form thereof, per day.

COMS ID No: SBMI-00987863 Received by IP Australia: Time 15:31 Date 2004-11-08 08-11-'04 15:23 FROM- T-607 P008/025 F-595 P~AepMt~JC4WltI W&@A"SJ uW -3- Typically, the method comprises the administration of 500 mg or 850 mg of metforznin or metformin hydrochloride, per day.

It will be understood that Compound is administered in a pharmaceutically acceptable form, including pharmnaceutically acceptable derivatives such as pharmnaeeutically acceptable salts, esters and solvates thereof, as appropriate, of the relevant pharmaceutically active agent. It will be understood that all 0-00: 0 0.

o 0 -0o oo*0* COMS ID No: SBMI-00987863 Received by IP Australia: Time 15:31 Date 2004-11-08 pharmaceutically acceptable forms of the active agent per se are encompassed by this invention.

Suitable pharmaceutically acceptable forms of Compound include those described in the above mentioned publications.

Suitable pharmaceutically acceptable forms of Compound include those described in EP 0306228 and W094/05659, especially pharmaceutically acceptable salted forms. A preferred pharmaceutically acceptable salt is a maleate.

Suitable pharmaceutically acceptable forms of Compound include those described in EP 0306228 and W094/05659, in particular hydrates.

A suitable pharmaceutically acceptable form of metformin is an acid addition salt, such as a hydrochloride.

Compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared using known methods, for example those disclosed in EP 0306228 and W094/05659. The disclosures of 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 stereoiosmeric forms, the term Compound encompasses all of these isomeric forms whether as individual isomers or as mixtures of isomers, including racemates.

"Compound pharmaceutically acceptable forms thereof, metformin and metformin hydrochloride are prepared according to known methods, such methods are Sfound 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 31st Edition on page 341 and pages cited therein) or as described in the abovementioned publications.

S When used herein the term 'conditions associated with diabetes' includes those conditions associated with the pre-diabetic state, conditions associated with diabetes mellitus itself and complications associated with diabetes mellirus.

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 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 and steroid induced insulin resistance and gestational diabetes.

'Complications associated with diabetes mellitus' includes renal disease, especially renal disease associated with Type II diabetes, neuropathy and retinopathy.

Renal diseases associated with Type II diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.

As used herein the term 'pharmaceutically acceptable' embraces both human and veterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.

For the avoidance of doubt, when reference is made herein to scalar amounts, including mg amounts, of Compound in a pharmaceutically acceptable form, the scalar amount referred to is made in respect of Compound per se: For example 2 mg of Compound in the form of the maleate salt is that amount of maleate salt which contains 2 mg of Compound Diabetes mellitus is preferably Type II diabetes.

The particularly beneficial effect on glycaemic control provided by the S: treatment of the invention is indicated to be a synergistic effect relative to the control expected for the sum of the effects of the individual active agents.

C-lycaemic 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 Alc). Such indices are determined using standard methodology, for example those described in: Tuescher A, Richterich, 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 used .ooo* in accordance with the treatment of the invention will be less than would have been required from a purely additive effect upon glycaemic control.

There is also an indication that the treatment of the invention will effect an improvement, relative to the individual agents, in the levels of advanced glycosylation 08-11-'04 15:23 FROM- T-607 P009/025 F-595 wrJpau2ur2 nIaoudl IM -6end products (AGEs), leptin and serum lipids including total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in the ratios thereof, in particular an improvement in serum lipids including total cholesterol, HDL-cholesterol, LDLcholesterol including improvements in the ratios thereof.

In the method of the invention, the active medicaments are preferably administered in pharmaceutical composition form. As indicated above, such compositions can include both medicaments or one only of the medicaments.

Such compositions may be prepared by admixing from 2 to 8 mg of Compound (I) or a pharmaceutically acceptable from thereof, metformin or metformin hydrochloride and a pharmaceutically acceptable carrier therefor.

Usually the compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets and capsules 20 and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable 25 wetting agents such as sodium lauryl sulphate.

The compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.

Suitable unit dosages of the Compound of formula comprise 2, 3, 4, 5, 6, 7 or 8 mg of Compound 30 The composition of the invention may be administered from 1 to 6 times a day, but most preferably 1 or 2 times per day.

Particular dosages of Compound are 2 mg/day, 4 mg/day, including 2 mg twice per day, and 8 mg/day, including 4 mg twice per day.

COMS ID No: SBMI-00987863 Received by IP Australia: Time 15:31 Date 2004-11-08 Suitable dosages of metformin or metformin hydrochloride 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.

Thus, one example of the method comprises the administration of 4 or 8mg of Compound (at 2mg twice per day or 4mg twice per day respectively) and 1000mg or 2 500mg of metformin (at 500mg twice per day or 500mg five times per day respectively).

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. 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, 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 (I)s suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.

Advantageously, a surfactant or wetting agent is included in the comoosition to facilitate uniform distribution of the comoound.

-6A- Compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.

Compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use.

The 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).

08-11-'04 15:24 FROMI- T-607 P010/025 F-595 P.MM1hIONa49I IdbII A range of 2 to 4 mg 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 to4, 2.7 to 4,2.8 to4, 2.9 to 4or 3to 4mg.

A range of 4 to 8 mg 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 9, 4.7 to 8, 4.8 to 8, 4.9 to 8, 5 to 8, 6to 8or 7to 8mg.

No adverse toxicological effects have been established for the compositions or methods of the invention in the above mentioned dosage ranges.

The following example illustrates the invention but does not limit it in any way.

COMS ID No: SBMI-00987863 Received by IP Australia: Time 15:31 Date 2004-11-08 Example S 55 5 5 This study evaluated the pharmacokinetics (PK) of Compound and metformin (M) administered alone and in combination. Sixteen male volunteers, aged 22 to 55 years, received oral Compound (2 mg Q12h), M (500 mg Ql2h), or the combination, each for 4 days. Plasma collected on day 4 of each regimen was assayed for Compound and M concentrations. Oral doses of Compound and M were safe and well tolerated alone or in combination. There were no episodes of hypoglycaemia and co-administration did not result in an increase in blood lactic acid concentration.

Parameter M Compound (I) [units| Alone Combn Alone Combn AUC(0-12) 626 629 6508 6575 [ng.h/mL] (494-866) (418-912) (4694-8705) (4773-9230) Cmax 105 104 901 918 [ng/mL] (78.9-150.2) (76.5-139.2) (620-1251) (635-1344) Tmax 3.0 3.5 3.0 [hours] (1.5-6.0) T1/2 3.22 3.21 3.24 3.41 [hours] (2.45-5.01) (2.56-4.64) (2.56-4.19) (2.64-4.58) Combo Compound M coadministration Coadministration of Compound and M did not affect the steady-state pharmacokinetics (AUC(0-12), Cmax, Tmax, or T1/2) of either drug. Because M plasma concentrations were unaffected, coadministration or Compound will not accentuate the concentrationdependent toxicities of M.

COMPOUND COMPOSITIONS A Concentrate Preparation Approximately two thirds of the lactose monohydrate is passed through a suitable screen and blended with the milled maleate salt of Compound Sodium starch glycollate, hydoxypropyl methylcellulose, microcrystalline cellulose and the remaining lactose are passed through a suitable screen and added to the mixture. Blending is then continued. The resulting mixture is then wet granulated with purified water. The wet granules are then screened, dried on a fluid bed drier and the dried granules are passed through a further screen and finally homogenised.

COMPOSITION OF GRANULAR CONCENTRATE a Ingredient Quantity Milled Compound as maleate 13.25 (pure salt maleate salt) Sodium Starch Glycollate 5.00 Hydoxypropyl Methylcellulose 5.00 2910 Microcrystalline Cellulose 20.0 Lactose Monohydrate, regular to 100 grade Purified water Removed during processing.

B Formulation of the concentrate into tablets.

The granules from above are placed into a tumble blender. Approximately two thirds of the lactose is screened and added to the blender. The microcrystalline cellulose, sodium starch glycollate, magnesium stearate and remaining lactose are screened and added to the blender and the mixture blended together. The resulting mix is then compressed on a rotary tablet press to a target weight of 150mg for the 1, 2 and 4mg tablets and to a target weight of 300mg for the 8mg tablets.

The tablet cores are then transferred to a tablet coating machine, pre-warmed with warm air (approximately 65 0 C) and film coated until the tablet weight has increased by 2.0% to Quantity (mg per Tablet) Tablet Strength 1.0mg 2.0mg 4.0mg Active Ingredient: Compound maleate Concentrate granules 10.00 20.00 40.00 80.00 Other Ingredients: Sodium Starch Glycollate 6.96 6.46 5.46 10.92 Microcrystalline Cellulose 27.85 25.85 21.85 43.70 Lactose monohydrate 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 Aqueous film coating material 4.5 4.5 4.5 Total Weight of Film Coated Tablet 154.5 154.5 154.5 309.0 P OPER'MIKR SPECI S'393-9S-di doc-10 01 0.

12- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion 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 acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

o

Claims (11)

  1. 08-11-'04 15:24 FROM- T-607 P011/025 F-595 -13- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A pharmaceutical composition which comprises from 2 to 8 mg of N-methyl-(N-(2 pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound or a pharmaceutically acceptable form thereof, up to 3000 mg of metformin or melformin hydrochloride and a pharmaceutically acceptable carrier therefor. 2, A composition. according to claim 1, which comprises from 2 to 4 or 4 to 8 mg of Compound or a pharmaceutically acceptable form thereof. 3. A composition according to claim 1 or claim 2, which comprises from 2 to 4 mg of Compound or a pharmaceutically acceptable form thereof. 4. A composition according to claim 1 or claim 2, which comprises from 4 to 8 mg of Compound or a pharmaceutically acceptable form thereof A composition according to any one of claims I to 3, which comprises 2 mg of Compound or a pharmaceutically acceptable form thereof. 6. A composition according to any one of claims I to 4, which comprises 4 mg of Compound or a pharmaceutically acceptable form thereof. 7. A composition according to any one of claims 1, 2 and 4, which comprises 8 mg of Compound or a pharmaceutically acceptable form thereof 8. A composition according to any one of claims 1 to 7, which comprises 500 mg or 850 mg of metformin or metformin hydrochloride.
  2. 9. A composition according to any one of claims I to 8 which comprises the maleate salt of Compound COMS ID No: SBMI-00987863 Received by IP Australia: Time 15:31 Date 2004-11-08 08-11-'04 15:24 FROM- T-607 P012/025 F-595 r.WhtMa0WnuattW91ifOWt1i4 -14- A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)cthoxy]benzyl]thiazolidinc-2,4-dionc (Compound or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride, per day, to a mammal in need thereof.
  3. 11. A method according to claim 10, which comprises the administration of from 2 to 4 or 4 to 8 mg of Compound or a pharmaceutically acceptable form thereof, per day.
  4. 12. A method according to claim 10 or claim 11, which comprises the administration of from 2 to 4 mg of Compound or a pharmaceutically acceptable form thereof, per day.
  5. 13. A method according to claim 10 or claim 11, which comprises the administration of from 4 to 8 mg of Compound or a pharmaceutically acceptable form thereof, per day.
  6. 14. A method according to any one of claims 10 to 12, which comprises the 20 administration of 2 mg of Compound or a pharmaceutically acceptable form thereof, per day. A method according to any one of claims 10 to 13, which comprises the administration of 4 mg of Compound or a pharmaceutically acceptable form thereof, S. 25 per day.
  7. 16. A method according to any one of claims 10, 11, or 13, which comprises the administration of 8 mg of Compound or a pharmaceutically acceptable form thereof, per day.
  8. 17. A. method according to any one of claims 10 to 16, which comprises the administration of 500 mg or 850 mg of metformin or metformin hydrochloride, per day. COMS ID No: SBMI-00987863 Received by IP Australia: Time 15:31 Date 2004-11-08 08-11-'04 15:24 FROM- T-607 P013/025 F-595
  9. 18. A method according to any one of claims 10 to 17, which comprises the nialeatc salt of Compound
  10. 19. Use of from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxyl benzyljthiazolidine-2,4--dione (Compound or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride in the manufacture of a medicament for use in the treatmnent of diabetes mellitus or a condition associated with diabetes mellitus. A composition according to any one of claims 1 to 9, substantially as hereinbefore described with references to the examples.
  11. 21. A method of treatment according to any one of claims 10 to 18, substantially as hereinbefore described with references to the examples. *22. A use according to claim 19, substantially as hereinbefore described with references to the examples. DATED this 8t day of November, 2004 Smith~line *Beechami p.l.c. By DAVIES COLLISON CAVE Patent Attorneys for the Applicants *see too* COMS ID No: SBMI-00987863 Received by IP Australia: Time 15:31 Date 2004-11-08
AU10119/02A 1997-06-18 1998-06-15 Treatment of diabetes with thiazolidinedione and metformin Ceased AU778947B2 (en)

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GB9712857 1997-06-18
GB9806706 1998-03-27
AU85393/98A AU8539398A (en) 1997-06-18 1998-06-15 Treatment of diabetes with thiazolidinedione and metformin
PCT/EP1998/003690 WO1998057634A1 (en) 1997-06-18 1998-06-15 Treatment of diabetes with thiazolidinedione and metformin

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0749751A2 (en) * 1995-06-20 1996-12-27 Takeda Chemical Industries, Ltd. Pharmaceutical composition for use in tteatment of diabetes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0749751A2 (en) * 1995-06-20 1996-12-27 Takeda Chemical Industries, Ltd. Pharmaceutical composition for use in tteatment of diabetes

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