Pharmaceutical composition for treating diabetes mellitus comprising an insulin sensitizer and a biguanide antihyperglycaemic agent

Ref: 10223/99 133142/3 -IT^DTIO ΓΠΟΓΝ ΤΌΠΓΙ H33DT 713^7 ΊΝ133 ΤΌΟΠ ^)^73139^133^ ΤυΚΙΓΞΙ T1D1!

A PHARMACEUTICAL COMPOSITION FOR TREATING DIABETES MELLITUS COMPRISING AN INSULIN SENSITIZER AND A BIGUANIDE ANTIHYPERGLYCAEMIC AGENT 133142/3 -1-

This invention provides a pharmaceutical composition for the treatment of diabetes mellitus, especially non-insulin dependent diabetes (NIDDM) or

Type II diabetes and conditions associated with diabetes mellitus.

Rignanirie. antihyperglycaemic agents are commonly used in the treatment of NIDDM (or Type H diabetes). 1,1- Dimetbylbiguanidine (or Metformin) is an example of a biguanides antihyperglycaemic agent.

European Patent Application, Publication Number 0,306,228 relates to certain thiazoiidinedione derivatives disclosed as having antihyperglycaemic and hypolipidaemic activity. One particular thiazoiidinedione disclosed in EP 0306228 is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyI]thiazolidine-2,4-dione (hereinafter 'Compound (I)'). WO94/Q5659 discloses certain salts of Compound (I) including the. maleate salt at example 1 thereof

Compound (I) is an example of a class of anti-hyperglycaemic agents known as 'insulin, sensitisers'. In particular Compound (I) is a thiazoiidinedione 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 547B852, also disclose certain thiazoiidinedione 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 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 WO92/03425 and wO91/I9702.

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.

It is now surprisingly indicated that Compound (I) in combination with a biguanide antihyperglycaemic agent 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. 133142/3 -2-

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

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

Typically, the combination comprises from 2 to 4 mg of Compound (I) or a pharmaceutically acceptable form thereof.

Typically, the combination comprises from 4 to 8 mg of Compound (I) or a pharmaceutically acceptable form thereof.

Preferably, the combination comprises 2 mg of Compound (I) or a pharmaceutically acceptable form thereof.

Preferably, the combination comprises 4 mg of Compound (I) or a pharmaceutically acceptable form thereof.

Preferably, the combination comprises 8 mg of Compound (I) or a pharmaceutically acceptable form thereof.

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

Preferably, the combination is one wherein Compound (I) or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride are formulated as a single pharmaceutical composition.

Preferably, the combination is one wherein Compound (I) or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride are formulated as separate pharmaceutical compositions.

Most preferably, the combination of the present invention is for the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

The treatment using a combination of the present invention comprises either co-administration of Compound (I) or a pharmaceutically acceptable form thereof, and metformin or metformin hydrochloride or the sequential administration thereof.

Co-administration includes administration of a formulation which includes 133142/3 -3- both Compound (I) or a pharmaceutically acceptable form thereof, and metformin or metformin hydrochloride, or tire essentially simultaneous administration of separate formulations of each agent.

In another aspect the present invention provides use of from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) 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.

Further, the present invention provides use of from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof in the manufacture of a medicament for use with up to 3000 mg of metformin or metformin hydrochloride in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

Still further the present invention provides use of up to 3000 mg of metformin or metformin hydrochloride in the manufacture of a medicament for use with from 2 to 8 mg of 5-[4-[2-(N-metliyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (1)) or a pharmaceutically acceptable form thereof in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

It will be understood that Compound (I) is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate. It will be understood that all pharmaceutically acceptable forms of the active agent per se are encompassed by this invention.

Suitable pharmaceutically acceptable forms of Compound (I) include those described in EP 0306228 and WO94/05659, especially pharmaceutically acceptable salted forms. A preferred pharmaceutically acceptable salt is a maleate.

Suitable pharmaceutically acceptable forms of Compound (I) include those described in EP 0306228 and WO94/05659, in particular hydrates.

Compound (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared using known methods, 133142/2 -4- for example those disclosed in EP 0306228 and WO94/05659. The disclosures of EP 0306228 and WO94/05659 are incorporated herein by reference.

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

Compound (I), pharmaceutically acceptable forms thereof, metformin and metformin hydrochloride are prepared according to known methods, such methods are found or are referred to in standard reference texts, such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition on page 341 and pages cited therein) or as described in the above-mentioned publications. 133142/3 -5-

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 mellitus.

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 hyperirtsnlinaemia. ‘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 'Ρητηρηrations associated with diabetes mellitus' includes renal disease, especially renal disease associated with Type Π diabetes, neuropathy and retinopathy.

Renal diseases associated with Type Π 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 (I) in a pharmaceutically acceptable fm-m, the scalar amount referred to is made in respect of Compound (I) per sez Fnr.eremple 2 mg of Compound (I) in the form of the maleate salt is that amount of maleate salt which contains 2 mg of Compound (I).

Diabetes mellitus is preferably Type H diabetes..

The particularly beneficial effect on glycaemic control provided by the 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.

Glycaemic control may be characterised using conventional methods, for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or glycosylated haemoglobin (Hb Ale). Such indices are determined using standard methodology, for example those described in: Tuescher A, Richterich, P, Schweiz, med. Wschr. 101 (1971), 345 and 390 and Frank P^ ’Monitoring the Diabetic Patent with dycosolated Hemoglobin Measurements’, Clinical Products 1988. 133142/2 -6-

In a preferred aspect, the dosage level of each of the active agents when used 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 end 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 Epids including total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in the ratios thereof

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.

Accordingly, in one aspect of the invention there is provided a pharmaceutical composition comprising from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2- pyridyl)ammo)ethoxyJbenzyl]thiazolidme-2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof, up to 3000 mg of metformin or metformin hydrochloride and a pharmaceutically acceptable carrier- therefor. Typically, said composition is for use in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

Such compositions may be prepared by admixing from 2 to 8 mg of Compound (I) or a pharmaceutically acceptable form 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 ΟΓ 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 and may contain conventional excipients such 2S binding agents, for example syrup, acacia, getatip, sorbitol, tragacanth, or polyvinylpyrrolidone; tillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; 133142/2 -7- tabletting lubricants, for example magnesium stearate; disintegrants, for example, starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable 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 (I) comprise 2,3,4,5, 6,7 or 8 mg of Compound (I).

The composition of the invention may be administered from 1 to 6 timeg a day, but most preferably 1 or 2 times per day.

Particular dosages of Compound (I) are are 2mg/day, 4tng/day, including 2mg twice per day, and 8 mg/day, including 4-mg twice per day.

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 administration of the combination of the present invention is 4 or 8mg of Compound (I) (at 2mg twice per day or 4mg twice per day respectively) and lOOOmg or 2500mg of metformin (at 500mg twice per day or 500mg five times per day respectively).

The soBd oral compositions may he 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 fillem 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 ofi 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, carboxymethyieellnlose, ainmmium stearate gel, hydrngenated edible fats; emulsifying agents, for example lecithin, sorbitan 133142/2 -8- monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for re ampin 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 foe compound and a sterile vehicle, and, depending on Ihe 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 t 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 Hi ssnlved, 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 composition to facilitate uniform distribution of the compound.

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

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 31 st Edition page 341 and pages cited therein) and Harry's Cosmeticology (Leonard Hill Books). A range of 2 to 4mg includes a range of 2.1 to 4,22 to 4, 23 to 4,2.4 to 4, 23 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, 43 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 Smg.

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

The following example ifrustraies the invention but does not limit it in any way. 133142/2 -9-

Example

This study evaluated the pharmacokinetics (PK) of Compound (I) and metformin (M) administered alone and in combination. Sixteen male volunteers, aged 22 to 55 years, received oral Compound (I) (2 mg Q12h), M (500 mg Q12h), or the combination, each for 4 days. Plasma collected on day 4 of each regimen was assayed for Compound (I) and M concentrations. Oral doses of Compound (I) 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 [ngh/mL] (494-866) (418-912) (4694-8705) (4773-9230) Cmax 105 104 901 918 [ng/rnL] (78.9-1502) (765-1392) (620-1251) (635-1344) Tmax 3.0 35 3.0 35 [hoars] ¢2.0-4.0) (15-4.0) (1.0-65) (15-6.0) Tl/2 322 321 324 .3.41 [hours] (2.45-5.D1) (256-454) (256-4.19) (254-458)

Combo = Compound (I) + M coadminisuarioa

Coadministration of Compound (I) and M did not afreet the steady-state pharmacokinetics (AUC(0-12), Cmax, Tmax, or Tl/2) of either drug. Because M plasma concentrations were unaffected, coadministration or Compound (I) win not accentuate the concentration-dependent toxicides of M. Ι 33142/2 -ΙΟ

COMPOUND (Ί) 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 (I)-Sodium starch glycollate, hydoxypropyl methylcellulose, microcrystaliine 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

Ingredient Quantity (%) Milled Compound (I) as maleate salt 1325 (pure maleate salt) Sodinm Starch Glycollate 5.00 Hydoxypropyl Methylcellulose 2910 5.00 Microcrystaliine Cellulose 20.0 Lactose Monohydrate, regular grade to 100 Purified water * * Removed during processing 133142/2 -11- B Formulation of the concentrate into tablets.

The granules fiom above are placed into a tumble blender. Approximately two thirds of tbe 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 Smg tablets.

The tablet cores are then transferred to a tablet coating machine, pm-warmed with warm air (apprnvimateJy 65 °C) and film coated until the tablet weight has increased by 2.0% to 3.5%.

Quantity (mg per Tablet)

Tablet Strength 1-ftmg 2-Bmg 4-0mg 8-0mg Active Ingredient: Compound (I) maleate Concentrate grannies 10.00 20.00 40.00 80.00 Other Ingredients: Sodium Starch Glycollate 6.96 6.46 5.46 1052 Microcrystalline Cellulose 27.85 25.85 21.85 43.70 Lactose monohydrate 104.44 9654 8154 163.88 Magnesium Stearate 0.75 0.75 0.75 150 Total Weight ofTablet Core 150.0 150.0 150.0 300.0 Aqueous film coating material 44 44 44 9.0 Total Weight of Film Coated Tablet 1544 1544 1545 309.0