Treatment of diabetes with thiazolidinedione, insulin secretagogue and diguanide.

This invention relates to a method of treatment, in particular to a method for the 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 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 diabètes). Examples of sulphonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.

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

European Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione dérivatives 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-2,4-dione (hereinafter ’Compound (1)). WO94/05659 discloses certain salts of Compound (I) including the maleate sait.

Compound (I) is an example of a class of anti-hyperglycaemic agents known as ’insulin sensitisers’. In particular Compound (I) 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 sériés 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 WO91/19702.

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.

- 2 0112'/ >

It is now surprisingly indicated that Compound (I) in combination with an insulin secretagogue and a biguanide antihyperglycaemic agent provides a particularly bénéficiai effect on glycaemic control, such combination is therefore particularly useful for the treatment of diabètes mellitus, especially Type 2 diabètes and conditions associated with diabètes mellitus. The treatment is also indicated to proceed with minimum side effects.

Accordingly, the invention provides a method for the treatment of diabètes mellitus, especially Type 2 diabètes, and conditions associated with diabètes mellitus, in a mammal such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, an insulin secretagogue and a biguanide antihyperglycaemic agent, to a mammal in need thereof.

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

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

In another aspect the invention provides the use of an insulin sensitiser, such as Compound (I), an insulin secretagogue and a biguanide antihyperglycaemic agent, in the manufacture of a composition for the treatment of diabètes mellitus, especially Type 2 diabètes and conditions associated with diabètes mellitus.

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-dihydro6-hydroxy-2, 5, 7, 8-tetramethyl-2H-l-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4thiazolidinedione (or troglitazone), 5-[4-[(l-methylcyclohexyl)methoxy]benzyI] 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)-5ylmethyl)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, glibornuride, gliquidone, glisentide, glisolamide, glisoxepide, glyclopyamide and glycylamide.

Further suitable insulin secretagogues include repaglinide.

A suitable biguanide antihyperglycaemic agent is metformin, buformin or phenformin, especially metformin.

- 3 0112 7 ;

In one particular aspect, the method comprises the administration of 2 to 12 mg of Compound (I), 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 (I) per day.

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

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

Particularly, the method comprises the administration of 8 to 12 mg of Compound (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), the insulin secretagogue and the biguanide antihyperglycaemic agent are each administered in a pharmaceutically acceptable form, including pharmaceutically acceptable dérivatives such as pharmaceutically acceptable salts, esters and solvatés thereof, as appropriate. In certain instances herein the names used for the relevant insulin secretagogues and the biguanide antihyperglycaemic agents may relate to a particular pharmaceutical form of the relevant active agent: It will be understood that ail pharmaceutically acceptable forms of the active agents per se are encompassed by this invention.

Suitable pharmaceutically acceptable salted forms of the insulin sensitîsers, 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). A preferred pharmaceutically acceptable sait for Compound (I) is a maleate.

Suitable pharmaceutically acceptable solvated forms of the insulin sensitîsers, 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.

Suitable pharmaceutically acceptable forms of the insulin secretagogue and the biguanide antihyperglycaemic agent dépend upon the particular compound used but include known pharmaceutically acceptable forms of the particular compound chosen. Such dérivatives are found or are referred to in standard reference texts such as the British and

US Pharmacopoeias, Remington’s Pharmaceutical Sciences (Mack Publishing Co.),

- 4 0112 7 >* Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 3 lst Edition page 341 and pages cited therein).

The insulin sensitisers, such as Compound (I) or, a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable soivate thereof, may be prepared using known methods, for example those disciosed in the above mentioned patents and patent applications, such as EP 0306228 and WO94/05659 for Compound (I). The disclosures of the above mentioned patents and patent applications, such as EP 0306228 and WO94/05659, are incorporated herein by reference.

Compound (I) may exist in one of several tautomeric forms, ail 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 stereoisomeric forms, the term Compound (I) encompasses ail of these isomeric forms 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 Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 3lst Edition page 341 and pages cited therein).

When used herein the term ’conditions associated with diabètes’ includes conditions associated with diabètes mellitus itself and complications associated with diabètes mellitus. Also included in ’conditions associated with diabètes’ are those conditions 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 associated with 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.

'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 stage rénal

- 5 01127, disease. Additional rénal diseases associated with Type 2 diabètes include nephrotic 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, the scalar amount referred to is made in respect of Compound (I) per se: For example 2 mg of Compound (I) in the form of the maleate sait is that amount of maleate sait which contains 2 mg of Compound (1).

Diabètes mellitus is preferably Type 2 diabètes.

The particularly bénéficiai 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.

Suitably the insulin sensitiser is the agent of first administration.

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 (HbAlc). 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 Glycosolated Hemoglobin Measurements’, Ciinical Products 1988

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 hâve 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 sérum lipids including total cholestérol, HDL-cholesterol, LDL-cholesterol including improvemehts in the ratios thereof, in particular an improvement in sérum lipids including total cholestérol, HDL-cholesterol, LDL-cholesterol including 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.

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 a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12

-60112 7 > mg thereof, an insulin secretagogue and a biguanide antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor.

Such compositions may be prepared by admixing an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and a biguanide antihyperglycaemic agent 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 parentéral administration, 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 oral or stérile parentéral 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 présentation forms for oral administration may be tablets and capsules 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 magnésium stéarate; 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 dosages for the insulin sensitisers include those disclosed in the abovementioned patents and patent applications.

Suitable dosages, including unit dosages, of Compound (I) comprise l j 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 a day, 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 biguanide antihyperglycaemic agent, 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 31 st Edition page 341 and pages cited therein).

- 7 0112 Ί

Thus for the sulphonylureas, a typical daily dosage of glibenclamide is in the range of from 2.5 to 20 mg, for example lOmg twice per day or 20mg once per day; a 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 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 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 or other suitable vehicle before use. Such liquid préparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stéarate 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 glycérine, 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 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 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.

- 8 0112 7, Parentéral suspensions are prepared in substantially the same manner, except that the Compound (I) is 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 stérile 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 administration.

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

The compositions are prepared and formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias, ’s Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry’s Cosmeticology (Leonard Hill Books) (for example see the 31 st Edition page 341 and pages cited therein).

The présent invention also provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and a biguanide antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor, for use as an active therapeutic substance.

The invention also provides the use of an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and a biguanide antihyperglycaemic agent for the manufacture of a médicament for the treatment of diabètes mellitus and conditions associated with diabètes.

In particular, the présent invention provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and a biguanide antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor, for use in the treatment of diabètes 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.

À 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.

A range of 8 to 12 mg includes a range of 8.1 to 12, 8.2 to 12, 8.3 to 12, 8.4 to 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 to 12mg.

No adverse toxicological effects are expected for the compositions or methods of the invention in the abovementioned dosage ranges

-901127,

Composition for compound (I)

Préparation of Concentrate: Tabletting concentrate was prepared using the following materials

<td> Ingrédient</td><td> Quantity (%)</td>

<td> Milled Compound (I) as maleate sait</td><td> 13.25 (pure maleate sait)</td>

<td> Sodium Starch Glycollate</td><td> 5.00</td>

<td> Hydoxypropyl Methylcellulose 2910</td><td> 5.00</td>

<td> Microcrystalline Cellulose (Avicel PH102)</td><td> 20.0</td>

<td> Lactose Monohydrate, regular grade</td><td> to 100</td>

<td> Purified water</td><td> *</td>

* Removed during processing.

P31853

- 10 01 1

The concentrate was then formulated into tablets using the following:

Quantity (mg per Tablet)

<td> Tablet Strength</td><td> l.Omg</td><td> 2.0m g</td><td> 4.0mg</td><td> 8.0mg</td>

<td> Active Ingrédient:</td><td></td><td></td><td></td><td></td>

<td> Compound (I) maleate Concentrate</td><td> 10.00</td><td> 20.00</td><td> 40.00</td><td> 80.00</td>

<td> granules</td><td></td><td></td><td></td><td></td>

<td> Other Ingrédients:</td><td></td><td></td><td></td><td></td>

<td> Sodium Starch Glycollate</td><td> 6.96</td><td> 6.46</td><td> 5.46</td><td> 10.92</td>

<td> Microcrystalline Cellulose (Avicel PH102)</td><td> 27.85</td><td> 25.85</td><td> 21.85</td><td> 43.70</td>

<td> Lactose monohydrate, (Pharmatose</td><td> 104.44</td><td> 96.94</td><td> 81.94</td><td> 163.88</td>

<td> DCL15),</td><td></td><td></td><td></td><td></td>

<td> Magnésium Stéarate</td><td> 0.75</td><td> 0.75</td><td> 0.75</td><td> 1.50</td>

<td> Total Weight of Tablet Core</td><td> 150.0</td><td> 150.0</td><td> 150.0</td><td> 300.0</td>

<td> Opadry</td><td> 4.5</td><td> 4.5</td><td> 4.5</td><td> 9.0</td>

<td> Total Weight of Film Coated Tablet</td><td> 154.5</td><td> 154.5</td><td> 154.5</td><td> 309.0</td>

Compositions for other active agents are as described in the above mentioned publications.