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Title:
PHARMACEUTICAL COMPOSITION COMPRISING A GLITAZONE AND A THIAZOLIDINEDIONE DERIVATIVE, AND USE THEREOF FOR TREATING DIABETES
Document Type and Number:
WIPO Patent Application WO/2003/041706
Kind Code:
A1
Abstract:
The present invention relates to a pharmaceutical composition comprising, as active principles, a derivative of the 5-phenoxyalkyl-2,4-thiazolidinedione type and a glitazone, in combination with one or more pharmaceutically acceptable excipients. These compositions are particularly suitable for treating diabetes.

Inventors:
MOINET GERARD (FR)
BOTTON GERARD (FR)
MESANGEAU DIDIER (FR)
Application Number:
PCT/EP2002/011660
Publication Date:
May 22, 2003
Filing Date:
October 18, 2002
Export Citation:
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Assignee:
MERCK PATENT GMBH (DE)
MOINET GERARD (FR)
BOTTON GERARD (FR)
MESANGEAU DIDIER (FR)
International Classes:
A61K31/425; A61P3/10; (IPC1-7): A61K31/425; A61P3/10
Domestic Patent References:
WO2001082916A22001-11-08
WO1997010819A11997-03-27
WO2000078333A22000-12-28
Attorney, Agent or Firm:
MERCK PATENT GMBH (Darmstadt, DE)
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Claims:
CLAIMS
1. Pharmaceutical composition comprising, as active principles, (i) at least one glitazone and (ii) at least one compound of the formula (i), in combination with one or more pharmaceutical acceptable excipients, the compound of the formula (I) being defined as follows : in which A represents a saturated or unsaturated, linear or branched hydrocarbonbased group containing from 2 to 16 carbon atoms, D represents a homocarbonbased or heterocarbonbased, mono, bi or tricyclic aromatic structure possibly including one or more hetero atoms, X represents a substituent of the aromatic structure, chosen from hydrogen, an alkyl group containing from 1 to 6 carbon atoms, an alkoxy group containing from 1 to 6 carbon atoms, an alkoxyalkyl group in which the alkoxy and alkyl groups are defined as above, an aryl group, defined as an aromatic cyclic structure comprising one or two rings optionally including one or two hetero atoms in the ring, such as, for example, a phenyl or an aor p naphthyl, an arylalkyl group. in which the alkyl group is defined as above and the aryl group is defined as above and optionally contains one or more substituents, an arylalkylaryl group in which the arylalkyl and aryl fractions are defined as above, a halogen, a trifluoromethyl, a cyano, a hydroxyl, a nitro, an amino, a carboxyl, an alkoxycarbonyl, a carboxamide, a sulfonyl, a sulfone, a sulfonamide, a sulfamoyl, an alkylsulfonylamino, an acylamino and a trifluoromethoxy, n is an integer ranging from 1 to 3, with the restriction that if A represents a butyl radical, does not represent a 4chlorophenyl group.
2. Composition according to Claim 1, characterised in that the glitazone is a compound of the general formula (il) below : in which: E represents a monocyclic, bicyclic or tricyclic aromatic hydrocarbon based structure that can include one or more hetero atoms, this structure possibly being substituted by at least one (C1C6) alkyl or acetyl radical, or possibly forming a 5or 6membered ring with the methylene radical attached to Y, n is equal to 1,2 or 3, Y represents an oxygen atom, anNHCO, CONHorCOfunction ; and F features an amino group or an aromatic or nonaromatic, cyclic or bicyclic hydrocarbonbased group, optionally containing a hetero atom chosen from oxygen and nitrogen, the amino and hydrocarbonbased groups possibly containing at least one substitution chosen from a (C1C6) alkyl radical, a halogen atom, an aryl or heteroaryl radical, an acetyl radical and a trifluoromethyl radical, or a pharmaceutically acceptable salt thereof.
3. Composition according to Claim 1 or 2, for treating diabetes.
4. Composition according to Claim 3, for treating noninsulindependent diabetes.
5. Pharmaceutical composition according to any one of Claims 1 to 4, characterised in that the weight ratio of the glitazone to the compound of the formula (I) ranges from 10'3 to 40, preferably from 103 to 10 and better still from 103 to 1.
6. Pharmaceutical composition according to any one of the preceding claims, characterised in that the glitazone is chosen from rosiglitazone, pioglitazone, isaglitazone, KRP 297, CS 011, T 174, NP 0110, englitazone, darglitazone and ciglitazone.
7. Pharmaceutical composition according to the preceding claim, charac terised in that the glitazone is chosen from rosiglitazone, pioglitazone, isaglitazone and KRP 297.
8. Composition according to any one of the preceaing c ! alms, character ised in that the compound of the formula (I) is chosen from: 5 [3 (4fluorophenoxy) propyl] thiazolidine2, 4dione 5(2phenoxyethyl)thiazolidine2,4dione 5 [2 (4fluorophenoxy) ethyi] thiazolidine2, 4dione 5{[1hydroxy2(4fluorophenoxy)]ethyl}thiazolidine2, 4dione 5{[2hydroxy3(4fluorophenoxy)]propyl}thiazolidine2, 4dione 5 [1methyl2phenoxyethyl] thiazolidine2, 4dione 5 [2 (4cyanophenoxy) ethyl)] thiazolidine2, 4dione 5 [2 (2fluorophenoxy) ethyl] thiazolidine2, 4dione 5[2(2naphthyloxy)ethyl]thiazolidine2, 4dione and pharmacologically acceptable salts thereof.
9. Composition according to Claim 8, characterised in that the compound of the formula (I) is 5 [2 (4cyanophenoxy) ethyl)] thiazolidine2, 4dione.
10. Composition according to any one of the preceding claims, which is suitable for oral administration.
11. Use of a glitazone in combination with a compound of the formula (I) as defined in Claim 1, for the preparation of a medicinal combination for treating diabetes.
12. Use according to Claim 11, for the preparation of a medicinal combina tion for treating noninsulindependent diabetes.
13. Use according to either of Claims 11 and 12, characterised in that the glitazone is of the formula (II) as defined in Claim 2.
14. Use according to the preceding claim, characterised in that the glitazone is chosen from rosiglitazone, pioglitazone, isaglitazone, KRP 297, CS 011, T 174, NP 0110, englitazone, darglitazone and ciglitazone.
15. Use according to one of Claims 11 to 14, characterised in that the compound of the formula (I) is chosen from: 5 [3 (4fluorophenoxy) propyl] thiazolidine2, 4dione 5 (2phenoxyethyl) thiazolidine2, 4dione 5 [2 (4fluorophenoxy) ethyl] thiazolidine2, 4dione 5{[1hydroxy2(4fluorophenoxy)] ethyl} thiazolidine2, 4dione 5{[2hydroxy3(4fluorophenoxy)] propyl} thiazolidine2, 4dione 5[1methyl2phenoxyethyl]thiazolidine2, 4dione 5 [2 (4cyanophenoxy) ethyl)] thiazolidine2, 4dione 5 [2 (2fluorophenoxy) ethyl] thiazolidine2, 4dione 5 [2 (2naphthyloxy) ethyl] thiazolidine2, 4dione and pharmacologically acceptable salts thereof.
16. Use according to any one of Claims 11 to 15, characterised in that the medicinal combination is in the form of a unit dose comprising a glitazone and a compound of the formula (I) as defined in Claim 1.
17. Use according to the preceding claim, characterised in that the unit dose comprises from 1 mg to 1 g of glitazone and from 12.5 to 200 mg of a compound of the formula (I).
Description:
PHARMACEUTICAL COMPOSITION COMPRISING A GLITAZONE AND A THIAZOLIDINEDIONE DERIVATIVE, AND USE THEREOF FOR TREATING DIABETES The present invention relates to a pharmaceutical composition comprising, as active principles, a derivative of the 5-phenoxyalkyl-2, 4-thiazolidinedione type described in WO 97/47612 and a glitazone.

The invention also relates to the use of a derivative of the 5-phenoxyalkyl- 2, 4-thiazolidinedione type and a glitazone for the preparation of a medicinal preparation for reducing hyperglycaemia, more particularly the hyper- glycaemia of non-insulin-dependent diabetes.

Diabetes is a chronic disease that has various pathological manifestations. It is accompanied by disorders of lipid and sugar metabolism and circulatory disorders. In many cases, diabetes tends to progress to a variety of patholo- gical complications. Thus, it is necessary to find the treatment that is suited to each individual suffering from diabetes.

Many thiazolidine-2, 4-dione derivatives have been described as anti-hyper- glycaemiants and hypolipaemiants and have thus been described as anti- diabetic agents (Takeda, patent EP 193 256 and Sankyo patent EP 207 581). These compounds, which are known as glitazones, are activa- tors of the peroxisome proliferator-activated receptor-y (PPARy). These com- pounds act by increasing the sensitivity of tissues containing insulin receptors, which leads to a reduction in the endogenous insulin requirements or allows the exogenous insulin requirement to be reduced or eliminated.

The combination of a glitazone, such as troglitazone, and a biguanide antidiabetic agent, more particularly metformin, has already been described

for the treatment of diabetes (US 6 011 049 from the Warner Lambert company).

The specific combination of a glitazone with a 5-phenoxyalkyl-2, 4-thia- zolidinedione that has no activity on the transactivation of PPARy has not been described and offers particular advantages, especially the absence of weight gain and/or of haemodilution.

Thus, one object of the present invention is to propose a composition for sig- nificantly improving the use of glucose.

A further object of the invention is to propose a composition that is suitable for treating diabetes by displaying considerable action on the metabolic syn- drome of insulin resistance.

A final object of the invention is to propose a composition that is particularly suitable for diabetics at the various stages of the disease.

These objects and others are achieved by the present invention, which relates to a pharmaceutical composition comprising, as active principles, at least one glitazone and at least one compound of the formula (I), in combination with one or more pharmaceutical acceptable excipients.

This composition is particularly suitable for treating diabetes, more particularly non-insulin-dependent diabetes. It is particularly suitable for reducing the hyperglycaemia of non-insulin-dependent diabetes.

The compound of the formula (1) is defined as follows :

in which A represents a saturated or unsaturated, linear or branched hydrocarbon-based group containing from 2 to 16 carbon atoms, D represents a homo-carbon-based or hetero-carbon-based, mono-, bi- or tricyclic aromatic structure possibly including one or more hetero atoms,, X represents a substituent of the aromatic structurel D, chosen from hydrogen, an alkyl group containing from 1 to 6 carbon atoms, an alkoxy group containing from 1 to 6 carbon atoms, an alkoxyalkyl group in which the alkoxy and alkyl groups are defined as above, an aryl group, defined as an aromatic cyclic structure comprising one or two rings optionally including one or two hetero atoms in the ring, such as, for example, a phenyl or an a-or naphthyl, an arylalkyl group in which the alkyl group is defined as above and the aryl group is defined as above and optionally contains one or more substituents, an arylalkylaryl group in which the arylalkyl and aryl fractions are defined as above, a halogen, a trifluoromethyl, a cyano, a hydroxl, a nitro, an amino, a carboxyl, an alkoxycarbonyl, a carboxamide, a sulfonyl, a sulfone, a sulfonamide, a sulfamoyl, an alkylsulfonylamino, an acylamino and a trifluoromethoxy, n is an integer ranging from 1 to 3, with the restriction that if A represents a butyl radical, does not represent a 4-chlorophenyl group. In the text hereinabove, among the aromatic radicals D, homo-carbon-based structures that may be mentioned include the phenyl, oc-naphthyl, ß-naphthyl, anthracenyl and fluorenyl radicals. Among the heterocyclic aromatic radicals that may be mentioned are pyridyl and the quinolyl or carbazolyl ring.

D preferably represents a phenyl or naphthyl radical.

Among the alkyl groups containing from 1 to 6 carbon atoms that may espe- cially be mentioned are the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy groups containing from 1 to 6 carbon atoms that may especially be mentioned are the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy radicals. Among the halogen groups that may especially be mentioned are fluorine, chlorine, bromine and iodine.

The A chain is a linear or branched hydrocarbon-based chain containing from 2 to 16 carbon atoms, that is saturated or contains one or more i ethylenic groups, optionally substituted by at least one hydroxyl radical or by , a phenyl radical. Examples of linear alkyl radicals that may especially ! be mentioned include the divalent ethyl, propyl, butyl, pëntyl, hexyl, octyl, nonyl, decyl, dodecyl and hexadecyl radicals. Among the branched alkyl chains that may especially be mentioned are the divalent 2-ethylhexyl,, 2-methylbutyl, 2- methylpentyl, 1-methylhexyl and 3-methylheptyl radicals. Among the monohydroxyalkyl chains that are preferred are radicals containing 2 or 3 carbon atoms, such as 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.

Among the polyhydroxyalkyl chains that are preferred are radicals containing 3 to 6 carbon atoms and 2 to 5 hydroxyl radicals, such as 2,3-dihydroxy- propyl, 2,3, 4-trihydroxybutyl or 2,3, 4, 5-tetrahydroxypentyl or a pentaerythritol residue. Among the hydrocarbon-based chains containing from 2 to 16 carbon atoms and one or more ethylenic groups, mention may be made especially of the divalent allyl radical.

The divalent ethyl or propyl radical is preferred.

The present invention relates also to the tautomeric forms of the compounds of the general formula (I), to the enantiomers, diastereoisomers and epimers of these compounds, and also to the solvates thereof.

It may be conceived that the ketone functions borne by the thiazolidine ring can enolise and give rise to mono-enols.

The thiazolidinedione derivatives may be salifie and be in ! the form of basic salts.

Examples of basic salts of the compounds of the general formula (I) include pharmacologically acceptable salts, such as sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc. ). The amine salts that are not pharmaco- logically acceptable may serve as a means of identification, purification or resolution.

Among the compounds of the general formula (I) according to the invention, mention will be made more particularly, as compounds that are currently preferred, of: - 5- [3- (4-fluorophenoxy) propyi] thiazolidine-2, 4-dione - 5- (2-phenoxyethyl) thiazolidine-2, 4-dione - 5- [2- (4-fluorophenoxy) ethyl] thiazolidine-2, 4-dione - 5-{[1-hydroxy-2-(4-fluorophenoxy)]ethyl}thiazolidine-2, 4-dione -5-{[2-hydroxy-3-(4-fluorophenoxy)] propyl} thiazolidine 2, 4-dione - 5- [1-methyl-2-phenoxyethyl] thiazolidine-2, 4-dione - 5- [2- (4-cyanophenoxy) ethyl)] thiazolidine-2, 4-dione - 5- [2- (2-fluorophenoxy) ethyl] thiazolidine-2, 4-dione - 5-[2-(2-naphthyloxy)ethyl]thiazolidine-2, 4-dione and pharmacologically acceptable salts thereof.

These compounds have been described in patent application WO 97/47612.

5- [2- (4-Cyanophenoxy) ethyl)] thiazolidine-2, 4-dione is preferaoly used.

Glitazones are a family of antidiabetic agents characterised as being aralkylthiazolidine-2, 4-dione derivatives or analogues thereof. The glitazones are preferably compounds of the general formula (II) below :, in which: E represents a monocyclic, bicyclic or tricyclic aromatic hydrocarbon- based structure that may include one or more hetero atoms, this structure possibly being substituted by at least one (C1-C6) alkyl or acetyl radical, or possibly forming a 5-or 6-membered ring with the methylene radical attached to Y, n is equal to 1,2 or 3, Y represents an oxygen atom, an-NHCO-, -CONH-or-CO-function ; and F features an amino group or an aromatic or non-aromatic, cyclic or bicyclic hydrocarbon group, optionally containing a hetero atom chosen from oxygen and nitrogen, the amino and hydrocarbon-based ! groups possibly containing at least one substitution chosen from a (C1-C6) alkyl radical, a halogen atom, an aryl or heteroaryl radical, an acetyl radical and a trifluoromethyl radical, and the pharmaceutical acceptable salts thereof.

In the text hereinabove, among the aromatic radicals E that may be mentioned as homocarbon-based structures are the phenyl, a-naphthyl, P-naphthyl, anthracenyl and fluorenyl radicals. Among'the heterocyclic aromatic radicals that may be mentioned are pyridyl and the quinolinyl and phenoxazole rings.

In the text hereinabove, among the aromatic radicals'F that may be mentioned as homocarbon-based structures are the phenyl, α-naphthyl, ß-naphthyl, anthracenyl and fluorenyl radicals. Among the heterocyclic aro- matic radicals that may be mentioned are pyridyl and the quinolinyl, benz- imidazole, oxazole and phenoxazole rings.

The preferred glitazones have the following formulae : These compounds have the following respective trade names or codes: rosiglitazone (or Avandia@) from the GlaxoSmithkline company, pioglitazone (or Actos@) from the Takeda company, isaglitazone (or MCC 555) from the Mitsubishi company, KRP 297 from the Kyorin company, CS 011 from the Sankyo company, T 174 from the company Tanabe, NP 0110 from the Nippon Chemiphar company, englitazone from the Pfizer company,

darglitazone from the Pfizer company and ciglitazone from the Takeda company.

The glitazone is advantageously chosen from rosiglitazone, pioglitazone, isaglitazone (MCC555) and KRP 297.

The compositions of the invention comprise therapeutical effective amounts of the various active principles. The ratios of the respective amounts of glitazone and the compound of the formula (I) thus vary in consequence.

Specifically, the dose of each active principle will vary as a function of the severity of the disease, the frequency of administration, the choice of combined active principles and other factors systematically considered by the prescribing doctor for the patient suffering from diabetes ! To give an order of magnitude, the weight ratio of glitazone ; to the compound of the formula (I) ranges from 10-3 to 40, preferably from 10-3 to 10 and better still from 10-3 to 1.

The compositions of the invention are preferably administered parenterally, or better still orally, although the other routes of administration, for instance such as rectal administration, are not excluded.

When oral administration is envisaged, the compositions of the invention are in the form of gel capsules, effervescent tablets, coated or uncoated tablets, sachets, sugar-coated tablets, drinkable vials or solutions, Microgranules or sustained-release forms.

When parenteral administration is envisaged, the compositions of the inven- tion are in the form of injectable solutions and suspensions packaged in via) s or bottles for slow venous infusion.

The forms for oral administration are prepared by mixing the active sub- stance with various types of excipients or vehicles, such as fillers, disintegra- tion (or crumbling) agents, binders, dyes, flavour enhances and the like, followed by shaping the mixture.

The dye can be any dye authorised for pharmaceutical use.

Examples of flavour enhancers include cocoa powder, mint, borneol and cinnamon powder.

Examples of binders that may be mentioned are polyvinylpyrrolidone, hydroxypropylmethylcellulose, alginic acid, carbomer, carboxymethyl- cellulose, dextrin, ethylcellulose, starch, sodium alginate, polymethacrylate, maltodextrin, liquid glucose, magnesium aluminium silicate, hydroxyethyl- cellulose, hydroxypropylcellulose, ethylcellulose, methylcellulose and guar gum.

It is possible to use alginic acid, sodium carboxymethylceliulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, methylellulose, microcrystalline cellulose, cellulose powder, pre-gelatinised starch, sodium alginate or sodium starch glycolate as disintegration agent.

The fillers are, for example, cellulose, lactose, calcium hydrogen phosphate and microcrystalline cellulose.

The tablets can be obtained in a conventional manner by compressing granules in the presence of one or more lubricants. Suitable lubricants are calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydro- genated castor oil, hydrogenated plant oil, light mineral'oil, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, stearyl

sodium fumarate, stearic acid, talc and zinc stearate. These tablets can then be coated using polymers in solution or suspension, such as hydroxypropyl- methylcellulose or ethylcellulose.

The granules used to do this are prepared, for example, by using the wet granulation process starting with a mixture of the active principles with one or more excipients such as a binder, a crumbling agent (or disintegration agent) and a filler.

To obtain hard capsules, the mixture of the active principles with a suitable filler (for example lactose) is incorporated into empty gelatine capsules optionally in the presence of a lubricant such as magnesium stearate, stearic acid, talc or zinc stearate.

Gel capsules or soft capsules are prepared by dissolving the active principles in a suitable solvent (for example polyethylene glycol), followed by incorporation into soft capsules.

The forms for parenteral administration are obtained in a conventional manner by mixing the active principles with buffers, stabilisers, preserving agents, solubilising agents, tonicity agents and suspension agents. In accordance with the known techniques, these mixtures are subsequently sterilised and then packaged in the form of intravenous injections.

As buffer, a person skilled in the art can use buffers based on organo- phosphate salts.

Examples of suspension agents include methylcellulose, hydroxyethyl- cellulose, hydroxypropylcellulose, acacia and sodium ;, carboxymethyl- cellulose.

Examples of solubilising agents include castor oil solidified with polyoxy- ethylene, polysorbate 80, nicotinamide or macrogol.

In addition, stabilisers that are useful according to the invention are sodium sulfite and sodium metasulfite, while mention may be made of sodium p-hydroxybenzoate, sorbic acid, cresol and chlorocresol as preserving agents. For the preparation of an oral solution or suspension, the active principles are dissolved or suspended in a suitable vehicle with a dispersant, a wetting agent, a suspension agent (for example polyviriylpyrrolidone), a preserving agent (such as methylparaben or propylparaben), a flavour enhancer or a dye.

For the preparation of suppositories, the active principles are mixed in a manner that is known per se with a suitable base constituent, such as polyethylene glycol or semisynthetic glycerides.

For the preparation of microcapsules, the active principles are combined with suitable diluents, suitable stabilisers, agents that promote the sustained release of the active substances or any other type of j additive for the formation of a central core which is then coated with a suitable polymer (for example a water-soluble resin or a water-insoluble resin). l The techniques known to those skilled in the. art will be used for this purpose.

The microcapsules thus obtained are then optionally formulated in suitable dosage units.

A subject of the present invention is also the use of a glitazone in combination with a compound of the formula (I) as defined above, for the preparation of a medicinal combination for treating diabetes, more particu- larly non-insulin-dependent diabetes.

, According to another of its aspects, the invention relates to the use of a glitazone in combination with the said compound of the formula (I), for the preparation of a medicinal combination for reducing the hyperglycaemia of non-insulin-dependent diabetes.

A subject of the present invention is also a process for treating diabetes, more particularly non-insulin-dependent diabetes, in a mammal, comprising the administration to the said mammal of the composition according to the present invention.

The glitazones are generally administered in doses ranging ! from about 5 mg to about 2500 mg per day and more specifically from about 50 mg to about 1500 mg per day. The preferred glitazone is rosiglitazone, and is used in doses ranging from about 5 mg to about 10 mg per day. Another preferred glitazone is pioglitazone, and is administered in doses ranging from about 50 mg to about 200 mg per day.

As regards the compound of the formula (I), it is generally administered in doses ranging from about 25 to 200 mg per day.

When the glitazone and the compound of the formula (I) are incorporated into the same unit dose, the. unit dose preferably comprises from 1 mg to 1 g of glitazone and from 12.5 to 200 mg of compound of the formula (I) (the dose depends especially on the active agents under consideration).

Naturally, the dosage depends on the active agent under consideration, the mode of administration, the therapeutic indication and the age and condition of the patient.

Concrete but non-limiting examples of the invention will now be presented. The percentages given are expressed on a weight basis, except where otherwise mentioned.

EXAMPLE 1: A tablet having the composition below is prepared: 4-[2-(2,4-Dioxothiazolidin-5- 50 mg 63.7 %' yl) ethoxy] benzonitrile* Rosiglitazone 4 5. 1 % Fine lactose powder 18 mg 22.9 Hydroxypropylcellulose 2 mg 2.5 % Croscarmellose sodium 4 mg 5.1 Magnesium stearate 0.5 mg 0.6 %

* also known as 5- [2- (4-cyanophenoxy) ethyl)] thiazolidine-2, 4-dione.

EXAMPLE 2: A tablet having the composition below is prepared: 4-[2-(2,4-Dioxothiazolidin-5- 50 mg 62. 5 % yl) ethoxy] benzonitrile Rosiglitazone 8 mg 10. 0% Fine lactose powder 15.5 mg 19.4 %' Hydroxypropylcellulose 2 mg 2. 5 % Croscarmellose sodium 4 mg 5. 0 % ; Magnesium stearate 0.5 mg 0. 6 % 'EXAMPLE 3: A tablet having the composition below is prepared:

4-[2-(2, 4-Dioxothiazolidin-5-100 mg 72. 2% yl) ethoxy] benzonitrile Rosiglitazone 4 mg 2. 9 % Fine lactose powder 22.5 mg 16. 2 % Hydroxypropylcellulose 4 mg 2. 9 % Croscarmellose sodium 7 mg 5.1 % Magnesium stearate 1 mg 0.7 % EXAMPLE 4: A tablet having the composition below is prepared :

4- [2- (2, 4-Dioxothiazolidin-5- 100 mg 71. 4 % yl) ethoxy] benzonitrile Rosiglitazone 8 mg 5.7 % Fine lactose powder 20 mg 14. 3 % Hydroxypropylcellulose 4 mg 2. 9 °/a ! Croscarmellose sodium 7 mg 5. 0 % Magnesium stearate 1 mg 0. 7 % EXAMPLE 5 : A tablet having the composition below is prepared: 4-[2-(2,4-Dioxothiazolidin-5- 200 mg 79. 5 % yl) ethoxy] benzonitrile Rosiglitazone 4 mg 1. 6 % Fine lactose powder 27.5 mg 10. 9 % Hydroxypropylcellulose 6.5 mg 2. 6% Croscarmellose sodium 12 mg 4.8 % Magnesium stearate 1.5 mg 0.6 %

EXAMPLE 6: A tablet having the composition below is prepared: 4- [2- (2, 4-Dioxothiazolidin-5- 200 mg 79. 1 % yl) ethoxy] benzonitrile Rosiglitazone 8 mg 3. 2 % Fine lactose powder 25 mg 9. 9 % Hydroxypropylcellulose 6.5 mg 2. 6 % Croscarmellose sodium 12 mg 4. 7 % Magnesium stearate 1.5 mg 0.6 %

Pharmacological study The antidiabetic effect of the combination of 4- [2- (2, 4- dioxothiazolidin-5-yl) ethoxy]- benzonitrile (compound A) * with pioglitazone was studied on n5STZ rats, an experimental model of non-insulin-dependent diabetes. This model is produced by intra- peritoneal injection of steptozotocin (STZ) 80 mg/kg, five days after birth.

The characteristics of this model are: - hyperglycaemia - absence of basal hypoinsulinaemia - glucose intolerance - insulin resistance * Compound A is also known as 5- [2- (4-cyanophenoxy) ethyl] thiazolidine- 2,4-dione > Experimental protocol 36 male n5STZ rats were used after a selection based on, the value of the hyperglycaemia after fasting for two hours to homogenize the groups.

They were then divided into four groups: - an n5STZ control group - a group treated with compound A at 12.5 mg/kg - a group treated with pioglitazone at 50 mg/kg - a group treated with compound A at 12.5 mg/kg and pioglitazone at 50 mg/kg The products were administered orally in the morning between 8 am and 9 am for four days. The glycaemia, insulinaemia and lactataemia were determined after four days of treatment by taking blood samples from the tail of the pre-anaesthetized rats two hours after the last administration of the products.

> Results Table 1: Change in the glycaemia (mol/1)

Normal n5STZ Compound A Pioglitazone Combination rats controls Glycaemia 7.44 10.04 8.53 9.87 8.20 (mol/1) S. E. M. 0.20 0.64 0.37 0.77 0.29 Change-15. 10-1. 73-18. 30 (%) Table 2: Change in the insulinaemia (pmol/l) Normal rats n5STZ Compound Pioglitazone Combination controls A Insulinaemia 320.83 428.00 396.33 461.78 226.63 (pmol/l) S. E. M. 68.97 38.58 73.95 146.29 32.29 Change (%)-7. 40 7.90-47. 10

Table 3: Change in the insulinoaenic index Normal rats n5STZ Compound Pioglitazone Combination controls A Ratio #I/#G 42.29 44.82 48.31 43.14 28.38 S. E. M. 8.24 5.89 9.81 10.58 4.74 Change (%)-7. 78 3. 75 36.69 * Insulinogenic index = A !/AG, where Al = change in piasmatic insulin level AG = change in plasmatic glucose > COMMENTS The n5STZ rats show a hyperglycaemia of 10.04 0.64 mmol/l.

The treatment with compound A orally at a very low dose of 12.5 mg/kg for four days does not significantly reduce the hyperglycaemia of the n5STZ rats (-15%). Pioglitazone at 50 mg/kg orally is totally lacking in any effect. These products administered separately do not modify the level of the plasmatic insulinaemia relative to the n5STZ control group.

The combination of compound A and pioglitazone, administered together at these doses, does not induce a reduction in the hyperglycaemia when compared with the effects of compound A alone.

However, the combination gives rise to an unforeseeable significant decrease in the plasmatic insulinaemia and the insulinogenic index.

Thus, the reduction in glycaemia observed with the combination is obtained for a 47% reduction in the circulating plasmatic insulin, reflecting a very marked increase in the effects of insulin.