SK5312000A3 - Use of thiazolidinediones for the treatment of hyperglycaemia - Google Patents

Abstract

A method for the treatment of hyperglycaemia wherein plasma glucose levels are in the range of elevated normal to </=126mg/dl, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.

Description

Technique Area

The present invention relates to the use of a glucose sensitiser for the manufacture of a medicament for the treatment and / or prevention of certain, specific hyperglycemia.

BACKGROUND OF THE INVENTION

European patent application no. No. 0,306,228 relates to certain thiazolidinedione derivatives which have been found to have a hypoglycemic and hypolipidemic effect. One of the thiazolidinediones described in EP 0306228 is 5- [4- [2- (N-methyl-N (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter "compound (I)"). 94/0569 discloses certain salts of compound (I), including maleic acid.

Compound (I) is an example of a class of antihyperglycaemic agents known as "insulin sensitizers" (or "insulin action enhancers"). In particular, compound (I) is a thizolidinedione insulin sensitizer.

European Patent Applications with numbers: 008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740; International Patent Applications with publication numbers 92/18501, 93/02079, 93/22445 and US Patents 5104888 and 5478852 also disclose some thiazolidinedione insulin sensitizers.

Other in a series of compounds generally considered to be insulin sensitizers are those described in International Patent Applications with publication numbers WO93 / 21166 and WO94 / 01420. These compounds are referred to herein as "acyclic insulin sensitizers". Other examples of acyclic insulin sensitisers are those disclosed in US Patent 5,239,445 and in International Patent Applications with publication numbers WO 92/03425 and WO 91/19702.

Examples of other insulin sensitisers are the compounds described in European Patent Application No. 0533933, Japanese Patent Application No. 05271204, and US Patent 5264451.

The report of the Committee of Experts in the Diagnosis and Classification of Diabetes Mellitus (Diabetes Čare, vol 20 (7), 1997, 1183-1197) states that type 2 diabetes is characterized by fasting glucose levels> 126 mg / dl (where fasting means that for at least 8 hours there was no caloric intake). This publication also describes how diabetes develops over several years characterized by an increase in fasting blood glucose levels from levels generally considered normal - plasma glucose levels of approximately 110 mg / dl after hyperglycaemia characterizing clinically proven type 2 diabetes. also metabolic conditions between normal glucose homeostasis and diabetes, including decreased glucose tolerance and decreased fasting glucose.

It is known from EPO306228 that compound (I) is suitable for the prevention of hyperglycemia and thus also for the treatment of reduced glucose tolerance. International Patent Application Publication Number WO95 / 07694 also discloses that thiazolidinediones can be used to treat reduced glucose tolerance, thereby preventing or delaying the onset of type 2 diabetes mellitus. However, EPO306228 and WO 95/07694 do not mention the treatment of any specified types of glycemia.

Compound (I) has been shown to have a particularly positive effect on regulating a range of hyperglycemia from higher than normal levels to £ 126 mg / dl while delaying or preventing further increases in hyperglycemia.

SUMMARY OF THE INVENTION

The present invention provides the use of a glucose sensitiser for the manufacture of a medicament for treating hyperglycemia in a mammal indicative of such treatment, wherein plasma glucose levels range from higher than normal levels to ^126 mg / dl.

Accordingly, the invention provides the use of a glucose sensitiser to improve glycemic control in conditions characterized by hyperglycemia, particularly fasting hyperglycemia, wherein improvement is achieved in hyperglycemia, wherein plasma glucose levels range from higher than normal levels to <126 mg / dl, wherein delay or prevent further increases in hyperglycaemia.

Further, the invention provides the use of an insulin sensitiser for prevention

- hyperglycemia, particularly fasting hyperglycemia, where plasma glucose levels range from higher than normal levels to ≥ 126 mg / dl.

One particular group of conditions as defined herein, in addition to being characterized by fasting hyperglycemia, wherein plasma glucose levels range from higher than normal levels to £ 126 mg / dl, is further characterized by hyperglycemia, where plasma glucose levels are following an oral glucose tolerance test of <140 mg / dl.

Another particular group of conditions as defined herein, in addition to being characterized by fasting hyperglycemia, where plasma glucose levels range from higher than normal levels to with 126 mg / dl, is further characterized by hyperglycemia where plasma glucose levels are following an oral glucose tolerance test ranging from 140 to <200 mg / dl.

A suitable insulin sensitiser is the thiazolidinedione insulin sensitiser.

A suitable thiazolidinedione insulin sensitizer is Compound (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

Other suitable thiazolidinedione insulin sensitizers include (+) - 5 [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] ] -phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4 - [(1-methylcyclohexyl) methoxy] benzyl] 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) -5-ylmethyl] thiazolidine-2,4-dione (or englitazone).

A preferred embodiment comprises administering 2 to 12 mg of Compound (I), especially when administered daily.

A more preferred embodiment comprises administering 2 to 4, 4 to 8 or 8 to 12 mg of Compound (I) daily.

An even more preferred embodiment comprises administering 2 to 4 mg of Compound (I), especially when administered daily.

Another embodiment may include administering 4 to 8 mg, e.g. more than 4, e.g. 4.1 to 8 mg of Compound (I), especially when administered daily.

Yet another embodiment may comprise administering 8 to 12 mg of Compound (I), especially when administered daily.

Another embodiment involves the administration of 2 mg of Compound (I), especially when administered daily.

Yet another embodiment involves the administration of 4 mg of Compound (I), especially when administered daily.

The most preferred embodiment involves the administration of 8 mg of Compound (I), especially when administered daily.

It is understood that an insulin sensitizer, such as e.g. Compound (I) is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives thereof, such as pharmaceutically acceptable salts, esters and solvates, if appropriate.

Suitable forms of insulin sensitisers, e.g. the compounds (i), in the form of pharmaceutically acceptable salts, include those described in the patents and patent applications mentioned above, such as e.g. in EP 0306228 and WO94 / 05659 for compound (I).

A preferred pharmaceutically acceptable salt of Compound (I) is a maleate.

Suitable forms of insulin sensitisers, e.g. the compounds (I), in the form of pharmaceutically acceptable solvates, include those described in the patents and patent applications mentioned above, such as e.g. in EP 0306228 and WO94 / 05659 for compound (I), in particular hydrates.

Insulin sensitizers, such as e.g. Compound (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof can be prepared by known methods, e.g. such as described in the patents and patent applications mentioned above, such as e.g. in EP 0306228 and WO94 / 05659 for compound (I). Findings from the aforementioned patents and patent applications, such as e.g. EP 0306228 and WO94 / 05659 are incorporated herein by reference.

Thiazolidinedione insulin sensitizers, e.g. the compound (I) may exist in one or more tautomeric forms included herein as individual tautomeric forms or mixtures thereof.

Thiazolidinedione insulin sensitizers, such as e.g. Compound (I) contains a chiral carbon atom, and thus can exist in up to two stereoisomeric forms, all of which are named "Compound (I)" whether they are individual isomeric forms or mixtures thereof, including racemates.

The term "pharmaceutically acceptable" as used herein applies to both human and veterinary medicine: e.g. the term "pharmaceutically acceptable" includes a veterinarily acceptable compound.

The oral glucose tolerance test used herein is the same as that reported by Diabetes

Čare vol. 20 (7), 1997, 1183-1197.

As used herein, the term higher than normal hyperglycemia is well known in the art, referring, for example, to the Expert Group Report in the Diagnosis and Classification of Diabetes Mellitus, but generally refers to glycemia where plasma glucose levels are> 110 mg / dl.

In the method of the invention, the active drugs are preferably administered in the form of a pharmaceutical composition. As indicated above, such formulations may contain multiple drugs or only one drug.

Such formulations may be made by mixing an insulin sensitiser, such as a human insulin. of compound (I), in particular at a dose of 2 to 12 mg with a pharmaceutically acceptable carrier.

Typically, the compositions are adapted for oral administration. However, they may also be adapted for other modes of administration, e.g. parenteral, sublingual or transdermal administration.

The formulations may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, soluble powders or liquid preparations, e.g. oral or sterile parenteral solutions or suspensions.

In order to achieve a uniform dosage when administered, it is preferred that the composition of the invention is in unit dosage form.

Single-dose forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting humectants, e.g. magnesium stearate; disintegrating agents, e.g. starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable humectants, such as e.g. sodium lauryl sulfate.

The formulations are preferably in unit dosage form in an amount suitable for the respective daily dose.

Suitable doses of insulin sensitisers include those described in the aforementioned patents and patent applications.

Suitable doses, including single doses, of compound (I) include 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of compound (I).

For treatment with compounds other than compound (I), the dosages and formulations required are generally as described in the aforementioned patent publications, which are referred to above: The example includes the administration of 200 to 800 mg of troglitazone, e.g. . 200, 300 or 400 mg.

In treatment, the drugs may be administered 1 to 6 times a day, but most preferably 1 to 2 times a day.

Solid formulations, e.g. oral preparations may be made by conventional methods of mixing, filling or tabletting. Repeated blending procedures may be used to distribute the active ingredient in those formulations where a large number of fillers are used. Such procedures are, of course, conventional. The tablets may be coated by methods well known in the pharmaceutical practice, particularly by coating.

Liquid oral preparations may be in the form of emulsions, syrups, or enemas, or may be in the form of a dry product, which may be dissolved in water or other suitable solvent before use. Such liquid preparations may contain conventional additives such as dispersing agents, e.g. sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, e.g. lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may be edible oils), e.g. almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol, or ethyl alcohol; preservatives, e.g. methyl or propyl p-hydroxybenzoate or sorbic acid; and optionally conventional flavoring and coloring agents.

Parenteral liquid unit dosage forms are prepared using the active ingredient and a sterile vehicle and, depending on the concentration used, may be suspended or dissolved in the vehicle. In the manufacture of solutions, the formulation of the invention may be dissolved in water for injection and sterilized by filtration prior to filling into suitable vials or ampoules and capped. Advantageously, other substances, such as local anesthetics, preservatives, may be dissolved in the vehicle

- substances and buffering agents. To enhance stability, the formulation 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 compound (I) is suspended in the vehicle, instead of being dissolved and sterilized by filtration. The compound may be sterilized with ethylene oxide prior to suspension in a sterile vehicle. Preferably, a surfactant or humectant is present in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight. of the active ingredient, depending on the route of administration.

The preparation may also be in the form of a pack with the accompanying instructions for use.

The formulations of the invention may be manufactured and formulated according to conventional procedures as set forth in standard instructions, e.g. in the British and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books).

Accordingly, the invention provides the use of an insulin sensitiser, e.g. Compound (I), and in particular a dose of 2 to 12 mg thereof, for the manufacture of a medicament for the treatment of hyperglycemia, in particular fasting hyperglycemia, wherein plasma glucose values range from higher than normal levels to £ 126 mg / dl.

The invention also provides the use of an insulin sensitiser, e.g. of compound (I), and in particular a dose of 2 to 12 mg thereof, for the manufacture of a medicament for improving glycemic control in conditions characterized by hyperglycemia, particularly fasting hyperglycemia, where improvement is achieved in hyperglycemia, where plasma glucose levels range from higher than normal levels of <126 mg / dl, delaying or preventing further increases in hyperglycaemia

In yet another aspect, the invention provides the use of an insulin sensitiser, e.g. Compound (I), and in particular doses of 2 to 12 mg thereof, for the manufacture of a medicament for improving glycemic control in conditions characterized by hyperglycemia, particularly fasting hyperglycemia, wherein plasma glucose levels are> 126 mg / dl.

In particular, the present invention provides a pharmaceutical composition comprising an insulin sensitiser, e.g. Compound (I), and in particular a dose of 2 to 12 mg, and a pharmaceutically acceptable carrier, for use in the treatment of hyperglycemia, in particular

-8 fasting hyperglycemia, where plasma glucose levels range from higher than normal to <126 mg / dl, or to improve glycemic control in conditions characterized by fasting hyperglycemia, with an improvement in the range of hyperglycemia where plasma glucose levels are in ranging from higher than normal levels to < 126 mg / dl, thereby delaying or preventing further increase in hyperglycemia or to prevent hyperglycemia, particularly fasting hyperglycemia, wherein plasma glucose levels are > 126 mg / dl.

No toxicological side effects are expected within the indicated dosage range for the compositions of the invention or for uses of the invention.

Claims (11)

PATENT CLAIMS Use of a glucose sensitiser for the manufacture of a medicament for treating hyperglycemia in a mammal indicating such treatment, wherein plasma glucose levels range from higher than normal levels to 126 126 mg / dl. Use according to claim 1, wherein the hyperglycemia is fasting hyperglycemia. Use according to claim 2, wherein the hyperglycemia is characterized by fasting plasma glucose levels ranging from higher than normal levels to £ 126 mg / dl, and further characterized by hyperglycemia after an oral glucose tolerance test, wherein the plasma glucose levels are <140 mg / dl. The use of claim 2, wherein the hyperglycemia is characterized by fasting plasma glucose levels ranging from higher than normal levels to £ 126 mg / dl, and further characterized by hyperglycemia or hyperglycemia following an oral glucose tolerance test, wherein plasma glucose levels are in the range of 140 to <200 mg / dl. Use according to any one of claims 1 to 4, wherein the insulin sensitiser is a thiazolidinedione insulin sensitiser. Use according to any one of claims 1 to 5, wherein the insulin sensitiser is compound (I). The use of claim 6, wherein 2 to 12 mg of Compound (I) is administered daily. Use according to any one of claims 1 to 4, wherein the insulin sensitiser is selected from the group consisting of: (+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8- tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione-troglitazone, 5- [4 [(1-methylcyclohexyl) methoxy] benzyl] thiazolidin-2,4-dione-ciglitazone 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidin-2,4-dione-pioglitazone or 5 - [(2-benzyl-2,3-dihydro-10-benzopyran) -5] -ylmethyl] thiazolidine-2,4-dione-englitazone or a tautomeric form thereof, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. Use according to any one of claims 1 to 8, wherein the insulin sensitiser is in the form of preparations adapted for oral administration. The use of claim 9, wherein the composition is in unit dosage form. A pharmaceutical composition comprising an insulin sensitiser and a pharmaceutically acceptable carrier for use in the treatment of hyperglycemia, wherein plasma glucose levels range from higher than normal levels to 126 126 mg / dl.