CZ20001298A3 - Medicament for treating hyperglycemia and pharmaceutical preparation containing insulin sensitizer - Google Patents

Abstract

A method for the treatment of hyperglycaemia wherein plasma glucose levels in the range of from > 126 mg/dl to 140 mg/dl, which method comprises administering an effective nontoxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.

Description

A medicament for the treatment of hyperglycemia and a pharmaceutical composition comprising an insulin sensitizer

Technical field

The invention is the use of an insulin sensitizer for the manufacture of a medicament for the treatment of hyperglycemia wherein the plasma glucose levels range from greater than 126 mg / dl to 140 mg / dl, and a pharmaceutical composition comprising an insulin sensitiser and a pharmaceutically acceptable carrier for use in therapy. hyperglycemia.

BACKGROUND OF THE INVENTION

European Patent Application, Publication Number 0 306 228, relates to certain thiazolidinedione derivatives which have been reported to have hypoglycemic and hypolipidemic activity. A particular thiazolidinedione disclosed in EP 0 306 228 is 5- [4- / 2- (N-methyl-N- (2-pyridyl) amino) ethoxy / benzyl] thiazolidine-2,4-dione (hereinafter Compound (I)) ). WO 94/05659 discloses certain salts of compound (I) including a maleate salt.

Compound (I) is an example of a class of antihyperglycaemic agents known as insulin sensitizers.

In particular, compound (I) is a thiazolidinedione insulin sensitizer.

European Patent Application Publication Nos. 0 008 203, 0 139 421, 0 032 128, 0 428 312, 0 489 663, 0 155 845, 0 257 781, 0 208 420, 0 177 353, 0 319 189 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

la 0 332 331, 0 332 332, 0 528 734 and 0 508 740, international patent applications publication numbers 92/18501, 93/02079 and 93/22445, and U.S. Patents Nos. 5,104,888 and 5,478,852 also disclose certain thiazolidinedione sensitizers. insulin.

Another series of compounds generally considered τ

the compounds with insulin sensitizing activity are those characterized in the international patent applications publication numbers WO 93/21166 and WO 94/01420. These compounds are referred to herein as acyclic insulin sensitizers. Other examples of acyclic insulin sensitizers are insulin sensitizers disclosed in U.S. Patent No. 5,232,945 and in International Patent Application Publication Nos. WO 92/03425 and WO 91/19702.

Examples of other insulin sensitizers are insulin sensitizers disclosed in European Patent Application Publication No. 0 533 933, Japanese Patent Application Publication No. 05 271 204, and US Patent No. 5 264 451.

The Diabetes Mellitus report (Diabetes Care, Vol. 20 (7), 1183-1197 (1997)) states that Type 2 diabetes is characterized by plasma glucose levels at or greater than 126 mg / dl (wherein fasting is defined as no caloric intake for at least 8 hours). It also describes how diabetes generally occurs over a period of several years characterized by an increase in serum glucose levels from levels generally considered normal - plasma glucose levels of approximately 110 mg / dl - to the established characteristic of hyperglycemia of clinically diagnosed type 2 diabetes. conditions between normal glucose homeostasis and diabetes, including impaired glucose tolerance and impaired fasting glucose.

It is known from EP 0 306 228 that compound (I) is useful in the prophylaxis of hyperglycemia and thus for the treatment of impaired glucose tolerance. International Patent

9 9 9999999 9 999 9

9 9 9 9 9 9

9 · 9 99 99 9 9 9 9 application publication number WO 95/07694 also discloses that thiazolidinediones can be used to treat impaired glucose tolerance: to prevent or delay the onset of type 2 diabetes mellitus. EP 0 306 228 and WO 95/07694 however, they do not mention the treatment of any specified range of glycemia.

It has now surprisingly been found that Compound (I) provides a particularly beneficial effect on glycemic control in the range of hyperglycemia of greater than 126 mg / dl to 140 mg / dl, thereby delaying or preventing further increase in hyperglycemia.

SUMMARY OF THE INVENTION

It is an object of the present invention to use an insulin sensitizer for the manufacture of a medicament for the treatment of hyperglycemia, wherein plasma glucose levels range from greater than 126 mg / dl to 140 mg / dl.

In a preferred embodiment, the use of hyperglycemia is fasting hyperglycemia.

In another preferred embodiment, the use of hyperglycemia is in the range of greater than 126 mg / dl to 140 mg / dl and is further characterized by hyperglycemia following an oral glucose tolerance test wherein plasma glucose levels are less than 140 mg / dl, preferably less than 200 mg / dl.

In another preferred embodiment, the use of the insulin sensitizer is a thiazolidinedione insulin sensitizer.

In another preferred embodiment, the use of the sensitizer is a sensitizer. Insulin is Compound (I).

In another preferred embodiment of the daily use, 2 to 12 mg of Compound (I) is administered.

In another preferred embodiment, the use of 2 to 12 mg of 5- [4- / 2- (N-methyl-N- (2-pyridyl) amino) ethoxy / benzyl] thiazolidine-2,4-dione is in the form of a pharmaceutically acceptable derivative.

In a preferred embodiment, the insulin sensitizer is selected from the list consisting of:

(+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2 4-thiazolidine-dione (or troglitazone)

5- [4 - [(1-methylcyclohexyl) methoxy / benzyl] thiazolidine-2,4-dione (or ciglitazone),

5- [4- / 2- (5-ethylpyrid-2-yl) ethoxy / benzyl] thiazolidin-2,4-dione (or pioglitazone); and

5 - [(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl] thiazolidin-2,4-dione (or englitazone), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

In a preferred embodiment, the insulin sensitizer is in the form of compositions adapted for oral administration.

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In another preferred embodiment, the composition is in the form of a dosage unit.

The present invention also provides a pharmaceutical composition comprising an insulin sensitizer and a pharmaceutically acceptable carrier for use in the treatment of hyperglycemia, wherein plasma glucose levels range from greater than 126 mg / dl to 140 mg / dl.

Further, the present invention is described in more detail and in a broader context.

The invention provides a method of treating hyperglycemia, particularly fasting hyperglycemia, wherein plasma glucose levels range from greater than 126 mg / dl to 140 mg / dl, the method comprising administering an effective, non-toxic and pharmaceutically acceptable amount of insulin sensitizers to a mammal in need thereof.

The invention also provides a method of improving glycemic control under conditions characterized by hyperglycemia, in particular starvation hyperglycemia, wherein the improvement is provided where plasma glucose levels range from greater than 126 mg / dl to 140 mg / dl, the method comprising administering an effective, non-toxic and a pharmaceutically acceptable amount of insulin sensitizers to a mammal in need thereof.

In yet another aspect, the present invention provides a method for prophylaxis of hyperglycemia, particularly fasting hyperglycemia, wherein plasma glucose levels are greater than 140 mg / dl, the method comprising administering an effective, non-toxic drug.

5a and a pharmaceutically acceptable amount of an insulin sensitizer to a mammal in need thereof.

Suitably, the hyperglycemia is hyperglycemia associated with type 2 diabetes mellitus.

A particularly suitable thiazolidinedione insulin sensitizer is compound (I).

In one particular aspect, the invention provides a method of administering 2 to 12 mg of Compound (I), especially when administered per day.

In particular, the method comprises administering 2 to 4, 4 to 8 or 8 to 12 mg of Compound (I) per day.

In particular, the method comprises administering 2 to 4 mg of Compound (I), especially when administered per day.

In particular, the method comprises administering 4 to 8, such as more than 4, for example 4.1, to 8 mg of Compound (I), especially when administered per day.

In particular, the method comprises administering 8 to 12 mg of Compound (I), especially when administered per day.

Preferably, the method comprises administering 2 mg of Compound (I), especially when administered per day.

Preferably, the method comprises administering 4 mg of Compound (I), especially when administered per day.

Preferably, the method comprises administering 8 mg of Compound (I), especially when administered per day.

The insulin sensitizer, such as compound (I), is believed to be administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate.

Suitable pharmaceutically acceptable salts of the insulin sensitiser, such as compound (I), include those described in the aforementioned patents and patent applications, such as EP 0 306 228 and WO 94/05659 for compound (I).

A preferred pharmaceutically acceptable salt of compound (I) is maleat.

Suitable pharmaceutically acceptable solvated forms of the insulin sensitiser, such as compound (I), include the solvated forms described in the aforementioned patents and patent applications, such as EP 0 306 228 and WO 94/05659 for compound (I), especially hydrates.

Thiazolidinedione insulin sensitizers, such as compound (I), may exist in one or more tautomeric forms, all of which are included herein either as individual tautomeric forms or mixtures thereof. Certain insulin sensitizers, such as compound (I), contain one or more chiral carbon atoms and may therefore exist in two or more. stereoisomeric forms.

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All such forms are included herein, either as individual isomers or as mixtures of isomers, including racemates.

As used herein, the term pharmaceutically acceptable includes both human and veterinary use. For example, the term pharmaceutically acceptable includes a veterinarily acceptable compound.

As used herein, the oral glucose tolerance test is the test set forth in Diabetes Care, Volume 20 (7), 1183-1197 (1997).

As used herein, elevated normal hyperglycaemia has the meaning as commonly understood in the art, referring, for example, to the Expert Committee of Diagnosis and Classification of Diabetes Mellitus, but is generally believed to mean glycemia where they are plasma glucose levels greater than 110 mg / dl.

Suitably, plasma glucose levels are fasting plasma glucose levels.

In the method of the invention, the active drugs are preferably administered in the form of pharmaceutical compositions. As shown above, such compositions may include both drugs and only one of the drugs.

Such compositions may be prepared by admixing an insulin sensitizer such as compound (I), in particular 2 to 12 mg of such agent, and a pharmaceutically acceptable carrier therefor.

Typically, the compositions are adapted for oral administration

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4444 44 44 44 44 44 submissions. However, they may be adapted for other modes of administration, for example parenteral, sublingual or transdermal administration.

The compositions may take the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations such as oral or parenteral solutions or suspensions.

In order to achieve consistency for administration, it is preferred that the composition of the invention is in the form of a dosage unit.

Dosage unit forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tract or polyvinylpyrrolidone, fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, tabletting lubricants such as magnesium stearate, disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose, or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

The compositions are preferably in unit dosage form in an amount suitable for the relevant daily dose.

Suitable doses for insulin sensitizers include those disclosed in the aforementioned patents and patent applications.

Suitable dosages, including dosage units, of Compound (I) include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. · To to to to to to to to to to to to to to to to to to to to to to to to to to to to to Mg mg of Compound (I).

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

In treatments involving compounds other than compound (I), the dosages and formulations required are generally as described in the above-mentioned patent publications, which, as mentioned above, are incorporated herein by reference. An example involves the administration of 200 to 800 mg of troglitazone, for example 200, 300 or 400 mg.

Solid oral compositions may be prepared by conventional methods of mixing, filling or tabletting. Repeated mixing procedures may be employed to distribute the active ingredient in those compositions where large quantities of fillers are used. Such procedures are, of course, conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, particularly by internal coating.

Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers, for example lecithin, sorbitan monooleat or acacia, non-aqueous carriers (which may contain edible oils) such as almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol.

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9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 ίο - ···· ** "·· ^M ** lu or ethyl alcohol, preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavoring or coloring agents.

For parenteral administration, liquid dosage unit forms are prepared using the compound and a sterile vehicle and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound may be dissolved in water for injection and sterilized by filtration prior to filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, a preservative, and buffering agents may be dissolved in the vehicle. To enhance stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that compound (I) is suspended in the vehicle instead of being dissolved and that sterilization cannot be accomplished by filtration. The compound may be sterilized by exposure to ethylene oxide prior to suspension in a sterile vehicle. Preferably, a surfactant or humectant is included in the composition to facilitate uniform distribution of the compound.

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

The composition may, if desired, be in the form of a package accompanied by written or printed instructions for use.

The compositions are prepared and formulated according to conventional procedures, such as those published in standard β.

11 reference texts, such as UK and US pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books).

The invention also provides the use of insulin sensitizers such as compound (I), in particular 2 to 12 mg of such a substance, for the manufacture of a medicament for the treatment of hyperglycemia, particularly fasting hyperglycemia, wherein plasma glucose levels range from more than 126 mg / dl to 140 mg / dl.

In addition, the invention provides the use of insulin sensitizers, such as Compound (I), in particular 2 to 12 mg of such a substance, for the manufacture of a medicament for improving glycemic control in conditions characterized by hyperglycemia, particularly starvation hyperglycemia. in the range of greater than 126 mg / dl to 140 mg / dl, thereby delaying or preventing further increase in hyperglycemia.

In yet another aspect, the invention provides the use of insulin sensitizers, such as compound (I), in particular 2 to 12 mg of such agent, for the manufacture of a medicament for the prophylaxis of hyperglycemia, particularly fasting hyperglycemia, wherein plasma glucose levels are greater than 140 mg / dl. .

The present invention also provides a pharmaceutical composition comprising an insulin sensitiser, such as compound (I), in particular 2 to 12 mg of such agent, and a pharmaceutically acceptable carrier thereof, for use in the treatment of hyperglycemia, especially starvation hyperglycemia.

9 · 9 9 9 99 ·

99,999 94 4. Where plasma glucose levels range from more than 12

126 mg / dl to 140 mg / dl, or to improve glycemic control in conditions characterized by fasting hyperglycemia, wherein the improvement is provided in the hyperglycemia range, wherein plasma glucose levels range from more than

126 mg / dl to 140 mg / dl, thereby delaying or preventing further elevation of hyperglycemia, or for the prophylaxis of hyperglycemia, particularly fasting hyperglycemia, wherein plasma glucose levels are greater than 140 mg / dl.

Within the above dosage ranges, no toxicological adverse effects are expected from the compositions or methods of the invention.

Claims (12)

PATENT CLAIMS Use of an insulin sensitiser for the manufacture of a medicament for the treatment of hyperglycemia, wherein plasma glucose levels range from greater than 126 mg / dl to 140 mg / dl. Use according to claim 1, an insulin sensitizer for the manufacture of a medicament for the treatment of hyperglycemia, wherein the hyperglycemia is fasting hyperglycemia. Use according to claim 2, an insulin sensitiser for the manufacture of a medicament for the treatment of hyperglycemia, wherein the hyperglycemia ranges from greater than 126 mg / dl to 140 mg / dl and is further characterized by hyperglycemia after the oral glucose tolerance test, wherein plasma glucose levels are lower. greater than 140 mg / dl. The use of claim 2, the insulin sensitizer for the manufacture of a medicament for the treatment of hyperglycemia, wherein the hyperglycemia ranges from more than 126 mg / dl to 140 mg / dl and is further characterized by hyperglycemia after the oral glucose tolerance test, wherein plasma glucose levels are lower. than 200 mg / dl. Use according to any one of claims 1 to 4, an insulin sensitiser for the manufacture of a medicament for the treatment of hyperglycemia, wherein the insulin sensitiser is a thiazolidinedione insulin sensitiser. Use according to any one of claims 1 to 5, an insulin sensitizer for the manufacture of a medicament for the treatment of hyperglycemia, wherein the insulin sensitizer is compound (I). • 9 999 999 99 9 • 9 9 9 9 9 • 999 9 9999 • 9999 999 9 • 9 9 9 · 99 9 99999 - 14 Use according to claim 6, an insulin sensitiser for the manufacture of a medicament for the administration of 2 to 12 mg of compound (I) for the treatment of hyperglycemia. Use according to claim 7, an insulin sensitizer for the manufacture of a medicament for the administration of 2 to 12 mg of 5- [4- / 2- (N-methyl-N- (2-pyridyl) amino) ethoxy / benzyl] thiazolidine-2,4- dione in the form of a pharmaceutically acceptable derivative for the treatment of hyperglycemia Use according to any one of claims 1 to 4, an insulin sensitiser for the manufacture of a medicament for the treatment of hyperglycemia, wherein the insulin sensitiser is selected from the list consisting of: (+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2 4-thiazolidine-dione (or troglitazone) 5- [4 - [(1-methylcyclohexyl) methoxy / benzyl] thiazolidine-2,4-dione (or ciglitazone), 5- [4- / 2- (5-ethylpyrid-2-yl) ethoxy / benzyl] thiazolidin-2,4-dione (or pioglitazone); and 5 - [(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl] thiazolidin-2,4-dione (or englitazone), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Use according to any one of claims 1 to 9, an insulin sensitizer for the manufacture of a medicament for the treatment of hyperglycemia, wherein: 4? *** 4 4 • 4 4 4 4 4 4 4444 4 4 4 4 4 4 4 4 4 4 4 · ··· 444 The insulin sensitizer is in the form of a formulation adapted for oral administration. The use of claim 10, the insulin sensitizer for the manufacture of a medicament for the treatment of hyperglycemia, wherein the composition is in the form of a dosage unit. 12. 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 greater than 126 mg / dl to 140 mg / dl.