MXPA00003633A - 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

USE OF TIAZOLIDINODIANS FOR THE TREATMENT OF HYPERGLYCAEMIA DESCRIPTIVE MEMORY This invention relates to a novel treatment method, in particular to a method for the treatment and / or prophylaxis of a certain specified hyperglycemia. European Patent Application, Publication No. 0,306,228, refers to certain thiazolidinedione derivatives described as having hypoglycemic and hypolipidemic activity. A particular thiazolidinedione described in EP 0306228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] -thiazolidino-2,4-dione (so-called in the sequential as "compound (I)"). WO94 / 05659 describes certain salts of compound (I) which include the maleate salt. Compound (I) is an example of a class of antihyperglycemic agents known as "insulin sensitizers" (or "insulin-enhancing agents"). In particular, the compound (I) is an insulin sensitizer of thiazolidinedione. European Patent Applications, Publication No.: 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 00177353, 0319189, 0332331, 0332332, 0528734, 0508740; international patent application, publication numbers 92/18501, 93/02079, 93/22445 and patent of E.U.A. Nos. 5104888 and 5478852, also disclose certain insulin sensitizers of thiazolidinedione. Another series of compounds generally recognized to have insulin sensitizing activity are those typified by the compounds described in the international patent applications, Publication Nos. WO93 / 21166 and WO94 / 01420. These compounds are referred to herein as "acyclic insulin sensitizers". Other examples of acyclic insulin sensitizers are those described in the patent of E.U.A. No. 5232945, and international patent applications publication numbers WO92 / 03425 and WO91 / 19702. Examples of other insulin sensitizers are those described in the European patent application, publication number 0533933, Japanese patent application publication No. 05271204 and US patent. No. 5264451. The report of the Expert Committee of the Diagnosis and Classification of Diabetes Mellitus (Diabetes Care, vol.20 (7), 1997, 1183-1197) states that type 2 diabetes is characterized by fasting plasma glucose levels > 126 mg / dl (where fasting is defined as lack of caloric intake for at least 8 hours). It also describes how the development of diabetes commonly occurs over a period of several years, characterized by an increase in fasting serum glucose levels from generally considered normal levels - plasma glucose levels of approximately 110 mg / dl - up to the established hyperglycemia characteristic of frank type 2 diabetes. The report also refers to intermediate metabolic stages between normal glucose homeostasis and diabetes, including impaired glucose tolerance and impaired fasting glucose. It is known from EP0306228 that the compound (I) is useful in the prophylaxis of hyperglycemia, and therefore for the treatment of impaired tolerance to glucose. International patent publication, publication No. WO95 / 07694, also discloses that thiazolidinedione can be used to treat impaired glucose tolerance to prevent or delay the onset of type 2 diabetes mellitus. However, EP0306228 and WO95 / 07694 do not mention the treatment of any specified range of glycemias. It is indicated that the compound (I) provides a particularly beneficial effect in the control of glycemia in the hyperglycemia scale from normal high to < 126 mg / dl, thereby delaying or preventing further elevation of hyperglycemia. Accordingly, the invention provides a method for the treatment of hyperglycemia, especially fasting hyperglycemia, where plasma glucose levels are in the normal high range up to <126 mg / dl, which method comprises administering a non-toxic and pharmaceutically acceptable effective amount of an insulin sensitizer to a mammal in need thereof. Accordingly, the invention provides a method for improving glycemic control in conditions characterized by hypergiukaemia, especially fasting hypergiukaemia, wherein the improvement is provided in hyperglycemia where the plasma glucose levels are in the high normal range a < 126 mg / dl, thereby delaying or preventing further elevation of hypergiukaemia, which method comprises administering a non-toxic and pharmaceutically acceptable effective amount of an insulin sensitizer to a mammal in need thereof. In still another aspect, the invention provides a method for the prophylaxis of hypergiukaemia, especially fasting hypergiukaemia, wherein plasma glucose levels are on the scale of > 126 mg / dl, which method comprises administering a non-toxic and pharmaceutically acceptable amount of an insulin sensitizer to a mammal in need thereof. A particular group of the conditions defined herein, in addition to being characterized by fasting hyperglycemia, wherein the plasma glucose levels are in the normal high range at < 126 mg / dl, is further characterized by hyperglycemia in which the plasma glucose levels following an oral glucose tolerance test are on the scale of < 140 mg / dl. Another group of conditions defined herein, in addition to being characterized by fasting hyperglycemia on the scale of normal high at < 126 mg / dl, is further characterized by hyperglycemia in which plasma glucose levels following an oral glucose tolerance test are on a scale of 140 to < 200 mg / dl. A suitable insulin sensitizer is an insulin sensitizer of thiazolidinedione. A suitable thiazolidinedione insulin sensitizer is the compound (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a 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] thiazolidino-2,4-dione (or ciglitazone), - [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazole-2,4-dione (or pioglitazone) or 5 - [(2-benzyl-2, 3-dihydrobenzopyran) -5-ylmethyl) thiazolidino-2,4-dione (or englitazone). In a particular aspect, the method comprises the administration of 2 to 12 mg of the 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 the compound (I) per day. Particularly, the method comprises the administration of 2 to 4 mg of the compound (I), especially when administered per day. Particularly, the method comprises the administration of 4 to 8 mg, such as greater than 4, for example, 4.1 to 8 mg of the compound (I), especially when administered per day. Particularly, the method comprises the administration of 8 to 12 mg of the compound (I), especially when administered per day. Preferably, the method comprises administration of 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 administration of 8 mg of compound (I), especially when administered per day. It will be understood that the insulin sensitizer, such as compound (I), is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate. Suitable pharmaceutically acceptable salt forms of insulin sensitizers, such as compound (I), include those described in the patents and patent applications mentioned above, such as in EP 0306228 and WO94 / 05659 for the compound (- A preferred pharmaceutically acceptable salt of compound (I) is a maleate Suitable pharmaceutically acceptable solvate forms of insulin sensitizers, such as compound (I), include those described in the patents and patent applications mentioned above, such as in documents EP 0306228 and WO94 / 05659 of the compound (I), in particular hydrates.

Insulin sensitizers, such as compound (I) or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, can be prepared using known methods, for example, those described in the aforementioned patents and patent applications. , such as EP 0306228 and WO94 / 05659 for compound (I). The descriptions of the patents and patent applications mentioned above, such as EP 0306228 and WO94 / 05659, are incorporated herein by reference. The thiazolidinedione insulin sensitizers, such as compound (I), can exist in one of several tautomeric forms, all of which are encompassed herein as individual tautomeric forms or as mixtures thereof. Some of the insulin sensitizers, such as compound (I), contain one or more chiral carbon atoms, and therefore may exist in two or more stereoisomeric forms: All these forms are encompassed herein as either individual isomers or as mixtures of isomers, including racemates. As used herein, the term "pharmaceutically acceptable" encompasses both human and veterinary use: for example, the term "pharmaceutically acceptable" encompasses a compound acceptable from the veterinary point of view. As used herein, the oral glucose tolerance test is that cited in Diabetes Care vol. 20 (7), 1997, 1183-1197.

As used herein, "elevated normal" hyperglycemia should be considered as generally understood in the art, with regard, for example, to the report of the Expert Committee of the Diagnosis and Classification of Diabetes Mellitus, but is usually considered to mean glycemia where the plasma glucose levels are > 110 mg / dl. In the method of the invention, the active medicaments are preferably administered in the form of a pharmaceutical composition. As indicated above, said compositions may include both or only one of them. Said compositions can be prepared by mixing an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg thereof, and a pharmaceutically acceptable carrier thereof. Usually, the compositions are adapted for oral administration. However, they can be adapted for other modes of administration, for example, parenteral, sublingual or transdermal administration. The compositions may be in the form of tablets, capsules, powders, granules, ointments, suppositories, reconstitutable powders, or liquid preparations such as sterile or oral parenteral suspensions or solutions. To obtain administration consistency, it is preferred that a composition of the invention be in the form of a unit dose. The unit dosage 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, corn starch, calcium phosphate, sorbitol or glycine; lubricants for obtaining tablets, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate. The compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage. Suitable dosages for insulin sensitizers include those described in the patents and patent applications mentioned above. Adequate dosages, including unit dosages of the compound (I) comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of the compound (I). In the treatment involving compounds other than compound (I), the dosages and formulations required are generally as described in the aforementioned patent publications which, as already mentioned above, are incorporated herein by reference: An example includes the administration of 200-800 mg of troglitazone, for example, 200, 300 or 400 mg. In the treatment, the medicaments can be administered from 1 to 6 times per day, but more preferably 1 or 2 times per day. The solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. Repeated mixing operations can be used to distribute the active agent in all those compositions that use large amounts of fillers. Said operations are in fact conventional in the art. The tablets can be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Said liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate 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 glycerin esters, propylene glycol 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, fluid unit dosage forms are prepared using the compound and a sterile vehicle and, depending on the concentration used, can be suspended or dissolved in the vehicle. In the preparation of solutions, the compound can be dissolved in water for injection and can be sterilized by filtration before filling in an ampoule or suitable container, and sealing. Advantageously, adjuvants such as a local anesthetic, a preservative and pH regulating agents can be dissolved in the vehicle. To improve stability, the composition can be frozen before filling in a container, and the water can be removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound (I) is suspended in the vehicle instead of being dissolved, and sterilization can not be achieved by filtration. The compound can be sterilized by exposing it to ethylene oxide before suspending it in the sterile vehicle. Advantageously, a surfactant or wetting agent is included 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 material, depending on the method of administration. If desired, the composition may be in the form of a package accompanied by written or printed instructions for use. The compositions are prepared and formulated according to conventional methods, such as those described in standard reference texts, for example The British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale, The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books). Accordingly, the invention provides the use of an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg thereof, for the manufacture of a medicament for the treatment of hypergiukaemia, especially fasting hypergiukaemia. , wherein the plasma glucose levels are in the range of normal high to < 126 mg / dl. The invention also provides the use of an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg thereof, for the manufacture of a medicament for improving glycemic control under conditions characterized by hypergiukaemia, especially hyperglycemia in fasting, the improvement being provided where the plasma glucose levels are in the normal high scale at < 126 mg / dl, thereby delaying or preventing further elevation of hypergiukaemia. In a further aspect, the invention provides the use of an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg thereof, for the manufacture of a medicament for the prophylaxis of hypergiukaemia, especially hypergiukaemia fasting, where the plasma glucose levels are > 126 mg / dl. In particular, the present invention provides a pharmaceutical composition comprising an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg thereof, and a pharmaceutically acceptable carrier thereof, for use in the treatment of hypergiukaemia, especially fasting hypergiukaemia, where plasma glucose levels are in the range of normal high to < 126 mg / dl, or for the improvement of glycemic control in conditions characterized by fasting hypergiukaemia, the improvement being provided on the hypergiukaemia scale, where the plasma glucose levels are in the normal high scale at < 126 mg / dl, thereby delaying or preventing the further elevation of hypergiukaemia, or for prophylaxis thereof, especially fasting hypergiukaemia, where plasma glucose levels are > 126 mg / dl. No adverse toxicological effects are expected for the compositions or methods of the invention in the dosage scales mentioned above.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a non-toxic and pharmaceutically acceptable effective amount of an insulin sensitizer, in the manufacture of a medicament for the treatment of hypergiukaemia in a mammal, wherein the plasma glucose levels are in the range of normal elevated to < 126 mg / dl.

2. The use as claimed in claim 1, wherein the hyperglycemia is hyperglycemia fasting.

3. The use as claimed in claim 2, wherein the hyperglycemia is characterized by fasting plasma glucose levels in the scale of normal high at < 126 mg / dL, and is further characterized by hyperglycemia following an oral glucose tolerance test wherein the plasma glucose levels are < 140 mg / dl.

4. The use as claimed in claim 2, wherein the hyperglycemia is characterized by fasting plasma glucose levels in the scale of normal high at < 126 mg / dl, and is further characterized by hyperglycemia following an oral glucose tolerance test in which the plasma glucose levels are in the range of 140 to < 200 mg / dl.

5. The use as claimed in any of claims 1 to 4, wherein the insulin sensitizer is insulin sensitizer of thiazolidinedione.

6. The use as claimed in any of claims 1 to 5, wherein the insulin sensitizer is the compound (I).

7. The use as claimed in claim 6, wherein 2 to 12 mg of the compound (I) are administered per day.

8. The use as claimed in any of claims 1 to 4, wherein 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-thiazolidinedione (or troglitazone), 5- [4 - [( 1-methylcyclohexyl) methoxy] benzyl] thiazolidino-2,4-dione (or ciglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidino-2,4- dione (or pioglitazone) or 5 - [(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidino-2,4-dione (or englitazone); or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

9. The use as claimed in any of claims 1 to 8, wherein the insulin sensitizer is in the form of compositions adapted for oral administration.

10. The use as claimed in claim 9, wherein the composition is in unit dosage form.

11. A pharmaceutical composition comprising an insulin sensitizer and a pharmaceutically acceptable carrier, for use in the treatment of hypergiukaemia, wherein the glucose levels in plasma are in the normal range elevated to 126 mg / dl.