JP2001523271A - Treatment of diabetes with thiazolidinedione and alpha-glucosidase inhibitors - Google Patents

Abstract

  (57) [Summary] A method of treating diabetes and diabetes-related symptoms in a mammal, comprising administering to the mammal in need thereof an effective, non-toxic and pharmaceutically acceptable amount of an insulin sensitizer and an alpha-glucosidase inhibitor anti-hyperglycemic agent. A method that includes:

Description

DETAILED DESCRIPTION OF THE INVENTION Treatment of Diabetes Using Thiazolidinedione and Alpha-Glucosidase Inhibitors The present invention relates to a method of treating diabetes, in particular a method of treating diabetes, particularly non-insulin dependent diabetes (NIDDM) or type II diabetes The present invention relates to a method for treating diabetes-related symptoms. Alpha glucosidase inhibitors, antihyperglycemic agents such as acarbose, emiglitate and miglitol are widely used in the treatment of NIDDM (or type II diabetes). EP 0 306 228 relates to certain thiazolidinedione derivatives disclosed as having anti-hyperglycemic and anti-hyperlipidemic activity. One particular thiazolidinedione disclosed in EP-A-0 306 228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-. Dione (hereinafter, referred to as “compound (I)”). WO 94/05659 discloses certain salts of compound (I), including the maleate salt in Example 1. Compound (I) is an example of a class of anti-hyperglycemic agents known as "insulin sensitizers". In particular, compound (I) is a thiazolidinedione insulin sensitizer. European Patent Application Publication Nos. 0008203, 0139421, 0032128, 04 28312, 048663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 05 28734, 0508740, International Patent Application Publication Nos. 92/18501, 93/02799, No. 93/22445, and U.S. Pat. Nos. 5,104,888 and 5,478,852 also disclose certain thiazolidinedione insulin sensitizers. Another series of compounds that are widely recognized as having insulin sensitizing activity are those compounds represented by the compounds disclosed in International Patent Application Publication Nos. WO 93/21166 and WO 94/01420. These compounds are referred to herein as "acyclic insulin sensitizers". Other examples of acyclic insulin sensitizers are those disclosed in U.S. Pat. No. 5,232,945 and International Patent Publication Nos. WO92 / 03425 and WO91 / 19702. Examples of other insulin sensitizers are those disclosed in EP-A-0533933, JP-A-05271204 and US Pat. No. 5,264,451. The above publications are deemed to be described herein by reference. It has now surprisingly been shown that compound (I) in combination with an alpha-glucosidase inhibitor antihyperglycemic agent exerts a particularly beneficial effect on glycemic control with minimal adverse side effects. Therefore, such combinations are particularly useful in the treatment of diabetes, especially type II diabetes and diabetes-related conditions. Accordingly, the present invention provides a method of treating diabetes, particularly type II diabetes and diabetes-related conditions, in a mammal, such as a human, comprising the use of an effective, non-toxic and pharmaceutically acceptable amount of compound (I). Administering an insulin sensitizer, such as an insulin sensitizer, and an alpha glucosidase inhibitor antihyperglycemic agent to a mammal in need of treatment. In another aspect, the present invention provides an insulin sensitizer, such as compound (I), mixed with an alpha glucosidase inhibitor antihyperglycemic agent for use in diabetes, especially type II diabetes and diabetes related conditions. . The method comprises the simultaneous administration of an insulin sensitizer such as compound (I) and an alpha-glucosidase inhibitor antihyperglycemic agent or their sequential administration. Simultaneous administration includes administration of a formulation containing both an insulin sensitizer such as Compound (I) and an alpha glucosidase inhibitor antihyperglycemic agent, or essentially simultaneous administration of separate formulations of each agent. In another aspect, the present invention relates to an insulin sensitizer such as compound (I) and an alpha glucosidase inhibitor used in the manufacture of a composition for the treatment of diabetes, especially type II diabetes and diabetes-related conditions. Provides use of hyperglycemic agents. A suitable thiazolidinedione insulin sensitizer is compound (I). Another suitable thiazolidinedione insulin sensitizer is (+)-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 suitable alpha-glucosidase inhibitor anti-hyperglycemic agent is acarbose. Other suitable alpha-glucosidase inhibitors anti-hyperglycemic agents are emiglitate and miglitol. In one particular embodiment, the method of the invention comprises, in particular, the administration of 2 to 12 mg of compound (I) per day. In particular, the method comprises the administration of 2 to 4, 4 to 8, or 8 to 12 mg of compound (I) per day. In particular, the method comprises the administration of 2 to 4 mg of compound (I) per day. In particular, the method comprises the administration of 4 to 8 mg of compound (I) per day. In particular, the method comprises the administration of 8 to 12 mg of compound (I) per day. Preferably, the method comprises the administration of 2 mg of compound (I) per day. Preferably, the method comprises administering 4 mg of compound (I) per day. Preferably, the method comprises administering 8 mg of compound (I) per day. An insulin sensitizer such as compound (I) and an alpha-glucosidase inhibitor antihyperglycemic agent are each in a pharmaceutically acceptable form (depending on the pharmacologically active ingredient, its pharmaceutically acceptable salts, esters and solvates). (Including pharmaceutically acceptable derivatives). In certain examples of the invention, the name used for the alpha glucosidase inhibitor antihyperglycemic agent may relate to the particular pharmaceutical form of the active ingredient. It will be understood that all pharmaceutically acceptable forms of the active ingredients are themselves encompassed by the present invention. Suitable pharmaceutically acceptable forms of the insulin sensitizer include those described in the above publications. Suitable pharmaceutically acceptable forms of compound (I) include those described in EP 0 306 228 and WO 94/05659, especially in the form of pharmaceutically acceptable salts. A preferred pharmaceutically acceptable salt is the maleate salt. Suitable pharmaceutically acceptable solvate forms of compound (I) include those described in EP 0 306 228 and WO 94/05659, especially hydrates. Suitable pharmaceutically acceptable forms of the alpha glucosidase inhibitor antihyperglycemic agent will depend on the particular agent used, but include the known pharmaceutically acceptable forms of the particular compound selected. Such derivatives are described in the British Pharmacopoeia, the United States Pharmacopeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (eg, pp. 341 of the 31st edition and pages cited therein). (See ref.) Or found in standard textbooks. Insulin sensitizers may be produced using known methods, for example, those disclosed in the above-mentioned publications, which are deemed to be described herein by reference. Compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof can also be prepared using a known method, for example, a method disclosed in EP 0306228 and WO 94/05659. Good. The disclosures of EP 0306228 and WO 94/05659 are deemed to be as described herein by reference. Compound (I) exists as one of several tautomers, and all tautomers, whether individual tautomers or mixtures thereof, have the term " Compound (I) ". Compound (I) contains a chiral carbon atom and therefore can exist as up to two stereoisomers, and the term “compound (I)” includes racemates, even if individual isomers Even these mixtures include all these isomers. Known methods of producing selective alpha-glucosidase inhibitor antihyperglycemic agents are described in the British Pharmacopoeia, the United States Pharmacopeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia. (See, eg, London, The Pharmaceutical Press) (see, for example, the thirty first edition at page 341 and the pages cited therein), or are mentioned in standard textbooks. As used herein, the term "diabetes-related condition" includes pre-diabetic condition-related conditions, conditions related to diabetes itself, and complications related to diabetes. As used herein, the term "pre-diabetic condition-related condition" encompasses conditions such as insulin resistance and includes hereditary insulin resistance, reduced glucose tolerance and hyperinsulinemia. "Symptoms associated with diabetes itself" include hyperglycemia, insulin resistance, and include acquired insulin resistance and obesity. Further symptoms associated with diabetes itself are hypertension, cardiovascular diseases, in particular atherosclerosis, certain eating disorders, in particular diseases requiring regulation of appetite and food intake, e.g. eating Diseases associated with deficiencies, such as anorexia nervosa, and diseases associated with overeating, such as obesity and nervous nervosa are included. Additional symptoms associated with diabetes itself include polycystic ovary syndrome and steroid-induced insulin resistance and gestational diabetes. "Diabetes-related complications" includes kidney disease, particularly kidney disease associated with type II diabetes, and includes neuropathy and retinopathy. Kidney diseases associated with type II diabetes include nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive renal sclerosis and the final stage of kidney disease. As used herein, the term "pharmaceutically acceptable" means used for both human and domestic animals, for example, the term "pharmaceutically acceptable" includes veterinarily acceptable compounds. I do. For the avoidance of doubt, scalar amounts herein include mg and% by weight of pharmaceutically acceptable forms of compound (I) and refer to compound (I) itself. For example, 2 mg of compound (I) in the maleate form is the amount of maleate containing 2 mg of compound (I). Preferably, the diabetes is type II. It is shown that a particularly beneficial effect on glycemic control provided by the treatment according to the invention is a synergistic effect on the expected control effect with respect to the sum of the effects of the individual active ingredients. Glycemic control may be characterized by conventional methods, for example, the glycemic control index typically used such as fasting plasma glucose or glycosylated hemoglobin (HbA1c). Standard methods, for example, Tuescher A, Richterich, P., Schweitz.med. W schr. Such indices are determined using the method described in 101 (1971), 345 and 390, and Frank P., 'Monitoring the Diabetic Patent with Glycosylated Hemoglobin Measurements', Clinical Products 1988. In a preferred embodiment, the dose level of each active agent used in accordance with the treatment of the invention will be lower than that required for a purely additive effect on glycemic control. The treatment of the present invention has also been shown to be improved as compared to individual drugs, including advanced glycosylated end products (AGEs), leptin and total cholesterol, HDL-cholesterol, LDL-cholesterol. Includes improved levels of serum lipids, as well as improved percentages of those levels, and in particular, improved levels of serum lipids, including total cholesterol, HDL-cholesterol, LDL-cholesterol, and their percentages. In the method of the present invention, the active drug is preferably administered in the form of a pharmaceutical composition. As noted above, such compositions include both drugs or only one drug. Accordingly, in a further aspect, the present invention provides a pharmaceutical composition comprising, in particular, 2 to 12 mg of an insulin sensitizer such as compound (I), an alpha glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. provide. In particular, such compositions may be prepared by mixing 2 to 12 mg of an insulin sensitizer such as compound (I), an alpha glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. Usually, the composition is for oral administration. However, they may be for other modes of administration, for example, parenteral, sublingual or transdermal. The administrable composition may be in the form of tablets, capsules, powders, granules, sweetened tablets, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. In order to achieve consistency of administration, the compositions of the present invention are preferably in unit dosage form. The oral unit dosage form can be a tablet or capsule, with a binder such as molasses, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; a filler, such as lactose, sugar, corn starch, calcium phosphate, Sorbitol or glycine; tableting lubricants, eg, magnesium stearate; disintegrants, eg, containing pharmaceutically acceptable wetting agents, such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or sodium lauryl sulfate. It may be. Preferably, the compositions are in unit dosage form in an amount suitable for a daily dose. Suitable unit doses of Compound (I) include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg. In treatment, the medicament may be administered one to six times daily, but most preferably once or twice daily. Particular doses of compound (I) are 2 mg / day, 4 mg / day (including 2 mg twice daily), and 8 mg / day (including 4 mg twice daily). Appropriate unit doses of alpha glucosidase inhibitors and antihyperglycemic agents, such as insulin sensitizers or metformin, include those in the United Kingdom Pharmacopeia, United States Pharmacopeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London). , The Pharmaceutical Press) (see, for example, the 31st edition, page 341 and the pages cited therein), including unit doses of these compounds described or mentioned in standard textbooks or in the above publications. Dose. Thus, a typical daily dose of acarbose will be in the range 50 to 600 mg, for example in the range 100 mg to 200 mg. Solid oral compositions may be prepared by conventional methods, such as mixing, filling or tableting. The active ingredient may be dispersed throughout the composition using a repetitive mixing operation using a large amount of filler. Of course, such operations are conventional in the art. Tablets may be coated with methods well known in normal pharmaceutical practice, especially with enteric coatings. Oral liquid preparations may be in the form of emulsions, syrups or elixirs, or they may be in the form of a dry product for constitution with water or a suitable carrier before use. Such liquid preparations may contain suspending agents, for example, sorbitol, molasses, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible oil; emulsifiers, for example, lecithin, sorbitan monooleate, or Gum arabic; non-aqueous carriers, which may include edible oils such as oily esters such as almond oil, fractionated coconut oil, glycerin, propylene glycol or the esters of ethyl alcohol; preservatives such as methyl p-hydroxybenzoate or Propyl or sorbic acid; and, if desired, conventional flavors or colorings. For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile carrier. The compound can be suspended or dissolved depending on the concentration used. 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, a local anaesthetic, preservative and buffering agents can be dissolved in the carrier. To improve stability, the composition can be filled into vials and then frozen to remove water under reduced pressure. Compound (I) is suspended in the carrier instead of being dissolved, and a non-daily suspension is prepared in substantially the same manner except that sterilization is not performed by filtration. The compound can be sterilized by exposure to ethylene oxide and then suspended in a sterile carrier. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. Depending on the method of administration, the compositions of the present invention may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active ingredient, unless otherwise specified. If desired, the composition may be in the form of a pack with written or printed instructions for use. Standard literature, such as the British Pharmacopoeia and the United States Pharmacopeia, Remington's Pharmaceutical Sciences (Mark Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (e.g., p. 341 of the 31st edition and cited therein. The compositions of the present invention may be prepared and formulated according to conventional methods, such as those disclosed in Harry's Cosmeticology (Leonard Hill Books). In a further aspect, the invention comprises an insulin sensitizer, such as 2 to 12 mg of compound (I), an alpha glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier, in particular, and is used as an active therapeutic substance. A pharmaceutical composition is provided. In particular, the present invention relates to an insulin sensitizer, such as 2 to 12 mg of compound (I), an alpha glucosidase inhibitor, an antihyperglycemic agent, especially for use in the treatment of diabetes, especially type II diabetes, and diabetes-related conditions. A pharmaceutical composition comprising an agent and a pharmaceutically acceptable carrier is provided. The range of 2 to 4 mg is defined as 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, A range of 2.8-4, 2.9-4 or 3-4 mg is included. The range of 4 to 8 mg is defined as 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, 4.8-8, 4.9-8, 5-8, 6-8 or 7-8 mg. The range of 8 to 12 mg is defined as 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 12 mg. No adverse toxicological effects were observed for the compositions or methods of the present invention in the above dosage ranges. The following examples illustrate the invention but do not limit it in any way. EXAMPLES This study investigated whether acarbose (A) administered alone or in combination alters the pharmacokinetics of co-administered compound (I). Sixteen male volunteers, aged 24 to 59 years, were dosed once with compound (I) (8 mg) on day 1 and then repeatedly with A for 7 days (100 mg three times daily with meals). Compound (I) was administered once together with A on the morning of the eighth day. Pharmacokinetic characteristics were compared after administration of compound (I) on days 1 and 8. Co-administration of compound (I) with A was well tolerated. Pharmacokinetic data and point assessment [95% confidence interval] for Compound (I) + A and Compound (I) alone were analyzed. ^* Data are median (range) Absorption (Cmax and Tmax) of compound (I) was not affected by co-administration with A, but exposure to compound (I) during compound (I) + A co-administration period (AUC [0-inf]) was reduced by an average of 12% (PE 0.88 [0.79, 0.98]) and T1 / 2 was reduced by 1 hour. Thus, acarbose slightly promoted the clearance of compound (I), but the changes were small and not clinically significant. In conclusion, Compound (I) can be co-administered with Acarbose and the pharmacokinetics of Compound (I) and / or its potential clinical benefit are not adversely affected. Composition A of compound (I) Concentrated preparation Approximately two thirds of lactose monohydrate is screened appropriately and mixed with the ground maleate of compound (I). The sodium starch glycolate, hydroxypropyl methylcellulose, microcrystalline cellulose and the remaining lactose are sifted through a suitable sieve and added to the above mixture. Thereafter, mixing is continued. The resulting mixture is then wet granulated with purified water. The wet granules are then sieved and dried on a fluid bed dryer, the dried granules are sieved further and finally homogenized. Ingredient% value of granular concentrate * Removed during processing B: Formulation of concentrate into tablets Put the granules obtained in Example 1 in a tumble blender. Sift about 2/3 lactose and add to blender. Microcrystalline cellulose, sodium starch glycolate, magnesium stearate and the remaining lactose are sieved, added to the blender and the mixture is mixed. The resulting mixture is then compressed on a rotary tablet press, weighing 150 mg for 1, 2 and 4 mg tablets and 300 mg for 8 mg tablets. The tablet cores are then transferred to a tablet coating machine, pre-warmed with warm air (about 65 ° C.), and then film coated until the tablet weight increases by 2.0-3.5%.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/702 A61K 31/702 31/7036 31/7036 A61P 3/10 A61P 3/10 // (A61K 31 / 4439 (A61K 31/4439 31: 7036) 31: 7036) (A61K 31/4439 (A61K 31/4439 31: 702) 31: 702) (A61K 31/4439 (A61K 31/4439 31: 7008) 31: 7008 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG , MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW

Claims (1)

[Claims]   1. A method of treating diabetes and diabetes-related symptoms in a mammal, comprising the steps of: , Non-toxic and pharmaceutically acceptable amounts of insulin sensitizer and alpha-glucosida A method comprising administering an anti-hyperglycemic agent to a mammal in need of treatment.   2. Acarbose, emiglitate, alpha glucosidase inhibitors 2. The method according to claim 1, wherein the compound is mitol or miglitol.   3. 2. The alpha-glucosidase inhibitor antihyperglycemic agent is acarbose. The described method.   4. If the insulin sensitizer is 5- [4- [2- (N-methyl-N- (2-pyridi L) amino) ethoxy] benzyl] thiazolidine-2,4-dione (compound I) The method according to any one of claims 1 to 3, wherein   5. The method according to claim 1, comprising administering 5.2 to 12 mg of the compound (I). The method according to any of the above.   6. Administration of 2 to 4, 4 to 8, or 8 to 12 mg of compound (I) The method according to any one of claims 1 to 5, comprising:   7. The method according to claim 1, which comprises administering 7.2 to 4 mg of the compound (I). The method described in.   7. The method according to claim 1, which comprises administering 8.4 to 8 mg of the compound (I). The method described in.   7. The method according to claim 1, comprising administering 9.8 to 12 mg of the compound (I). The method described in Crab.   7. The method according to claim 1, which comprises administering 10.2 mg of the compound (I). the method of.   7. The method according to claim 1, which comprises administering 11.4 mg of the compound (I). the method of.   7. The method according to claim 1, which comprises administering 12.8 mg of the compound (I). the method of.   13. When the insulin sensitizer is (+)-5-[[4-[(3,4-dihydro-6) -Hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-i L) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or Glitazone), 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-dihydride (Lobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or eng Ritazone) or a pharmaceutically acceptable form thereof. .   14． Insulin sensitizer, alpha-glucosidase inhibitor anti-hyperglycemic agent and A pharmaceutical composition comprising a pharmaceutically acceptable carrier.   15. Acarbose, Emiglite, Alpha Glucosidase Inhibitor The composition according to claim 14, which is a salt or miglitol.   16. The claim wherein the alpha-glucosidase inhibitor antihyperglycemic agent is acarbose. A composition according to claim 14 or claim 15.   17． 17. The method according to claim 14, wherein the insulin sensitizer is the compound (I). A composition according to any of the preceding claims.   18. Any of claims 14 to 17 comprising 18.2 to 12 mg of compound (I). A composition according to any one of claims 1 to 3.   19. Insulin sensitizer, alpha-glucosidase inhibitor anti-hyperglycemic agent and A pharmaceutical composition comprising a pharmaceutically acceptable carrier and used as an active therapeutic substance.   20. Insulin sensitizer, alpha-glucosidase inhibitor anti-hyperglycemic agent and Contains a pharmaceutically acceptable carrier, used for the treatment of diabetes and diabetes-related symptoms Pharmaceutical composition.   21. When the insulin sensitizer is (+)-5-[[4-[(3,4-dihydro-6) -Hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-i L) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or Glitazone), 5- [4-[(1-methylcyclohexyl) methoxy] benzyl ] Cheer Zolidine-2,4-dione (or ciglitazone), 5- [4- [2- (5-E Tylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (Or pioglitazone), or 5-[(2-benzyl-2,3-dihydroben) Zopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englitazo Or a pharmaceutically acceptable form thereof. A composition according to any one of the preceding claims.