Europäisches Patentamt *EP001145717B1* (19) European Patent Office Office européen des brevets (11) EP 1 145 717 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: A61K 31/64, A61K 31/4545, of the grant of the patent: A61P 3/10 12.05.2004 Bulletin 2004/20 // (A61K31/64, 31:4545) (21) Application number: 01303020.0 (22) Date of filing: 30.03.2001 (54) Synergistic effect of glyburide and milrinone Synergistische Wirkung von Glyburide und Milrinone Effet synergique de glyburide et milrinone (84) Designated Contracting States: (56) References cited: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU WO-A-98/36755 MC NL PT SE TR • PARKER J C ET AL: "EFFECT OF CYCLIC AMP (30) Priority: 13.04.2000 US 196728 PHOSPHODIESTERASE INHIBITORS ON INSULIN SECRETION AND GLYCEMIA" (43) Date of publication of application: DIABETOLOGIA, BERLIN, DE, vol. 39, no. SUPPL 17.10.2001 Bulletin 2001/42 1, 1 September 1996 (1996-09-01), page A225 XP001061977 ISSN: 0012-186X (73) Proprietor: Pfizer Products Inc. • FUJIMOTO SHIMPEI ET AL: "The novel Groton, Connecticut 06340 (US) insulinotropic mechanism of pimobendan: Direct enhancement of the exocytotic process of (72) Inventors: insulin secretory granules by increased Ca2+ • Fryburg, David Albert sensitivity in beta-cells." ENDOCRINOLOGY, Groton, Connecticut 06340 (US) vol. 139, no. 3, March 1998 (1998-03), pages • Parker, Janice Catherine 1133-1140, XP001070282 ISSN: 0013-7227 Groton, Connecticut 06340 (US) • HÖHN H ET AL: "Potential Antidiabetic Agents. Pyrazolo[3,4-b]pyridines" JOURNAL OF (74) Representative: Wood, David John et al MEDICINAL CHEMISTRY, AMERICAN PFIZER LIMITED, CHEMICAL SOCIETY. WASHINGTON, US, vol. European Patents Department, 16, no. 12, 1973, pages 1340-1346, XP002097814 Ramsgate Road, ISSN: 0022-2623 Sandwich, Kent CT13 9NJ (GB) • GRILL V ET AL: "INTERACTING EFFECTS OF SULFONYL UREAS AND GLUCOSE ON CYCLIC AMP METABOLISM AND INSULIN RELEASE IN PANCREATIC ISLETS OF THE RAT" JOURNAL OF CLINICAL INVESTIGATION, vol. 61, no. 5, 1978, pages 1346-1354, XP001070381 EN ISSN: 0021-9738 Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 145 717 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 145 717 B1 Description Cross-Reference to Related Application 5 [0001] This application claims priority of U.S. provisional application number 60/196,728, filed April 13, 2000. Field of the Invention [0002] The present invention relates to the use of synergistic amounts of glyburide and milrinone for the manufacture 10 of a medicament for treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neu- ropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance. The present invention also relates to kits and pharmaceutical compo- sitions that comprise synergistic amounts of 1) glyburide; and 2) milrinone. The present invention also relates to kits and pharmaceutical compositions that comprise synergistic amounts of 1) glyburide; 2) milrinone; and 3) an additional 15 compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance. Background of the Invention 20 [0003] In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes can be improved. [0004] A group of compounds that stimulate insulin secretion and stimulate de novo synthesis of insulin are the cAMP 25 phosphodiesterase type 3 inhibitors. It is believed that cAMP phosphodiesterase type 3 inhibitors act to increase insulin secretion by increasing intracellular levels of cAMP in pancreatic β-cells in the islet of Langerhans. In contrast, sulfo- nylureas act on the K+ ATP channels of pancreatic β-cells in the islet of Langerhans. Moreover, cAMP phosphodieste- rase type 3 is known to exist in two forms: type A and type B. Type A cAMP phosphodiesterase 3 is associated with cardiac tissue and with platelets, and type B is associated with liver and adipose tissue, and β-cells in the pancreas. 30 [0005] In addition to sulfonylureas, which stimulate insulin secretion by acting on the K+ATP channels, a group of non-sulfonylureas are known to stimulate insulin secretion by acting on K+ATP channels. Examples of such non-sul- fonylurea insulin secretagogues include nateglinide and repaglinide. [0006] The present invention provides an improved method of treating non-insulin dependent diabetes mellitus, in- sulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, 35 polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance using a synergistic amount of: 1) glyburide; and 2) milrinone. [0007] The present invention also relates to kits and pharmaceutical compositions that comprise: 1) glyburide; and 2) milrinone. [0008] In addition, the present invention relates to kits and pharmaceutical compositions that comprise: 1) glyburide; 40 2) milrinone; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance. Summary of the Invention 45 [0009] The present invention provides the use of a synergistic amount of: 1) glyburide; and 2) milrinone for the manufacture of a medicament for treating non-insulin dependent diabetes mellitus, [0010] Also provided is the use of a synergistic amount of: 1) glyburide; and 2) milrinone for the manufacture of a medicament for treating insulin resistance. 50 [0011] Also provided is the use of a synergistic amount of: 1) glyburide; and 2) milrinone for the manufacture of a medicament for treating Syndrome X. [0012] Also provided is the use of a synergistic amount of: 1) glyburide: and 2) milrinone for the manufacture of a medicament for treating diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, poly- cystic ovary syndrome, or cataracts. 55 [0013] Also provided is the use of a synergistic amount of: 1) glyburide: and 2) milrinone for the manufacture of a medicament for treating hyperglycemia [0014] Also provided is the use of a synergistic amount of: 1) glyburide; and 2) milrinone for the manufacture of a medicament for treating impaired glucose tolerance. 2 EP 1 145 717 B1 [0015] Also provided are pharmaceutical compositions comprising synergistic amounts of glyburide, and milrinone. [0016] Also provided are kits for the treatment of non-insulin dependent diabetes mellitus, the kits comprising: a) a first pharmaceutical composition comprising: synergistic amounts of 1) glyburide; and 2) milrinone; further 5 b) a second pharmaceutical composition comprising a further compound useful for the treatment of non-insulin dependent diabetes mellitus; and c) a container for the first and second compositions. [0017] In a preferred embodiment of the kits, the further compound is selected from: 10 insulin and insulin analogs; GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH2; biguanides; glycogen phosphorylase inhibitors; 15 aldose reductase inhibitors; α2-antagonists; imidazolines; glitazones (thiazolidinediones); PPAR-gamma agonists; 20 fatty acid oxidation inhibitors; α-glucosidase inhibitors; β-agonists; lipid-lowering agents; antiobesity agents; 25 vanadate, vanadium complexes and peroxovanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin agonists and antagonists; or 30 antilipolytic agents. [0018] In a more preferred embodiment of the kits, the further compound is selected from LysPro insulin, GLP-1 (7-37) (insulinotropin), GLP-1 (7-36)-NH2, metformin, phenformin, buformin, midaglizole, isaglidole, deriglidole, ida- zoxan, efaroxan, fluparoxan, linogliride, ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, rosiglitazone, 35 clomoxir, etomoxir, acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945, BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, benfluorex, fenfluramine, Naglivan®, acipimox, WAG 994, Symlin™, or AC2993. [0019] In another preferred embodiment of the kits, the further compound is selected from insulin, biguanides, or thiazolidinediones. 40 [0020] Also provided are kits for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syn- drome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the kits comprising: a) a first pharmaceutical composition comprising: synergistic amounts of 1) glyburide; and 2) milrinone; 45 b) a second pharmaceutical composition comprising