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(12) United States Patent (10) Patent N0.: US 7,888,382 B2 Kiyono Et A] US007888382B2 (12) United States Patent (10) Patent N0.: US 7,888,382 B2 Kiyono et a]. (45) Date of Patent: Feb. 15, 2011 (54) COMBINED PHARMACEUTICAL 2005/0197376 A1* 9/2005 Kayakiri et al. ........... .. 514/394 PREPARATION FOR TREATMENT OF TYPE 2 DIABETES FOREIGN PATENT DOCUMENTS EP 1 532 979 5/2005 (75) Inventors: Yuji Kiyono, Tokyo (JP); Yoshio JP 2001-316293 11/2001 Okubo, Tokyo (JP); Katsumi Hontani, WO 2007/033292 3/2007 Tokyo (JP); Imao Mikoshiba, Tokyo (JP); Kazuma Ojima, AZumino (JP) OTHER PUBLICATIONS International Search Report issued Jul. 5, 2006 in the International (73) Assignee: Kissei Pharmaceutical Co., Ltd., (PCT) Application of which the present application is the US. Nagano (JP) National Stage. K. Ojima et al., “Pharmacological and Clinical Pro?le of Mitiglinide ( * ) Notice: Subject to any disclaimer, the term of this Calcium Hydrate (Glufast®), A New Insulinotropic Agent With patent is extended or adjusted under 35 Rapid Onset”, Folia Pharmacol. Jpn. (Nippon Yakurigaku Zasshi), 2004, vol. 124, No. 4, pp. 245-255 (English Abstract enclosed). U.S.C. 154(b) by 102 days. K. Ojima et al., “Rapid Onset-Insulinotropic Effect of Mitiglinide Calcium Dihydrate (KAD-1229), A Novel Antipostprandial (21) Appl. No.: 11/918,654 Hyperglycemic Agent”, Jpn. Pharmacol Ther, 2004, vol. 32, No. 2, pp. 73-80. (22) PCT Filed: Apr. 18,2006 R. F. Coniffet al., “Multicenter, Placebo-Controlled Trial Comparing Acarbose (BAY g 5421) With Placebo, Tolbutamide, and (86) PCT No.: PCT/JP2006/308110 Tolbutamide-Plus-Acarbose in Non-Insulin-Dependent Diabetes Mellitus”, The American Journal of Medicine, vol. 98, pp. 443 -451, § 371 (0X1)’ May 1995. (2), (4) Date: Dec. 19, 2007 J. L. Chiasson et al., “Ef?cacy of Acarbose in the Treatment of Patients With Non-Insulin-Dependent Diabetes Mellitus: A (87) PCTPub.No.: WO2006/115115 Multicenter Controlled Clinical Trial”, Annals of Internal Medicine, vol. 121, No. 12, pp. 928-935, Dec. 5, 1994. PCT Pub. Date: Nov. 2, 2006 European Of?ceAction issued Jul. 29, 2010 in European Application No. 06 732 039.0 which is a foreign counterpart of the present (65) Prior Publication Data application. US 2009/0030063 A1 Jan. 29, 2009 * cited by examiner Primary ExamineriSreeni Padmanabhan (30) Foreign Application Priority Data Assistant ExamineriTimothy E Betton Apr. 20, 2005 (JP) ........................... .. 2005-121862 (74) Attorney, Agent, or FirmiWenderoth, Lind & Ponack, Jun. 7, 2005 (JP) ........................... .. 2005-166314 L.L.P. (51) Int. Cl. (57) ABSTRACT A01N 43/38 (2006.01) A01N 33/02 (2006.01) For controlling the condition of type 2 diabetes, a pharma ceutical including a combination of mitiglinide, a pharmaco (52) US. Cl. ..................................... .. 514/416; 514/659 logically acceptable salt thereof or a hydrate thereof and an (58) Field of Classi?cation Search ................ .. 514/416 See application ?le for complete search history. ot-glucosidase inhibitor such as voglibose or acarbose, and a therapeutic method using the pharmaceutical are provided. (56) References Cited The pharmaceutical according to the present invention has an extremely strong effect of decreasing a morning fasting blood U.S. PATENT DOCUMENTS glucose level, a postprandial blood glucose level and HbAlC 2003/0040490 A1 2/ 2003 Sugiyama et al. of a patient With type 2 diabetes, and can improve glucose 2004/0002544 A1 1/ 2004 Makino et al. spike, insulin resistance and lipid metabolism. 2005/0020654 A1* 1/ 2005 Pershadsingh et al. .... .. 514/394 2005/0037980 A1* 2/ 2005 RybcZynski et al. ........ .. 514/23 7 Claims, 11 Drawing Sheets US. Patent Feb. 15, 2011 Sheet 2 0f 11 US 7,888,382 B2 :msZNTEQ3 531524;:E; “Some 22.9;@279;E; 5352558,.5-2222525, ,2:2.A526E“52am cod N.mI omdc owdl cod! omdl 72302,25 “.35: cs US. Patent Feb. 15, 2011 Sheet 8 0f 11 US 7,888,382 B2 ammmw“52w wmmszowwmzwmaowz mmwmtmmm5i :wammmmwm” o @N: ow; my?!“8:W323 US. Patent Feb. 15, 2011 Sheet 9 0f 11 US 7,888,382 B2 wlllll; 355526.25... v3;5o25m“$5332 ovw 03 com MEENGZEE x3;:822.33235» aI.m com 02 c2 oi om; cow US. Patent Feb. 15, 2011 Sheet 11 0111 US 7,888,382 B2 133%;025522+ 33%?82538“:+ mmA525;-U525a.5228 1, Amucv i*cmumon=mo>¢uE=mmaom w?m+- 6x3238 .a.mcdvaSdvmtwin-E35::5:35:50mmon=mo>362562::new cm, mv.1 a mm- 23.0034 C.mE $83.5Q83 £25.95 US 7,888,382 B2 1 2 COMBINED PHARMACEUTICAL In addition, a combination therapy of nateglinide and an PREPARATION FOR TREATMENT OF TYPE ot-glucosidase inhibitor has been reported to reproduce a 2 DIABETES blood glucose response comparable to that of a healthy per son (RyuZo KaWamori, “NAIBUNPI TONYOBYOKA (En TECHNICAL FIELD docrinology & Diabetology)”, 12(6): 574-578, 2001). This report, hoWever, does not include a detailed comparison The present invention relates to a pharmaceutical useful for betWeen a monotherapy of nateglinide or the ot-glucosidase treatment of type 2 diabetes. More speci?cally, the present inhibitor and the combination therapy, and there is no descrip invention relates to a pharmaceutical including a combination tion regarding or suggesting the speci?c effects of combina of mitiglinide and an ot-glucosidase inhibitor. tion as described above. BACKGROUND ART DISCLOSURE OF THE INVENTION A patient With type 2 diabetes is usually treated by giving Problems to be Solved by the Invention a patient education for improving a life style such as a diet therapy or exercise therapy, medication including admini stra An object of the present invention is to provide a novel tion of an oral hypoglycemic agent or insulin, or a combina pharmaceutical including a combination of a plurality of tion thereof. pharmaceuticals for controlling a condition of type 2 diabe As an oral hypoglycemic agent, an insulin secretagogue tes, and a method for treatment of type 2 diabetes using the such as a sulfonylurea-based medicine, a sugar absorption 20 pharmaceutical. regulator such as an ot-glucosidase inhibitor, an insulin resis tance improving agent such as a thiaZolidine-based medicine Means for Solving the Problems or a biguanide-based medicine, or the like is used correspond ing to a condition of the patient. As a result of an earnest study in vieW of the above-de Recently, a rapid-acting insulin secretagogue such as 25 scribed object, the inventors found that a pharmaceutical nateglinide, repaglinide, mitiglinide calcium hydrate (prod including a combination of mitiglinide calcium hydrate and uct name: Glufast (registered trademark)) or the like, Which is an ot-glucosidase inhibitor has an extremely good therapeutic a kind of the oral hypoglycemic agent, has been proposed and effect on a patient With type 2 diabetes, in particular, signi? received attention since a signi?cant therapeutic effect cantly suppresses glucose spike occurring Within 1 hour after thereof on improvement of a course of postprandial blood 30 meal, and that the pharmaceutical is safe, and completed the glucose has been shoWn. In a patient With type 2 diabetes, an present invention. increase in early-phase of insulin secretion after sugar load ing, especially the increase Within 30 minutes after the sugar Effect of the Invention loading is knoWn to be signi?cantly smaller than that of a healthy person. That is, While a blood glucose level of a 35 A pharmaceutical according to the present invention is a healthy person gradually increases for 30 to 60 minutes after medicine for improving a course of postprandial blood glu loading of glucose and then sloWly decreases, When glucose cose of a patient With type 2 diabetes, and is an extremely safe is loaded to a patient With type 2 diabetes, a phenomenon of a pharmaceutical having an extremely strong effect of decreas precipitous increase in a blood glucose level Within 30 to 90 ing a morning fasting blood glucose level, a postprandial minutes, Which is called “glucose spike”, is observed, 40 blood glucose level and HbAlc, and alloWing improvement because of loW insulin secretion capability (Mebio, May of glucose spike, insulin resistance and lipid metabolism. 2003, Supplement “SYOKUGO KOUKETTO/IGT TO DAIKEKKANSYOUGAI (Postprandial Hyperglycemia/ BRIEF DESCRIPTION OF THE DRAWINGS IGT and Macroangiopathy)” pp. 26-37). Therefore, a prefer able drug exhibits e?icacy in an early period after meal, 45 FIG. 1 shoWs courses of changes from a start time of a especially Within 30 to 60 minutes, to make a blood glucose treatment period in HbAl C values. course similar to that of a healthy person. The rapid-acting FIG. 2 shoWs changes from the start time of the treatment insulin secretagogue, particularly mitiglinide calcium period in HbAlC at a time of a ?nal assessment. hydrate is knoWn to shoW a signi?cant effect on improvement FIG. 3 shoWs HbAlC goal achievement rates at the time of of a course of postprandial blood glucose. Mitiglinide cal 50 the ?nal assessment from the start time of the treatment cium hydrate, hoWever, is not knoWn to effectively suppress period. glucose spike, especially glucose spike occurring Within 1 FIG. 4 shoWs changes from the start time of the treatment hour after meal. period in HbAlC value at the time of the ?nal assessment, On the other hand, a combination therapy including admin Which are strati?ed With a blood insulin value (IRI) of 5 istration of a combination of various drugs has been 55 uU/mL at the start time of the treatment period. VK10 indi attempted to improve conditions of diabetes. As an example, cates Test Example 1, VKS indicates Test Example 2, V a combined pharmaceutical including a combination of an indicates Comparative Example 1, K10 indicates Compara ot-glucosidase inhibitor and a non-sulfonylurea-based insulin tive Example 2, and IRI indicates a blood insulin value.
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