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WO 2013/115740 Al 8 August 2013 (08.08.2013) P O P C T

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WO 2013/115740 Al 8 August 2013 (08.08.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/115740 Al 8 August 2013 (08.08.2013) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/198 (2006.01) A61K 31/445 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/385 (2006.01) A61P 3/10 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, A61K 31/4035 (2006.01) A61K 9/20 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (21) International Application Number: NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, PCT/TR20 13/000049 RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (22) International Filing Date: TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 3 1 January 2013 (3 1.01 .2013) ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 2012/01096 31 January 2012 (3 1.01.2012) TR TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventor; and MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant : BILGIC, Mahmut [TR/TR]; Yildiz Teknik TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Univ. Davutpasa Kampusu, Teknopark Alani D Blok, Es- ML, MR, NE, SN, TD, TG). enler Istanbul (TR). Published: (74) Agent: SIMSEK, Meliha Merve; Yildiz Teknik Univ. — with international search report (Art. 21(3)) Davutpasa Kampusu, Teknopark Alani D Blok, Esenler, Istanbul (TR). — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: SYNERGISCTIC COMBINATION COMPRISING A MEGLITINIDE DERIVATIVE AND LIPOIC ACID (57) Abstract: The present invention relates to pharmaceutical compositions comprising a meglitinide derivative agent and alpha-li- poic acid that shall be used in the treatment of type 2 diabetes. SYNERGISCTIC COMBINATION COMPRISING A MEGLITINIDE DERIVATIVE AND LIPOIC ACID The present invention relates to combinations of meglitinide derivative agents and alpha-lipoic acid, use of these combinations in the treatment of type 2 diabetes and pharmaceutical compositions comprising said combinations. Meglitinide derivative agents, also known as glinides, are effective on insulin secretion. Some examples of the agents belonging to this group are nateglinide, repaglinide, mitiglinide. Alpha-lipoic acid, on the other hand, is an agent with anti-oxidant effects. According to the studies conducted, it is known that alpha-lipoic acid prevents organ dysfunction and cardiovascular diseases, migraine, age-related cognitive dysfunction, progression of Alzheimer's disease; provides to heal chronic wounds and treat multiple sclerosis. It has surprisingly been found that an unexpected therapeutic benefit, particularly a synergistic therapeutic benefit, can be obtained with the combination therapy wherein meglitinide derivative agents and alpha-lipoic acid are used together in the treatment of diabetes type 2. Said therapeutic benefit comes into existence as; • reducing the dose amount necessary to obtain the required therapeutic benefit compared to the amount required in the case that only a meglitinide derivative agent or alpha-lipoic acid is used and/or • reducing undesired side effects and/or • observing the therapeutic effect sooner and/or • observing the therapeutic effect for a longer period of time and/or • providing a more efficient treatment. In another aspect, the pharmaceutical composition wherein a meglitinide derivative agent and alpha- lipoic acid are used together or simultaneously presents higher therapeutic benefit compared to the compositions in which these agents are used separately. The term "meglitinide derivative agent" refers to agents such as nateglinide, repaglinide, mitiglinide. In another aspect, use of a meglitinide derivative agent and alpha-lipoic acid in combination provides the therapeutic effect to be observed sooner and be stronger compared to use of these active agents alone. A more effective treatment is enabled for patients this way. Surprisingly, all these positive effects are present when both active agents are administered in a single dosage form at the same time or in independent dosage forms simultaneously as well as in combinations wherein both active agents are administered sequentially. High therapeutic benefit can also be observed as long-standing therapeutic effect. According to this, the present invention relates to pharmaceutical compositions comprising a meglitinide derivative agent and alpha-lipoic acid for sequential use in separate dosage forms, so as to be administered in separate dosage forms simultaneously or in the same dosage form at the same time. In another aspect, the present invention provides a method treating diabetes type 2 by administering effective amounts of a meglitinide derivative agent and alpha-lipoic acid. The meglitinide derivative agent that shall be used in the combinations of the present invention can be selected from a group comprising nateglinide, repaglinide, mitiglinide. In this aspect, the present invention relates to pharmaceutical compositions comprising pharmaceutically effective amounts of a meglitinide derivative agent and alpha-lipoic acid and at least one pharmaceutically acceptable excipient. In said pharmaceutical compositions, meglitinide derivative agent and alpha-lipoic acid can be comprised in a single formulation together with at least one excipient while meglitinide derivative agent and alpha-lipoic acid can also be formulated separately with at least one pharmaceutically acceptable excipient. The different formulations obtained separately can be combined in a single dosage form or prepared as separate dosage forms. In the case that the formulations are in separate dosage forms, said dosage forms can be the same or different. At the same time, the present invention relates to use of the combination of a meglitinide derivative active agent and alpha-lipoic acid according to the present invention for preparation of a medicament that shall be used in combination therapy so as to be administered simultaneously, sequentially or separately in the treatment of type 2 diabetes. The meglitinide derivative agent used in the pharmaceutical compositions of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers in terms of chemical structure and/or in amorphous, crystalline forms or in the form of any mixture thereof in terms of polymorphic structure or combinations thereof. Alpha-lipoic acid used in the pharmaceutical compositions of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers and/or in any of polymorphic forms such as amorph, crystal or combinations thereof. The pharmaceutical compositions of the present invention comprising a meglitinide derivative agent and alpha-lipoic acid can be prepared in any of the dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film-coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged-release tablet, modified-release tablet, delayed-release tablet, orodispersible tablet, chewing tablet. The pharmaceutical compositions comprising a meglitinide derivative agent and alpha-lipoic acid can be together in any of these dosage forms while in the case that the meglitinide derivative agent and alpha-lipoic acid are stored in separate dosage forms, said formulations can also be in the form of any of these dosage forms. In other terms, compositions comprising the combination of the present invention can be in the form of any abovementioned dosage form or in the form of a combination of these dosage forms or in the form of a treatment pack comprising this combination. In the case that the meglitinide derivative agent and alpha-lipoic acid are in the same dosage form, the pharmaceutical compositions of the present invention comprising a meglitinide derivative agent and alpha-lipoic acid are preferably in film tablet or effervescent tablet or prolonged-release tablet form. The pharmaceutical composition of the present invention comprising a meglitinide derivative agent and alpha-lipoic acid can comprise various excipients in addition to the meglitinide derivative agent and alpha-lipoic acid. The pharmaceutical compositions of the present invention comprising a meglitinide derivative agent and alpha-lipoic acid comprise at least one excipient selected from a group comprising disintegrant, diluent, lubricant glidant, binder, effervescent couple comprising at least one effervescent acid and at least one effervescent base, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent in addition to the active agents. The disintegrant that can be used in the pharmaceutical compositions of the present
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