(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 invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
The diluent that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
The lubricant that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
The glidant that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
The binder that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch. The acidic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic agent can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
The pH regulating agent that can be used in the pharmaceutical compositions of the present invention can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
The surfactant that can be used in the pharmaceutical compositions of the present invention can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
The stabilizing agent that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
The sweetener and/or taste regulating agent that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
The flavoring agent that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising menthol, lemon, orange, vanilla, berry, raspberry, caramel and similar flavors.
The pharmaceutical compositions of the present invention comprise a meglitinide derivative agent in the range of 0.1% to 99% by weight, preferably in the range of 1% to 98% by weight, more preferably in the range of 5% to 95% by weight, for instance in the range of 5, 10, 15, 20, 25, 30% to 35, 40, 45, 50, 55, 60, 65, 70, 80, 90% by weight.
The pharmaceutical compositions of the present invention comprise alpha-lipoic acid in the range of 0.1% to 99% by weight, preferably in the range of 1% to 98% by weight, more preferably in the range of 5% to 95% by weight, for instance in the range of 5, 10, 15, 20, 25, 30% to 35, 40, 45, 50, 55, 60, 65, 70, 80, 90% by weight.
The pharmaceutical compositions of the present invention comprise a meglitinide derivative agent in the range of 0.01 mg to 500 mg, preferably in the range of 0.1 mg to 300 mg, more preferably in the range of 0.5 mg to 250 mg. The pharmaceutical compositions of the present invention comprise alpha-lipoic acid in the range of 100 mg to 1500 mg, preferably in the range of 150 mg to 1200 mg, more preferably in the range of 200 mgto 1000 mg.
The pharmaceutical compositions of the present invention comprising a meglitinide derivative agent and alpha-lipoic acid can optionally comprise a third active agent in addition to the meglitinide derivative agent and alpha-lipoic acid. The third active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin B vitamin C, vitamin E, vitamin 6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
In the pharmaceutical compositions of the present invention comprising a meglitinide derivative agent and alpha-lipoic acid, there is optionally a third active agent in addition to these two agents, preferably an anti-diabetic agent; meglitinide, thiazolidinedione, sulfonylurea, peptide analogue, biguanide, organosulfur compound, more preferably an agent selected from a group comprising voglibose, acarbose, miglitol, nateglinide, repaglinide, rosiglitazone, pioglitazone, rivoglitazone, troglitazone, rosiglitazone maleate, pioglitazone hydrochloride, tolbutamide, acetohexamide, glibenclamide, chlorpropamide, carbutamide, glibornuride, glipizide, gliquidone, glyburide, glimepiride, gliclazide, vildagliptin, sitagliptin, saxagliptin, phenformin, metformin, metformin hydrochloride, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate, linagliptin.
The pharmaceutical composition of the present invention can be obtained by a method comprising the steps of;
• mixing the active agents meglitinide derivative agent and alpha-lipoic acid homogeneously and adding at least one of the abovementioned excipients if required or • granulating the active agents meglitinide derivative agent and alpha-lipoic acid with a granulation solution comprising at least one excipient and mixing them homogeneously with the other excipients afterwards or • granulating a mixture comprising the active agents meglitinide derivative agent, alpha-lipoic acid and at least one of the abovementioned excipients with a granulation solution and then mixing them together homogeneously with the other excipients or • mixing the active agents meglitinide derivative agent and alpha-lipoic acid with at least one of the abovementioned excipients and granulating them with the granulation solution comprising at least one excipient or • using any of the abovementioned methods separately for active agent compositions and combining the obtained formulations or storing them in different dosage forms in the case that the meglitinide derivative agent and alpha-lipoic acid are prepared in two different formulations.
The pharmaceutical composition or compositions obtained can be formed into any of the abovementioned dosage forms. In the case that the pharmaceutical composition is in tablet form, the tablets obtained can be treated with film coating agents, for instance with sugar-based coating agents, water soluble film coating agents, enteric coating agents, delayed-release coating agents or with coating compositions comprising any combination thereof.
Saccharose can be used singly or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof as the sugar based coating agent.
The water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.
The enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.
The delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, emulsion copolymer of ethyl acrylate-methyl methacrylate or combinations thereof.
The pharmaceutical composition of the present invention can be used in the prophylaxis and treatment of type 2 diabetes. Dio value of the meglitinide derivative agent (for instance; nateglinide, repaglinide, mitiglinide) in the pharmaceutical compositions of the present invention is in the range of 0.1 µη to 50 µηι, preferably in µ µ µπ µπι the range of 1 to 30 ; d 0 value of alpha-lipoic acid is in the range of 0.1 to 80 , preferably in the range of 1 µπ to 50 µ .
The examples below are given in order to explain the present invention, yet the scope of the invention cannot be limited to these examples.
EXAMPLE 1: Pharmaceutical compositions comprising nateglinide and alpha-lipoic acid combination
Nateglinide and alpha-lipoic acid are granulated. The granules obtained are dried and then mixed with the other excipients. Lubricant is added to the obtained mixture and the final mixture is compressed in tablet compression machine. The tablets are coated with release regulating agent and dried.
EXAMPLE 2 : Pharmaceutical compositions comprising repaglinide and alpha lipoic acid combination
Repaglinide and some part of the other excipients are mixed and subjected to wet-granulation process with the granulation solution. The granules are dried and mixed with the rest of the excipients and alpha-lipoic acid. The homogenous mixture obtained is mixed with the lubricant and compressed in tablet form in the tablet compression machine. EXAMPLE 3: Film tablet formulation comprising mitiglinide and alpha-lipoic acid combination
Mitiglinide and the other excipients are mixed and granulated. The obtained granules are added to alpha-lipoic acid and the lubricant. The final mixture is compressed in tablet form and coated with the coating agent and then dried. CLAIMS
1. A pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid combination as active agent. 2. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic
acid according to claim 1, characterized in that said composition comprises a meglitinide derivative agent in the range of 0.01 mg to 500 mg. 3. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-2, characterized in that said composition comprises a meglitinide derivative agent in the range of 0.1 mg to 300 mg. 4. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-3, characterized in that said composition comprises a meglitinide derivative agent in the range of 0.5 mg to 250 mg. 5. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-4, characterized in that said composition comprises alpha-lipoic acid in the range of 100 mg to 1500 mg. 6. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-5, characterized in that said composition comprises alpha-lipoic acid in the range of 150 mg to 1200 mg. 7 . The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-6, characterized in that said composition comprises alpha-lipoic acid in the range of 200 mg to 1000 mg. 8. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-7, characterized in that the meglitinide derivative agent is 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 any mixtures of these forms in terms of polymorphic structure or combinations thereof. 9. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-8, characterized in that alpha lipoic acid is 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 any mixtures of these forms in terms of polymorphic structure or combinations thereof. 10. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-9, characterized in that the meglitinide derivative agent and alpha- lipoic acid are in the same pharmaceutical formulation. 11. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-9, characterized in that the meglitinide derivative agent and alpha- lipoic acid are in different pharmaceutical formulations. 12. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-9, 11, characterized in that the different formulations comprising the meglitinide derivative agent and alpha-lipoic acid are combined in the same dosage form. 13. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-9, 11, characterized in that the different formulations comprising the meglitinide derivative agent and alpha-lipoic acid are in different dosage forms. 14. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-13, characterized in that said composition is in the form of any dosage forms of 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 or combinations thereof. 15. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claims 1-14, characterized in that said composition is in the form of film tablet, effervescent tablet or prolonged-release tablet. 16. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to any preceding claims, characterized in that said composition comprises at least one excipient in addition to the meglitinide derivative agent and alpha-lipoic acid. 17. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to claim 16, characterized in that said composition comprises at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent along with the meglitinide derivative agent and alpha-lipoic acid. 18. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to any preceding claims, characterized in that said composition comprises a meglitinide derivative agent in the range of 0.1% to 99% by weight. 19. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to any preceding claims, characterized in that said composition comprises alpha-lipoic acid in the range of 0.1% to 99% by weight. 20. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to any preceding claims, characterized in that said composition comprises at least a third active agent selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanalytic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE
inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin Bi_
vitamin C, vitamin E, vitamin B vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium in addition to the meglitinide derivative agent and alpha-lipoic acid in addition to the meglitinide derivative agent and alpha-lipoic acid. 21. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to any preceding claims, characterized in that the third active agent that shall be used in addition to the meglitinide derivative agent and alpha-lipoic acid is an anti-diabetic agent. 22. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to any preceding claims, characterized in that the third active agent that shall be used in addition to the meglitinide derivative agent and alpha-lipoic acid is selected from thiazolidinedione, sulfonylurea, peptide analogue, organosulfur compounds. 23. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to any preceding claims, characterized in that the third active agent that shall be used in addition to the meglitinide derivative agent and alpha-lipoic acid is selected from a group comprising voglibose, acarbose, miglitol, rosiglitazone, pioglitazone, rivoglitazone, troglitazone, rosiglitazone maleate, pioglitazone hydrochloride, tolbutamide, acetohexamide, glibenclamide, chlorpropamide, carbutamide, glibornuride, glipizide, gliquidone, glyburide, glimepiride, gliclazide, vildagliptin, sitagliptin, saxagliptin, phenformin, metformin, metformin hydrochloride, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate, linagliptin. 24. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid according to any preceding claims, characterized in that the meglitinide derivative agent is selected from a group comprising nateglinide, repaglinide, meglitinide. 25. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid combination according to any preceding claims, characterized in that said composition comprises nateglinide and alpha-lipoic acid combination. 26. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid combination according to claims 1-24, characterized in that said composition comprises repaglinide and alpha-lipoic acid combination. 27. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid combination according to claims 1-24, characterized in that said composition comprises mitiglinide and alpha-lipoic acid combination. 28. The pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid combination according to any preceding claims, characterized in that said composition is used in production of a medicament that shall be used in the treatment of type 2 diabetes. 29. A pharmaceutical composition comprising a meglitinide derivative agent and alpha-lipoic acid combination as active agent used sequentially, at the same time or simultaneously. 30. A pharmaceutical composition comprising the combination of a meglitinide derivative agent in the range of 0.1 mg to 300 mg and alpha-lipoic acid in the range of 200 g to 1000 mg as active agent. 31. A pharmaceutical composition comprising nateglinide and alpha-lipoic acid combination as active agent used sequentially, at the same time or simultaneously wherein dio value of µ µπ nateglinide is in the range of 0.1 to 50 and d10 value of alpha-lipoic acid is in the range of 0.1 µι ί ο 80 µ ι. 32. A pharmaceutical composition comprising repaglinide and alpha-lipoic acid combination as
active agent used sequentially, at the same time or simultaneously wherein di0 value of repaglinide is in the range of 0.1 µηι to 50 µ and dio value of alpha-lipoic acid is in the range
of 0.1 µπ ί ο 80 µπ . 33. A pharmaceutical composition comprising mitiglinide and alpha-lipoic acid combination as active agent used sequentially, at the same time or simultaneously wherein dio value of mitiglinide is in the range of 0.1 µ to 50 µ η and dio value of alpha-lipoic acid is in the range of 0.1 µ to 80 µπ . INTERNATIONAL SEARCH REPORT International application No PCT/TR2013/0OQ049
A. CLASSIFICATION O F SUBJECT MATTER INV. A61K31/198 A61K31/385 A61K31/4035 A61K31/445 A61P3/10 A61K9/20 ADD. According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K A61P
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
EPO-Internal WPI Data, BIOSIS, EMBASE
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
WO 2O09/085223 Al (INDIGENE 1-33 PHARMACEUTICALS INC [US] ; MYLARI BANAVARA L [US] ) 9 July 2009 (2009-07-09) page , l ast paragraph page 8 , paragraph 1
EP 1 283 054 Al (AJIN0M0T0 KK [ P] ) 1-19, 12 February 2003 (2003-02-12) 24-29 paragraphs [0025] , [0026] , [0031] 20-23 , c l aim 8 31-33
W0 02/072146 A2 (N0VARTIS AG [CH] ; 1-33 N0VARTIS ERFIND VERWALT GMBH [AT] ; VI LLHAUER EDWIN B) 19 September 2002 (2002-09-19) c l aims
/ -
X Further documents are listed in the continuation of Box C. See patent family annex.
* Special categories of cited documents : "T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation or other " document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to a n oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family
Date of the actual completion of the international search Date of mailing of the international search report
6 June 2013 25/06/2013
Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Biittner, U f INTERNATIONAL SEARCH REPORT International application No PCT/TR2013/0OQ049
C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
US 5 312 924 A (GRELL WOLFGANG [DE] ET AL) 1-33 17 May 1994 (1994-05-17) col umn 79 , l i nes 47-59
SONG K-H ET AL: "alpha-Li poi c aci d 1-33 prevents diabetes mel l i tus i n d i abetes-prone obese rats" , BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol . 326, no. 1 , 3 1 December 2004 (2004-12-31) , pages 197-202, XP004672568, ISSN : 0006-291X, D0I : 10. 1016/J . BBRC.2004. 10.213 page 200, col umn 1, l i ne n , l ast paragraph - col umn 2
KANDEI L M A ET AL: " Role of l ipoi c acid 1-33 on insul i n resi stance and leptin i n experimental l y d i abeti c rats" , JOURNAL OF DIABETES AND ITS COMPLICATIONS, ELSEVI ER SCI ENCE, NEW YORK, NY, US, vol . 25, no. 1, 1 January 2011 (2011-01-01) , pages 31-38, XP027554187, ISSN : 1056-8727 [retri eved on 2009-10-29] page 33, l ast paragraph - page 34, col umn 1
SINGH U ET AL: "Alpha-l i poi c aci d 1-33 suppl ementati on and d i abetes" , NUTRITION REVI EWS, ALLEN PRESS, LAWRENCE, KS, US, vol . 66, no. 11, 1 November 2008 (2008-11-01) , pages 646-657, XP002551024, ISSN : 0029-6643, D0I : 10. 1111/J . 1753-4887. 2008. 00118.X [retri eved on 2008-10-27] page 655
P0H Z X ET AL: "A Current Update on the 1-33 Use of Al pha Lipoi c Acid i n the Management of Type 2 Diabetes Mel l i tus" , ENDOCRINE, METABOLIC & IMMUNE DISORDERS - DRUG TARGETS, BENTHAM SCI ENCE PUBLISHERS LTD, BUSSUM, NL, vol . 9 , no. 4 , 1 December 2009 (2009-12-01) , pages 392-398, XP009170039 , ISSN : 1871-5303 page 395 , last paragraph INTERNATIONAL SEARCH REPORT International application No Information on patent family members PCT/TR2013/0OQ049
Patent document Publication Patent family Publication cited in search report date member(s) date
WO 2009085223 Al 09 -07 -2009 NON E
EP 1283054 Al 12 -02 -2003 AU 411680 1 A 24--09 -2001 AU 2001241 168 B2 16- 06--2005 BR 0109336 A 24-- 6 -2003 CA 2403442 Al 17 - 09 -2002 CN 14 18109 A 14--05 -2003 CN 1768735 A 10- 05 -2006 CZ 20023 12 1 A3 14--05 -2003 EP 1283054 Al 12 - 02 -2003 HK 1055674 Al 25--08--2006 HU 0300325 A2 28- 07 -2003 KR 20070 104953 A 29--10--2007 MX PA02009130 A 12 - 03 -2003 NO 20024429 A 06--11--2002 NZ 521366 A 29- 07 -2005 PL 3577 19 Al 26- 07 -2004 RU 2281764 C2 2 - 08--2006 SK 14922002 A3 01- 4 -2003 T 1305726 B 01- 02 -2009 US 2003073729 Al 17 - 04--2003 O 0168136 Al 2 - 09 -2001 ZA 200207223 A 09- 9 -2003
W0 02072 146 A2 19 -09 -2002 AU 2002254940 Al CA 2439063 Al EP 1385549 A2 US 2004 1430 15 Al US 2008261864 Al W0 02072 146 A2
US 53 12924 A 17 -05 - 1994 US RE37035 El 30-0 1-2001 US 53 12924 A 17 -05 - 1994 US 6143769 A 07- 11-2000