EP2809316A1 - Synergisctic combination comprising a meglitinide derivative and lipoic acid - Google Patents
Synergisctic combination comprising a meglitinide derivative and lipoic acidInfo
- Publication number
- EP2809316A1 EP2809316A1 EP13715475.3A EP13715475A EP2809316A1 EP 2809316 A1 EP2809316 A1 EP 2809316A1 EP 13715475 A EP13715475 A EP 13715475A EP 2809316 A1 EP2809316 A1 EP 2809316A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alpha
- lipoic acid
- agent
- meglitinide derivative
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 97
- 229960002663 thioctic acid Drugs 0.000 title claims abstract description 97
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 title claims abstract description 86
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 title 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims abstract description 190
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 109
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 73
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 35
- 239000013543 active substance Substances 0.000 claims description 23
- 239000002552 dosage form Substances 0.000 claims description 21
- 239000003826 tablet Substances 0.000 claims description 21
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 claims description 11
- 229960000698 nateglinide Drugs 0.000 claims description 11
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 claims description 11
- 229960002354 repaglinide Drugs 0.000 claims description 11
- -1 glidant Substances 0.000 claims description 9
- 229960003365 mitiglinide Drugs 0.000 claims description 9
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 8
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 7
- 239000008187 granular material Substances 0.000 claims description 7
- 230000001105 regulatory effect Effects 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 4
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 4
- 230000003115 biocidal effect Effects 0.000 claims description 4
- 239000007938 effervescent tablet Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000000796 flavoring agent Substances 0.000 claims description 4
- 229960004580 glibenclamide Drugs 0.000 claims description 4
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 230000002035 prolonged effect Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229960004034 sitagliptin Drugs 0.000 claims description 4
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 229940123208 Biguanide Drugs 0.000 claims description 3
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 229930003427 Vitamin E Natural products 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 235000013355 food flavoring agent Nutrition 0.000 claims description 3
- 235000003599 food sweetener Nutrition 0.000 claims description 3
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 235000001055 magnesium Nutrition 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 239000003765 sweetening agent Substances 0.000 claims description 3
- 235000019165 vitamin E Nutrition 0.000 claims description 3
- 239000011709 vitamin E Substances 0.000 claims description 3
- 229940046009 vitamin E Drugs 0.000 claims description 3
- TUAZNHHHYVBVBR-NHKADLRUSA-N (1s,3s,5s)-2-[(2s)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile;hydrochloride Chemical compound Cl.C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 TUAZNHHHYVBVBR-NHKADLRUSA-N 0.000 claims description 2
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 2
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 2
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 claims description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000005541 ACE inhibitor Substances 0.000 claims description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 2
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 claims description 2
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 claims description 2
- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 2
- 229940100389 Sulfonylurea Drugs 0.000 claims description 2
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 claims description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 claims description 2
- 229930003268 Vitamin C Natural products 0.000 claims description 2
- 229930003316 Vitamin D Natural products 0.000 claims description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 2
- 229930003448 Vitamin K Natural products 0.000 claims description 2
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 claims description 2
- 229960002632 acarbose Drugs 0.000 claims description 2
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 claims description 2
- 229960001466 acetohexamide Drugs 0.000 claims description 2
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003288 aldose reductase inhibitor Substances 0.000 claims description 2
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 claims description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 2
- 230000000202 analgesic effect Effects 0.000 claims description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 2
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- 239000003159 antacid agent Substances 0.000 claims description 2
- 230000000507 anthelmentic effect Effects 0.000 claims description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 claims description 2
- 230000001458 anti-acid effect Effects 0.000 claims description 2
- 230000003255 anti-acne Effects 0.000 claims description 2
- 230000001466 anti-adreneric effect Effects 0.000 claims description 2
- 230000003266 anti-allergic effect Effects 0.000 claims description 2
- 230000000567 anti-anemic effect Effects 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 230000001078 anti-cholinergic effect Effects 0.000 claims description 2
- 230000001142 anti-diarrhea Effects 0.000 claims description 2
- 230000003474 anti-emetic effect Effects 0.000 claims description 2
- 230000003556 anti-epileptic effect Effects 0.000 claims description 2
- 230000001567 anti-fibrinolytic effect Effects 0.000 claims description 2
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- 230000003276 anti-hypertensive effect Effects 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 230000001857 anti-mycotic effect Effects 0.000 claims description 2
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 2
- 230000003579 anti-obesity Effects 0.000 claims description 2
- 230000000648 anti-parkinson Effects 0.000 claims description 2
- 230000002937 anti-propulsive effect Effects 0.000 claims description 2
- 230000000842 anti-protozoal effect Effects 0.000 claims description 2
- 230000001139 anti-pruritic effect Effects 0.000 claims description 2
- 230000002682 anti-psoriatic effect Effects 0.000 claims description 2
- 230000002421 anti-septic effect Effects 0.000 claims description 2
- 230000002921 anti-spasmodic effect Effects 0.000 claims description 2
- 230000002785 anti-thrombosis Effects 0.000 claims description 2
- 230000000840 anti-viral effect Effects 0.000 claims description 2
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 2
- 239000003146 anticoagulant agent Substances 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 229940125708 antidiabetic agent Drugs 0.000 claims description 2
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- 239000002543 antimycotic Substances 0.000 claims description 2
- 239000000939 antiparkinson agent Substances 0.000 claims description 2
- 239000003904 antiprotozoal agent Substances 0.000 claims description 2
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- VDTNNGKXZGSZIP-UHFFFAOYSA-N carbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 VDTNNGKXZGSZIP-UHFFFAOYSA-N 0.000 claims description 2
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- 239000003158 myorelaxant agent Substances 0.000 claims description 2
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- 150000002898 organic sulfur compounds Chemical class 0.000 claims description 2
- 239000000810 peripheral vasodilating agent Substances 0.000 claims description 2
- 229960002116 peripheral vasodilator Drugs 0.000 claims description 2
- 229960003243 phenformin Drugs 0.000 claims description 2
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 claims description 2
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 claims description 2
- 229960005095 pioglitazone Drugs 0.000 claims description 2
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- 239000011591 potassium Substances 0.000 claims description 2
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- 108090000765 processed proteins & peptides Chemical class 0.000 claims description 2
- 229950010764 rivoglitazone Drugs 0.000 claims description 2
- XMSXOLDPMGMWTH-UHFFFAOYSA-N rivoglitazone Chemical compound CN1C2=CC(OC)=CC=C2N=C1COC(C=C1)=CC=C1CC1SC(=O)NC1=O XMSXOLDPMGMWTH-UHFFFAOYSA-N 0.000 claims description 2
- 229960004586 rosiglitazone Drugs 0.000 claims description 2
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- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- XPNLOZNCOBKRNJ-UHFFFAOYSA-N ethyl prop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C=C.COC(=O)C(C)=C XPNLOZNCOBKRNJ-UHFFFAOYSA-N 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229940091249 fluoride supplement Drugs 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002160 maltose Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940091258 selenium supplement Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- 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 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.
- 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.
- meglitinide derivative agent refers to agents such as nateglinide, repaglinide, mitiglinide.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 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.
- 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.
- 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.
- 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 mg to 1000 mg.
- 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, antiinflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, big
- compositions of the present invention comprising a meglitinide derivative agent and alpha-lipoic acid
- 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, gli
- composition of the present invention can be obtained by a method comprising the steps of;
- the pharmaceutical composition or compositions obtained can be formed into any of the abovementioned dosage forms.
- 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.
- 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.
- 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.
- 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 ⁇ to 50 ⁇ , preferably in the range of 1 ⁇ to 30 ⁇ ;
- d 10 value of alpha-lipoic acid is in the range of 0.1 ⁇ to 80 ⁇ , preferably in the range of 1 ⁇ to 50 ⁇ .
- 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.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to pharmaceutical compositions comprising a meglitinide derivative agent and alpha-lipoic acid that shall be used in the treatment of type 2 diabetes.
Description
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 mg to 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, antiinflammatory, 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 Bi; vitamin C, vitamin E, vitamin E$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 μηι to 50 μηι, preferably in the range of 1 μπι to 30 μπι; d10 value of alpha-lipoic acid is in the range of 0.1 μπι to 80 μπι, preferably in the range of 1 μπι to 50 μπι.
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.
1 1. 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 B6 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 mg 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 nateglinide is in the range of 0.1 μπι to 50 μπι and d10 value of alpha-lipoic acid is in the range of 0.1 μι ίο 80 μπι.
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 μπι and dio value of alpha-lipoic acid is in the range of 0.1 μπι ίο 80 μπι.
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 μπι to 50 μιη and dio value of alpha-lipoic acid is in the range of 0.1 μπι to 80 μπι.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201201096 | 2012-01-31 | ||
| PCT/TR2013/000049 WO2013115740A1 (en) | 2012-01-31 | 2013-01-31 | Synergisctic combination comprising a meglitinide derivative and lipoic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2809316A1 true EP2809316A1 (en) | 2014-12-10 |
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| EP13715475.3A Withdrawn EP2809316A1 (en) | 2012-01-31 | 2013-01-31 | Synergisctic combination comprising a meglitinide derivative and lipoic acid |
Country Status (2)
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| EP (1) | EP2809316A1 (en) |
| WO (2) | WO2013115739A1 (en) |
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| US20140127296A1 (en) * | 2012-11-05 | 2014-05-08 | Kenneth John Tibbs | Pharmaceutical preparation and method for treatment of diabetes |
| CN109864974A (en) * | 2017-12-01 | 2019-06-11 | 王辉 | Rosiglitazone maleate dispersible tablet and preparation method thereof |
| BR112021008602A2 (en) | 2018-11-26 | 2021-08-03 | The Procter & Gamble Company | solid pharmaceutical preparation containing lipoic acid and its use |
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| US5312924A (en) * | 1983-12-30 | 1994-05-17 | Dr. Karl Thomae Gmbh | Phenylacetic acid benzylamides |
| IE904034A1 (en) * | 1989-11-09 | 1991-05-22 | Asta Medica Ag | A medicament containing r-ó-lipoic acid or s-ó-lipoic acid¹as active substance |
| CN1234414C (en) * | 2000-03-17 | 2006-01-04 | 味之素株式会社 | Drugs for complications of diabetes and neuropathy and utilization thereof |
| CA2426764C (en) * | 2000-10-24 | 2010-04-20 | Ajinomoto Co., Inc. | Nateglinide-containing hydrophilic pharmaceutical preparation |
| US20040143015A1 (en) * | 2001-03-12 | 2004-07-22 | Villhauer Edwin Bernard | Combination of organic compounds |
| JP4505859B2 (en) * | 2003-08-08 | 2010-07-21 | 味の素株式会社 | Nateglinide-containing preparation |
| WO2005020979A1 (en) * | 2003-09-03 | 2005-03-10 | Ranbaxy Laboratories Limited | A process for the preparation of pharmaceutical compositions of nateglinide |
| WO2009085223A1 (en) * | 2007-12-20 | 2009-07-09 | Indigene Pharmaceuticals, Inc. | Combination of metformin r-(+)-lipoate and antihyperglycemic agents for the treatment of diabetic hyperglycemia and diabetic complications |
| IT1399923B1 (en) * | 2010-05-11 | 2013-05-09 | Cbb Net S A | PROCEDURE FOR THE PREPARATION OF SALTS OF THE ACID (R) ALPHA-LIPOIC THEIR FORMULATION AND USE IN PHARMACEUTICAL COMPOSITIONS IN THE FORM OF TABLETS THAT CONTAIN THEM |
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2013
- 2013-01-31 EP EP13715475.3A patent/EP2809316A1/en not_active Withdrawn
- 2013-01-31 WO PCT/TR2013/000048 patent/WO2013115739A1/en active Application Filing
- 2013-01-31 WO PCT/TR2013/000049 patent/WO2013115740A1/en active Application Filing
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| WO2013115739A1 (en) | 2013-08-08 |
| WO2013115740A1 (en) | 2013-08-08 |
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