WO2013077821A1 - Homogeneous biguanide composition - Google Patents
Homogeneous biguanide composition Download PDFInfo
- Publication number
- WO2013077821A1 WO2013077821A1 PCT/TR2012/000155 TR2012000155W WO2013077821A1 WO 2013077821 A1 WO2013077821 A1 WO 2013077821A1 TR 2012000155 W TR2012000155 W TR 2012000155W WO 2013077821 A1 WO2013077821 A1 WO 2013077821A1
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- WIPO (PCT)
- Prior art keywords
- metformin
- pharmaceutical composition
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- composition
- vitamin
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- 239000000203 mixture Substances 0.000 title claims description 34
- 229940123208 Biguanide Drugs 0.000 title claims description 8
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 title claims description 4
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 93
- 229960003105 metformin Drugs 0.000 claims abstract description 90
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 59
- 239000013543 active substance Substances 0.000 claims description 31
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 239000002245 particle Substances 0.000 claims description 17
- 239000003826 tablet Substances 0.000 claims description 16
- -1 glidant Substances 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 11
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 6
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 6
- 239000007938 effervescent tablet Substances 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 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 5
- 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 claims description 5
- 150000004283 biguanides Chemical class 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 5
- 239000007941 film coated tablet Substances 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 229950004994 meglitinide Drugs 0.000 claims description 5
- 230000002035 prolonged effect Effects 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 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
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 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
- 229940100389 Sulfonylurea Drugs 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 230000003115 biocidal effect Effects 0.000 claims description 4
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 claims description 4
- 239000000796 flavoring agent Substances 0.000 claims description 4
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical group Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-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
- 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
- 150000001467 thiazolidinediones Chemical class 0.000 claims description 4
- 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 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
- 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
- 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
- 229960000698 nateglinide Drugs 0.000 claims description 3
- 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 3
- 229960002354 repaglinide Drugs 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
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 239000003765 sweetening agent Substances 0.000 claims description 3
- 239000011720 vitamin B Substances 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
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-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
- 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 2
- 239000005541 ACE inhibitor Substances 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
- 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
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 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
- 229930003427 Vitamin E Natural products 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-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
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- 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 2
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- 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
- 229940091250 magnesium supplement Drugs 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
- 238000007909 melt granulation Methods 0.000 description 1
- 229940041616 menthol Drugs 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
- 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
- 201000010065 polycystic ovary syndrome Diseases 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
- 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
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 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
- 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
- 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
- 238000003860 storage Methods 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
- 229920001059 synthetic polymer Polymers 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
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
Definitions
- the present invention relates to pharmaceutical compositions comprising metformin that shall be used in the treatment of type 2 diabetes.
- Metformin (Formula 1) having the chemical name of N,N- dimethylimidodicarbonimidic diamide is a molecule belonging to the class of biguanides. Metformin was first disclosed in the application numbered US3174901. It is known that metformin is effective particularly in the treatment of type 2 diabetes of overweight and obese patients who have healthy kidney functions. In different resources, it has been disclosed that said active agent can also be used in treatment of polycystic ovary syndrome or different diseases caused by insulin resistance.
- Metformin is available in metformin hydrochloride salt form in 500 mg, 750 mg and 1000 mg film coated tablet and prolonged release tablet forms on the market.
- the physical characteristics of the formulation comprising said active agent such as flow rate, homogenization, dissolution etc. are quite important as well as the active agent itself.
- the formulation comprising the active agent has required flow rate in terms of providing content uniformity. Furthermore, in the case that a formulation having good flow characteristics is formed into tablets, the tablets can be prepared by direct compression method. In this way, a possible granulation step is prevented and production costs are reduced.
- the formulation comprising the active agent is homogeneous and remains homogeneous throughout the process are important for the quality of the end product and providing equal amount of the active agent in each dose.
- the active agent mixed with the excipients used in the process can separate from the mixture and cause an inhomogeneous composition in progressive phases of the process.
- Wet granulation and melt granulation methods can be used in order to solve this problem in production method. However, these methods require particular and expensive equipments and increase production costs significantly.
- the present invention relates to pharmaceutical compositions comprising metformin having an average particle size (d 50 ) in the range of 20 ⁇ to 250 ⁇ .
- metformin having an average particle size (dso) preferably in the range of 30 ⁇ to 200 ⁇ , more preferably in the range of 50 ⁇ to 150 ⁇ is used in the formulations of the present invention.
- average particle size refers to average particle size by volume and it is also shown with dso in short. In this sense, the term dso signifies that half of the said substance by volume has a particle size over the value stated with dso and the other half of the substance by volume has a particle size below the value stated with d 5 o.
- Metformin comprised in the pharmaceutical compositions of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof. Metformin is preferably in form of its salts, more preferably in form of its hydrochloride salt.
- D 50 value can be measured with one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
- a device which measures particle distribution by laser diffraction for instance, Malvern Mastersizer etc.
- Metformin of the present invention having a d 50 value in the range of 20 ⁇ to 250 ⁇ can be bought and used as a product which is commercially provided in this form.
- metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ can also be obtained by pulverizing a product having coarser particle size singly or with an excipient (for instance microcrystalline cellulose etc.).
- pulverization can be performed by using the methods of impact mill, jet mill, blade mill etc. Pulverization can be performed before preparation of the pharmaceutical composition comprising metformin as well as during preparation of the pharmaceutical composition of the present invention or before post- production storage of the pharmaceutical composition prepared. In the case that blade mill is used, pulverization is performed by the impact of the rotating blades in the device.
- pulverization is performed by the impact of the rotating hammers in the device.
- pulverization is performed by providing collision of the particles with each other with the help of high-pressured and high-speed airstream.
- compositions of the present invention comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ can be prepared in 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.
- compositions of the present invention comprising metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ are preferably in the form of tablet, prolonged release tablet, film coated tablet or effervescent tablet, more preferably in effervescent tablet form.
- the present invention relates to pharmaceutical compositions in effervescent tablet form comprising metformin having an average particle size (d 5 o) in the range of 20 ⁇ to 250 ⁇ .
- the pharmaceutical composition obtained can be formed into any dosage form mentioned above.
- the composition is in tablet form
- the tablets obtained can be treated with film coating agents for instance sugar based coating agents, water soluble film coating agents, enteric-coating agents, delayed release coating agents or coating compositions comprising a 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.
- 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, ethyl acrylate-methyl methacrylate copolymer emulsion or combinations thereof.
- compositions of the present invention comprising metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ can comprise various excipients in addition to the active agent metformin.
- the disintegrant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 ⁇ to 250 ⁇ 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 comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ 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 comprising metformin having a dso value in the range of 20 ⁇ to 250 ⁇ 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 comprising metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ 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 comprising metformin having a dso value in the range of 20 ⁇ to 250 ⁇ 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 comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ 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 comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ 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 comprising metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ 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 comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ 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 comprising metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ 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 flavouring agent that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
- compositions of the present invention comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ can comprise metformin in the range of 0.1 to 100% by weight, preferably in the range of 1 to 99% by weight, preferably in the range of 5 to 95% by weight and more preferably in the range of 10 to 50% by weight.
- the present invention relates to pharmaceutical compositions comprising metformin having a d 90 value in the range of 70 ⁇ to 400 ⁇ .
- the inventors have seen that the formulations have proper flow rate, the active agent and the excipients are mixed homogeneously during preparation of the pharmaceutical compositions comprising metformin having a d 90 value in the range of 70 ⁇ to 400 ⁇ and consequently, each unit dosage form prepared with said formulation comprises equal amount of the active agent.
- the present invention relates to pharmaceutical compositions comprising metformin having a d 9 o value in the range of 70 ⁇ to 400 ⁇ .
- D 90 value of metformin comprised in the pharmaceutical compositions of the present invention is in the range of 70 ⁇ to 400 ⁇ , preferably in the range of 100 ⁇ to 350 ⁇ , more preferably in the range of 150 ⁇ to 300 ⁇ .
- the present invention relates to pharmaceutical compositions comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ and a d 90 value in the range of 70 ⁇ to 400 ⁇ .
- the term 090 signifies that 90% of the said substance by volume has a particle size below the stated value and 10% of the said substance by volume has a particle size over the stated value.
- compositions of the present invention comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ can optionally comprise a second active agent in addition to metformin.
- the second 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
- compositions of the present invention comprising metformin having a dso value in the range of 20 ⁇ to 250 ⁇ can optionally comprise a second active agent in addition to metformin.
- the second active agent can be selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulfonylureas, thiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors.
- said second active agent can be selected from a group comprising the agents such as repaglinide, nateglinide belonging to the groups of meglitinides; alpha- glucosidase inhibitor acarbose; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, glibenclamide, chlorpropamide, tolbutamide belonging to the group of sulfonylureas; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to the group of thiazolidinediones; phenformin belonging to the group of biguanides or a pharmaceutically acceptable salt thereof; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxa
- the pharmaceutical composition of the present invention can be obtained by:
- the pharmaceutical composition of the present invention can be used in prevention and treatment of type 2 diabetes.
- EXAMPLE 1 Tablet formulation comprising metformin
- Metformin hydrochloride, organic base, organic acid are mixed and they are subjected to precompression and they are sieved; the granules obtained are mixed with the excipients.
- Glidant is added into the mixture obtained and mixed.
- the lubricant is added into the final mixture and the pharmaceutical composition obtained is compressed in tablet compression machine.
- Metformin hydrochloride, organic base, organic acids are mixed, the excipients and glidant are added into the mixture obtained.
- the lubricant is added into the final mixture and the pharmaceutical composition obtained is compressed in tablet compression machine.
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Abstract
The present invention relates to pharmaceutical formulations comprising metformin that shall be used in treatment of type 2 diabetes.
Description
HOMOGENEOUS BIGUANIDE COMPOSITION
The present invention relates to pharmaceutical compositions comprising metformin that shall be used in the treatment of type 2 diabetes.
Metformin (Formula 1) having the chemical name of N,N- dimethylimidodicarbonimidic diamide is a molecule belonging to the class of biguanides. Metformin was first disclosed in the application numbered US3174901. It is known that metformin is effective particularly in the treatment of type 2 diabetes of overweight and obese patients who have healthy kidney functions. In different resources, it has been disclosed that said active agent can also be used in treatment of polycystic ovary syndrome or different diseases caused by insulin resistance.
Formula 1
Metformin is available in metformin hydrochloride salt form in 500 mg, 750 mg and 1000 mg film coated tablet and prolonged release tablet forms on the market.
For efficiency of an active agent, the physical characteristics of the formulation comprising said active agent such as flow rate, homogenization, dissolution etc. are quite important as well as the active agent itself.
When said formulations are formed into a specific dosage form, it is advantageous that the formulation comprising the active agent has required flow rate in terms of providing content uniformity. Furthermore, in the case that a formulation having good flow characteristics is formed into tablets, the tablets can be prepared by direct compression method. In this way, a possible granulation step is prevented and production costs are reduced.
In addition to these, the facts that the formulation comprising the active agent is homogeneous and remains homogeneous throughout the process are important for the quality of the end product and providing equal amount of the active agent in each dose. In some cases, the active agent mixed with the excipients used in the process can separate from the mixture and cause an inhomogeneous composition in progressive phases of the process.
Wet granulation and melt granulation methods can be used in order to solve this problem in production method. However, these methods require particular and expensive equipments and increase production costs significantly.
As a result of the studies they conducted so as to improve flow rate and homogenization characteristics of the formulations comprising metformin, the inventors have found that the pharmaceutical compositions comprising metformin having an average particle size (d5o) in the range of 20 μιτι to 250 μηι have the required flow rate and the pharmaceutical compositions comprising metformin having an average particle size (dso) in the range of 20 μηι to 250 μπι have a homogeneous mixture throughout the process. In this respect, the present invention relates to pharmaceutical compositions comprising metformin having an average particle size (d50) in the range of 20 μιη to 250 μηι.
In another aspect, metformin having an average particle size (dso) preferably in the range of 30 μηι to 200 μιη, more preferably in the range of 50 μιη to 150 μηι is used in the formulations of the present invention. The term "average particle size" refers to average particle size by volume and it is also shown with dso in short. In this sense, the term dso signifies that half of the said substance by volume has a particle size over the value stated with dso and the other half of the substance by volume has a particle size below the value stated with d5o.
Metformin comprised in the pharmaceutical compositions of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof. Metformin is preferably in form of its salts, more preferably in form of its hydrochloride salt.
D50 value can be measured with one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
Metformin of the present invention having a d50 value in the range of 20 μιη to 250 μηι can be bought and used as a product which is commercially provided in this form. In addition, metformin having a d5o value in the range of 20 μηι to 250 μπι can also be obtained by pulverizing a product having coarser particle size singly or with an excipient (for instance microcrystalline cellulose etc.). At this point, pulverization can be performed by using the
methods of impact mill, jet mill, blade mill etc. Pulverization can be performed before preparation of the pharmaceutical composition comprising metformin as well as during preparation of the pharmaceutical composition of the present invention or before post- production storage of the pharmaceutical composition prepared. In the case that blade mill is used, pulverization is performed by the impact of the rotating blades in the device.
In the case that impact mill is used, pulverization is performed by the impact of the rotating hammers in the device.
In the case that jet mill is used, pulverization is performed by providing collision of the particles with each other with the help of high-pressured and high-speed airstream.
The pharmaceutical compositions of the present invention comprising metformin having a d50 value in the range of 20 μπ to 250 μιη can be prepared in 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.
The pharmaceutical compositions of the present invention comprising metformin having a d5o value in the range of 20 μιτι to 250 μπι are preferably in the form of tablet, prolonged release tablet, film coated tablet or effervescent tablet, more preferably in effervescent tablet form.
In another aspect, the present invention relates to pharmaceutical compositions in effervescent tablet form comprising metformin having an average particle size (d5o) in the range of 20 μηι to 250 μπι.
The pharmaceutical composition obtained can be formed into any dosage form mentioned above. In the case that the composition is in tablet form, the tablets obtained can be treated with film coating agents for instance sugar based coating agents, water soluble film coating agents, enteric-coating agents, delayed release coating agents or coating compositions comprising a 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, ethyl acrylate-methyl methacrylate copolymer emulsion or combinations thereof.
The pharmaceutical compositions of the present invention comprising metformin having a d5o value in the range of 20 μιη to 250 μηι can comprise various excipients in addition to the active agent metformin.
The pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 μηι to 250 μιη comprise 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 in addition to the active agent metformin.
The disintegrant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 μιη to 250 μηι 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 comprising metformin having a d50 value in the range of 20 μηι to 250 μιη 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 comprising metformin having a dso value in the range of 20 μιη to 250 μιη 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 comprising metformin having a d5o value in the range of 20 μπι to 250 μηι 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 comprising metformin having a dso value in the range of 20 μιη to 250 μπι 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 comprising metformin having a d50 value in the range of 20 μιη to 250 μπι 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 comprising metformin having a d50 value in the range of 20 μηι to 250 μιη 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 comprising metformin having a d5o value in the range of 20 μηι to 250 μιη 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 comprising metformin having a d50 value in the range of 20 μηι to 250 μπι 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 comprising metformin having a d5o value in the range of 20 μηι to 250 μπι 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 flavouring agent that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d50 value in the range of 20 μηι to 250 μηι can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
The pharmaceutical compositions of the present invention comprising metformin having a d50 value in the range of 20 μπι to 250 μπι can comprise metformin in the range of 0.1 to 100% by weight, preferably in the range of 1 to 99% by weight, preferably in the range of 5 to 95% by weight and more preferably in the range of 10 to 50% by weight.
In another aspect, the present invention relates to pharmaceutical compositions comprising metformin having a d90 value in the range of 70 μιη to 400 μιη. The inventors have seen that the formulations have proper flow rate, the active agent and the excipients are mixed homogeneously during preparation of the pharmaceutical compositions comprising metformin having a d90 value in the range of 70 μηι to 400 μηι and consequently, each unit dosage form prepared with said formulation comprises equal amount of the active agent.
According to this, the present invention relates to pharmaceutical compositions comprising metformin having a d9o value in the range of 70 μπι to 400 μιη. D90 value of metformin comprised in the pharmaceutical compositions of the present invention is in the range of 70 μηι to 400 μπι, preferably in the range of 100 μιη to 350 μιτι, more preferably in the range of 150 μιη to 300 μιη.
In another aspect, the present invention relates to pharmaceutical compositions comprising metformin having a d50 value in the range of 20 μηι to 250 μηι and a d90 value in the range of 70 μπι to 400 μιη.
The term 090 signifies that 90% of the said substance by volume has a particle size below the stated value and 10% of the said substance by volume has a particle size over the stated value.
The pharmaceutical compositions of the present invention comprising metformin having a d50 value in the range of 20 μηι to 250 μπι can optionally comprise a second active agent in addition to metformin. The second 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 Blt vitamin C, vitamin E, vitamin B6> vitamin B2j vitamin , calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
The pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 μιη to 250 μηι can optionally comprise a second active agent in addition to metformin. The second active agent can be selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulfonylureas, thiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors.
In another aspect, said second active agent can be selected from a group comprising the agents such as repaglinide, nateglinide belonging to the groups of meglitinides; alpha- glucosidase inhibitor acarbose; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, glibenclamide, chlorpropamide, tolbutamide belonging to the group of sulfonylureas; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to the group of thiazolidinediones; phenformin belonging to the group of biguanides or a pharmaceutically acceptable salt thereof; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate.
Optionally, the pharmaceutical compositions of the present invention comprising metformin having a d50 value in the range of 20 μηι to 250 μπι comprise a second active agent preferably
belonging to the group of meglitinides, more preferably nateglinide or repaglinide as a second active agent in addition to metformin.
The pharmaceutical composition of the present invention can be obtained by
• mixing the active agent metformin and, if available, the second active agent homogeneously and adding at least one of the excipients listed above if required or
• after granulating the active agent metformin and, if available, the second active agent with at least one of the excipients, mixing them homogeneously or
• mixing the active agent metformin and, if available, the second active agent with at least one of the excipients and at least one of the excipients listed above and optionally granulating them with the granulation solution comprising excipient or
• a method which is composed of using any abovementioned methods separately for the active agent compositions and combining the formulations obtained in the case that two active agents are used.
The pharmaceutical composition of the present invention can be used in prevention and treatment of type 2 diabetes.
EXAMPLE 1 : Tablet formulation comprising metformin
Metformin hydrochloride, organic base, organic acid are mixed and they are subjected to precompression and they are sieved; the granules obtained are mixed with the excipients. Glidant is added into the mixture obtained and mixed. The lubricant is added into the final
mixture and the pharmaceutical composition obtained is compressed in tablet compression machine.
EXAMPLE 2: Tablet formulation comprising metformin
Claims
1. A pharmaceutical composition comprising metformin, characterized in that average particle size (dso) of metformin is in the range of 20 μπι to 250 μπι.
2. The pharmaceutical composition comprising metformin according to claim 1, characterized in that average particle size (d5o) of metformin is in the range of 30 μιη to 200 μιη.
3. The pharmaceutical composition comprising metformin according to claims 1 and 2, characterized in that average particle size (dso) of metformin is in the range of 50 μπι
4. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition can be prepared in 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.
5. The pharmaceutical composition comprising metformin according to claim 4, wherein said formulation is in the form of effervescent tablet, prolonged release tablet, film coated tablet.
6. The pharmaceutical composition comprising metformin according to any preceding claims, wherein metformin can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof.
7. The pharmaceutical composition comprising metformin according to any preceding claims, wherein metformin is in its pharmaceutically acceptable salt form.
8. The pharmaceutical composition comprising metformin according to any preceding claims, wherein metformin is in metformin hydrochloride form.
9. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition can comprise pharmaceutically acceptable excipients along with metformin.
10. The pharmaceutical composition comprising metformin according to claim 9, wherein 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 active agent metformin.
11. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises metformin in the range of 0.1 to 100 % by weight.
12. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises metformin in the range of 1 to 99% by weight.
13. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises metformin in the range of 5 to 95% by weight.
14. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises metformin in the range of 10 to 50% by weight.
15. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises at least a second active agent 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 analogs, vitamin Bi; vitamin C, vitamin E, vitamin B6; vitamin B2j vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium in addition to metformin.
16. The pharmaceutical composition comprising metformin according to claim 15, wherein said composition comprises at least a second active agent selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulfonylureas, thiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors in addition to metformin.
17. The pharmaceutical composition comprising metformin according to claim 16, wherein said composition comprises at least a second active agent selected from a group comprising the agents repaglinide, nateglinide belonging to the group of meglitinides; alpha-glucosidase inhibitor acarbose; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, glibenclamide, tolbutamide belonging to the group of sulfonylureas; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to the group of thiazolidinediones; phenformin, belonging to the group of biguanides; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate in addition to metformin.
18. The pharmaceutical composition comprising metformin, characterized in that dgo value of metformin comprised in said composition is in the range of 70 μιη to 400 μιη.
19. The pharmaceutical composition comprising metformin according to claim 16, characterized in that d o value of metformin comprised in said composition is in the range of 100 μπι to 350 μιη.
20. The pharmaceutical composition comprising metformin according to claim 17, characterized in that dgo value of metformin comprised in said composition is in the range of 150 μπι to 300 μηι.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2011/11590 | 2011-11-23 | ||
| TR201111590 | 2011-11-23 | ||
| TR201111959 | 2011-12-02 | ||
| TR2011/11959 | 2011-12-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013077821A1 true WO2013077821A1 (en) | 2013-05-30 |
Family
ID=47297385
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2012/000155 WO2013077821A1 (en) | 2011-11-23 | 2012-09-28 | Homogeneous biguanide composition |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2013077821A1 (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3174901A (en) | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
| US20040175424A1 (en) * | 2000-11-17 | 2004-09-09 | Catherine Castan | Medicine based on anti-hyperglycaemic microcapsules with prolonged release and method for preparing same |
| US20050163842A1 (en) * | 2003-12-31 | 2005-07-28 | Garth Boehm | Rosiglitazone and metformin formulations |
| EP1559419A1 (en) * | 2004-01-23 | 2005-08-03 | Fournier Laboratories Ireland Limited | Pharmaceutical formulations comprising metformin and a fibrate, and processes for their obtention |
| EP1738754A1 (en) * | 2004-04-14 | 2007-01-03 | Takeda Pharmaceutical Company Limited | Solid pharmaceutical preparation |
| US20070020335A1 (en) * | 2005-07-07 | 2007-01-25 | Farnam Companies, Inc. | Sustained release pharmaceutical compositions for highly water soluble drugs |
| WO2008101943A1 (en) * | 2007-02-21 | 2008-08-28 | Laboratori Guidotti S.P.A. | Pharmaceutical metformin hydrochloride formulation and tablet comprising said formulation |
-
2012
- 2012-09-28 WO PCT/TR2012/000155 patent/WO2013077821A1/en active Application Filing
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3174901A (en) | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
| US20040175424A1 (en) * | 2000-11-17 | 2004-09-09 | Catherine Castan | Medicine based on anti-hyperglycaemic microcapsules with prolonged release and method for preparing same |
| US20050163842A1 (en) * | 2003-12-31 | 2005-07-28 | Garth Boehm | Rosiglitazone and metformin formulations |
| EP1559419A1 (en) * | 2004-01-23 | 2005-08-03 | Fournier Laboratories Ireland Limited | Pharmaceutical formulations comprising metformin and a fibrate, and processes for their obtention |
| EP1738754A1 (en) * | 2004-04-14 | 2007-01-03 | Takeda Pharmaceutical Company Limited | Solid pharmaceutical preparation |
| US20070020335A1 (en) * | 2005-07-07 | 2007-01-25 | Farnam Companies, Inc. | Sustained release pharmaceutical compositions for highly water soluble drugs |
| WO2008101943A1 (en) * | 2007-02-21 | 2008-08-28 | Laboratori Guidotti S.P.A. | Pharmaceutical metformin hydrochloride formulation and tablet comprising said formulation |
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