WO2023181077A1 - Composition liquide stable comprenant de l'acide obéticholique ou des sels de celui-ci - Google Patents
Composition liquide stable comprenant de l'acide obéticholique ou des sels de celui-ci Download PDFInfo
- Publication number
- WO2023181077A1 WO2023181077A1 PCT/IN2023/050284 IN2023050284W WO2023181077A1 WO 2023181077 A1 WO2023181077 A1 WO 2023181077A1 IN 2023050284 W IN2023050284 W IN 2023050284W WO 2023181077 A1 WO2023181077 A1 WO 2023181077A1
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- WO
- WIPO (PCT)
- Prior art keywords
- acid
- sodium
- agent
- oil
- group
- Prior art date
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- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 title claims abstract description 66
- 229960001601 obeticholic acid Drugs 0.000 title claims abstract description 64
- 239000007788 liquid Substances 0.000 title claims abstract description 54
- 150000003839 salts Chemical class 0.000 title claims abstract description 49
- 239000000203 mixture Substances 0.000 title claims description 52
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 47
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 27
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims abstract description 20
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 82
- 238000003756 stirring Methods 0.000 claims description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 39
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 35
- 239000003755 preservative agent Substances 0.000 claims description 35
- 239000002904 solvent Substances 0.000 claims description 35
- 230000002335 preservative effect Effects 0.000 claims description 30
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 28
- 239000000796 flavoring agent Substances 0.000 claims description 28
- 235000003599 food sweetener Nutrition 0.000 claims description 28
- 239000003765 sweetening agent Substances 0.000 claims description 28
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 22
- 235000013355 food flavoring agent Nutrition 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000006172 buffering agent Substances 0.000 claims description 18
- 235000019264 food flavour enhancer Nutrition 0.000 claims description 18
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 18
- 239000006184 cosolvent Substances 0.000 claims description 17
- 235000011187 glycerol Nutrition 0.000 claims description 16
- 229960005150 glycerol Drugs 0.000 claims description 16
- 230000000845 anti-microbial effect Effects 0.000 claims description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 15
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 15
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 13
- 239000001509 sodium citrate Substances 0.000 claims description 13
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 claims description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 12
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 12
- CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical compound CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 claims description 12
- 229960001031 glucose Drugs 0.000 claims description 12
- 239000003921 oil Substances 0.000 claims description 12
- 235000019198 oils Nutrition 0.000 claims description 12
- 239000000811 xylitol Substances 0.000 claims description 12
- 235000010447 xylitol Nutrition 0.000 claims description 12
- 229960002675 xylitol Drugs 0.000 claims description 12
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 11
- 229930006000 Sucrose Natural products 0.000 claims description 11
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 11
- 235000011087 fumaric acid Nutrition 0.000 claims description 11
- 239000001530 fumaric acid Substances 0.000 claims description 11
- 229960002598 fumaric acid Drugs 0.000 claims description 11
- 239000005720 sucrose Substances 0.000 claims description 11
- 239000011975 tartaric acid Substances 0.000 claims description 11
- 235000002906 tartaric acid Nutrition 0.000 claims description 11
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 10
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 10
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 10
- -1 invert sugar Chemical compound 0.000 claims description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 10
- 235000011083 sodium citrates Nutrition 0.000 claims description 10
- 235000010356 sorbitol Nutrition 0.000 claims description 10
- 239000000600 sorbitol Substances 0.000 claims description 10
- 229960002920 sorbitol Drugs 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 claims description 9
- 235000010449 maltitol Nutrition 0.000 claims description 9
- 239000000845 maltitol Substances 0.000 claims description 9
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol 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-WUJBLJFYSA-N 0.000 claims description 9
- 229940035436 maltitol Drugs 0.000 claims description 9
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 9
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 8
- 235000019634 flavors Nutrition 0.000 claims description 8
- 229910001220 stainless steel Inorganic materials 0.000 claims description 8
- 239000010935 stainless steel Substances 0.000 claims description 8
- 239000005711 Benzoic acid Substances 0.000 claims description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 235000010233 benzoic acid Nutrition 0.000 claims description 7
- 235000015165 citric acid Nutrition 0.000 claims description 7
- 229960004106 citric acid Drugs 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- 229960001855 mannitol Drugs 0.000 claims description 7
- 229960001367 tartaric acid Drugs 0.000 claims description 7
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 6
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 6
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 6
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 claims description 6
- SERLAGPUMNYUCK-YJOKQAJESA-N 6-O-alpha-D-glucopyranosyl-D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-YJOKQAJESA-N 0.000 claims description 6
- 244000144730 Amygdalus persica Species 0.000 claims description 6
- 244000099147 Ananas comosus Species 0.000 claims description 6
- 235000007119 Ananas comosus Nutrition 0.000 claims description 6
- 108010011485 Aspartame Proteins 0.000 claims description 6
- 241000167854 Bourreria succulenta Species 0.000 claims description 6
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 6
- 235000005979 Citrus limon Nutrition 0.000 claims description 6
- 244000131522 Citrus pyriformis Species 0.000 claims description 6
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 6
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 6
- YIKYNHJUKRTCJL-UHFFFAOYSA-N Ethyl maltol Chemical compound CCC=1OC=CC(=O)C=1O YIKYNHJUKRTCJL-UHFFFAOYSA-N 0.000 claims description 6
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 6
- 240000009088 Fragaria x ananassa Species 0.000 claims description 6
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 6
- 229930091371 Fructose Natural products 0.000 claims description 6
- 239000005715 Fructose Substances 0.000 claims description 6
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 6
- 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 6
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 claims description 6
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 6
- 241000220225 Malus Species 0.000 claims description 6
- 235000011430 Malus pumila Nutrition 0.000 claims description 6
- 235000015103 Malus silvestris Nutrition 0.000 claims description 6
- 244000246386 Mentha pulegium Species 0.000 claims description 6
- 235000016257 Mentha pulegium Nutrition 0.000 claims description 6
- 235000004357 Mentha x piperita Nutrition 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 235000006040 Prunus persica var persica Nutrition 0.000 claims description 6
- 240000007651 Rubus glaucus Species 0.000 claims description 6
- 235000011034 Rubus glaucus Nutrition 0.000 claims description 6
- 235000009122 Rubus idaeus Nutrition 0.000 claims description 6
- 244000228451 Stevia rebaudiana Species 0.000 claims description 6
- 239000004376 Sucralose Substances 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 6
- 239000000605 aspartame Substances 0.000 claims description 6
- 235000010357 aspartame Nutrition 0.000 claims description 6
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 6
- 229960003438 aspartame Drugs 0.000 claims description 6
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 6
- 235000019693 cherries Nutrition 0.000 claims description 6
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 6
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- 235000013399 edible fruits Nutrition 0.000 claims description 6
- 229940093503 ethyl maltol Drugs 0.000 claims description 6
- 229940073505 ethyl vanillin Drugs 0.000 claims description 6
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 6
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- 235000010448 lactitol Nutrition 0.000 claims description 6
- 229960003451 lactitol Drugs 0.000 claims description 6
- 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 claims description 6
- 229940043353 maltol Drugs 0.000 claims description 6
- 229940041616 menthol Drugs 0.000 claims description 6
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 6
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 claims description 6
- 229940049703 saccharin sodium dihydrate Drugs 0.000 claims description 6
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- 229910052700 potassium Inorganic materials 0.000 claims description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
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- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000000473 propyl gallate Substances 0.000 claims description 4
- 235000010388 propyl gallate Nutrition 0.000 claims description 4
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- 235000015424 sodium Nutrition 0.000 claims description 4
- 229960001790 sodium citrate Drugs 0.000 claims description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 4
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- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- AYGJDUHQRFKLBG-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;dihydrate Chemical compound O.O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 AYGJDUHQRFKLBG-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K9/08—Solutions
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising obeticholic acid or its salts, its process of preparation and method of use of said pharmaceutical composition.
- the present invention relates to a stable liquid composition for oral administration comprising obeticholic acid or its salts, its process of preparation and its indication for the treatment of adult patients with primary biliary cholangitis (PBC).
- PBC primary biliary cholangitis
- PBC Primary biliary cirrhosis
- ALP alkaline phosphatase
- Obeticholic acid is a semi- synthetic bile acid analogue which is a farnesoid X receptor (FXR) agonist.
- FXR farnesoid X receptor
- obeticholic acid is 3a, 7a-dihydroxy-6a-ethyl-5P-cholan-24-oic acid. It is a white to off-white powder. It is soluble in methanol, acetone and ethyl acetate. Its solubility in water is pH dependent. It is slightly soluble at low pH and very soluble at high pH.
- Obeticholic acid Tablet, Oral was first approved by U.S. FDA on May 27, 2016 under the brand name OCALIVA for Intercept Pharmaceuticals Inc. it is available in 5mg and lOmg strength. The product is indicated for the treatment of adult patients with primary biliary cholangitis (PBC)
- PBC primary biliary cholangitis
- U.S. Patent No. RE48,286 discloses compound Obeticholic acid generically, further U.S. Patent No. 7,138,390, U.S. Patent No. 8,058,267, U.S. Patent No. 8,377,916 also discloses compound generically and method of treating cholestatic liver disease by using compound generically.
- U.S. Patent No. 9,238,673 discloses composition comprising obeticholic acid Form 1 and a pharmaceutically acceptable carrier.
- U.S. Patent No. 10,047,117 discloses a method of treating an FXR mediated disease or condition in a subject comprising administering to the subject a pharmaceutical formulation comprising an effective amount of a substantially pure solid form of obeticholic acid, wherein the solid form of obeticholic acid comprises less than 1% of chenodeoxy cholic acid, and wherein the formulation comprises about 1 mg to about 30 mg of obeticholic acid.
- U.S. Patent No. 10,174,073 discloses a pharmaceutical composition comprising crystalline or non-crystalline obeticholic acid (OCA).
- U.S. Patent No. 10,052,337, U.S. Patent No. 10,751,349 and U.S. Patent No. 10,758,549 discloses a pharmaceutical composition and a method of treating primary biliary cholangitis (PBC) by using said composition respectively.
- PBC primary biliary cholangitis
- Obeticholic acid is a BCS Class II compound which has low solubility and soluble in the organic solvents like ethanol, methanol, acetone and ethyl acetate.
- compositions of Obeticholic acid which are tedious, expensive or technologically demanding to prepare or are unlikely to remain stable over the shelf life of the product. Still, there is a need to prepare alternate compositions of Obeticholic acid that are stable, cost effective, easy to administer and provides the desired bioavailability.
- Obeticholic acid is presently marketed only in solid dosage forms, i.e., Tablet.
- solid dosage forms are not suitable for some patients who have difficulty in swallowing solid dosage forms, e.g., pediatric patients or older patients or incapacitated patients.
- a drug administered in liquid dosage form is immediately available for absorption from gastrointestinal tract and can be absorbed faster than the same amount of the drug administered in a tablet dosage form.
- solid dosage forms may not be convenient, when chronic therapy is needed. Therefore, there exists a clear need in the art for stable oral liquid compositions of Obeticholic acid.
- the present stable liquid composition for oral administration comprising Obeticholic acid or salt thereof can be manufactured without using costly and tedious formulation manufacturing instruments.
- the present stable liquid composition for oral administration comprising Obeticholic acid or salt thereof exhibit properties such as but not limited to storage stability, ready to use composition, easy administration, minimum side effects, high therapeutic efficiency, better patient compliance, functionally reproducible and significant advancement over the available solid dosage forms of Obeticholic acid.
- the stable oral liquid compositions described herein are also provided with a pleasant mouth feel thereby further enhancing patient compliance and ease of administration.
- Another object of the present invention to provide a stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; b) Buffering agent; c) Preservative or Antimicrobial preservative; d) Flavor enhancer; e) Co-solvent; f) Sweetening agent; g) Flavouring agent; and h) Solvent.
- step (c) Stirring solution of step (b) after addition of every excipient and API until it’s become clear;
- step (e) Filling the solution of step (d) into suitable bottle or container.
- step (b) Adding buffering agent in solution of step (a) under continuous stirring, till solution becomes clear;
- step (c) Adding sweetening agent in solution of step (b) under continuous stirring, till solution becomes clear;
- step (d) Adding co-solvent in solution of step (c) under continuous stirring, till solution becomes clear;
- step (e) Adding sweetening agent in solution of step (d) under continuous stirring, till solution becomes clear;
- step (f) Adding active pharmaceutically ingredient (API) in solution of step (e) under continuous stirring, till solution becomes clear;
- step (g) Adding flavoring agent in solution of step (f) under continuous stirring, till solution becomes clear;
- step (h) Adding flavor enhancer in solution of step (g) under continuous stirring, till solution becomes clear;
- step (j) Filling the solution of step (i) into suitable bottle or container.
- the further object of the present invention to provide a method of using a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients for the treatment of adult patients with primary biliary cholangitis (PBC).
- PBC primary biliary cholangitis
- the present invention discloses a liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; and b) One or more pharmaceutically acceptable excipients.
- the present invention discloses a stable liquid pharmaceutical composition for oral administration, comprising: a) Obeticholic acid or its salts and b) One or more pharmaceutically acceptable excipients.
- the present invention provides a stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; b) Buffering agent; c) Preservative or Antimicrobial preservative; d) Flavor enhancer; e) Co-solvent; f) Sweetening agent; g) Flavoring agent; and h) Solvent.
- the present invention provides a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the buffering agent; c) 0.001-50 mg/ml of the preservative or antimicrobial preservative; d) 0.01- 600 mg/ml of the flavor enhancer; e) 1-1200 mg/ml of the co-solvent; f) 0.1-6000 mg/ml of the sweetening agent; g) 0.001-10 mg/ml of the flavoring agent; and h) q.s.to the solvent.
- the present invention relates to a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the sodium citrate; c) 0.001-50 mg/ml of the benzoic acid; d) 0.01- 600 mg/ml of the citric acid anhydrous; e) 1-1200 mg/ml of the glycerin; f) 0.1-6000 mg/ml of the sucrose; g) 0.01- 450 mg/ml of the saccharin sodium dihydrate h) 0.001-10 mg/ml of the flavoring agent; and i) q.s.to the Solvent.
- the present invention provides a process for the preparation of a stable liquid pharmaceutical composition, comprises steps of:
- step (c) Stirring solution of step (b) after addition of every excipient and API until it’s become clear;
- step (e) Filling the solution of step (d) into suitable bottle or container.
- the present invention provides a process for the preparation of a stable liquid pharmaceutical composition, comprises steps of:
- step (b) Adding buffering agent in solution of step (a) under continuous stirring, till solution becomes clear;
- step (c) Adding sweetening agent in solution of step (b) under continuous stirring, till solution becomes clear;
- step (d) Adding co-solvent in solution of step (c) under continuous stirring, till solution becomes clear;
- (e) Adding sweetening agent in solution of step (d) under continuous stirring, till solution becomes clear;
- step (f) Adding active pharmaceutically ingredient (API) i.e., Obeticholic acid or its salts in solution of step (e) under continuous stirring, till solution becomes clear;
- API active pharmaceutically ingredient
- step (g) Adding flavoring agent in solution of step (f) under continuous stirring, till solution becomes clear;
- step (h) Adding flavor enhancer in solution of step (g) under continuous stirring, till solution becomes clear;
- step (j) Filling the solution of step (i) into suitable bottle or container.
- the present invention provides a method of using a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients for the treatment of adult patients with primary biliary cholangitis (PBC).
- PBC primary biliary cholangitis
- compositions or “pharmaceutical composition” or “liquid composition” or “liquid pharmaceutical composition” or “stable liquid pharmaceutical composition” or “stable liquid composition for oral administration” as used herein synonymously include dosage forms such as a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion or the like.
- the composition of the invention is a stable liquid pharmaceutical composition for oral administration.
- composition as in pharmaceutical composition, is intended to encompass a drug product comprising Obeticholic acid or salt thereof and other inert ingredient(s) (pharmaceutically acceptable excipients).
- the present invention relates to a stable liquid pharmaceutical composition
- a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipient.
- stable refers to any composition comprising a drug having sufficient physical and chemical stability at the time of manufacturing of the composition and during shelf life.
- liquid composition includes ready-to-use liquid composition or reconstituted liquid composition.
- the ready-to-use liquid composition comprises a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion or the like.
- the reconstituted liquid compositions comprise solution and/or suspension reconstituted from dry powder comprising pellets, granules, beads or the like.
- Oleticholic acid is used in broad sense to include not only “Obeticholic acid” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, stereoisomers, diastereoisomers, metabolites, prodrugs thereof, also its various crystalline and amorphous forms or mixtures thereof.
- the Obeticholic acid is present in an amount from about 0.01 mg/ml to about 100 mg/ml, preferably in a range from about 0.1 mg/ml to about 75 mg/ml, more preferably in a range from about 0.1 mg/ml to about 50 mg/ml by total volume of composition.
- “Pharmaceutically acceptable salts” or “salt thereof’ or “its salt” as used herein includes those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art.
- Pharmaceutically acceptable salts include, but are not limited to, any of the salts or cocrystals of Obeticholic acid selected from acid salts, base salts, amino acid salts, such as but not limited to sodium, potassium, citrate, hydrochloride, hydrobromide, sulphate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate, benzoate, L-arginine salt, L-lysine salt, Tris (hydroxymethyl) aminomethane salt, or the like.
- amino acid salts such as but not limited to sodium, potassium, citrate, hydrochloride, hydrobromide, sulphate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate, benzoate, L-arginine salt, L-lysine salt, Tris (hydroxymethyl) aminomethane salt, or the like.
- treating refers to obtaining desired pharmacological and/or physiological effect.
- the effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.
- compositions are components that are added to the pharmaceutical composition other than the active ingredient.
- “Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient Obeticholic acid or its salts. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance patient acceptability etc.
- Pharmaceutically acceptable excipient(s) includes, but not limited to, solvent(s), vehicle, co-solvents, buffer or buffering agent or pH adjusting agent, preservatives or antimicrobial preservative, flavor enhancer, sweeteners or sweetening agent, flavor or flavoring agent, surface- active agents or surfactant or solubilizer, antioxidant, coloring agent, antifoaming agent, taste-masking agents, suspending agent, emulsifying agent, stabilizers, diluents, resin, anticaking agent, chelating agent, acidifying agent, viscosity modifier, one or more lipid, pharmaceutical-grade dyes/pigments and any other excipient known to the art for making pharmaceutical composition.
- solvents according to the present invention include but not limited to group comprising water, purified water, glycerin, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethylene glycol monoethyl ether, ethyl acetate, monoethyl acetate, cyclohexane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, hydrochloric acid (HC1), sodium chloride, calcium chloride, acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol and combination thereof.
- the solvent is purified water.
- the solvent according to present invention may be present in an amount to make up volume to quantity sufficient.
- co-solvent examples include but not limited to group comprising of glycerin or glycerol, maltitol, sorbitol and propylene glycol and combination thereof.
- the co-solvent is glycerin.
- the co-solvent is present in an amount of from about 1 mg/ml to about 1200 mg/ml of the composition, preferably from about 10 mg/ml to about 800 mg/ml; more preferably from about 10 mg/ml to about 600 mg/ml based on the total volume of the composition.
- buffer or buffering agents or pH adjusting agents include but not limited to a group comprising citrate buffers, phosphate buffers, monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, trisodium citrate, acetic acid, maleic acid, tartaric acid, fumaric acid, sodium phosphate, sodium gluconate, sodium lactate, sodium citrate, sodium acetate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Potassium, sodium, ammonium salt of acetic acid and combinations thereof.
- the buffering agent is sodium citrate.
- the buffering agents or pH adjusting agents are present in an amount of from about 0.01 mg/ml to about 150 mg/ml of the composition, preferably from about 0.01 mg/ml to about 125 mg/ml; more preferably from about 0.01 mg/ml to about 100 mg/ml based on the total volume of the composition.
- preservatives or antimicrobial preservative include but not limited to group comprising alcohol, benzyl alcohol, bronopol, methylparaben, propylparaben, butylparaben, boric acid and borate salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, phenol, methylhydroxybenzoate, ethyl parahydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorbutol, chlorocresol, chlorhexidine, diazolidinyl urea, sodium citrate, chlorbutanol, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g.
- preservatives and antimicrobial preservative are similar reference in the context of describing the invention.
- the preservatives or antimicrobial preservative is benzoic acid.
- the preservatives or antimicrobial preservative are present in an amount of from about 0.001 mg/ml to about 50 mg/ml of the composition, preferably from about 0.001 mg/ml to about 45 mg/ml; more preferably from about 0.001 mg/ml to about 40 mg/ml based on the total volume of the composition.
- sweeteners or sweetening agent or first sweetening agent or second sweetening agent include but not limited to a group comprising sucrose, glucose, dextrose, fructose, lactose, maltose, invert sugar, sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol, thaumatin, saccharin sodium, saccharin sodium dihydrate, aspartame, acesulfame, and sucralose, and combinations thereof.
- the sweetening agent is sucrose and saccharin sodium dihydrate.
- the sweeteners or sweetening agent are present in an amount of from about 0.1 mg/ml to about 6000 mg/ml of the composition, preferably from about 0.1 mg/ml to about 4000 mg/ml; more preferably from about 0.1 mg/ml to about 3000 mg/ml based on the total volume of the composition.
- flavor enhancer include but not limited to a group comprising citric acid anhydrous, alanine, threonine, proline, serine, sucrose, fructose, dextrose, maltose, trehalose, glucose, stevia, glycerin, lactitol, maltitol, xylitol, sorbitol and mannitol, sucralose, saccharin, acesulfame potassium, aspartame, ethyl maltol, ethyl vanillin, fumaric acid, malic acid, maltol, menthol, monosodium glutamate, sodium chloride, stevia, tartaric acid, and vanillin, cherry, orange, peppermint, strawberry, apple, pineapple, anise fruit, peach, raspberry, orange cream and combinations thereof.
- the flavor enhancer is citric acid anhydrous.
- the flavor enhancer is present in an amount of from about 0.01 mg/ml to about 600 mg/ml, preferably about 0.1 mg/ml to 100 mg/ml; more preferably about 0.5 mg/ml to 50 mg/ml based on the total volume of the composition.
- flavors or flavoring agent include but not limited to a group comprising banana, lemon, xylitol, lemon and xylitol, orange, grape, lime and grapefruit, vanilla, butterscotch, bubble gum, peppermint, fantasy fruit flavor, tutti-frutti, apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, plant leaves, flowers, fruits, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil; maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof.
- flavouring or flavoring also known as flavor (or flavour) or flavorant.
- the flavouring agent is lemon or
- the flavoring agent are present in an amount of from about 0.001 mg/ml to about 10 mg/ml of the composition, preferably about 0.001 mg/ml to about 9 mg/ml; more preferably from about 0.01 mg/ml to 8 mg/ml based on the total volume of the composition.
- stabilizers according to the present invention include but not limited to a group comprising of EDTA disodium salt, amino acids such as glutamic acid and combination thereof.
- emulsifying agent examples include but not limited to a group comprising of gun acacia, tragacanth and combination thereof.
- diluent(s) or filler include but not limited to a group comprising of Emdex/dextrates, citric acid, mannitol, sorbitol, sucrose, microcrystalline cellulose, carboxymethyl cellulose (carmellose), sodium carboxymethyl cellulose (carmellose sodium), corn starch, potato starch, anhydrous lactose, lactose monohydrate and combination thereof.
- antioxidant examples include but not limited to a group comprising of butylated hydroxyl toluene, butylated hydroxyl anisole, DL-alpha-tocopherol, propyl gallate, octylgallate, ascorbyl palmitate, acetyl cysteine, L- cysteine hydrochloride, vitamin E acetate, ascorbic acid, Monothio glycerol, sodium ascorbate, fumaric acid, lecithin, sodium metabisulfite, sodium sulfite and combination thereof.
- viscosity modifier include but not limited to a group comprising of methylcellulose, sodium carboxy methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, acacia, guar gum, xanthan gum, Tragacanth, crosscaremellose sodium, microcrystalline cellulose, ethyl cellulose, magnesium aluminum silicate and combination thereof.
- pH modifier/adjusting agent include but not limited to a group comprising of sodium hydroxide, potassium hydroxide, hydrochloric acid carbonic acid, phosphoric acid, succinic acid, tartaric acid, lactic acid, and their sodium, potassium, calcium, ammonium salts and combination thereof.
- solubilizers according to the present invention include but not limited to a group comprising of polysorbate and combination thereof.
- coloring agent according to the present invention include but not limited to a group comprising of titanium dioxide, carotene, ferric oxide, erythrosine, tetrazine and combination thereof.
- acidic agents or acidifying agents include but not limited to a group comprising of citric acid maleic acid, tartaric acid, fumaric acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha-hydroxy acids, ascorbic acid and amino acids, anhydrides, salts and derivatives of these acids and combination thereof.
- the present invention provides a liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; and b) One or more pharmaceutically acceptable excipients.
- the present invention provides a stable liquid pharmaceutical composition for oral administration, comprising: a) Obeticholic acid or its salts and b) One or more pharmaceutically acceptable excipients.
- the present invention provides a stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; b) Buffering agent; c) Preservative or Antimicrobial preservative; d) Flavor enhancer; e) Co-solvent; f) Sweetening agent; g) Flavoring agent; and h) Solvent.
- the present invention provides a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the buffering agent; c) 0.001-50 mg/ml of the preservative or antimicrobial preservative; d) 0.01- 600 mg/ml of the flavor enhancer; e) 1-1200 mg/ml of the co-solvent; f) 0.1-6000 mg/ml of the sweetening agent; g) 0.001-10 mg/ml of the flavoring agent; and h) q.s.to the solvent.
- the present invention provides a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the sodium citrate; c) 0.001-50 mg/ml of the benzoic acid; d) 0.01- 600 mg/ml of the citric acid anhydrous; e) 1-1200 mg/ml of the glycerin; f) 0.1-6000 mg/ml of the sucrose; g) 0.01- 450 mg/ml of the saccharin sodium dihydrate h) 0.001-10 mg/ml of the flavoring agent; and i) q.s.to the Solvent.
- the present invention also relates to a process of preparation of a liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipient.
- the present invention also relates to a process of preparation of a stable liquid pharmaceutical composition, comprise steps of:
- step (b) Adding and dissolving one or more pharmaceutically acceptable excipients and active pharmaceutically ingredient (API) sequentially under continuous stirring to a solvent of step (a);
- step (c) Stirring solution of step (b) after addition of every excipient and API until it’s become clear;
- step (d) Finally make up the volume with solvent; and (e) Filling the solution of step (d) into suitable bottle or container.
- the present invention also relates to a process of preparation of a stable liquid pharmaceutical composition, comprise steps of:
- step (b) Adding buffering agent in solution of step (a) under continuous stirring, till solution becomes clear;
- step (c) Adding sweetening agent in solution of step (b) under continuous stirring, till solution becomes clear;
- step (d) Adding co-solvent in solution of step (c) under continuous stirring, till solution becomes clear;
- step (e) Adding sweetening agent in solution of step (d) under continuous stirring, till solution becomes clear;
- step (f) Adding active pharmaceutically ingredient (API) i.e., Obeticholic acid or its salts in solution of step (e) under continuous stirring, till solution becomes clear;
- API active pharmaceutically ingredient
- step (g) Adding flavoring agent in solution of step (f) under continuous stirring, till solution becomes clear;
- step (h) Adding flavor enhancer in solution of step (g) under continuous stirring, till solution becomes clear;
- step (j) Filling the solution of step (i) into suitable bottle or container.
- the present invention provides a method of using a liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients for the treatment of adult patients with primary biliary cholangitis (PBC)
- PBC primary biliary cholangitis
- the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts according to present invention can be used in combination with other medicines for prophylaxis and treatment of adult patients with primary biliary cholangitis (PBC).
- the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts can be prepared into single dose or multi dose pharmaceutical composition having immediate release or modified release or controlled release or delayed release or any combination thereof.
- the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts can be packaged in a suitable pack/container such as amber-colored polyethylene terephthalate (PET) bottle, glass bottle, vials, high-density polyethylene (HDPE) bottle, low- density polyethylene (LDPE) bottle, polypropylene (PP) bottle, vial, packets, pouches, sachets and the like.
- a suitable pack/container such as amber-colored polyethylene terephthalate (PET) bottle, glass bottle, vials, high-density polyethylene (HDPE) bottle, low- density polyethylene (LDPE) bottle, polypropylene (PP) bottle, vial, packets, pouches, sachets and the like.
- dispensing and/or dosing syringe (Marked in mL)
- a measuring cup for administering the composition can be included in the package with container.
- the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts of the present invention is expected to have suitable organoleptic properties in terms of taste, after taste, odor, flavor, and acceptability.
- the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts of the present invention is exhibit desirable technical attributes such as appearance, pH, assay, specific gravity/density, relative standard (RS), viscosity, physical stability, microbiological stability, preservative efficacy test (PET) and storage stability.
- desirable technical attributes such as appearance, pH, assay, specific gravity/density, relative standard (RS), viscosity, physical stability, microbiological stability, preservative efficacy test (PET) and storage stability.
- Example No 1 and 2 Manufacturing process for Example No 1 and 2: 1. In suitable Stainless-Steel container of purified water and under stirring add accurately weighed quantity of Benzoic acid, under continuous stirring, keep stirring till solution becomes clear;
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Abstract
La présente invention concerne une composition pharmaceutique liquide stable comprenant de l'acide obéticholique ou ses sels et un ou plusieurs excipients pharmaceutiquement acceptables et son procédé de préparation et son utilisation pour le traitement de patients adultes atteints d'une cholangite biliaire primitive (CBP).
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IN202121043434 | 2022-03-24 | ||
IN202121043434 | 2022-03-24 |
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WO2023181077A1 true WO2023181077A1 (fr) | 2023-09-28 |
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PCT/IN2023/050284 WO2023181077A1 (fr) | 2022-03-24 | 2023-03-24 | Composition liquide stable comprenant de l'acide obéticholique ou des sels de celui-ci |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016046680A2 (fr) * | 2014-09-27 | 2016-03-31 | Mohan M Alapati | Compositions et procédés de traitement de maladies métaboliques hépatiques |
WO2016176208A1 (fr) * | 2015-04-27 | 2016-11-03 | Intercept Pharmaceuticals, Inc. | Compositions d'acide obéticholique et procédés d'utilisation |
WO2019106043A1 (fr) * | 2017-11-29 | 2019-06-06 | Hexal Ag | Composition pharmaceutique comprenant de l'acide obéticholique |
-
2023
- 2023-03-24 WO PCT/IN2023/050284 patent/WO2023181077A1/fr unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016046680A2 (fr) * | 2014-09-27 | 2016-03-31 | Mohan M Alapati | Compositions et procédés de traitement de maladies métaboliques hépatiques |
WO2016176208A1 (fr) * | 2015-04-27 | 2016-11-03 | Intercept Pharmaceuticals, Inc. | Compositions d'acide obéticholique et procédés d'utilisation |
WO2019106043A1 (fr) * | 2017-11-29 | 2019-06-06 | Hexal Ag | Composition pharmaceutique comprenant de l'acide obéticholique |
Non-Patent Citations (2)
Title |
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"HANDBOOK OF PHARMACEUTICAL MANUFACTURING FORMULATIONS LIQUID PRODUCTS, vol. 3", 1 January 2004, CRC PRESS, USA, article NIAZI SARFARAZ: "Table of contents", pages: 1 - 10, XP093094110 * |
R.C. ROWE ET AL., HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, 2009, USA, XP009549958, ISBN: 9781582121352 * |
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