WO2006112649A1 - Pharmaceutical composition containing sibutramine free base and manufacturing method thereof - Google Patents
Pharmaceutical composition containing sibutramine free base and manufacturing method thereof Download PDFInfo
- Publication number
- WO2006112649A1 WO2006112649A1 PCT/KR2006/001434 KR2006001434W WO2006112649A1 WO 2006112649 A1 WO2006112649 A1 WO 2006112649A1 KR 2006001434 W KR2006001434 W KR 2006001434W WO 2006112649 A1 WO2006112649 A1 WO 2006112649A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- free base
- solid dispersion
- sibutramine free
- sibutramine
- Prior art date
Links
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 title claims abstract description 113
- 229960004425 sibutramine Drugs 0.000 title claims abstract description 112
- 239000012458 free base Substances 0.000 title claims abstract description 96
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 title description 7
- 239000007962 solid dispersion Substances 0.000 claims abstract description 86
- 239000002253 acid Substances 0.000 claims abstract description 45
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims description 37
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 20
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 18
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 17
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 17
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 16
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 15
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 15
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 15
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 15
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 12
- 235000015165 citric acid Nutrition 0.000 claims description 12
- 229920001577 copolymer Polymers 0.000 claims description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims description 12
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 12
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 12
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 10
- 235000011007 phosphoric acid Nutrition 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 9
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 9
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 9
- 239000011248 coating agent Substances 0.000 claims description 7
- 238000000576 coating method Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 6
- 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 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 6
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 6
- 239000001530 fumaric acid Substances 0.000 claims description 6
- 235000011087 fumaric acid Nutrition 0.000 claims description 6
- 239000004310 lactic acid Substances 0.000 claims description 6
- 235000014655 lactic acid Nutrition 0.000 claims description 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 6
- 239000011976 maleic acid Substances 0.000 claims description 6
- 239000001630 malic acid Substances 0.000 claims description 6
- 235000011090 malic acid Nutrition 0.000 claims description 6
- 235000006408 oxalic acid Nutrition 0.000 claims description 6
- 239000011975 tartaric acid Substances 0.000 claims description 6
- 235000002906 tartaric acid Nutrition 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 abstract description 35
- 239000000203 mixture Substances 0.000 abstract description 18
- UWAOJIWUVCMBAZ-UHFFFAOYSA-N [1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-dimethylazanium;chloride Chemical compound Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UWAOJIWUVCMBAZ-UHFFFAOYSA-N 0.000 abstract description 10
- 229960003466 sibutramine hydrochloride Drugs 0.000 abstract description 7
- 238000003860 storage Methods 0.000 abstract description 5
- 238000007922 dissolution test Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000008366 buffered solution Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- KFNNPQDSPLWLCX-UHFFFAOYSA-N 1-[1-(4-chlorophenyl)cyclobutyl]-n,n,3-trimethylbutan-1-amine;hydron;chloride;hydrate Chemical compound O.Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 KFNNPQDSPLWLCX-UHFFFAOYSA-N 0.000 description 11
- 229960005303 sibutramine hydrochloride monohydrate Drugs 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 239000008187 granular material Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 8
- 229920000642 polymer Polymers 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000012738 dissolution medium Substances 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 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 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 230000030136 gastric emptying Effects 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical class CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Chemical class 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- SGXDXUYKISDCAZ-UHFFFAOYSA-N N,N-diethylglycine Chemical compound CCN(CC)CC(O)=O SGXDXUYKISDCAZ-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229920003072 Plasdone™ povidone Polymers 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 239000004208 shellac Substances 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
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate 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
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—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
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
Definitions
- the present invention relates to a composition comprising sibutramine free base and manufacturing method thereof.
- Sibutramine is a common name of N,N-dimethyl- 1 - [ 1 -(4-chlorophenyl)-cyclobutyl]
- sibutramine may be used for reducing the resistance to insulin or enhancing the resistance to sugar, and for preventing or treating such diseases as gout, hyperuricemia, hyperlipemia, osteoarthritis, anxiety disorder, somnipathy, sexual dysfunction, chronic fatigue syndrome and cholelithiasis (see U.S. Patent Nos. 6,174,925, 5,459,164, 6,187,820, 6,162,831, 6,232,347, 6,355,685, 6,365,631, 6,376,554, 6,376,551 and 6,376,552).
- the change of gastric emptying time can be also thought to be related with the solubility of sibutramine hydrochloride because the big pH difference between stomach and upper intestine causes the solubility difference of sibutramine hydrochloride, which causes the difference of absorption or bioavailability.
- the absorption variation of sibutramine free base may be bigger than sibutramine hydroc hloride because the solubility difference of sibutramine free base is much bigger than sibutramine hydrochloride evaluated by Zohreh Abolfathi et al.
- sibutramine free base may become sticky gel phase during storage, that is, the stability of sibutramine free base is so bad that it is difficult to make a sibutramine free base-containing preparation by conventional manufacturing methods.
- Publication No. 90-00274 disclose methods for preparing sibutramine hydrochloride anhydrous as a pharmaceutically acceptable acid-addition salt.
- the sibutramine hydrochloride anhydrous is highly hygroscopic, so that it is difficult to keep the content of the active ingredient constant, and absorbed water may cause hydrolysis or chemical degradation of the active ingredient. Accordingly, it is difficult to use the sibutramine hydrochloride anhydrous in a pharmaceutical composition (See U.S. Patent No. 6,900,245).
- sibutramine hydrochloride monohydrate was developed (See British Patent No. 2,184,122 and Korean Patent Publication No. 94-08913) and the sibutramine hydrochloride monohydrate is now used as an active ingredient in MeridiaTM or ReductilTM for treating obesity.
- the object of the present invention is to provide a sibutramine free base- containing composition that has good dissolution property and little dissolution variation according to pH.
- the object of the present invention is to provide a sibutramine free base-containing composition that can be easily mass-produced and is stable.
- Another object of the present invention is to provide manufacturing method thereof.
- the present invention provides a sibutramine free base- containing solid dispersion wherein sibutramine free base, acid and hydrophilic polymer are uniformly dispersed.
- the present invention provides said sibutramine free base- containing solid dispersion wherein the acid is at least one selected from the group consisting of citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid and phosphoric acid.
- the present invention provides said sibutramine free base- containing solid dispersion wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
- the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
- the present invention provides said sibutramine free base- containing solid dispersion wherein the acid is comprised in an amount of 0.1-20 moles per mole of the sibutramine free base.
- the present invention provides said sibutramine free base- containing solid dispersion wherein the acid is comprised in an amount of 0.06-10 parts by weight per part by weight of the sibutramine free base.
- the present invention provides said sibutramine free base- containing solid dispersion wherein the hydrophilic polymer is comprised in an amount of 0.125-30 parts by weight per part by weight of the sibutramine free base.
- the present invention provides said sibutramine free base- containing solid dispersion wherein the solid dispersion is coated by at least one selected from the group consisting of hydroxypropylmethylcellulose, vinylpyrrolidone- vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
- the present invention also provides a pharmaceutical preparation comprising any one of the sibutramine free base-containing solid dispersions.
- the present invention also provides a method for manufacturing sibutramine free base-containing solid dispersion comprising (Sl) making a solution wherein sibutramine free base, acid and hydrophilic polymer are dissolved; and (S2) drying the solution of (Sl) step.
- the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the acid is at least one selected from the group consisting of citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid and phosphoric acid.
- the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropy- lmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
- the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropy- lmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
- the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the acid is comprised in an amount of 0.1-20 moles per mole of the sibutramine free base.
- the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the acid is comprised in an amount of 0.06-10 parts by weight per part by weight of the sibutramine free base.
- the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the hydrophilic polymer is comprised in an amount of 0.125-30 parts by weight per part by weight of the sibutramine free base.
- the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the method further comprises (S3) coating the solid dispersion of (S2) step with at least one selected from the group consisting of hydroxypropylmethylcellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
- sibutramine free base-containing composition and manufacturing method thereof according to the present invention will be described in detail.
- the present invention provides a sibutramine free base-containing solid dispersion wherein sibutramine free base, acid and hydrophilic polymer are uniformly dispersed.
- the solubility of sibutramine free base decreases rapidly according to increase of pH of dissolution medium, but the improved solubility and dissolution rate of the sibutramine free base contained in the solid dispersion of the present invention can keep even in high pH solution because acid and hydrophilic polymer in the solid dispersion are uniformly and minutely distributed around sibutramine free base to make micro-environmental condition acidic and keep the acidic micro-environments in dissolution medium.
- the improving effect of the solid dispersion of the present invention is surprisingly great, so that it is possible to keep high dissolution rate even if acid and hydrophilic polymer are used in a small amount compared to the content of sibutramine free base.
- the solid dispersion of the present invention improves the stability of severely hygroscopic sibutramine free base by making stable hydrophilic polymer surround sibutramine free base uniformly and minutely to block sibutramine free base from contacting exterior water.
- the acid that may be used in the present invention includes, but is not limited to, organic acids such as citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid, aspartic acid, glutamic acid, palmitic acid, propionic acid, ascorbic acid, chitic acid, hippuric acid, alginic acid, cholic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, salicylic acid, gluconic acid, glycolic acid, mandelic acid and cinnamic acid; inorganic acids such as hydrochloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, hydrobromic acid and sulphuric acid; and their mixtures.
- organic acids such as citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid,
- citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid and phosphoric acid are preferable if considering manufacturing difficulty such as bad smell (for example, hydrochloric acid), solubility (for example, hippuric acid) and viscosity (for example, chitic acid and alginic acid), etc.; safety (for example, propionic acid, sulphuric acid and salicylic acid); and the improving degree of dissolution rate of solid dispersion.
- the hydrophilic polymer that can be used in the present invention includes, but is not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol, polyvinylalcohol-polyethyleneglycol copolymer, methylcellulose, ethylcellulose, hy- droxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, car- boxymethylcellulose, polyvinylacetate, polyalkeneoxide, polyalkeneglycol, poly- oxyethylene-polyoxypropylene polymer (for example, PoloxamerTM), zein, shellac, di- ethylaminoacetate (for example, AEATM), aminoalkylmethacrylate copolymer (for example, Eudragit ETM), Sodium alginate, chitosan derivatives, gelatin, gum, poly- L
- Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol, polyvinylalcohol- polyethyleneglycol copolymer and their mixtures are preferable if considering the solubility of the hydrophilic polymer and solid dispersion-forming ability with sibutramine free base.
- Polyvinylpyrrolidone is more preferable because of its high solubility if considering mass-production, and hydroxypropylcellulose and hydroxypropylmethylcellulose are more preferable if considering storage stability.
- the present invention also provides a sibutramine free base- containing solid dispersion wherein the solid dispersion is coated by non-hygroscopic or little hygroscopic hydrophilic polymer.
- a hydrophilic polymer used for making a solid dispersion is hygroscopic, it has negative influence on stability of sibutramine free base, and this problem can be solved by coating the solid dispersion with non-hygroscopic or little hygroscopic polymer.
- Non-hygroscopic or little hygroscopic hydrophilic polymer includes, but is not limited to, hydroxypropylmethyl- cellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol, poly vinylalcohol-polyethylenegly col copolymer and their mixtures.
- a sibutramine free base-containing solid dispersion made with hygroscopic polyvinylpyrrolidone can be coated with hydroxypropylmethylcellulose to improve stability.
- the present invention is also based on the surprising result that the improving effect of dissolution rate can be kept with only small amount of acid compared to the content of sibutramine free base, even if the improving effect increases according to the content of acid. This can be very advantageous when considering that it is preferable that the contents of additional ingredients except sibutramine free base is minimal in view of safety.
- the content of the acid in the solid dispersion of the present invention is 0.1-20 moles per mole the sibutramine free base or 0.06-10 parts by weight per part by weight of the sibutramine free base.
- the dissolution rate of the solid dispersion according to pH may be worse than conventional preparations containing sibutramine hydrochloride monohydrate.
- the stability of the composition comprising the solid dispersion may be worse because of the hygroscopic property of some acids.
- the content of the hydrophilic polymer in the solid dispersion of the present invention is 0.125-30 parts by weight per part by weight of the sibutramine free base.
- the content of the hydrophilic polymer is less than 0.125 parts by weight, making granules is so difficult that solid dispersions may have bad flow- ability, which makes following manufacturing processes difficult.
- the stability of the solid dispersion may be too bad to keep the improved dissolution rate during storage.
- the size of the preparation comprising the solid dispersion is too big to be taken, and it is difficult to make micro-environmental condition around sibutramine free base acidic because the content of the acid becomes small relatively.
- the present invention also provides a pharmaceutical composition or preparation comprising the solid dispersion.
- the pharmaceutical composition or preparation can further comprise pharmaceutically acceptable excipients such as disintegrator, dilutor, flavor, colorant, lubricant, filler, etc., which are conventionally used to make an oral preparation (for example, tablet, granule, capsule and pellet).
- the present invention also provides a method for manufacturing sibutramine free base-containing solid dispersion comprising (Sl) making a solution wherein sibutramine free base, acid and hydrophilic polymer are dissolved; and (S2) drying the solution of (Sl) step.
- the method of the present invention can easily prepare a solid dispersion wherein the acid and the sibutramine free base are minutely and uniformly mixed between uniformly entangled polymers.
- the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the method further comprises (S3) coating the solid dispersion of (S2) step with non-hygroscopic or little hygroscopic polymer to more improve the stability of the solid dispersion.
- the non- hygroscopic or little hygroscopic polymer includes, but is not limited to, hydrox- ypropylmethylcellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol, poly vinylalcohol-polyethylenegly col copolymer and their mixtures.
- the solvent to make the solution of (S 1) step includes, but is not limited to, water, ethanol, methanol, isopropylalcohol, dichloromethane, chloroform, acetone and their mixtures.
- Drying of (S2) step can be performed with heated air, and methods to do such a drying are well known to those skilled in the art. It is preferable to do mixing such as stirring, shaking, rotating and so on during drying procedure to keep uniformity of the solution of (Sl) step. Spray-drying method is more preferable in view of mass- production. Fluidized bed granulator, spray-dryer, fluidized bed dryer, C/F granulator, etc. can be used for spray-drying. Mode for the Invention
- Sibutramine free base-containing solid dispersions were prepared with various hydrophilic polymers. Sibutramine free base-containing solid dispersions and simple mixtures were prepared according to ingredients and contents of the below table 1.
- example 1 was prepared as follows: Sibutramine free base and citric acid were dissolved in 20 D of ethanol, and then hydroxypropylcellulose was added slowly to the solution with continuous stirring. After hydroxypropylcellulose was dissolved completely, lactose and silicon dioxide were added to the solution and the solution was mixed. Then, the final solution was dried at 40°C with continuous stirring. After drying, the dried product was ground slightly and sieved with 30 mesh size of sieve to form the solid dispersion of example 1. Examples 2-6 were prepared according to the same method as used in example 1.
- Comparative examples 1-2 were prepared by simply mixing ingredients of the below table 1 and sieving the mixture with 30 mesh size of sieve. [48] Table 1
- HPMC2910 Plasdone K29TM and Aerosil 200TM were used as hydroxypropylmethylcellulose, polyvinylpyrrolidone and silicone dioxide, respectively.
- Results in pH 4.5 and pH 6.8 buffered solutions were shown in table 2 and 3, respectively. Results were shown as percent (%) of sibutramine dissolved into dissolution media from test samples compared to the total amount of sibutramine contained in each sample.
- mole ratio* means the ratio of mole of the citric acid contained in solid dispersion per mole of sibutramine free base in solid dispersion.
- Example 20 was prepared to evaluate mass-production ability of the solid dispersion of the present invention and the dissolution rate of mass-produced solid dispersion. 30.5 g of sibutramine free base and 23.2 g of citric acid were dissolved in 620 D of ethanol, and then 91.4 g of poly vinylpyrrolidone was added slowly to the solution and dissolved. 609.3 g of lactose and 20.1 g of silicon dioxide (aerosol 200TM, Degussa, Germany) were fluidized in the bed of fluidized bed granulator (GX-20, Freund, Japan), and then the solution prepared above was sprayed in the following conditions to form example 20.
- sibutramine free base and 23.2 g of citric acid were dissolved in 620 D of ethanol, and then 91.4 g of poly vinylpyrrolidone was added slowly to the solution and dissolved. 609.3 g of lactose and 20.1 g of silicon dioxide (aerosol 200TM, Degussa, Germany) were fluidized
- hydroxypropylmethylcellulose, 9 g of polyethyleneglycol ⁇ OOO and 15 g of talc were dissolved or suspended in mixture of 700 D of ethanol and 300 D of distilled water to make a coating solution.
- the coating solution was sprayed in the following conditions to make a coated solid dispersion.
- Example 20 showed better stability in both appearance and content than comparative example 3 having the same ingredients and contents as example 20.
- Example 20 showed a little aggregation of granules over time, which is thought to be caused by the hygroscopic property of polyvinylpyrrolidone. This aggregation could be blocked by coating the granules with hydroxypropylmethylcellulose without change of dissolution rate.
- mole ratio* means the ratio of mole of the phosphoric acid contained in solid dispersion per mole of sibutramine free base in solid dispersion.
- the present invention provides a solid dispersion comprising sibutramine free base, acid and hydrophilic polymer; a pharmaceutical composition comprising the solid dispersion; and a manufacturing method thereof.
- Sibutramine free base-containing solid dispersion according to the present invention shows higher dissolution rate in high pH medium than conventional preparations containing sibutramine free base or sibutramine hydrochloride monohydrate.
- the solid dispersion according to the present invention is very stable compared to conventional preparations containing sibutramine free base.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a composition comprising sibutramine free base. The present invention provides a solid dispersion wherein sibutramine free base, acid and hydrophilic polymer are uniformly dispersed and a manufacturing method thereof. The composition of the present invention has improved dissolution rate compared to conventional compositions containing sibutramine free base or sibutramine hydrochloride, and is also stable during storage and can be easily mass-produced.
Description
Description
PHARMACEUTICAL COMPOSITION CONTAINING SIBUTRAMINE FREE BASE AND MANUFACTURING
METHOD THEREOF
Technical Field
[1] The present invention relates to a composition comprising sibutramine free base and manufacturing method thereof. Background Art
[2] Sibutramine is a common name of N,N-dimethyl- 1 - [ 1 -(4-chlorophenyl)-cyclobutyl]
-3-methylbutylamine, and known as being used for treating or preventing depression, Parkinson disease and obesity (See British Patent No. 2,098,602 and PCT international publication No. WO 88/06444). Further, sibutramine may be used for reducing the resistance to insulin or enhancing the resistance to sugar, and for preventing or treating such diseases as gout, hyperuricemia, hyperlipemia, osteoarthritis, anxiety disorder, somnipathy, sexual dysfunction, chronic fatigue syndrome and cholelithiasis (see U.S. Patent Nos. 6,174,925, 5,459,164, 6,187,820, 6,162,831, 6,232,347, 6,355,685, 6,365,631, 6,376,554, 6,376,551 and 6,376,552).
[3] The solubility of sibutramine free base rapidly decreases according to the increase of pH of dissolution medium so that sibutramine free base does not almost dissolve in distilled water and pH 6.8 buffered solution, which means that there may be a problem in body absorption of sibutramine free base, that is, bioavailability. Zohreh Abolfathi et al. reported that intake of food severely changes the area under the curve of blood concentration (AUC), the maximum blood concentration (Cmax) and the time required for the maximum blood concentration (Tmax) ("A pilot study to evaluate the pharmacokinetics of sibutramine in healthy subjects under fasting and fed conditions", J Pharm Pharmaceut Sci, 7(3): 345-349, 2004), and these changes of the pharmacokinetic data are expected to be caused by the changes of sibutramine hydrochloride solubility and gastric emptying time which made by food intake, even if there may be other reasons. The change of gastric emptying time can be also thought to be related with the solubility of sibutramine hydrochloride because the big pH difference between stomach and upper intestine causes the solubility difference of sibutramine hydrochloride, which causes the difference of absorption or bioavailability. The absorption variation of sibutramine free base may be bigger than sibutramine hydroc hloride because the solubility difference of sibutramine free base is much bigger than sibutramine hydrochloride evaluated by Zohreh Abolfathi et al.
[4] In addition, sibutramine free base may become sticky gel phase during storage, that
is, the stability of sibutramine free base is so bad that it is difficult to make a sibutramine free base-containing preparation by conventional manufacturing methods.
[5] To solve these problems, British Patent No. 2,098,302 and Korean Patent
Publication No. 90-00274 disclose methods for preparing sibutramine hydrochloride anhydrous as a pharmaceutically acceptable acid-addition salt. However, the sibutramine hydrochloride anhydrous is highly hygroscopic, so that it is difficult to keep the content of the active ingredient constant, and absorbed water may cause hydrolysis or chemical degradation of the active ingredient. Accordingly, it is difficult to use the sibutramine hydrochloride anhydrous in a pharmaceutical composition (See U.S. Patent No. 6,900,245).
[6] To solve said problems, non-hygroscopic sibutramine hydrochloride sibutramine hydrochloride monohydrate was developed (See British Patent No. 2,184,122 and Korean Patent Publication No. 94-08913) and the sibutramine hydrochloride monohydrate is now used as an active ingredient in Meridia™ or Reductil™ for treating obesity.
[7] Then again, U.S. Patent No. 6,900,245 said that an active ingredient used in a pharmaceutical composition should be soluble in water or water solution having broad range of pH to guarantee in vivo dissolution rate (consequently, bioavailability) and from this point of view, the solubility of sibutramine hydrochloride monohydrate is insufficient for being used as an active ingredient, so that sibutramine methanesulfonate hemihydrate having improved solubility was developed. As shown in U.S. Patent No. 6,900,245, the dissolution rate of a preparation containing sibutramine hydrochloride monohydrate in pH 6.8 buffered solution was evaluated to be not good.
[8] However, all of the above methods are to make a salt through additional synthesis steps from sibutramine free base, which may increase manufacturing cost. In addition, the salt should be separated when a preparation containing sibutramine salt is evaluated. Further, it is preferable for reducing potential side-effects to decrease the content of additional ingredients including acid (for example, methanesulfonic acid) used in making a salt. Disclosure of Invention Technical Problem
[9] Therefore, the object of the present invention is to provide a sibutramine free base- containing composition that has good dissolution property and little dissolution variation according to pH. In addition, the object of the present invention is to provide a sibutramine free base-containing composition that can be easily mass-produced and is stable. Another object of the present invention is to provide manufacturing method thereof.
Technical Solution
[10] To achieve the object, the present invention provides a sibutramine free base- containing solid dispersion wherein sibutramine free base, acid and hydrophilic polymer are uniformly dispersed.
[11] More preferably, the present invention provides said sibutramine free base- containing solid dispersion wherein the acid is at least one selected from the group consisting of citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid and phosphoric acid.
[12] More preferably, the present invention provides said sibutramine free base- containing solid dispersion wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
[13] More preferably, the present invention provides said sibutramine free base- containing solid dispersion wherein the acid is comprised in an amount of 0.1-20 moles per mole of the sibutramine free base.
[14] More preferably, the present invention provides said sibutramine free base- containing solid dispersion wherein the acid is comprised in an amount of 0.06-10 parts by weight per part by weight of the sibutramine free base.
[15] More preferably, the present invention provides said sibutramine free base- containing solid dispersion wherein the hydrophilic polymer is comprised in an amount of 0.125-30 parts by weight per part by weight of the sibutramine free base.
[16] More preferably, the present invention provides said sibutramine free base- containing solid dispersion wherein the solid dispersion is coated by at least one selected from the group consisting of hydroxypropylmethylcellulose, vinylpyrrolidone- vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
[17] The present invention also provides a pharmaceutical preparation comprising any one of the sibutramine free base-containing solid dispersions.
[18] The present invention also provides a method for manufacturing sibutramine free base-containing solid dispersion comprising (Sl) making a solution wherein sibutramine free base, acid and hydrophilic polymer are dissolved; and (S2) drying the solution of (Sl) step.
[19] More preferably, the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the acid is at least one selected from the group consisting of citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid and phosphoric acid.
[20] More preferably, the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropy- lmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
[21] More preferably, the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the acid is comprised in an amount of 0.1-20 moles per mole of the sibutramine free base.
[22] More preferably, the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the acid is comprised in an amount of 0.06-10 parts by weight per part by weight of the sibutramine free base.
[23] More preferably, the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the hydrophilic polymer is comprised in an amount of 0.125-30 parts by weight per part by weight of the sibutramine free base.
[24] More preferable, the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the method further comprises (S3) coating the solid dispersion of (S2) step with at least one selected from the group consisting of hydroxypropylmethylcellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
[25] Hereinafter, sibutramine free base-containing composition and manufacturing method thereof according to the present invention will be described in detail.
[26] The present invention provides a sibutramine free base-containing solid dispersion wherein sibutramine free base, acid and hydrophilic polymer are uniformly dispersed. The solubility of sibutramine free base decreases rapidly according to increase of pH of dissolution medium, but the improved solubility and dissolution rate of the sibutramine free base contained in the solid dispersion of the present invention can keep even in high pH solution because acid and hydrophilic polymer in the solid dispersion are uniformly and minutely distributed around sibutramine free base to make micro-environmental condition acidic and keep the acidic micro-environments in dissolution medium. Further, the improving effect of the solid dispersion of the present invention is surprisingly great, so that it is possible to keep high dissolution rate even if acid and hydrophilic polymer are used in a small amount compared to the content of sibutramine free base.
[27] In addition, the solid dispersion of the present invention improves the stability of severely hygroscopic sibutramine free base by making stable hydrophilic polymer surround sibutramine free base uniformly and minutely to block sibutramine free base from contacting exterior water.
[28] The acid that may be used in the present invention includes, but is not limited to, organic acids such as citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid, aspartic acid, glutamic acid, palmitic acid, propionic acid, ascorbic acid, chitic acid, hippuric acid, alginic acid, cholic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, salicylic acid, gluconic acid, glycolic acid, mandelic acid and cinnamic acid; inorganic acids such as hydrochloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, hydrobromic acid and sulphuric acid; and their mixtures.
[29] However, citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid and phosphoric acid are preferable if considering manufacturing difficulty such as bad smell (for example, hydrochloric acid), solubility (for example, hippuric acid) and viscosity (for example, chitic acid and alginic acid), etc.; safety (for example, propionic acid, sulphuric acid and salicylic acid); and the improving degree of dissolution rate of solid dispersion.
[30] The hydrophilic polymer that can be used in the present invention includes, but is not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol, polyvinylalcohol-polyethyleneglycol copolymer, methylcellulose, ethylcellulose, hy- droxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, car- boxymethylcellulose, polyvinylacetate, polyalkeneoxide, polyalkeneglycol, poly- oxyethylene-polyoxypropylene polymer (for example, Poloxamer™), zein, shellac, di- ethylaminoacetate (for example, AEA™), aminoalkylmethacrylate copolymer (for example, Eudragit E™), Sodium alginate, chitosan derivatives, gelatin, gum, poly- L-lysine and their mixtures.
[31] Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol, polyvinylalcohol- polyethyleneglycol copolymer and their mixtures are preferable if considering the solubility of the hydrophilic polymer and solid dispersion-forming ability with sibutramine free base. Polyvinylpyrrolidone is more preferable because of its high solubility if considering mass-production, and hydroxypropylcellulose and hydroxypropylmethylcellulose are more preferable if considering storage stability.
[32] More preferably, the present invention also provides a sibutramine free base- containing solid dispersion wherein the solid dispersion is coated by non-hygroscopic or little hygroscopic hydrophilic polymer. In case that a hydrophilic polymer used for making a solid dispersion is hygroscopic, it has negative influence on stability of sibutramine free base, and this problem can be solved by coating the solid dispersion with non-hygroscopic or little hygroscopic polymer. Non-hygroscopic or little hygroscopic hydrophilic polymer includes, but is not limited to, hydroxypropylmethyl-
cellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol, poly vinylalcohol-polyethylenegly col copolymer and their mixtures. For example, a sibutramine free base-containing solid dispersion made with hygroscopic polyvinylpyrrolidone can be coated with hydroxypropylmethylcellulose to improve stability.
[33] The present invention is also based on the surprising result that the improving effect of dissolution rate can be kept with only small amount of acid compared to the content of sibutramine free base, even if the improving effect increases according to the content of acid. This can be very advantageous when considering that it is preferable that the contents of additional ingredients except sibutramine free base is minimal in view of safety.
[34] It is preferable that the content of the acid in the solid dispersion of the present invention is 0.1-20 moles per mole the sibutramine free base or 0.06-10 parts by weight per part by weight of the sibutramine free base.
[35] In case that the content of the acid is less than 0.1 mole or 0.06 parts by weight, the dissolution rate of the solid dispersion according to pH may be worse than conventional preparations containing sibutramine hydrochloride monohydrate. In case that the content of the acid is more than 20 mole or 10 parts by weight, the stability of the composition comprising the solid dispersion may be worse because of the hygroscopic property of some acids.
[36] It is preferable that the content of the hydrophilic polymer in the solid dispersion of the present invention is 0.125-30 parts by weight per part by weight of the sibutramine free base. In case that the content of the hydrophilic polymer is less than 0.125 parts by weight, making granules is so difficult that solid dispersions may have bad flow- ability, which makes following manufacturing processes difficult. In addition, in case that the content of the hydrophilic polymer is too low, the stability of the solid dispersion may be too bad to keep the improved dissolution rate during storage. In case that the content of the hydrophilic polymer is more than 30 parts by weight, the size of the preparation comprising the solid dispersion is too big to be taken, and it is difficult to make micro-environmental condition around sibutramine free base acidic because the content of the acid becomes small relatively.
[37] The present invention also provides a pharmaceutical composition or preparation comprising the solid dispersion. The pharmaceutical composition or preparation can further comprise pharmaceutically acceptable excipients such as disintegrator, dilutor, flavor, colorant, lubricant, filler, etc., which are conventionally used to make an oral preparation (for example, tablet, granule, capsule and pellet).
[38] The present invention also provides a method for manufacturing sibutramine free base-containing solid dispersion comprising (Sl) making a solution wherein
sibutramine free base, acid and hydrophilic polymer are dissolved; and (S2) drying the solution of (Sl) step. The method of the present invention can easily prepare a solid dispersion wherein the acid and the sibutramine free base are minutely and uniformly mixed between uniformly entangled polymers.
[39] More preferable, the present invention provides said method for manufacturing sibutramine free base-containing solid dispersion wherein the method further comprises (S3) coating the solid dispersion of (S2) step with non-hygroscopic or little hygroscopic polymer to more improve the stability of the solid dispersion. The non- hygroscopic or little hygroscopic polymer includes, but is not limited to, hydrox- ypropylmethylcellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol, poly vinylalcohol-polyethylenegly col copolymer and their mixtures.
[40] The solvent to make the solution of (S 1) step includes, but is not limited to, water, ethanol, methanol, isopropylalcohol, dichloromethane, chloroform, acetone and their mixtures.
[41] Drying of (S2) step can be performed with heated air, and methods to do such a drying are well known to those skilled in the art. It is preferable to do mixing such as stirring, shaking, rotating and so on during drying procedure to keep uniformity of the solution of (Sl) step. Spray-drying method is more preferable in view of mass- production. Fluidized bed granulator, spray-dryer, fluidized bed dryer, C/F granulator, etc. can be used for spray-drying. Mode for the Invention
[42] Hereinafter, a preferred embodiment of the present invention will be described in detail. Prior to the description, it should be understood that various modifications are possible to the embodiments of the present invention, and it should be understood that the scope of the invention is not limited to the following embodiments. The embodiments are purposed to merely give better explanation of the invention to those ordinarily skilled in the art.
[43]
[44] Preparations of examples 1-6 and comparative examples 1~2>
[45] Sibutramine free base-containing solid dispersions were prepared with various hydrophilic polymers. Sibutramine free base-containing solid dispersions and simple mixtures were prepared according to ingredients and contents of the below table 1.
[46] For example, example 1 was prepared as follows: Sibutramine free base and citric acid were dissolved in 20 D of ethanol, and then hydroxypropylcellulose was added slowly to the solution with continuous stirring. After hydroxypropylcellulose was dissolved completely, lactose and silicon dioxide were added to the solution and the solution was mixed. Then, the final solution was dried at 40°C with continuous stirring.
After drying, the dried product was ground slightly and sieved with 30 mesh size of sieve to form the solid dispersion of example 1. Examples 2-6 were prepared according to the same method as used in example 1.
[47] Comparative examples 1-2 were prepared by simply mixing ingredients of the below table 1 and sieving the mixture with 30 mesh size of sieve. [48] Table 1
[49] Hereinafter, unless otherwise stated, HPMC2910, Plasdone K29™ and Aerosil 200™ were used as hydroxypropylmethylcellulose, polyvinylpyrrolidone and silicone dioxide, respectively.
[50] [51] <Dissolution tests of examples 1-6 and so on> [52] Dissolution tests were performed with examples 1-6, comparative examples 1-2, sibutramine free base itself and Reductil™ (Abbott Korea Limited) containing 10 D of sibutramine hydrochloride monohydrate. To keep dissolution test condition similar, the contents of sibutramine in examples and comparative examples were evaluated with the below HPLC analysis condition and then the pre-determined amount of examples, comparative examples and sibutramine free base itself were filled in one capsule to make capsules having 8.37 D of sibutramine free base. These capsules were used in dissolution tests.
[53] 500 D of pH 4.5 buffered solution [2.99 g of Sodium acetate trihydrate and 1.66 D of acetic acid anhydrous were dissolved in 1 L of distilled water and then pH of the solution was adjusted to pH 4.5+0.05] and 500 D of pH 6.8 buffered solution [118 D of 0.2 mol/L NaOH solution was added to 250 D of 0.2 mol/L KHPO , and then distilled
2 4
water was added to make the solution 1000 D] were used as dissolution media. Paddle method of dissolution test of the Korean Pharmacopoeia was used and paddle was rotated at 50 rpm. Dissolution test was performed for 45 minutes and sinker was also used.
[54] For HPLC analysis, mixture (350:640:10) of acetonitrile, water and tetrahydrofuran was used as mobile phase and ion pair reagent PIC B5 (Low UV) was added to the mobile phase to adjust retention time of peak, and then pH was adjusted to 3.0 with phosphoric acid. Wavelength for determination was 229 D and flow rate was 1.5 D/min and injection volume was 20 D.
[55] Results in pH 4.5 and pH 6.8 buffered solutions were shown in table 2 and 3, respectively. Results were shown as percent (%) of sibutramine dissolved into dissolution media from test samples compared to the total amount of sibutramine contained in each sample.
[56] Table 2
[57] As shown in table 2, all test samples including sibutramine free base itself and comparative examples showed high dissolution rates in pH 4.5 buffered solution. [58] Table 3
[59] As shown in table 3, in dissolution tests using pH 6.8 buffered solution, sibutramine free base did not practically dissolve and comparative examples made by simple mixing of sibutramine free base, acid and hydrophilic polymer showed 20 % of low dissolution rate at 45 minutes, but examples 1 and 2 having the same ingredients and contents as comparative examples showed more than 70 % of dissolution rate at 45 minutes, and these dissolution rates of examples 1 and 2 were much higher than that of Reductil™ containing sibutramine hydrochloride monohydrate. In addition, examples 3-6 using other polymer and/or other acid showed very high dissolution rates in pH 6.8 buffered solution.
[60] [61] Preparations of examples 7-15> [62] Sibutramine free base-containing solid dispersions were prepared with various acids as shown in the below table 4 according to the same method as used in example 1.
[63] Table 4
[64]
[65] <Dissolution tests of examples 7-15 and so on> [66] Dissolution tests on examples 7-15, sibutramine free base itself and Reductil™ were performed according to the same method as used in dissolution test on example 1. Distilled water and pH 6.8 buffered solution were used as dissolution media. Results of pH 6.8 buffered solution and distilled water were shown in table 5 and 6, respectively.
[67] Table 5
[68]
[69] In comparison with sibutramine free base, the improved dissolution rate had nothing to do with the kind of acid. However, example 13 using palmitic acid showed lower dissolution rate than Reductil™ in dissolution test using distilled water, and example 12 using glutamic acid and example 15 using aspartic acid showed lower dissolution rate that Reductil™ in both distilled water and pH 6.8 buffered solution. It means that there are more preferable acids for improving dissolution rate.
[70]
[71] Preparations of examples 16~19> [72] Solid dispersions having various content ratios of acid were prepared by increasing the content of acid per mole or part by weight of sibutramine free base to determine the amount of acid needed, as shown in the below table 7 according to the same method as used in example 1.
[73] Table 7
[74] In table 7, "mole ratio*" means the ratio of mole of the citric acid contained in solid dispersion per mole of sibutramine free base in solid dispersion.
[75] [76] <Dissolution tests of examples 16-19 and so on> [77] Dissolution test on examples 3 and 16-19, sibutramine free base itself and Reductil™ were performed according to the same method as used in dissolution test on example 1. Results were shown in table 8.
[78] Table 8
[79] As shown in table 8, the decrease of the content of citric acid lowered slightly the improving effect of dissolution rate. However, the solid dispersion of the present invention showed much higher dissolution rate than the conventional preparation containing sibutramine hydrochloride monohydrate even if the content of citric acid is very small (for example, 0.1 mole or 0.068 parts by weight per mole or part by weight of sibutramine free base in example 19).
[80] This result that dissolution rate does not in proportion to the content of acid is very surprising, which means that the solid dispersion of the present invention can make micro-environmental condition around sibutramine free base acidic even in case that the content of acid is very small.
[81] [82] <Preparation of example 20> [83] Example 20 was prepared to evaluate mass-production ability of the solid dispersion of the present invention and the dissolution rate of mass-produced solid dispersion. 30.5 g of sibutramine free base and 23.2 g of citric acid were dissolved in 620 D of ethanol, and then 91.4 g of poly vinylpyrrolidone was added slowly to the solution and dissolved. 609.3 g of lactose and 20.1 g of silicon dioxide (aerosol 200™, Degussa, Germany) were fluidized in the bed of fluidized bed granulator (GX-20, Freund, Japan), and then the solution prepared above was sprayed in the following conditions to form example 20.
[84] - Operating condition of the fluidized bed granulator [85] Temperature and amount of inlet air: 65°C, 0.5 L/min [86] Temperature and amount of slit air: 65°C, 0.4 L/min [87] Speed of revolution of rotor: 250 rpm [88] [89] <Preparation of example 21> [90] Solid dispersion containing sibutramine free base, citric acid, polyvinylpyrrolidone,
lactose and silicon dioxide was prepared according to the same method as used in example 20. Then, 59.1 g of hydroxypropylmethylcellulose, 9 g of polyethyleneglycolόOOO and 15 g of talc were dissolved or suspended in mixture of 700 D of ethanol and 300 D of distilled water to make a coating solution. After fluidizing the solid dispersion granules in the fluidized bed granulator, the coating solution was sprayed in the following conditions to make a coated solid dispersion.
[91] - Operating condition of the fluidized bed granulator [92] Temperature and amount of inlet air: 65°C, 0.3 L/min
[93] Temperature and amount of slit air: 65°C, 0.3 L/min [94] Speed of revolution of rotor: 250 rpm [95] [96] <Dissolution tests of examples 20 and 21> [97] Dissolution tests on solid dispersions made in examples 20 and 21 were performed according to the same method as used in dissolution test on example 1. Results were shown in table 9.
[98] Table 9
[99] As shown in table 9, mass-produced solid dispersions of the present invention showed high dissolution rates.
[100] [101] <Evaluation of mass-production ability according to the content of polymer> [102] Sibutramine free base-containing solid dispersions were prepared according to the same method as used in example 20 except that 61, 30.5, 15.3 or 7.7 g of polyvinylpyrrolidone was used instead of 91.4 g of polyvinylpyrrolidone.
[103] In case that the hydrophilic polymer was comprised in a small amount per the amount of sibutramine free base, it was difficult to make granules even if the dissolution rate of the solid dispersion comprising a small amount of polymer was higher than the conventional preparation containing sibutramine hydrochloride monohydrate in dissolution test using pH 6.8 buffered solution. In case using 7.7 g of polyvinylpyrrolidone, formed granules were easily broken. This caused lowering of flow-ability of granules, which made it difficult to fill capsules.
[104]
[105] <Stability test on content and dissolution of example 20> [106] Stability test was performed at 40°C, 75% RH for 2 months with sibutramine free base-containing solid dispersion made in example 20. After 2 months, the content and dissolution rate were determined according to the same method as used in evaluation of example 1. Changes of content and dissolution rate were shown in table 10 and 11, respectively.
[107] Table 10
[108] Table 11
[109] As shown in table 10 and 11, the content and dissolution rate of sibutramine free base-containing solid dispersion were not changed after 2 months of storage in accelerated condition. These results mean that the solid dispersion of the present invention is very stable.
[HO] [111] <Stability tests on appearance and content of examples 20-21 and so on> [112] Appearance and content stability test were performed at 60°C, 75%RH with solid dispersions of examples 20 and 21. Comparative example 3 was prepared by simply mixing the ingredients of example 20 having the same contents without making the solid dispersion. Results were shown in table 12 and evaluation criteria of appearance are as follows:
[113] - Evaluation criteria of appearance - [114] ++++: no change of appearance and good flow-ability [115] +++: small amount of aggregates of granules and normal flow-ability [116] ++: aggregates of granules and bad flow-ability [117] +: hardened aggregates and no flow [118] Table 12
Appearance / content(%)
O wk l wk 2 wks 3 wks 4 wks
[119] As shown in table 12, the solid dispersion of example 20 according to the present invention showed better stability in both appearance and content than comparative example 3 having the same ingredients and contents as example 20. Example 20 showed a little aggregation of granules over time, which is thought to be caused by the hygroscopic property of polyvinylpyrrolidone. This aggregation could be blocked by coating the granules with hydroxypropylmethylcellulose without change of dissolution rate.
[120] [121] Preparations of examples 22~23> [122] Sibutramine free base-containing solid dispersions were prepared with inorganic acid instead of organic acid according to the same method as used in example 1, as shown in the table 13.
[123] Table 13
[124] In table 13, "mole ratio*" means the ratio of mole of the phosphoric acid contained in solid dispersion per mole of sibutramine free base in solid dispersion.
[125] [126] <Dissolution tests of example 22 and 23> [127] Dissolution tests on example 22 and 23 were performed in distilled water, pH 4.0 buffered solution and pH 6.8 buffered solution according to the same method as used in the dissolution test on example 1. Results were shown in table 14, 15 and 16, respectively.
[128] Table 14
[129] Table 15
[130] Table 16
[131] As shown in table 14, 15 and 16, solid dispersions using phosphoric acid as acid showed much higher dissolution rates than both sibutramine free base itself and the conventional preparations containing sibutramine hydrochloride monohydrate. In addition, solid dispersion containing 0.5 mole or 0.175 parts by weight of phosphoric acid compared to the amount of sibutramine free base also showed higher dissolution rates than Reductil™ similar to dissolution results of examples 16-19. Industrial Applicability
[132] The present invention provides a solid dispersion comprising sibutramine free base, acid and hydrophilic polymer; a pharmaceutical composition comprising the solid dispersion; and a manufacturing method thereof. Sibutramine free base-containing solid dispersion according to the present invention shows higher dissolution rate in high pH medium than conventional preparations containing sibutramine free base or sibutramine hydrochloride monohydrate. The solid dispersion according to the present invention is very stable compared to conventional preparations containing sibutramine free base.
Claims
[I] A sibutramine free base-containing solid dispersion wherein sibutramine free base, acid and hydrophilic polymer are uniformly dispersed.
[2] The solid dispersion of claim 1, wherein the acid is at least one selected from the group consisting of citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid and phosphoric acid.
[3] The solid dispersion of claim 1, wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropyl- methylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
[4] The solid dispersion of claim 1, wherein the acid is comprised in an amount of
0.1-20 moles per mole of the sibutramine free base.
[5] The solid dispersion of claim 1, wherein the acid is comprised in an amount of
0.06-10 parts by weight per part by weight of the sibutramine free base.
[6] The solid dispersion of claim 1, wherein the hydrophilic polymer is comprised in an amount of 0.125-30 parts by weight per part by weight of the sibutramine free base.
[7] The solid dispersion of claim 1, wherein the solid dispersion is coated by at least one selected from the group consisting of hydroxypropylmethylcellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
[8] A pharmaceutical preparation comprising the solid dispersion of any of claims
1-7.
[9] A method for manufacturing sibutramine free base-containing solid dispersion comprising (Sl) making a solution wherein sibutramine free base, acid and hydrophilic polymer are dissolved; and (S2) drying the solution of (Sl) step.
[10] The method of claim 9, wherein the acid is at least one selected from the group consisting of citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, malic acid, oxalic acid and phosphoric acid.
[II] The method of claim 9, wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
[ 12] The method of claim 9, wherein the acid is comprised in an amount of 0.1 -20 moles per mole of the sibutramine free base. [13] The method of claim 9, wherein the acid is comprised in an amount of 0.06-10 parts by weight per part by weight of the sibutramine free base. [14] The method of claim 9, wherein the hydrophilic polymer is comprised in an amount of 0.125-30 parts by weight per part by weight of the sibutramine free base.
[15] The method of claim 9, wherein the method further comprises (S3) coating the solid dispersion of (S2) step with at least one selected from the group consisting of hydroxypropylmethylcellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinylalcohol and polyvinylalcohol-polyethyleneglycol copolymer.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11/912,081 US20080194695A1 (en) | 2005-04-20 | 2006-04-18 | Pharmaceutical Composition Containing Sibutramine Free Base and Manufacturing Method Thereof |
| EP06757489A EP1871346A4 (en) | 2005-04-20 | 2006-04-18 | Pharmaceutical composition containing sibutramine free base and manufacturing method thereof |
| JP2008507544A JP2008536913A (en) | 2005-04-20 | 2006-04-18 | Composition containing sibutramine free base and method for producing the same |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2005-0032744 | 2005-04-20 | ||
| KR20050032744 | 2005-04-20 | ||
| KR1020060010046A KR100627687B1 (en) | 2005-04-20 | 2006-02-02 | Sibutramine free base containing composition and preparation method thereof |
| KR10-2006-0010046 | 2006-02-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006112649A1 true WO2006112649A1 (en) | 2006-10-26 |
Family
ID=37115335
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2006/001434 WO2006112649A1 (en) | 2005-04-20 | 2006-04-18 | Pharmaceutical composition containing sibutramine free base and manufacturing method thereof |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP1871346A4 (en) |
| WO (1) | WO2006112649A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007040306A1 (en) * | 2005-08-31 | 2007-04-12 | Daewoong Pharmaceutical Co., Ltd. | A solid dispersion comprising sibutramine and surfactants, and a preparation method thereof |
| JP2010510306A (en) * | 2006-11-22 | 2010-04-02 | エスケー ケミカルズ カンパニー リミテッド | Inclusion complex of sibutramine and beta-cyclodextrin |
| JP2010513356A (en) * | 2006-12-22 | 2010-04-30 | ノバルティス アーゲー | Formulation containing a neurokinin antagonist |
| JP2011515444A (en) * | 2008-03-25 | 2011-05-19 | フォーマック ファーマシューティカルズ ナムローゼ フェンノートシャップ | Method for preparing solid dispersion |
| US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6548555B1 (en) * | 1999-02-09 | 2003-04-15 | Pfizer Inc | Basic drug compositions with enhanced bioavailability |
| US6677362B1 (en) * | 1991-12-18 | 2004-01-13 | Warner-Lambert Company | Solid pharmaceutical dispersions |
| WO2004096202A1 (en) * | 2003-04-28 | 2004-11-11 | Cipla Limited | Pharmaceutical formulation comprising anti-obesity agent and acidulant |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE364374T1 (en) * | 1997-08-11 | 2007-07-15 | Pfizer Prod Inc | SOLID PHARMACEUTICAL DISPERSIONS WITH INCREASED BIOAVAILABILITY |
-
2006
- 2006-04-18 EP EP06757489A patent/EP1871346A4/en not_active Withdrawn
- 2006-04-18 WO PCT/KR2006/001434 patent/WO2006112649A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6677362B1 (en) * | 1991-12-18 | 2004-01-13 | Warner-Lambert Company | Solid pharmaceutical dispersions |
| US6548555B1 (en) * | 1999-02-09 | 2003-04-15 | Pfizer Inc | Basic drug compositions with enhanced bioavailability |
| WO2004096202A1 (en) * | 2003-04-28 | 2004-11-11 | Cipla Limited | Pharmaceutical formulation comprising anti-obesity agent and acidulant |
Non-Patent Citations (2)
| Title |
|---|
| See also references of EP1871346A4 * |
| SERAJUDIN A.T.M.: "Solid Dispersion of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, and Recent Breakthroughs", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 88, no. 10, October 1999 (1999-10-01), pages 1058 - 1066, XP000851882 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007040306A1 (en) * | 2005-08-31 | 2007-04-12 | Daewoong Pharmaceutical Co., Ltd. | A solid dispersion comprising sibutramine and surfactants, and a preparation method thereof |
| JP2010510306A (en) * | 2006-11-22 | 2010-04-02 | エスケー ケミカルズ カンパニー リミテッド | Inclusion complex of sibutramine and beta-cyclodextrin |
| JP2010513356A (en) * | 2006-12-22 | 2010-04-30 | ノバルティス アーゲー | Formulation containing a neurokinin antagonist |
| JP2011515444A (en) * | 2008-03-25 | 2011-05-19 | フォーマック ファーマシューティカルズ ナムローゼ フェンノートシャップ | Method for preparing solid dispersion |
| US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1871346A4 (en) | 2012-07-18 |
| EP1871346A1 (en) | 2008-01-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20080194695A1 (en) | Pharmaceutical Composition Containing Sibutramine Free Base and Manufacturing Method Thereof | |
| US8202542B1 (en) | Abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings | |
| CN100528157C (en) | Form of presentation for 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino] propionic acid ethyl ester to be administered oral | |
| JP5547865B2 (en) | Sustained release pharmaceutical composition comprising aprindole and its derivatives | |
| TWI425944B (en) | Sustained-release formulation of zonisamide | |
| CN109562072B (en) | Pharmaceutical formulation for oral administration with controlled dissolution comprising slow-release pellets containing tamsulosin hydrochloride | |
| TWI836243B (en) | Pharmaceutical compositions and pharmacokinetics of a gamma-hydroxybutyric acid derivative | |
| AU2007338359B2 (en) | Pharmaceutical formulation comprising neurokinin antagonist | |
| WO2006112649A1 (en) | Pharmaceutical composition containing sibutramine free base and manufacturing method thereof | |
| WO2013119231A1 (en) | Abuse resistant opioid drug - ion exchange resin complexes having hybrid coatings | |
| JP2011513498A (en) | Drug delivery system comprising weakly basic drug and organic acid | |
| JP2002513760A (en) | Aqueous method for producing paroxetine solid dispersion | |
| BR112012023654B1 (en) | Method for producing granules containing anticoagulant agent and method for producing a pharmaceutical composition containing said agent | |
| CN1341014A (en) | Pharmaceutical capsule compositions containing loratadine and pseudoephedrine | |
| JP2009507875A (en) | 3- (2-Dimethylaminomethyl-cyclohexyl) -phenol sustained release formulation | |
| TWI859242B (en) | Modified release formulation of a pyrimidinylamino-pyrazole compound, and methods of treatment | |
| CN100404025C (en) | Orally disintegrating tablet containing tramadol hydrochloride and acetaminophen and preparation method thereof | |
| KR20180096530A (en) | Immediate-release and sustained-release pharmaceutical preparation comprising Itopride hydrochloride | |
| KR101761983B1 (en) | Fast dissolving oral thin film composite and preparing method thereof | |
| EP3995136A1 (en) | Pharmaceutical composition containing tamsulosin or hydrochloride thereof and preparation method therefor | |
| JP2000502066A (en) | Sustained-release cisapride | |
| BR112021012259A2 (en) | PHARMACEUTICAL COMPOSITION CONTAINING TANSULOSIN HYDROCHLORIDE WITH EXCELLENT ACID RESISTANCE AND METHOD OF PREPARING IT | |
| DK2736496T3 (en) | PHARMACEUTICAL COMPOSITION CONTAINING AN ANTI-MUSCARINE AND PROCEDURE FOR PREPARING THEREOF | |
| KR20180035723A (en) | Controlled release formulation for administration of Lacosamide | |
| CN114903850A (en) | A kind of famotidine hydrochloride sustained-release suspension preparation and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WWE | Wipo information: entry into national phase |
Ref document number: 200680012868.7 Country of ref document: CN |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| WWE | Wipo information: entry into national phase |
Ref document number: 2006757489 Country of ref document: EP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 11912081 Country of ref document: US |
|
| ENP | Entry into the national phase |
Ref document number: 2008507544 Country of ref document: JP Kind code of ref document: A |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 8461/DELNP/2007 Country of ref document: IN |
|
| NENP | Non-entry into the national phase |
Ref country code: RU |
|
| WWP | Wipo information: published in national office |
Ref document number: 2006757489 Country of ref document: EP |