CN1373656A - 含有脂酶抑制剂的分散体制剂 - Google Patents
含有脂酶抑制剂的分散体制剂 Download PDFInfo
- Publication number
- CN1373656A CN1373656A CN00812680A CN00812680A CN1373656A CN 1373656 A CN1373656 A CN 1373656A CN 00812680 A CN00812680 A CN 00812680A CN 00812680 A CN00812680 A CN 00812680A CN 1373656 A CN1373656 A CN 1373656A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- mixture
- composition
- surfactant
- dispersant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims description 90
- 239000006185 dispersion Substances 0.000 title description 4
- 238000009472 formulation Methods 0.000 title description 4
- 229940127470 Lipase Inhibitors Drugs 0.000 title description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 38
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims abstract description 37
- 229960001243 orlistat Drugs 0.000 claims abstract description 34
- 239000002270 dispersing agent Substances 0.000 claims abstract description 28
- 239000004094 surface-active agent Substances 0.000 claims abstract description 24
- 102000004882 Lipase Human genes 0.000 claims abstract description 11
- 108090001060 Lipase Proteins 0.000 claims abstract description 11
- 239000004367 Lipase Substances 0.000 claims abstract description 11
- 235000019421 lipase Nutrition 0.000 claims abstract description 11
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
- 102000019280 Pancreatic lipases Human genes 0.000 claims abstract description 5
- 108050006759 Pancreatic lipases Proteins 0.000 claims abstract description 5
- 230000002496 gastric effect Effects 0.000 claims abstract description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 36
- 229940086609 Lipase inhibitor Drugs 0.000 claims description 33
- -1 fatty acid esters Chemical class 0.000 claims description 27
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 24
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 18
- 239000000194 fatty acid Substances 0.000 claims description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 15
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 15
- 229930195729 fatty acid Natural products 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 11
- 239000000787 lecithin Substances 0.000 claims description 11
- 235000010445 lecithin Nutrition 0.000 claims description 11
- 229940067606 lecithin Drugs 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 10
- 229940040461 lipase Drugs 0.000 claims description 10
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-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 9
- 229930003427 Vitamin E Natural products 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 9
- 125000005456 glyceride group Chemical group 0.000 claims description 9
- 239000011709 vitamin E Substances 0.000 claims description 9
- 235000019165 vitamin E Nutrition 0.000 claims description 9
- 229940046009 vitamin E Drugs 0.000 claims description 9
- 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 8
- 208000008589 Obesity Diseases 0.000 claims description 8
- 235000020824 obesity Nutrition 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000000600 sorbitol Substances 0.000 claims description 8
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 8
- 150000005215 alkyl ethers Chemical class 0.000 claims description 7
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 229940099352 cholate Drugs 0.000 claims description 6
- 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 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 5
- 239000004359 castor oil Substances 0.000 claims description 5
- 235000019438 castor oil Nutrition 0.000 claims description 5
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical compound OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 claims description 4
- 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
- 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 4
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 claims description 4
- 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 4
- 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 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- 229920002774 Maltodextrin Polymers 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 4
- 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 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 150000008051 alkyl sulfates Chemical class 0.000 claims description 4
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 239000000693 micelle Substances 0.000 claims description 4
- 229940116369 pancreatic lipase Drugs 0.000 claims description 4
- 239000000344 soap Substances 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 229960002622 triacetin Drugs 0.000 claims description 4
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 3
- 239000003945 anionic surfactant Substances 0.000 claims description 3
- 230000036760 body temperature Effects 0.000 claims description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 3
- 239000002736 nonionic surfactant Substances 0.000 claims description 3
- 230000006320 pegylation Effects 0.000 claims description 3
- 229960000502 poloxamer Drugs 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
- 239000002888 zwitterionic surfactant Substances 0.000 claims description 3
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 239000004064 cosurfactant Substances 0.000 claims description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 2
- 229940031439 squalene Drugs 0.000 claims description 2
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000005846 sugar alcohols Chemical class 0.000 claims description 2
- 150000003505 terpenes Chemical class 0.000 claims description 2
- 235000007586 terpenes Nutrition 0.000 claims description 2
- IQXJCCZJOIKIAD-UHFFFAOYSA-N 1-(2-methoxyethoxy)hexadecane Chemical compound CCCCCCCCCCCCCCCCOCCOC IQXJCCZJOIKIAD-UHFFFAOYSA-N 0.000 claims 2
- 229950009789 cetomacrogol 1000 Drugs 0.000 claims 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims 2
- MOKBFXZQXUZAMV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCO MOKBFXZQXUZAMV-UHFFFAOYSA-N 0.000 claims 1
- 230000002421 anti-septic effect Effects 0.000 claims 1
- 239000003963 antioxidant agent Substances 0.000 claims 1
- 230000003078 antioxidant effect Effects 0.000 claims 1
- 235000006708 antioxidants Nutrition 0.000 claims 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims 1
- 150000001720 carbohydrates Chemical group 0.000 claims 1
- 235000014633 carbohydrates Nutrition 0.000 claims 1
- 239000006184 cosolvent Substances 0.000 claims 1
- 239000000314 lubricant Substances 0.000 claims 1
- 239000002562 thickening agent Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 description 15
- 239000003921 oil Substances 0.000 description 14
- 239000002775 capsule Substances 0.000 description 13
- 239000003925 fat Substances 0.000 description 11
- 235000019197 fats Nutrition 0.000 description 11
- 238000003756 stirring Methods 0.000 description 9
- 210000003608 fece Anatomy 0.000 description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 8
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 8
- 235000012054 meals Nutrition 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 5
- SIKWOTFNWURSAY-UHFFFAOYSA-N Lipstatin Natural products CCCCCCC1C(CC(CC=CCC=CCCCCC)C(=O)OC(CC(C)C)NC=O)OC1=O SIKWOTFNWURSAY-UHFFFAOYSA-N 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- OQMAKWGYQLJJIA-CUOOPAIESA-N lipstatin Chemical compound CCCCCC[C@H]1[C@H](C[C@H](C\C=C/C\C=C/CCCCC)OC(=O)[C@H](CC(C)C)NC=O)OC1=O OQMAKWGYQLJJIA-CUOOPAIESA-N 0.000 description 5
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical class [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 5
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 4
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 4
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000002550 fecal effect Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000008389 polyethoxylated castor oil Substances 0.000 description 3
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000003900 succinic acid esters Chemical class 0.000 description 3
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 2
- 239000004147 Sorbitan trioleate Substances 0.000 description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 2
- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 description 2
- 235000015220 hamburgers Nutrition 0.000 description 2
- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 description 2
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000001587 sorbitan monostearate Substances 0.000 description 2
- 235000011076 sorbitan monostearate Nutrition 0.000 description 2
- 229940035048 sorbitan monostearate Drugs 0.000 description 2
- 229950004959 sorbitan oleate Drugs 0.000 description 2
- 235000019337 sorbitan trioleate Nutrition 0.000 description 2
- 229960000391 sorbitan trioleate Drugs 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N trilaurin Chemical compound CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 229940002552 xenical Drugs 0.000 description 2
- OQQOAWVKVDAJOI-UHFFFAOYSA-N (2-dodecanoyloxy-3-hydroxypropyl) dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCC OQQOAWVKVDAJOI-UHFFFAOYSA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic 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)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- XLMXUUQMSMKFMH-UZRURVBFSA-N 2-hydroxyethyl (z,12r)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCCO XLMXUUQMSMKFMH-UZRURVBFSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 102100031416 Gastric triacylglycerol lipase Human genes 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- AHLBNYSZXLDEJQ-UHFFFAOYSA-N N-formyl-L-leucylester Natural products CCCCCCCCCCCC(OC(=O)C(CC(C)C)NC=O)CC1OC(=O)C1CCCCCC AHLBNYSZXLDEJQ-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 229920002651 Polysorbate 85 Polymers 0.000 description 1
- 244000173166 Pyrus ussuriensis Species 0.000 description 1
- 235000011572 Pyrus ussuriensis Nutrition 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241001655322 Streptomycetales Species 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- ZPVGIKNDGJGLCO-VGAMQAOUSA-N [(2s,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)O[C@@]1([C@]2(CO)[C@H]([C@H](O)[C@@H](CO)O2)O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O ZPVGIKNDGJGLCO-VGAMQAOUSA-N 0.000 description 1
- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000003858 bile acid conjugate Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000013367 dietary fats Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108010091264 gastric triacylglycerol lipase Proteins 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- UHUSDOQQWJGJQS-UHFFFAOYSA-N glycerol 1,2-dioctadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCC UHUSDOQQWJGJQS-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229940113171 polysorbate 85 Drugs 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 229950006451 sorbitan laurate Drugs 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 229950003429 sorbitan palmitate Drugs 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000021195 test diet Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005303 weighing Methods 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Obesity (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
本发明涉及含有至少一种脂酶抑制剂、至少一种表面活性剂和至少一种分散剂的药物组合物,其中脂酶抑制剂优选为胃肠和胰脂酶的抑制剂,例如奥利司他。
Description
本发明涉及含有至少一种脂酶抑制剂的药物组合物。
此类脂酶抑制剂的示例为脂抑素(lipstatin)和奥利司他(orlistat)。后者也称为四氢脂抑素(tetrahydrolipstatin)或THL，它是毒三素链霉菌天然排泄物的衍生物。发现此类化合物在体外及体内均具有抗各种脂酶如舌脂酶、胰脂酶、胃脂酶和羧酸酯脂酶的活性。US598,089描述它们可用于控制或预防肥胖症和高脂血症。
目前，每顿膳食给予120mg的奥利司他，剂量与人受试者的体重无关。奥利司他局部作用于胃肠(GI)道，可防止脂酶消化甘油三酸酯，并抑制可吸收脂质降解物的形成。因此，无需考虑脂酶抑制剂的全身利用度，相反，其在胃肠道中的局部滞留则是优先考虑的。
目前的脂酶抑制剂组合物可抑制混合膳食后约30％摄入脂肪的吸收；增加药物组合物中脂酶抑制剂的浓度并不能提高其临床功效和/或效力，相反可增强局部副作用的强度。
肛门漏油(油斑)是一种副作用，这在施用脂酶抑制剂治疗的患者中偶而发生。这种现象表现为：低位大肠处一些液状未吸收的饮食脂肪与固体本体发生了物理分离。
为了从根本上解决上述问题，需要提供一种脂酶抑制剂组合物，它可提高所述抑制剂分临床功效和/或效力，并可使上述缺点最小化或受到抑制。
本发明解决了这个问题，本发明提供含有至少上述一种脂酶抑制剂和至少一种表面活性剂和至少一种分散剂的药物组合物。
″分散剂″或″分散物质″是指促进组合物开始崩解和并促进其在所处环境中分布更佳的物质。
″表面活性剂″(表面活性物质)指例如洗涤剂类的物质，它可降低液体的亲油相与亲水相间表面张力。所述表面活性分子必须是部分亲水的(水溶性)且部分亲油性的(可溶于脂类或油类)。它富集于水与油或类脂的界面上，起到乳化剂或起泡剂作用。表面活性剂优选为阴离子-、非离子-和两性离子表面活性剂。
本发明中的术语″脂酶的抑制剂″和″脂酶抑制剂″指能抑制脂酶如胃和胰脂酶作用的化合物。例如US4,598,089描述的奥利司他和脂抑素即为有效的脂酶抑制剂。脂抑素来源于微生物的天然产物，而奥利司他则是脂抑素的氢化产物。其他脂酶抑制剂包括例如panclicins类化合物，它们是奥利司他的类似物(Mutoh等，1994)。术语″脂酶抑制剂″也指如PCT申请WO99/34786(Geltex制药公司)中描述的与聚合物结合的脂酶抑制剂。这些聚合物的特征在于它们已被一个或多个可抑制脂酶的基团所取代。术语″脂酶抑制剂″还包括这些化合物的可药用盐。术语″脂酶抑制剂″优选指奥利司他。
奥利司他是已知的用于控制或预防肥胖症和高脂血症的化合物。参见1986年7月1日公开的US4,598,089，其中披露了奥利司他的制备方法；US6,004,996公开了适宜的药物组合物。其他适宜的药物组合物参见PCT申请WO 00/09122和WO 00/09123的实施例。另一制备奥利司他的方法参见EP185,359、189,577、443,449和524,495。
优选每天分2-3次经口服给予奥利司他60-720mg/天，优选给予脂酶抑制剂180-360mg、最优选360mg/天，优选每天分2次或尤其是3次给予。受治疗者优选为肥胖或过重的人，即体重指数为25或更高的人。通常，优选在摄取含有脂肪的膳食时给予脂酶抑制剂。通常，优选采用上述脂酶抑制剂治疗有严重肥胖症史的人和体重指数为25或更高的人。
令人惊奇地发现，通过给药在含有至少一种上述表面活性剂和至少一种分散剂的药物组合物中的脂酶抑制剂，可明显地提高脂酶抑制剂的功效和效力。此外，受试者间功效和/或效力的个体差异以及副作用的频率和强度也得以降低。
已发现，人在进食期间口服施用本发明药物组合物，表现出非常有利的效果。令人惊奇地是，与现有的组合物比较，本发明药物组合物具有增强的功效和效力。此外，尽管有大量脂肪未被吸收，但是与目前已知的组合物相比，本发明组合物降低了单次膳食试验中(参见实施例1)的副作用。对人受试者进行的单次膳食研究结果表明，与常规制剂相比，摄取本发明组合物后收集的粪便中与粪便本体分离的油量较低。这是出人意料的，因为收集的粪便中存有相等或更高量的脂肪。
本发明脂酶抑制剂优选为胃肠道和胰脂酶抑制剂，最优选为奥利司他，其含量占组合物总重量的1-50％、优选5-30％。
至少一种表面活性剂的存在，对于在胃中得到最佳的颗粒分布是必要的。在本发明的一个优选实施方案中，表面活性剂选自阴离子-、非离子-和两性离子表面活性剂及其混合物。最优选的表面活性剂选自：维生素E聚乙二醇1000丁二酸酯(TPGS)、聚氧乙烯脱水山梨醇脂肪酸酯、聚氧乙烯硬脂酸酯、聚氧乙烯烷基醚、聚乙二醇化的(polyglycolyzed)甘油酯、聚氧乙烯蓖麻油、脱水山梨醇脂肪酸酯、泊洛沙姆、脂肪酸盐、胆盐、烷基硫酸盐、卵磷脂、胆盐与卵磷脂的混合胶束(micelle)、糖酯及它们的混合物。
″聚氧乙烯脱水山梨脂肪酸酯″为市售产品，包括脱水山梨醇的单-、二-或三脂肪酸酯(C8-C18)，例如POE(20)脱水山梨醇一月桂酸酯(聚山梨酯20)、POE(20)脱水山梨醇一棕榈酸酯(聚山梨酯40)、POE(20)脱水山梨醇一硬脂酸酯(聚山梨酯60)、POE(20)脱水山梨醇三硬脂酸酯(聚山梨酯65)、POE(6)脱水山梨醇一硬脂酸酯(PEG-6脱水山梨醇硬脂酸酯)、POE(20)脱水山梨醇一油酸酯(聚山梨酯80)、POE(20)脱水山梨醇三油酸酯(聚山梨酯85)、POE(6)脱水山梨醇一油酸酯(PEG-6脱水山梨醇油酸酯)和POE(20)脱水山梨醇单异硬脂酸酯(PEG-20脱水山梨醇异硬脂酸酯)。
术语″聚氧乙烯硬脂酸酯″是指聚乙二醇的硬脂酸酯，例如PEG 22硬脂酸酯、PEG 32硬脂酸酯和PEG 40硬脂酸酯。这些化合物是已知和市售的产品，例如Myrj类商品。
术语″聚氧乙烯烷基醚″指由聚氧乙烯和烷基基团构成的醚，例如POE(7)C12-14烷基醚、POE(9)C12-14烷基醚、POE(3)C12-14烷基醚和POE(9)C12-14烷基醚，例如Brij类商品。
″聚乙二醇化的甘油酯″指如下制备的表面活性剂：a)油类皂化，和b)用聚乙二醇(PEG)对脂肪酸进行再酯化，例如Gelucire类；或者是甘油酯与聚氧乙烯脂肪酸酯的混合物。
术语″聚氧乙烯蓖麻油″是指经聚乙二醇处理的蓖麻油，例如聚氧乙烯35蓖麻油(Cremophor EL)、PEG-30蓖麻油、PEG-40蓖麻油、PEG-25氢化蓖麻油和PEG-40氢化蓖麻油(Cremophor RH)。
术语″脂肪酸盐″指C12-C18脂肪酸、优选天然脂肪酸的可药用盐，例如油酸钠。
术语″烷基硫酸盐″指C12-C18烷基硫酸盐，例如十二烷基硫酸钠。
术语″脱水山梨醇脂肪酸酯″指C12-C18脂肪酸、优选天然脂肪酸的酯，例如脱水山梨醇月桂酸酯、脱水山梨醇油酸酯、脱水山梨醇棕榈酸酯、脱水山梨醇硬脂酸酯、脱水山梨醇三硬脂酸酯、脱水山梨醇三油酸酯等。
术语″卵磷脂″是指天然卵磷脂或合成卵磷脂。卵磷脂具有以下结构：其中R1-COOH和R2-COOH为如上定义的脂肪酸R1-COOH和R2-COOH(参见脂肪酸盐的定义)。
卵磷脂可选自天然卵磷脂、合成卵磷脂、大豆卵磷脂、蛋黄卵磷脂、合成的二棕榈酰卵磷脂、部分或完全氢化的卵磷脂及其混合物。
术语″胆盐″指可药用盐，如胆汁酸的钠盐例如胆酸盐、结合胆汁酸的钠盐，例如甘氨胆酸钠。
术语″糖酯″指糖的脂肪酸例如C12-C18脂肪酸酯，例如蔗糖硬脂酸酯或蔗糖棕榈酸酯。
术语″泊洛沙姆″指聚氧乙烯(poly(ethylenglykols))与聚氧丙烯(poly(propylenglykols))的嵌段共聚物，例如具有以下通式：其中a为2-130，b为15-67。
上述混合物均属已知且有市售产品。
术语″可药用的″指赋形剂的毒性是可接受的。
优选的表面活性剂选自： 维生素E聚乙二醇1000丁二酸酯，例如TPGS，Eastman化学公司；聚氧乙烯化的蓖麻油，例如Cremophor El，BASF公司；和聚乙二醇40硬脂酸酯，Myrj 52，Serva公司；Crodet S40，Croda公司。
表面活性剂通常至少占组合物总重量的0.1％，优选为0.1-90％，更优选为1-20％。
对于促进物质在脂酶抑制剂起作用的生理环境中的最初分散而言，存在至少一种分散剂的是重要的。分散剂可选自水溶或脂熔的化合物。通常，分散剂至少占组合物总重量的5％，优选为5-70％。
在本发明的一个优选实施方案中，分散剂指水溶性分散剂。适宜的水溶性分散剂可选自糖、糖醇、醇、泡腾剂、崩解剂和它们的混合物。更优选分散剂选自葡萄糖、山梨醇、甘露醇、麦芽糖糊精、乳糖、蔗糖、聚乙二醇、甘油、甘油三乙酸酯、glycofurol、泡腾剂例如NaHCO3/酸混合物如NaHCO3/柠檬酸，以及它们的混合物。最优选水溶性分散剂选自山梨醇、甘露醇、麦芽糖糊精、乳糖、蔗糖、聚乙二醇例如聚乙二醇100-10000、更优选为聚乙二醇400-6000例如聚乙二醇400、甘油、甘油三乙酸酯、glycofurol和以及它们的混合物。γ闪烁图研究表明，泡腾剂混合物(NaHCO3/柠檬酸)对胃内羟丙基甲基纤维素(HPMC)胶囊中内含物的分散具有显著的作用。
本发明中某些含有脂溶性化合物作为分散剂的组合物属于已知的自乳化给药系统(SEDDS)。SEDDS的特性在于：经温和振荡即可对油性成分进行乳化并形成微-或亚微乳。对SEDDS组合物的描述可参见C.W.Pouton，Advanced Drug Delivery Reviews，25，(1997)，47-58。将SEDDS分散于水性环境中后，可观察到它分成透明澄清的胶束(micellar)相和类脂液滴状乳液，其中加入的脂酶抑制剂分布于两相中。
因此，另一方面，上述本发明药物组合物包括至少一种体温下呈液态的脂溶性分散剂。
本发明中脂溶性分散剂的含量优选占组合物总重量的20-90％，并且在体温(即＞37℃)时呈液态。所述分散剂可选自甘油三酸酯、甘油二酸酯、甘油一酸酯、甘油二/一/三酸酯的混合物、维生素E、醋酸生育酚、萜烯、角鲨烯及它们的混合物。更优选的脂溶性化合物选自甘油三酸酯、甘油二酸酯、甘油一酸酯、甘油二/一/三酸酯的混合物、维生素E、醋酸生育酚及它们的混合物。优选的示例为中等链长的甘油三酸酯或中等链长的甘油三酸酯的混合物，例如精制椰子油(中等链长的甘油三酸酯，MCT，例如Miglyol 812，Huls AG，NeobeEM-5，Stepan，Captex 355，Abitec)。优选地，本发明组合物还包括另外的表面活性剂(共表面活性剂)。
术语″甘油酯″指甘油的脂肪酸酯，其中脂肪酸酯具有2-7个(短；短链甘油酯)、8-12个(中等；中等链甘油酯)和＞12个(长；长链甘油酯)碳原子。其示例为甘油三月桂酸酯、甘油三硬脂酸酯等。甘油二酸酯的示例为甘油二月桂酸酯、甘油二硬脂酸酯等。甘油一酸酯的示例为甘油一月桂酸酯、甘油一硬脂酸酯。本发明还包括甘油一/二/三酸酯的相应混合物。
本发明组合物的适施用可采用常规剂型如羟丙基甲基纤维素(HPMC)胶囊、软明胶胶囊、硬明胶胶囊、淀粉胶囊、片剂、咀嚼片和胶囊剂、糖浆剂等。
本发明适于采用任何脂酶抑制剂，但是尤其适于采用胃和胰的脂酶的抑制剂，特别是活性化合物奥利司他。本发明的一个优选组合物包括：
a)占组合物总重1-50％的至少一种脂酶抑制剂；
b)占组合物总重5-70％的至少一种分散剂；
c)占组合物总重0.1-90％的至少一种表面活性剂，和任选
d)一种或多脂可药用赋形剂。
更优选地，脂酶抑制剂例如奥利司他的含量占组合物总重3-30％，表面活性剂的含量占组合物总重1-20％。本发明还涉及上述药物组合物的制备方法，包括将至少一种脂酶抑制剂与至少一种表面活性剂、至少一种分散剂混合。
本发明另一方面提供了控制或预防肥胖症的方法，其中包括给患者施用上述药物组合物。
本发明还涉及上述组合物在制备用于预防和治疗肥胖症的药物中的应用。
通过下面的实施例，将对本发明作详细阐明。
表1列出了实施例1-7中奥利司他制剂和Xenical的脂肪排泄效果，以供参考。
实施例
实施例1
称取150mg MCT(中等链长的甘油三酸酯，精制椰子油，Miglyol 812，Huls AG；NeobeEM-5，Stepan；Captex 355，Abitec)和120mg维生素E聚乙二醇1000丁二酸酯(TPGS，Eastman化学公司)，置于玻璃容器中，于45℃加热/搅拌使之混合。然后将30mg奥利司他溶解得一澄清液体，并搅拌使之均匀。搅拌下加入200mg细研的泡腾剂维生素C片，然后冷却至室温(25℃)，得到固化的混合物。将所得组合物填入羟丙基甲基纤维素胶囊。
于单一膳食试验中，将上述含有60mg奥利司他组合物的胶囊剂给予人志愿者。受试者的膳食包括130g汉堡肉(hamburger meat)、10g奶油和100g炸薯条(花生油炸制)，总共含有约35g脂肪。收集单一膳食试验前1天至膳食试验后5天的粪便。取第一次和最后一次粪便，供本底(background)脂肪排泄的分析。冷冻储存粪便，并按Bligh和Dyer方法(Bligh，E.G.，和Dyer，W.J.，Can.J.Biochem.Physiol.，37，(1959年)，911)提取总脂质。减去本底脂质排泄量，得到由于奥利司他治疗所致的脂肪排泄量。采用重量法定量排泄的脂肪，并表示为试验膳食中脂肪含量的百分率。
实施例2
按实施例1方法，制备含有180mg Cremophor EL(聚氧乙烯蓖麻油，BASF公司)、60mg MCT、60mg奥利司他和200mg细研的泡腾剂维生素C的组合物。按实施例1方法，将每个装有含60mg奥利司他的上述组合物的羟丙基甲基纤维素胶囊给予人志愿者。
实施例3
按实施例1方法，制备含有450mg Gelucire 44/14(月桂酰聚乙二醇-32甘油酯，Gattefosse，法国)、90mg MCT、60mg奥利司他和200mg细研的泡腾剂维生素C的组合物。按实施例1的方法，将每个装有含60mg奥利司他的上述组合物的羟丙基甲基纤维素胶囊给予人志愿者。
实施例4
按实施例1方法制备组合物，其中以200mg细研的葡萄糖作为附加的赋形剂替代泡腾剂混合物。按实施例1方法，将每个装有含30mg奥利司他的上述组合物的羟丙基甲基纤维素胶囊给予人志愿者。
实施例5
将含有1700mg TPGS和300mg奥利司他的组合物加到行星式(planet)搅拌器中，其内部金属烧杯加热到60℃。待熔融后，搅拌混合物，并于150rpm连续搅拌下加入10g固体山梨醇。连续搅拌30分钟至制剂冷却到室温。然后将固体混合物过2mm筛。按实施例1方法，将每个装有含30mg奥利司他的上述组合物的羟丙基甲基纤维素胶囊给予人志愿者。
实施例6
将210mg聚乙二400(PEG 400，Clariant公司)与300mg甘油混合。加入30mg聚乙二醇40硬脂酸酯(Myrj 52，Serva德国公司；Crodet S40，Croda英国公司)。将混合物加热到60℃，然后搅拌下冷却至室温。向制得的混悬液中加入60mg奥利司他并搅拌均匀。将所得的组合物填入羟丙基甲基纤维素胶囊中。按实施例1方法，将每个装有含60mg奥利司他的上述组合物的羟丙基甲基纤维素胶囊给予人志愿者。
实施例7
将340mg甘油与30mg聚乙二醇40硬脂酸酯混合。将混合物加热到60℃，然后搅拌下冷却至室温。向制得的混悬液中加入30mg奥利司他、100mg聚乙二醇400(PEG 400)和100mg葡萄糖，并搅拌均匀。按实施例1方法，将每个装有含30mg奥利司他的上述组合物的羟丙基甲基纤维素胶囊给予人志愿者。
如表1所示，本发明组合物的功效和/或效力明显高于常规制剂。仅含有已知组合物一半或四分之一量脂酶抑制剂的本发明组合物，即具有相同的、甚至是更高的功效和/或效力。即使明显地降低组合物中活性化合物的用量，也能达到相同的脂酶抑制水平，因此明显降低了副作用。
表1列出了施用上述每个组合物后含有游离油的粪便样品个数。摄取本发明组合物后收集的粪便样品偶尔出现油从主要粪便中分离的现象，或者根本未发生分离。因此，本发明组合物可最小化或完全抑制已知组合物中最不利的副作用-肛门渗油。
表1：体内试验结果
| 实施例 | 奥利司他剂量(mg) | 排泄的脂肪 (1) | n(2) | 粪便样品中游离油(3) |
| 参考 | 120(Xenical) | 41.8±11.5 | 18 | 9/18 |
| 1 | 60 | 64.5±3.0 | 5 | 1/5 |
| 2 | 60 | 72.0±3.4 | 5 | 0/5 |
| 3 | 60 | 61.1±10.0 | 4 | 0/5 |
| 4 | 30 | 39.9±11.4 | 5 | 0/5 |
| 5 | 30 | 57.6±27.8 | 5 | 0/5 |
| 6 | 60 | 53.7±13.0 | 5 | 0/5 |
| 7 | 30 | 26.5±9.9 | 5 | 0/5 |
(1)排泄的脂肪量占脂肪摄入量的百分率
(2)接受试验的志愿者人数
(3)粪便含有游离油的人数/志愿者人数
Claims (29)
1.一种药物组合物，其含有至少一种脂酶抑制剂、至少一种表面活性剂和至少一种分散剂。
2.如权利要求1的药物组合物，其中所述表面活性剂选自阴离子-、非离子-和两性离子表面活性剂及它们的混合物。
3.如权利要求2的药物组合物，其中所述表面活性剂选自维生素E(聚乙二醇1000)丁二酸酯(TPGS)、聚氧乙烯脱水山梨醇脂肪酸酯、聚氧乙烯硬脂酸酯、聚氧乙烯烷基醚、聚氧乙烯蓖麻油、聚乙二醇化的甘油酯、脱水山梨醇脂肪酸酯、泊洛沙姆、脂肪酸盐、胆盐、烷基硫酸盐、卵磷脂、胆盐与卵磷脂和混合胶束、糖酯及它们的混合物。
4.如权利要求3的药物组合物，其中所述表面活性剂选自维生素E(聚乙二醇1000)丁二酸酯(TPGS)、聚乙氧基化的蓖麻油和聚乙二醇40硬脂酸酯。
5.如权利要求1-4之一的药物组合物，其中所述表面活性剂的含量至少占组合物总重量的0.1％。
6.如权利要求5的药物组合物，其中所述表面活性剂的含量占组合物总重量的0.1-90％。
7.如权利要求1-6之一的药物组合物，其中包括水溶性分散剂。
8.如权利要求7的药物组合物，其中所述分散剂选自糖、糖醇、醇、泡腾剂、崩解剂及它们的混合物。
9.如权利要求8的药物组合物，其中所述分散剂选自葡萄糖、山梨醇、甘露醇、麦芽糖糊精、乳糖、蔗糖、聚乙二醇、甘油、甘油三乙酸酯、glycofurol、泡腾剂及它们的混合物。
10.如权利要求8或9的药物组合物，其中所述分散剂选自山梨醇、甘露醇、麦芽糖糊精、乳糖、蔗糖、聚乙二醇、甘油、甘油三乙酸酯、glycofurol及它们的混合物。
11.如权利要求1-10之一的药物组合物，其中包括至少一种在体温下呈液态的脂溶性化合物。
12.如权利要求11的药物组合物，其中所述脂溶性化合物选自甘油三酸酯、甘油二酸酯、甘油一酸酯、甘油二/一/三酸酯的混合物、维生素E、醋酸生育酚、萜烯、角鲨烯及它们的混合物。
13.如权利要求12的药物组合物，其中所述脂溶性化合物选自甘油三酸酯、甘油二酸酯、甘油一酸酯、甘油二/一/三酸酯的混合物、维生素E、醋酸生育酚及它们的混合物。
14.如权利要求13的药物组合物，其中所述脂溶性化合物为中等链长的甘油三酸酯或中等链长甘油三酸酯的混合物。
15.如权利要求1-14之一的药物组合物，其中所述分散剂的含量至少占组合物总重量的5％。
16.如权利要求15的药物组合物，其中所述分散剂的含量占组合物总重量的5-70％。
17.如权利要求1-16之一的药物组合物，其中所述脂溶性分散剂的含量占组合物总重量的20-90％。
18.如权利要求1-17之一的药物组合物，还包括另外的共表面活性剂。
19.如权利要求1-18之一的药物组合物，其中所述脂酶抑制剂为胃肠道和胰脂酶的抑制剂。
20.如权利要求19的药物组合物，其中所述胃肠道脂酶的抑制剂为奥利司他。
21.如权利要求1-20之一的药物组合物，其中脂酶抑制剂的含量占组合物总重量的1-50％。
22.如权利要求21的药物组合物，其中脂酶抑制剂的含量占组合物总重量的5-30％。
23.如权利要求1-21之一的药物组合物，还包括选自碳水化合物、抗氧剂、共溶剂以及增稠剂、防腐剂和润滑剂的可药用赋形剂。
24.如权利要求1-23之一的药物组合物，包括：
a)占组合物总重量1-50％的至少一种脂酶抑制剂；
b)占组合物总重量5-70％的至少一种分散剂；
c)占组合物总重量0.1-90％的至少一种表面活性剂，和任选
d)一种或多种可药用赋形剂。
25.一种制备如权利要求1-24中任一所限定的药物组合物的方法，包括将至少一种脂酶抑制剂与至少一种表面活性剂及至少一种分散剂混合。
26.如权利要求1-24中任一所限定的药物组合物用于控制或预防肥胖症的用途。
27.一种控制或预防肥胖症的方法，给患者施用如权利要求1-24中任一所限定的药物组合物的步骤。
28.如权利要求1-24中任一所限定的药物组合物在制备用于预防和治疗肥胖症的药物中的应用。
29.以上所述的本发明。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP99118180.1 | 1999-09-13 | ||
| EP99118180 | 1999-09-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1373656A true CN1373656A (zh) | 2002-10-09 |
| CN1197551C CN1197551C (zh) | 2005-04-20 |
Family
ID=8238990
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB008126801A Expired - Lifetime CN1197551C (zh) | 1999-09-13 | 2000-09-11 | 含有脂酶抑制剂的分散体制剂 |
Country Status (39)
| Country | Link |
|---|---|
| US (3) | US20030181512A1 (zh) |
| EP (1) | EP1216025B1 (zh) |
| JP (1) | JP4217016B2 (zh) |
| KR (1) | KR100572434B1 (zh) |
| CN (1) | CN1197551C (zh) |
| AR (1) | AR025587A1 (zh) |
| AT (1) | ATE333866T1 (zh) |
| AU (1) | AU769415B2 (zh) |
| BR (2) | BR0013939A (zh) |
| CA (1) | CA2383916C (zh) |
| CO (1) | CO5180587A1 (zh) |
| CY (1) | CY1106180T1 (zh) |
| CZ (1) | CZ301901B6 (zh) |
| DE (1) | DE60029602T2 (zh) |
| DK (1) | DK1216025T3 (zh) |
| EG (1) | EG24117A (zh) |
| ES (1) | ES2267563T3 (zh) |
| HK (1) | HK1049966A1 (zh) |
| HR (1) | HRP20020205B1 (zh) |
| HU (1) | HU228858B1 (zh) |
| IL (1) | IL148494A0 (zh) |
| JO (1) | JO2386B1 (zh) |
| MA (1) | MA26818A1 (zh) |
| ME (1) | MEP90808A (zh) |
| MX (1) | MXPA02002034A (zh) |
| MY (1) | MY130200A (zh) |
| NO (1) | NO331906B1 (zh) |
| NZ (1) | NZ517545A (zh) |
| PE (1) | PE20010595A1 (zh) |
| PL (1) | PL199870B1 (zh) |
| PT (1) | PT1216025E (zh) |
| RS (1) | RS50422B (zh) |
| RU (1) | RU2239428C2 (zh) |
| SI (1) | SI1216025T1 (zh) |
| TR (1) | TR200200606T2 (zh) |
| TW (1) | TWI243060B (zh) |
| UY (1) | UY26338A1 (zh) |
| WO (1) | WO2001019340A1 (zh) |
| ZA (1) | ZA200201518B (zh) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007033522A1 (fr) * | 2005-09-21 | 2007-03-29 | Shenzhen Tys R & D Co., Ltd. | Formulation de gélule contenant de la moxifloxacine et son procédé de préparation |
| US8246985B2 (en) | 2006-04-20 | 2012-08-21 | Amorepacific Corporation | Pharmaceutical composition comprising lipase inhibitor and lipophilic oil absorbent and oral formulation prepared therefrom |
| CN106310287A (zh) * | 2015-06-25 | 2017-01-11 | 山东省药学科学院 | 新利司他药用组合物及其制备方法 |
| CN114983938A (zh) * | 2022-05-19 | 2022-09-02 | 广东嘉博制药有限公司 | 一种奥利司他口服复合乳液及其制备方法 |
| CN115105476A (zh) * | 2021-03-23 | 2022-09-27 | 山东新时代药业有限公司 | 一种奥利司他冻干口服制剂及其制备工艺 |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI1307264T1 (en) | 2000-07-28 | 2005-02-28 | F. Hoffmann-La Roche Ag | New pharmaceutical composition |
| US20030027786A1 (en) * | 2001-06-06 | 2003-02-06 | Karsten Maeder | Lipase inhibiting composition |
| US6730319B2 (en) * | 2001-06-06 | 2004-05-04 | Hoffmann-La Roche Inc. | Pharmaceutical compositions having depressed melting points |
| US8372430B2 (en) * | 2002-12-17 | 2013-02-12 | The Procter & Gamble Company | Compositions, methods, and kits useful for the alleviation of gastrointestinal effects |
| FI20045076A (fi) * | 2004-03-15 | 2005-09-16 | Bioferme Oy | Funktionaalinen elintarvike |
| AU2006236564B2 (en) * | 2005-04-15 | 2011-02-17 | Tolmar, Inc. | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
| KR100910000B1 (ko) * | 2005-05-13 | 2009-07-29 | 씨제이제일제당 (주) | 리파아제 저해제 함유 약학 조성물 |
| PL1897558T3 (pl) * | 2005-06-09 | 2014-01-31 | Norgine Bv | Stały preparat 2-heksadecyloksy-6-metylo-4H-3,1-benzoksazyn-4-onu |
| KR100669497B1 (ko) * | 2005-08-17 | 2007-01-16 | 보람제약주식회사 | 안정성과 용출률이 뛰어난 약리학적 조성물 및 그 제조방법 |
| TR200607613A2 (tr) * | 2006-12-29 | 2008-07-21 | NOBEL İLAÇ SAN.ve TiC.A.Ş. | Lipaz inhibitörü içeren farmasötik formülasyonlar |
| EP1970051A1 (en) * | 2007-03-14 | 2008-09-17 | Merz Pharma GmbH & Co.KGaA | Use of an aqueous micro-emulsion for the preparation of a formulation for the treatment of adipose diseases |
| KR101439470B1 (ko) * | 2007-05-22 | 2014-09-16 | 한미사이언스 주식회사 | 오를리스타트 및 대변 연화제를 포함하는 비만의 예방 또는치료용 조성물 |
| PL2036575T3 (pl) * | 2007-09-12 | 2011-02-28 | Mader S R L | Kompozycje farmaceutyczne do stosowania doustnie w leczeniu pacjentów dotkniętych otyłością |
| EP2044930A1 (en) * | 2007-10-01 | 2009-04-08 | Nestec S.A. | Composition for controlling lipase catalyzed reactions |
| PL216542B1 (pl) | 2008-03-20 | 2014-04-30 | Zakłady Farmaceutyczne POLPHARMA Spółka Akcyjna | Sposób wytwarzania stabilnej kompozycji orlistatu w postaci kapsułkowanego proszku |
| WO2010042499A1 (en) * | 2008-10-06 | 2010-04-15 | Banner Pharmacaps, Inc. | Stable solutions of orlistat for pharmaceutical dosage forms |
| KR20100075260A (ko) * | 2008-12-24 | 2010-07-02 | 주식회사종근당 | 리파아제 저해제의 부작용 개선을 위한 신규한 약제학적 조성물 |
| BRPI0901602B8 (pt) | 2009-04-03 | 2021-05-25 | Ems S/A | formulação farmacêuticas |
| ITRM20120331A1 (it) | 2012-07-12 | 2014-01-13 | Guidotti & C Spa Labor | Composizioni pediatriche orali liquide contenenti nepadutant. |
| WO2016166767A1 (en) * | 2015-04-14 | 2016-10-20 | Zim Laboratories Limited | Pharmaceutical formulation comprising low melting, highly lipophilic drugs |
| MY196635A (en) * | 2018-06-22 | 2023-04-25 | Sime Darby Plantation Intellectual Property Sdn Bhd | Method For Reducing Formation of Free Fatty Acids in Plants |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1247547A (en) | 1983-06-22 | 1988-12-28 | Paul Hadvary | Leucine derivatives |
| DE3887179T2 (de) * | 1987-03-02 | 1994-06-16 | Brocades Pharma Bv | Pharmazeutische Zusammensetzung, pharmazeutisches Granulat und Verfahren zu ihrer Herstellung. |
| TW381025B (en) | 1993-08-05 | 2000-02-01 | Hoffmann La Roche | Pharmaceutical composition containing a glucosidase inhibitor and a lipase inhibitor |
| IT1282673B1 (it) | 1996-02-23 | 1998-03-31 | Ist Naz Stud Cura Dei Tumori | Derivati della camptotecina e loro uso come agenti antitumorali |
| EP1017366A4 (en) | 1996-09-01 | 2006-03-22 | Pharmos Corp | SOLID COPARCIPITATES FOR IMPROVED BIOVERABILITY OF LIPOPHILIC SUBSTANCES |
| US5891469A (en) * | 1997-04-02 | 1999-04-06 | Pharmos Corporation | Solid Coprecipitates for enhanced bioavailability of lipophilic substances |
| US6004996A (en) * | 1997-02-05 | 1999-12-21 | Hoffman-La Roche Inc. | Tetrahydrolipstatin containing compositions |
| DK1017408T3 (da) * | 1997-02-05 | 2005-08-01 | Hoffmann La Roche | Anvendelse af tetrahydrolipstatin i behandling af diabetes type II |
| US6267952B1 (en) | 1998-01-09 | 2001-07-31 | Geltex Pharmaceuticals, Inc. | Lipase inhibiting polymers |
| DK1105122T3 (da) | 1998-08-14 | 2005-08-08 | Hoffmann La Roche | Pharmaceutical compositions containing lipase inhibitors |
| ES2217797T3 (es) | 1998-08-14 | 2004-11-01 | F. Hoffmann-La Roche Ag | Vinileteres heterociclicos contra trastornos neurologicos. |
| US6368622B2 (en) * | 1999-01-29 | 2002-04-09 | Abbott Laboratories | Process for preparing solid formulations of lipid regulating agents with enhanced dissolution and absorption |
-
2000
- 2000-09-07 AR ARP000104679A patent/AR025587A1/es not_active Application Discontinuation
- 2000-09-11 TR TR2002/00606T patent/TR200200606T2/xx unknown
- 2000-09-11 EP EP00960643A patent/EP1216025B1/en not_active Expired - Lifetime
- 2000-09-11 IL IL14849400A patent/IL148494A0/xx active IP Right Grant
- 2000-09-11 WO PCT/EP2000/008858 patent/WO2001019340A1/en active IP Right Grant
- 2000-09-11 CA CA002383916A patent/CA2383916C/en not_active Expired - Lifetime
- 2000-09-11 PL PL356174A patent/PL199870B1/pl unknown
- 2000-09-11 CN CNB008126801A patent/CN1197551C/zh not_active Expired - Lifetime
- 2000-09-11 ES ES00960643T patent/ES2267563T3/es not_active Expired - Lifetime
- 2000-09-11 PT PT00960643T patent/PT1216025E/pt unknown
- 2000-09-11 DE DE60029602T patent/DE60029602T2/de not_active Expired - Lifetime
- 2000-09-11 BR BR0013939-4A patent/BR0013939A/pt not_active IP Right Cessation
- 2000-09-11 CZ CZ20021276A patent/CZ301901B6/cs not_active IP Right Cessation
- 2000-09-11 RS YUP-172/02A patent/RS50422B/sr unknown
- 2000-09-11 BR BRPI0013939-4A patent/BRPI0013939B1/pt unknown
- 2000-09-11 MX MXPA02002034A patent/MXPA02002034A/es active IP Right Grant
- 2000-09-11 AU AU72863/00A patent/AU769415B2/en not_active Expired
- 2000-09-11 SI SI200030888T patent/SI1216025T1/sl unknown
- 2000-09-11 JP JP2001522975A patent/JP4217016B2/ja not_active Expired - Lifetime
- 2000-09-11 NZ NZ517545A patent/NZ517545A/en not_active IP Right Cessation
- 2000-09-11 DK DK00960643T patent/DK1216025T3/da active
- 2000-09-11 ME MEP-908/08A patent/MEP90808A/xx unknown
- 2000-09-11 HU HU0202737A patent/HU228858B1/hu unknown
- 2000-09-11 AT AT00960643T patent/ATE333866T1/de active
- 2000-09-11 KR KR1020027003269A patent/KR100572434B1/ko active IP Right Grant
- 2000-09-11 RU RU2002107428/15A patent/RU2239428C2/ru active
- 2000-09-12 EG EG20001159A patent/EG24117A/xx active
- 2000-09-12 UY UY26338A patent/UY26338A1/es not_active Application Discontinuation
- 2000-09-12 JO JO2000157A patent/JO2386B1/en active
- 2000-09-12 CO CO00068859A patent/CO5180587A1/es active IP Right Grant
- 2000-09-13 MY MYPI20004253A patent/MY130200A/en unknown
- 2000-09-13 PE PE2000000949A patent/PE20010595A1/es not_active IP Right Cessation
- 2000-10-19 TW TW089121968A patent/TWI243060B/zh not_active IP Right Cessation
-
2002
- 2002-02-22 ZA ZA200201518A patent/ZA200201518B/xx unknown
- 2002-03-07 HR HR20020205A patent/HRP20020205B1/xx not_active IP Right Cessation
- 2002-03-11 MA MA26545A patent/MA26818A1/fr unknown
- 2002-03-12 NO NO20021204A patent/NO331906B1/no not_active IP Right Cessation
-
2003
- 2003-03-25 HK HK03102148A patent/HK1049966A1/xx not_active IP Right Cessation
- 2003-04-21 US US10/419,346 patent/US20030181512A1/en not_active Abandoned
-
2004
- 2004-03-05 US US10/794,123 patent/US8012494B2/en not_active Expired - Lifetime
-
2006
- 2006-09-29 CY CY20061101416T patent/CY1106180T1/el unknown
-
2011
- 2011-07-19 US US13/185,558 patent/US20110275706A1/en not_active Abandoned
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007033522A1 (fr) * | 2005-09-21 | 2007-03-29 | Shenzhen Tys R & D Co., Ltd. | Formulation de gélule contenant de la moxifloxacine et son procédé de préparation |
| US8246985B2 (en) | 2006-04-20 | 2012-08-21 | Amorepacific Corporation | Pharmaceutical composition comprising lipase inhibitor and lipophilic oil absorbent and oral formulation prepared therefrom |
| CN106310287A (zh) * | 2015-06-25 | 2017-01-11 | 山东省药学科学院 | 新利司他药用组合物及其制备方法 |
| CN106310287B (zh) * | 2015-06-25 | 2019-03-19 | 山东省药学科学院 | 新利司他药用组合物及其制备方法 |
| CN115105476A (zh) * | 2021-03-23 | 2022-09-27 | 山东新时代药业有限公司 | 一种奥利司他冻干口服制剂及其制备工艺 |
| CN115105476B (zh) * | 2021-03-23 | 2023-11-14 | 山东新时代药业有限公司 | 一种奥利司他冻干口服制剂及其制备工艺 |
| CN114983938A (zh) * | 2022-05-19 | 2022-09-02 | 广东嘉博制药有限公司 | 一种奥利司他口服复合乳液及其制备方法 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1197551C (zh) | 含有脂酶抑制剂的分散体制剂 | |
| CN1197554C (zh) | 固体类脂制剂 | |
| AU2007265836B8 (en) | An effective pharmaceutical carrier for poorly bioavailable drugs | |
| AU2018100110A4 (en) | Ubiquinone And Ubiquinol Compositions, And Methods Relating Thereto | |
| US8685455B2 (en) | Oil-in-water emulsions containing lignan-class compounds and compositions containing the same | |
| CN1339963A (zh) | 可自发分散的n－苯甲酰基－星形孢菌素组合物 | |
| DE60218845T2 (de) | Einen Lipase-Inhibtor und einen Saccharosefettsäuremonoester enthaltende pharmazeutische Zusammensetzung | |
| CN1791400A (zh) | 用于降低体内脂质的组合物 | |
| CN101450039A (zh) | 一种含两性霉素b的长效制剂 | |
| JP2017535611A (ja) | トコトリエノールを効果的に送達するための製剤 | |
| CN1586599A (zh) | 含有鸦胆子油的药物制剂 | |
| CN1736412A (zh) | 含丹参脂溶性成分的口服组合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1049966 Country of ref document: HK |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20180801 Address after: Greifswald, Germany Patentee after: Koplar Pharmaceutical Pharmaceutical Company Limited Address before: Basel Patentee before: F. Hoffmann-La Roche AG |
|
| TR01 | Transfer of patent right | ||
| CX01 | Expiry of patent term |
Granted publication date: 20050420 |
|
| CX01 | Expiry of patent term |