CN102949343B - A kind of improve the method for fat-soluble medicine useful load in liposome - Google Patents
A kind of improve the method for fat-soluble medicine useful load in liposome Download PDFInfo
- Publication number
- CN102949343B CN102949343B CN201110246902.XA CN201110246902A CN102949343B CN 102949343 B CN102949343 B CN 102949343B CN 201110246902 A CN201110246902 A CN 201110246902A CN 102949343 B CN102949343 B CN 102949343B
- Authority
- CN
- China
- Prior art keywords
- liposome
- paclitaxel
- medicine
- fat
- phospholipid
- 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.)
- Active
Links
- 239000002502 liposome Substances 0.000 title claims abstract description 58
- 239000003814 drug Substances 0.000 title claims abstract description 52
- 238000011068 load Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 229940079593 drugs Drugs 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 230000000694 effects Effects 0.000 claims abstract description 5
- RCINICONZNJXQF-MZXODVADSA-N Intaxel Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 50
- 229960001592 Paclitaxel Drugs 0.000 claims description 48
- 229930003347 taxol Natural products 0.000 claims description 48
- 150000003904 phospholipids Chemical class 0.000 claims description 23
- 239000012071 phase Substances 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 239000008346 aqueous phase Substances 0.000 claims description 8
- 150000002632 lipids Chemical class 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 7
- 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 claims description 6
- 229940067606 Lecithin Drugs 0.000 claims description 6
- 239000000787 lecithin Substances 0.000 claims description 6
- 235000010445 lecithin Nutrition 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 239000000839 emulsion Substances 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutic aid Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 230000003078 antioxidant Effects 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 230000003204 osmotic Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 8
- 230000001988 toxicity Effects 0.000 abstract description 8
- 239000002245 particle Substances 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 210000000481 Breast Anatomy 0.000 abstract description 2
- 238000010025 steaming Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 17
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 229940090044 Injection Drugs 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 238000004108 freeze drying Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 229940108949 Paclitaxel Injection Drugs 0.000 description 7
- 229940107161 Cholesterol Drugs 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000010408 film Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 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 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000008389 polyethoxylated castor oil Substances 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 230000000259 anti-tumor Effects 0.000 description 3
- 210000004027 cells Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N Camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N Dipalmitoylphosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 description 2
- 210000003205 Muscles Anatomy 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 210000003462 Veins Anatomy 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940045698 antineoplastic Taxanes Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical class CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000003203 everyday Effects 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- -1 oleic acid trimethylammonium propane Chemical compound 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4S,4aS,5aS,6S,12aR)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine zwitterion Chemical class CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 description 1
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 description 1
- PPWHTZKZQNXVAE-UHFFFAOYSA-N 2-(dimethylamino)ethyl 4-(butylamino)benzoate;hydron;chloride Chemical compound Cl.CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 PPWHTZKZQNXVAE-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 208000003455 Anaphylaxis Diseases 0.000 description 1
- 206010003084 Areflexia Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- 240000006954 Cunninghamia lanceolata Species 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- 101710040861 DCN Proteins 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N DMPC Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N EPIRUBICIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- 229960001904 EPIRUBICIN Drugs 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 229960003088 Loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N Loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Natural products CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 231100000614 Poison Toxicity 0.000 description 1
- 241000195474 Sargassum Species 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N Trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 229940046009 Vitamin E Drugs 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 231100000494 adverse effect Toxicity 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 230000003266 anti-allergic Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000003556 assay method Methods 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 201000009030 carcinoma Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000001472 cytotoxic Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 1
- 230000000670 limiting Effects 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 102000005614 monoclonal antibodies Human genes 0.000 description 1
- 108010045030 monoclonal antibodies Proteins 0.000 description 1
- 210000004493 neutrocyte Anatomy 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- IYNDLOXRXUOGIU-UHFFFAOYSA-M potassium;3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [K+].O=C1N2C(C([O-])=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-UHFFFAOYSA-M 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 101710004466 rgy Proteins 0.000 description 1
- 101710030364 rgy1 Proteins 0.000 description 1
- 101710030359 rgy2 Proteins 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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 description 1
Abstract
The invention discloses the preparation method of a kind of liposome improving fat-soluble medicine useful load, the method is to be dissolved in organic solvent by fat-soluble medicine, one-tenth breast the most mixed with water, high pressure homogenize obtains the liposome of uniform particle size, finally revolves steaming, concentration, the liposome of lyophilizing acquisition high drug load.The method can not only obtain high envelop rate, and can improve the curative effect of medicine, reduce toxicity.
Description
Technical field
The present invention relates to a kind of improve the method for fat-soluble medicine useful load in liposome, and by the party's legal system
The liposome obtained, and in preparation purposes in the medicine treating tumor disease.
Background technology
Liposome has raising curative effect of medication as pharmaceutical carrier, alleviates adverse effect and targeting, slow release
Etc. feature, during especially as the carrier of antitumor drug, most drug targeting tumor area can be made to rise
To attenuation, potentiation.
The antitumor drug applied clinically at present is numerous, is broadly divided into cell toxicant class, hormones, biology
This five class of reaction control agent, monoclonal antibody and other antitumor drug.Wherein cytotoxic drug accounts for city
Market share is maximum, and it can be divided into following five classes according to mechanism of action: (1) acts on DNA chemical constitution
Medicine, such as: alkylating agent and platinum class；(2) medicine of nucleic acid synthesis is affected, such as: methotrexate, fluorine are urinated phonetic
Pyridine etc.；(3) medicine of transcribed nucleic acid is acted on, such as: amycin, epirubicin etc.；(4) act on micro-
The medicine of tubulin synthesis, such as: taxanes, vinca；Act on the medicine of topoisomerase, such as:
Camptothecin；(5) other Cytotoxic drugs.
Paclitaxel is the representative medicine of taxanes, and it, by promoting tubulin polymerization suppression depolymerization, keeps
Tubulin is stable, and suppression cell mitogen realizes antitumor action, is that an outstanding wide spectrum is anti-swollen
Tumor medicine.But paclitaxel can produce bone marrow depression, peripheral nervous toxicity, muscle/arthralgia, rhythm of the heart mistake
Often and the toxic and side effects such as gastrointestinal toxicity, its dose limiting toxicity is for biting neutrophilic leukocyte minimizing.Due to purple
China fir alcohol is fat-soluble medicine, and its solvability in water is very poor, so commercially available preparation uses Cremophor
EL and ethanol are as solvent.Cremophor EL is a kind of surfactant, can cause serious anaphylaxis,
Even if using 17-hydroxy-11-dehydrocorticosterone and Loratadine in advance, the incidence rate of this untoward reaction is still about 41%.
And the use of Cremophor EL so that paclitaxel, in vivo in nonlinear kinetics, is unfavorable for clinical application
Safety.
In order to avoid the use of Cremophor EL, reduce the toxic and side effects of medicine, it is considered to made by paclitaxel
Liposomal formulation.The drug delivery technologies of Liposomal formulation is divided into Active loading technology and Passive loading technology two kinds,
Fat-soluble medicine is typically chosen Passive loading technology, and water soluble drug generally uses Active loading technology.Ramulus et folium taxi cuspidatae
Alcohol belongs to fat-soluble medicine, so selecting Passive loading technology, its conventional method for preparing lipidosome includes thin
Film dispersion method, alcohol injection, organic solvent lyophilization, single phase soln lyophilization etc., be described below.
(1) film dispersion method
The liposoluble constituents such as medicine, phospholipid and cholesterol are dissolved in organic solvent, usually chloroform, second
Ether etc., concentration is 10～40mg/ml, is placed in round-bottomed flask reduction vaporization, obtains one layer of dry adipose membrane,
Add appropriate buffer salt aquation adipose membrane, i.e. can get liposome.The shortcoming of the method is: 1. need to make
With organic solvents such as chloroforms.Although also having use ethanol to make solvent, but ethanol being the most volatile,
Film property is poor.2. it is difficult to produce amplify.Although someone devises the special device that surface area is bigger, it is desirable to
Improve technique whereby, but be not the most applied.
(2) alcohol injection
By medicine, phospholipid ethanol solution at a suitable temperature, the aqueous phase being slowly injected into high-speed stirred is molten
In liquid, ethanol spreads rapidly, thus causes phospholipid molecule to be assembled due to thermodynamic (al) reason and form liposome.
The granularity of the liposome formed and the concentration being distributed with phospholipid solution, mixing speed, phospholipid composition and fat phase
Much relations are had with the ratio of aqueous phase.Said method is too many due to influence factor, it is more difficult to industrialization, therefore needs
Improve.
(3) organic solvent lyophilization
Medicine, phospholipid, cholesterol are dissolved in suitable organic solvent, are most commonly used that the tert-butyl alcohol, so
Postlyophilization obtains loose powdered, after its aquation, then can obtain liposome.This kind of method should
With industrialization, and the tert-butyl alcohol toxicity used is similar with ethanol, is unlikely to cause problem for security.
(4) single phase soln lyophilization
Medicine, phospholipid and cholesterol, disaccharide are dissolved in the butanol/water cosolvent that ratio is suitable, are formed
Single phase soln, by above-mentioned single phase soln lyophilization, the solid dispersion of available fat/sugar.Such as fructose/fat ratio
Properly, aquation lyophilized products, i.e. can obtain the liposome of the submicron order of even particle size distribution.This kind of work
Skill can solve the stability problem of Liposomal formulation, and technique is simple, and be easy to get sterile preparation.But only
It is suitable for the natural phospholipid that phase transition temperature is low, and prescription should add the most charged phospholipid.
Paclitaxel liposome is prepared owing to there being more method can apply to, in order to reduce trial stretch,
First we investigated the successful case of some domestic and international Paclitaxel liposomes, and analysis result is as follows.
The Paclitaxel liposome that code name is EndoTAG-1 that the medigene company of Germany develops has entered
Enter second phase clinical stage, United States Patent (USP) US7794747, title: Method of producing a cationic
Liposomal preparation comprising a lipophilic compound, disclosed preparation method is by 50
Double oleic acid trimethylammonium propane (DOTAP) of mol%, double oleic acid phosphatidylcholines (DOPC) of 47mol%
It is dissolved in ethanol with the paclitaxel of 3mol%, then uses pin pump to inject Sargassum sucrose solution with the speed of 0.4ml/min
In phase solution, hatch at least 5 minutes.The liposome formed is extruded by the polycarbonate membrane of 200nm, so
Afterwards by 0.22um filter membrane aseptic filtration, last lyophilizing obtains finished product.This preparation technology belongs to above-mentioned
Alcohol injection, it is less than normal that it there is problems of 1. paclitaxel carried medicine amount；2. DOTAP and DOPC is the most very
Costliness, domestic being difficult to is buied.
The Paclitaxel liposome that code name is LEP-ETU that the neopharm company of the U.S. develops also comes into two
Phase clinical stage, United States Patent (USP) US7314637, title: Method of administering liposomal
Encapsulated taxane, disclosed preparation method is by heart phosphorus that weight ratio is 1.8: 9.0: 3.0: 0.1: 1
Fat, phosphatidylcholine, cholesterol, vitamin E and paclitaxel, heating for dissolving, in the tert-butyl alcohol, is then passed through
0.22 μm filter membrane, subpackage lyophilization.Addition normal saline during Clinical practice, room temperature aquation 1 hour,
Thereafter by bottle whirling motion ten minutes, finally with peak frequency ultrasonic ten minutes in water bath sonicator agitator.Should
Preparation technology belongs to organic solvent lyophilization above-mentioned, its there is problems of 1. cuorin costly,
Domestic being difficult to is buied；2. clinical application complex operation, the lipid that different operator and ultrasonic device obtain
Body solution at end may there are differences；3. liposomal particle size is not controlled effectively, and may affect it
Curative effect and toxicity.
The taxusol-lipid muscle power that domestic Nanjing Sike Pharmaceutical Co., Ltd develops is flutterred element and has been listed, and it is prepared
Method is paclitaxel, lecithin and cholesterol that mass ratio is 6: 72: 10.8 to be dissolved in ethanol in proper amount,
By the mannitol solution aquation containing lysine after constant temperature drying under reduced pressure film forming, then Ultrasonic Pulverization or high pressure are even
Slurry, finally by 0.22 μm filter membrane aseptic filtration, subpackage postlyophilization.First add in bottle before Clinical practice
Enter 10ml 5% glucose solution, put and shake on agitator 5 minutes, until completely dissolved, inject 250-500ml
In 5% glucose solution, intravenous drip 3 hours.This preparation technology belongs to films mentioned above dispersion method, its
There is problems of 1. Clinical practice time comparatively laborious, shake on the oscillator after needing aquation 5 minutes.2. divide
Analysis power flutter element quality standard find its redissolve after particle size range be 4.5-5 μm, illustrate that it is multilamelar liposome,
It not that we intend the nanometer liposome category of exploitation.3. flutter in element operation instructions visible by power, using
Within first 30 minutes, still need to carry out antiallergic pretreatment, and by analyzing its patent (Chinese patent
CN00119039.3, title: taxusol-lipid composition and preparation method thereof) find its drug effect also with Ramulus et folium taxi cuspidatae
Alcohol normal injection agent is suitable, it is believed that it does not embody the advantage of Liposomal formulation.
Analyzed it is considered that film dispersion method, organic solvent lyophilization and ethanol mentioned above are noted by above
It is feasible for entering method, and therefore we use these three kinds of methods to carry out the preparation of Paclitaxel liposome respectively, but
It is all not succeeded after having groped multiple prescription.First two method problem appear to is that paclitaxel can not obtain
The crystallize to good encapsulating, causes content to decline, the results are shown in Table 1.Use the ethanol injection that needle tubing pump is implemented
Method can realize the good encapsulating of paclitaxel, but drug loading is on the low side, paclitaxel and the molar percentage of phospholipid
3mol% only up to be reached.And the clinical administration amount of paclitaxel injection is up to 135-175mg/m2, so
The phospholipid calculating about paclitaxel 30 times amount needs to be infused in human body, it may be assumed that the patient per of 70kg body weight needs
8.1-10.5g phospholipid to be used.Such substantial amounts of this pharmaceutic adjuvant of use phospholipid, first safety need to comment
Estimating, the phospholipid cost secondly expended is higher, is unfavorable for extensive application clinically, and therefore the method is also
Undesirable.
The content loss of the Paclitaxel liposome that the different preparation method of table 1 obtains
Wherein, content of taxol loss=(the paclitaxel total amount/paclitaxel inventory comprised in 1-liposome) ×
100%.
Wherein, prescription information is as shown in table 2.
Table 2 Paclitaxel liposome prescription information
The paclitaxel total amount wherein comprised in liposome is obtained by high effective liquid chromatography for measuring.
Liquid phase chromatogram condition is: use octadecyl silane chromatographic column, with acetonitrile: water (9: 11) mixes
Solution is flowing phase, flow velocity 1.5ml/min, detects wavelength 227nm.
Assay method: take Paclitaxel liposome 2ml, with in methanol dissolving also constant volume to 10ml measuring bottle, takes 10 μ l
It is injected in chromatograph of liquid and carries out assay.
Summary of the invention
The present invention is a kind of improves the method for fat-soluble medicine useful load in liposome, and this liposome contains as work
The fat-soluble medicine of property composition and the bilayer of liposome, bilayer contains one or more phospholipid and
Plant or the lipid of multiple hydrophilic polymer-modified, the method is characterized in that fat-soluble medicine is initially formed Emulsion,
Form liposome the most again.
The method comprises the steps: (1) lipid by fat-soluble medicine, phospholipid and hydrophilic polymer-modified
It is dissolved in organic solvent, forms oil phase；(2) oil phase is slowly injected in aqueous phase solution, grinds to form Emulsion；
(3) Emulsion homogenizing is obtained liposome.
Wherein said medicine is taxane antitumor medicine.
Wherein said taxane antitumor medicine is paclitaxel.
Wherein said phospholipid is selected from lecithin, hydrogenated soy phosphatidyl choline (HSPC), double myristic acid lecithin
(DMPC), DPPC (DPPC) or DSPC (DSPC) or it is any
Combination.
The lipid of wherein said hydrophilic polymer-modified is selected from polyethyleneglycol modified distearoylphosphatidyl ethanol
Amine (DSPE-PEG), polyethyleneglycol modified DSPG (DSPG-PEG), poly-second two
The DSPE that the cholesterol (chol-PEG) of alcohol modification, polyvidone are modified
(DSPE-PVP) DSPG (DSPG-PVP), polyvidone that, polyvidone is modified are modified
Cholesterol (chol-PVP) or its combination in any.
Wherein said organic solvent is selected from chloroform.
Wherein said aqueous phase solution is selected from lactose, maltose, sucrose, glucose or aqueous trehalose solution.
The present invention also provides for a kind of liposomal pharmaceutical preparation, it is characterised in that containing obtain according to the method described above
Liposome, and pharmaceutically acceptable carrier and/or excipient.
This liposomal pharmaceutical preparation is possibly together with changing the salt of osmotic pressure, buffer substance and/or antioxidant.
The present invention also provides for above-mentioned liposomal pharmaceutical preparation and is preparing the use in the medicine treating tumor patient
On the way.
The present invention uses a kind of brand-new method to achieve the preparation of high drug load Paclitaxel liposome.It is prepared
Technique is that the first filmogen such as lipid by paclitaxel, phospholipid and hydrophilic polymer-modified is dissolved in organic molten
Agent is formed oil phase, then oil phase is slowly injected in aqueous phase solution grinding and forms o/w Emulsion, then by height
Instrument homogenizing of extruding out obtains the liposome of uniform particle size, and paclitaxel carried medicine amount can be brought up to 6 by this preparation method
Mol%.Due in conventional liposome parcel be the core of aqueous phase mostly, therefore fat-soluble medicine paclitaxel is only
Can be inserted in phospholipid bilayer；And the core that our preparation method is wrapped up in making liposome becomes chloroform, therefore
Paclitaxel can not only be inserted in phospholipid bilayer, moreover it is possible to be present in the chloroform of liposome internal phase with unbodied state
In core, thus substantially increase the drug loading of Paclitaxel liposome.
The toxicity of the Paclitaxel liposome preparation prepared by technical solution of the present invention and commercially available paclitaxel injection,
Medicine generation, comparative efficacy test's result show: Paclitaxel liposome drug effect improves, toxicity reduces.
Detailed description of the invention
Following example are to illustrate the present invention, should not be construed as limiting the scope of the present invention.
The preparation of embodiment 1 Paclitaxel liposome
Taking lecithin, DSPE-PEG and paclitaxel that mol ratio is 100: 0.5: 3～8, stirring and dissolving is in suitable
In amount chloroform, this is oil-phase solution.Appropriate 10% aqueous sucrose solution is added in colloid mill, instills oil phase molten
Liquid is ground into breast, then uses high pressure extrusion instrument extrusion to obtain the liposome of particle diameter about 140nm.30-40
DEG C decompression rotary evaporation removes chloroform, and then using cross-flow dialysis equipment, that liposome is concentrated to Ramulus et folium taxi cuspidatae is pure and strong
Degree is about 1.5mg/ml, is finally sub-packed in lyophilization in cillin bottle and obtains Paclitaxel liposome finished product.No
More as shown in table 3 than the Paclitaxel liposome envelop rate of prescription with medicine fat, it is seen that when paclitaxel carried medicine amount is up to 6
During mol%, envelop rate remains at more than 95%.
The different medicine fat of table 3 is than the envelop rate of Paclitaxel liposome
Embodiment 2 Paclitaxel liposome and the anxious poison Experimental comparison of ordinary preparation
Taking male mouse of kunming, often group 2, is divided into 7 groups, gives taxusol-lipid respectively at tail vein injection
Body (drug loading 5mol%) and commercially available paclitaxel injection, dosage is 13.4,17.4,22.6,29.4,
38.3、49.7、64.8mg/kg.After administration, every day observes the weight of animals and survival condition, puts to death after 21 days.
Interpretation of result: commercially available injection dosage reaches to show during 29.4mg/kg that overt toxicity, mice go out
Now go into a coma, palpitate quickly, the symptom such as areflexia；When dose advancement to 38.3mg/kg, after being administered 2 minutes
Two mices are the most dead.Liposomal formulation reaches the highest dosage, i.e. during 64.8mg/kg, under Mouse Weight
Fall the most about 12%.As can be seen here, Paclitaxel liposome toxicity is less than commercially available injection.
Embodiment 3 Paclitaxel liposome contrasts with the pharmacodynamics of ordinary preparation
Take male mouse of kunming, every subcutaneous vaccination 8 × 106Individual H22 hepatoma carcinoma cell.After inoculating 24 hours
Animal is randomly divided into 5 groups, and often group 10, gives Paclitaxel liposome (drug loading respectively at tail vein
5mol%) 20mg/kg, 35mg/kg, paclitaxel normal injection 20mg/kg, 35mg/kg and glucose
Solution, is administered once for every two days, is administered 3 times altogether.
After administration, animal is normally raised, and every day weighs, and puts to death after 9 days, peels off tumor body and weighs.Experiment knot
Fruit uses SPSS 11.5 statistical software, and between One-way ANOVA comparable group, the tumor method of double differences is different, the results are shown in Table 4.
P ＜ 0.05, has significant difference.
Table 4 Paclitaxel liposome and the commercially available paclitaxel injection tumor-inhibiting action to H22
Interpretation of result: compared with blank group, front 3 groups of tumor control rates are all higher than 40%, it was demonstrated that two kinds
The paclitaxel of dosage form is all effective.When dosage is 20mg/kg, the anticancer therapeutic of liposome and city
Sell paclitaxel injection there was no significant difference.When liposome dosage rises to 35mg/kg, its tumor-inhibiting action shows
Work is better than commercially available paclitaxel injection, and the paclitaxel injection of same dose i.e. causes after giving mice 0.5 hour
Extremely.
Claims (5)
1. improving a method for fat-soluble medicine useful load in liposome, this liposome contains to become as activity
Point fat-soluble medicine and the bilayer of liposome, bilayer contain one or more phospholipid and a kind of or
The lipid of multiple hydrophilic polymer-modified, the method is characterized in that and comprise the steps: that (1) is by fat-soluble
The lipid of medicine, phospholipid and hydrophilic polymer-modified is dissolved in organic solvent, forms oil phase；(2) by oil
It is slowly injected into mutually in aqueous phase solution, grinds to form Emulsion；(3) Emulsion homogenizing is obtained liposome, wherein activity
Composition is paclitaxel, and phospholipid is lecithin, and the lipid of hydrophilic polymer-modified is DSPE-PEG, lecithin,
The molar ratio of DSPE-PEG and paclitaxel is 100:0.5:3-8, and wherein aqueous phase solution is selected from aqueous sucrose solution.
Method the most according to claim 1, it is characterised in that described organic solvent is selected from chloroform.
3. a liposomal pharmaceutical preparation, it is characterised in that containing obtaining in accordance with the method for claim 1
Liposome, and pharmaceutically acceptable carrier and/or excipient.
Liposomal pharmaceutical preparation the most according to claim 3, it is characterised in that possibly together with changing osmotic pressure
Salt, buffer substance and/or antioxidant.
5. the liposomal pharmaceutical preparation according to any one of claim 3-4 is used for treating tumor patient in preparation
Medicine in purposes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110246902.XA CN102949343B (en) | 2011-08-26 | A kind of improve the method for fat-soluble medicine useful load in liposome |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110246902.XA CN102949343B (en) | 2011-08-26 | A kind of improve the method for fat-soluble medicine useful load in liposome |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102949343A CN102949343A (en) | 2013-03-06 |
| CN102949343B true CN102949343B (en) | 2016-12-14 |
Family
ID=
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275076A (en) * | 1998-07-01 | 2000-11-29 | 尼奥法姆公司 | Method of administering liposomal encapsulated taxane |
| US6348491B1 (en) * | 1999-07-01 | 2002-02-19 | National Science Council | Oil-in-water emulsion for encapsulating paclitaxel |
| CN101439033A (en) * | 2007-11-22 | 2009-05-27 | 沈阳沃森药物研究所 | Polyenic taxusol lipid complexes and micelle composition thereof for injection |
| CN102048688A (en) * | 2009-10-29 | 2011-05-11 | 中国医学科学院药物研究所 | Taxol submicroemulsion taking cholesterol complex as intermediate carrier |
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275076A (en) * | 1998-07-01 | 2000-11-29 | 尼奥法姆公司 | Method of administering liposomal encapsulated taxane |
| US6348491B1 (en) * | 1999-07-01 | 2002-02-19 | National Science Council | Oil-in-water emulsion for encapsulating paclitaxel |
| CN101439033A (en) * | 2007-11-22 | 2009-05-27 | 沈阳沃森药物研究所 | Polyenic taxusol lipid complexes and micelle composition thereof for injection |
| CN102048688A (en) * | 2009-10-29 | 2011-05-11 | 中国医学科学院药物研究所 | Taxol submicroemulsion taking cholesterol complex as intermediate carrier |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Noble et al. | Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy | |
| CN1840193B (en) | Nanometer capsule of anthracene nucleus anticancer antibiotic with polyethylene glycol-phospholipid | |
| CN105853403B (en) | A kind of paclitaxel palmitate liposome and preparation method thereof | |
| CN101991538B (en) | TPGS-containing liposome composition and application thereof | |
| CN102188713A (en) | Liver targeting pharmaceutical composition and its preparation method | |
| CN108567742B (en) | SN38 lipid composition, preparation method and application thereof | |
| JP2014133764A (en) | Taxol submicroemulsion with steroidal compound as intermediate carrier | |
| CN102357075A (en) | Docetaxel nano preparation and preparation method thereof | |
| CN106474064A (en) | A kind of Artemether nanometer liposome and preparation method and application | |
| CN101732349B (en) | Venenum bufonis nanometer long-circulating liposome and preparation method thereof | |
| CN101129375A (en) | Vinorelbine solid lipid nano granule, freeze drying formulated product and method of preparing the same | |
| CN101028251A (en) | Camptothecine derivative phosphatide composite liposome nano-preparation and its making method | |
| CN103181897B (en) | Gefitinib liposome preparation and preparation method thereof | |
| CN102370623B (en) | Liquid-state lipid micro-particles used for delivering cerebric medicine through olfactory pathway, preparation method thereof, and preparation thereof | |
| CN103585639A (en) | Lactoferrin modified solid lipid nanoparticles, as well as preparation method and application thereof | |
| CN101322681B (en) | Method for preparing nano micelle formulation of anthracene nucleus antineoplastic antibiotic | |
| CN112386586A (en) | Preparation method of albumin nanoparticles | |
| CN102085189B (en) | Docetaxel liposome sterile lyophilized preparation and preparation method thereof | |
| CN105997942B (en) | A kind of nano particle and its preparation method and application of human serum albumins load CHROMATOGRAPHIC FRACTIONATION AND MASS drug | |
| CN102166189B (en) | Targeted and fluorescence dual-functional slightly-soluble antitumor medicament nano structural lipid carrier | |
| CN101411690B (en) | 2-methoxyestradiol lipidosome freeze-dried injection and preparation method thereof | |
| CN105287612B (en) | Salinomycin Sodium and adriamycin nano liposome and the preparation method and application thereof are carried altogether | |
| CN102949343B (en) | A kind of improve the method for fat-soluble medicine useful load in liposome | |
| CN102028655B (en) | Zanamivir solid lipid nanosphere oral preparation and preparation method thereof | |
| CN101352418B (en) | Pirarubicin or pirarubicin hydrochloride lipid nano granule and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant |