CN1314401C - Polyenic phosphatide acylcholine freeze-dried powder injecta medicine - Google Patents
Polyenic phosphatide acylcholine freeze-dried powder injecta medicine Download PDFInfo
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- CN1314401C CN1314401C CNB2005100216365A CN200510021636A CN1314401C CN 1314401 C CN1314401 C CN 1314401C CN B2005100216365 A CNB2005100216365 A CN B2005100216365A CN 200510021636 A CN200510021636 A CN 200510021636A CN 1314401 C CN1314401 C CN 1314401C
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- Prior art keywords
- freeze
- acylcholine
- polyenic
- phosphatide
- dried powder
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- 239000003814 drug Substances 0.000 title claims abstract description 37
- 239000000843 powder Substances 0.000 title claims abstract description 21
- 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 claims abstract description 38
- 150000004291 polyenes Chemical class 0.000 claims abstract description 37
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 238000004108 freeze drying Methods 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 239000004615 ingredient Substances 0.000 claims abstract description 12
- 229930003231 vitamin Natural products 0.000 claims abstract description 6
- 235000013343 vitamin Nutrition 0.000 claims abstract description 6
- 239000011782 vitamin Substances 0.000 claims abstract description 6
- 229940088594 vitamin Drugs 0.000 claims abstract description 6
- 150000003722 vitamin derivatives Chemical class 0.000 claims abstract description 6
- 150000002148 esters Chemical class 0.000 claims description 13
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 10
- 229960003964 deoxycholic acid Drugs 0.000 claims description 8
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[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 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 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 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 4
- 108010007979 Glycocholic Acid Proteins 0.000 claims description 4
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 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 claims description 4
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-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 claims description 4
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic 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)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 claims description 4
- 229940099347 glycocholic acid Drugs 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- RPKLZQLYODPWTM-KBMWBBLPSA-N cholanoic acid Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 RPKLZQLYODPWTM-KBMWBBLPSA-N 0.000 claims description 3
- 235000002639 sodium chloride Nutrition 0.000 claims description 3
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 2
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 239000004380 Cholic acid Substances 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- 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 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 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 2
- 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 2
- 229920002472 Starch Polymers 0.000 claims description 2
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 claims description 2
- 150000001413 amino acids Chemical class 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
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims description 2
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic 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)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 claims description 2
- 229960002471 cholic acid Drugs 0.000 claims description 2
- 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 2
- 235000019416 cholic acid Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000001727 glucose Nutrition 0.000 claims description 2
- WVULKSPCQVQLCU-BUXLTGKBSA-N glycodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 WVULKSPCQVQLCU-BUXLTGKBSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic 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)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 claims description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 238000002347 injection Methods 0.000 abstract description 10
- 239000007924 injection Substances 0.000 abstract description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 7
- 235000019445 benzyl alcohol Nutrition 0.000 abstract description 3
- 239000003223 protective agent Substances 0.000 abstract description 3
- 229960004217 benzyl alcohol Drugs 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000007788 liquid Substances 0.000 description 12
- 239000008215 water for injection Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- 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 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 150000003904 phospholipids Chemical class 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 229910001873 dinitrogen Inorganic materials 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229930003270 Vitamin B Natural products 0.000 description 3
- 229930003427 Vitamin E Natural products 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 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 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 235000019156 vitamin B Nutrition 0.000 description 3
- 239000011720 vitamin B Substances 0.000 description 3
- 235000019165 vitamin E Nutrition 0.000 description 3
- 229940046009 vitamin E Drugs 0.000 description 3
- 239000011709 vitamin E Substances 0.000 description 3
- 239000012491 analyte Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 210000003463 organelle Anatomy 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-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
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N linoleic acid group Chemical group C(CCCCCCC\C=C/C\C=C/CCCCC)(=O)O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a polyene phosphatidyl choline freeze-drying powder injection which is composed of polyene phosphatidyl choline as an effective medicine ingredient and auxiliary ingredients comprising a necessary solubilizing agent and a freeze-drying protective agent. The weight of the ingredients comprises that the polyene phosphatidyl choline weighs 0.1 to 1.5 parts, the weight ratio of the solubilizing agent to the polyene phosphatidyl choline is 0.1 to 2.5: 1, and the weight ratio of the freeze-drying protective agent to the polyene phosphatidyl choline is 0.1 to 10: 1. As required, other auxiliary ingredients including pharmaceutically acceptable vitamin can also be added to the ingredients. The medicine solves the problem of the stability of effective medicine ingredients under normal conditions including storage and transportation and reduces transportation cost and transportation difficulty. The curative effects of the medicine are enhanced, potential safety hazards caused by phenylmethanol are eliminated, and the safety of medication is improved.
Description
Technical field
What the present invention relates to is a kind of polyenic phosphatide acylcholine freeze-dried powder injecta medicine that the liver plasma membrane protective agent uses that can be used as.
Background technology
Polyene phosphatidylcholine is as a kind of liver plasma membrane protection composition, in the various types of acute and chronic hepatopathys of treatment, is employed at present, and be a most sure hepatic of present curative effect.In hepatic disease, regardless of the cause of disease, the damage of hepatic parenchymal cells and organelle takes place inevitably all, simultaneously losing with phospholipid.Polyene phosphatidylcholine can replenish the exogenous phospholipid of human body, and be attached in cell membrane or the organelle film, hepatocellular regeneration and reconstruct had important effect, and can obviously improve nutrient substance and the electrolytical membrane process of striding, increase the activity of phospholipid dependent enzyme, make impaired membrane structure obtain repairing.
The main component of polyene phosphatidylcholine is linoleic acid (accounting for 70%), linolenic acid and oleic acid, is a kind of high-purity soybean oil phospholipid that extracts from soybean phospholipid, is " essential " phospholipid of human body.Owing to be rich in the phosphatidylcholine of polyunsaturated fatty acid, so be called polyene phosphatidylcholine again.At present, this medicine has two kinds of oral and injections, can have only Polyene Phosphatidylcholine injection liquid for the dosage form of injection use.The open defect of this injection products, the one, principal agent instability in the aqueous solution, easily degraded in storage, effect duration is short, needs in storage below 8 ℃, so must protect with ice bag in transportation, transport difficulty and cost of transportation have been increased, also increase patient's financial burden, also can cause the decline of drug content simultaneously inevitably, influenced the curative effect of this product; The 2nd, in the aqueous solution of its hydro-acupuncture preparation, need be added with benzyl alcohol as antiseptic, therefore these product also can make patient produce anaphylaxis except can not being used for neonate and premature infant.
Summary of the invention
The objective of the invention is provides a kind of safe, stable, effective polyenic phosphatide acylcholine freeze-dried powder injecta to extensive patients, its preparation technology is simple, solve active drug composition polyene phosphatidylcholine and under normal condition, (comprised and having preserved and transportation) a stable difficult problem, cost of transportation and transport difficulty have been reduced, when having improved curative effect of medication, also eliminate the potential safety hazard of bringing because of benzyl alcohol, improved the safety of medication.
Polyenic phosphatide acylcholine freeze-dried powder injecta medicine of the present invention is the active drug composition with the polyene phosphatidylcholine, forms jointly with comprising the necessary solubilizing agent and the auxiliary element of freeze drying protectant, and its weight consists of:
Polyene phosphatidylcholine 0.1-1.5 part,
Solubilizing agent/polyene phosphatidylcholine 0.1-2.5: 1,
Freeze drying protectant/polyene phosphatidylcholine 0.1-10: 1,
Wherein, said solubilizing agent can be selected cholanic acid or its esters, and a kind of as in cholic acid, glycocholic acid, cholyltaurine or its esters etc. wherein is preferably glycocholic acid or its esters; Or deoxycholic acid or its esters, a kind of as in chenodeoxy cholic acid, glycodesoxycholic acid, Calculus Bovis deoxycholic acid and its esters etc., wherein preferred deoxycholic acid or its esters; Can also be in the compositions such as poloxamer, tween a kind of.Because polyene phosphatidylcholine is water insoluble, use this type of solubilizing agent can increase its water solublity.Can exchange use between these heterogeneities and there is no the significant adverse influence.
Said freeze drying protectant can be in sodium chloride, aminoacid, glucose, mannitol sugar, Sionit, sucrose, trehalose, lactose, low molecular dextran, cyclodextrin, soluble starch, the cellulose family a kind of, they all can protect micelle not to be destroyed in freeze-drying process.
Test shows that in the above-mentioned polyenic phosphatide acylcholine freeze-dried powder injecta medicine, said polyene phosphatidylcholine is preferably 0.1-0.8 part.The preferred proportion of said polyene phosphatidylcholine and solubilizing agent is 0.5-2.0: 1.The usage ratio of freeze drying protectant/polyene phosphatidylcholine is preferably 0.1-5: 1.
On the basis of above-mentioned composition, can also add the auxiliary element that comprises one or more vitamin ingredients of acceptable in the medicine as required.Said vitamin ingredients can comprise as vitamin A, C, H, E, K, vitamin D family, the vitamin B same clan and derivant etc.During use, the cholic usage ratio of vitamin ingredients/polyene phosphatidyl can be 0.0005-0.05: 1.
The freeze-dried powder injecta medicine that the present invention is above-mentioned is investigated with the long-time stability parallel test that the injection liquid drugs injection that uses at present carries out under 25 ± 2 ℃ of temperature conditions, leading indicator is as shown in table 1, principal agent wherein is the effective ingredient polyene phosphatidylcholine, and the principal agent analyte is the related substances that polyene phosphatidylcholine produces because of degraded, oxidation etc.
Table 1 stability test is investigated the result
| Time (moon) | Outward appearance | PH value | Principal agent analyte (%) | Drug content (%) | Aseptic | Bacterial endotoxin | |
| The liquid drugs injection injection | 0 | Yellow clear liquid | 8.7 | 1.36 | 102.4 | Qualified | Qualified |
| 3 | Yellow clear liquid | 8.0 | 2.56 | 97.5 | Qualified | Qualified | |
| 6 | Yellow clear liquid | 7.8 | 4.01 | 95.8 | Qualified | Qualified | |
| 9 | Yellow clear liquid | 7.5 | 5.66 | 94.6 | Qualified | Qualified | |
| Freeze-dried powder of the present invention | 0 | Yellow block | 8.7 | 1.02 | 102.4 | Qualified | Qualified |
| 3 | Yellow block | 8.6 | 1.39 | 101.3 | Qualified | Qualified | |
| 6 | Yellow block | 8.5 | 2.01 | 100.6 | Qualified | Qualified | |
| 9 | Yellow block | 8.6 | 2.61 | 99.2 | Qualified | Qualified |
Above-mentioned result of the test shows, freeze-dried powder injecta medicine of the present invention stores for a long time not using under composition such as benzyl alcohol and room temperature, the normal condition, its pH value variation, the increase of principal agent decomposed substance, the every index of the following degradation aspect of drug content, all obviously be better than the corresponding injection that uses at present, show and to improve stability of drug and clinical application safety, effectiveness effectively.
The general preparation method of the polyenic phosphatide acylcholine freeze-dried powder injecta medicine that the present invention is above-mentioned is; with polyene phosphatidylcholine, solubilizing agent and after optionally auxiliary element dissolves with water for injection; homogenizing becomes clear liquid under nitrogen current; add an amount of freeze drying protectant then; abundant homogenize; add to full dose with water for injection in case of necessity, with the microporous filter membrane filtration of 0.2 μ m, lyophilization promptly.
The specific embodiment by the following examples is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
The specific embodiment
Embodiment 1
Form: polyene phosphatidylcholine 5.0g
NaGC 9g
Mannitol 4g
Water for injection adds to 100ml
Preparation method: under logical condition of nitrogen gas, in the polyene phosphatidylcholine 5.0g of recipe quantity, an amount of water for injection that NaGC 9g joins 60 ℃, stir clear liquid, add the mannitol dissolving again after, regulating pH with NaoH is 6.5～8.0, and adds water to 100ml.Solution filters with the microporous filter membrane of 0.2 μ m, is sub-packed in the cillin bottle, puts in the freeze dryer and is chilled to-35 ℃～-40 ℃, is warming up to-20 ℃～-5 ℃ then, vacuum (0.1-0.5kPa) drying.Be warming up to 30 ℃ hours by 5 ℃/hour, jump a queue, roll lid pack promptly.
Embodiment 2
Form: polyene phosphatidylcholine 4.65g
NaTDC 10g
Vitamin E 0.05g
Sucrose 5g
Preparation method: under logical condition of nitrogen gas, in polyene phosphatidylcholine 4.65g, the NaTDC 10g of recipe quantity, an amount of water for injection that vitamin E 0.05g joins 60 ℃, stir clear liquid, after adding the dissolving of sugarcane alcohol again, regulating pH with NaoH is 6.5～8.0, and adds water to 100ml.Solution filters with the microporous filter membrane of 0.2 μ m, is sub-packed in the cillin bottle, puts in the freeze dryer and is chilled to-35 ℃～-40 ℃, is warming up to-20 ℃～-5 ℃ then, vacuum (0.1-0.5kPa) drying.Be warming up to 30 ℃ hours by 5 ℃/hour, jump a queue, roll lid pack promptly.
Embodiment 3
Form: polyene phosphatidylcholine 4.65g
Poloxamer 2g
Vitamin E 0.05g
Sucrose 5g
Water for injection adds to 100ml
Preparation method: under logical condition of nitrogen gas, in polyene phosphatidylcholine 4.65g, the poloxamer 2g of recipe quantity, an amount of water for injection that biotin 0.05g joins 60 ℃, stir clear liquid, add sucrose dissolved again after, regulating pH with NaoH is 6.5～8.0, and adds water to 100ml.Solution filters with the microporous filter membrane of 0.2 μ m, is sub-packed in the cillin bottle, puts in the freeze dryer and is chilled to-35 ℃～-40 ℃, is warming up to-20 ℃～-5 ℃ then, vacuum (0.1-0.5kPa) drying.Be warming up to 30 ℃ hours by 5 ℃/hour, jump a queue, roll lid pack promptly.
Embodiment 4
Form: polyene phosphatidylcholine 5.0g
NaTDC 10g
Vitamin B
120.02g
Trehalose 6g
Water for injection adds to 100ml
Preparation method: under logical condition of nitrogen gas, with polyene phosphatidylcholine 5.0g, NaTDC 10g, the vitamin B of recipe quantity
120.02g, biotin 0.05g joins in 60 ℃ an amount of water for injection, stir clear liquid, add the trehalose dissolving again after, regulating pH with NaoH is 6.5～8.0, and adds water to 100ml.Microporous filter membrane with 0.2 μ m filters, and is sub-packed in the cillin bottle, puts in the freeze dryer and is chilled to-35 ℃～-40 ℃, is warming up to-20 ℃～-5 ℃ then, vacuum (0.1-0.5kPa) drying.Be warming up to 30 ℃ hours by 5 ℃/hour, jump a queue, roll lid pack promptly.
Although described the present invention by concrete enforcement preparation method, but make some modification or carry out some replacement and equivalent process according to the inventor's method, for the technical staff who is proficient in this field is easily, and these variations are believed to comprise within the scope of the invention.
Claims (10)
1. polyenic phosphatide acylcholine freeze-dried powder injecta medicine is characterized in that with the polyene phosphatidylcholine being the active drug composition, forms jointly with comprising the necessary solubilizing agent and the auxiliary element of freeze drying protectant, and its weight consists of:
Polyene phosphatidylcholine 0.1-1.5 part,
Solubilizing agent/polyene phosphatidylcholine 0.1-2.5: 1,
Freeze drying protectant/polyene phosphatidylcholine 0.1-10: 1,
Solubilizing agent wherein is a kind of in cholanic acid or its esters, deoxycholic acid or its esters, poloxamer, the tween; Freeze drying protectant is a kind of in sodium chloride, aminoacid, glucose, mannitol sugar, Sionit, sucrose, trehalose, lactose, low molecular dextran, cyclodextrin, soluble starch, the cellulose family.
2. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1 is characterized in that said polyene phosphatidylcholine is preferably 0.1-0.8 part.
3. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1 is characterized in that cholanic acid or its esters in the said solubilizing agent is that one of cholic acid, glycocholic acid, cholyltaurine and their salt apoplexy due to endogenous wind are planted.
4. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 3 is characterized in that preferred glycocholic acid of said solubilizing agent or its esters.
5. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1 is characterized in that deoxycholic acid in the said solubilizing agent or its esters are a kind of in chenodeoxy cholic acid, glycodesoxycholic acid, Calculus Bovis deoxycholic acid, deoxycholic acid or its esters.
6. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 5 is characterized in that preferred deoxycholic acid of said solubilizing agent or its esters.
7. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1, the preferred proportion that it is characterized in that said solubilizing agent and polyene phosphatidylcholine is 0.5-2.0: 1.
8. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1 is characterized in that the usage ratio of said freeze drying protectant/polyene phosphatidylcholine is preferably 0.1-5: 1.
9. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 8 is characterized in that the preferred mannitol of said freeze drying protectant.
10. as the described polyenic phosphatide acylcholine freeze-dried powder injecta medicine of one of claim 1 to 9, it is characterized in that including in the said auxiliary element acceptable vitamin ingredients in the medicine, the cholic usage ratio of vitamin ingredients/polyene phosphatidyl is 0.0005-0.05: 1.
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| CN1602878A (en) * | 2004-08-26 | 2005-04-06 | 北京瑞伊人科技发展有限公司 | Preparation process of polyene phosphatidylcholine injection |
Non-Patent Citations (1)
| Title |
|---|
| 复方多烯磷脂酰胆碱治疗慢性乙型活动性肝炎的随机对照双盲临床试验 张孝秋等，药物流行病学杂志，第4卷第1期 1995 * |
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Address after: 610500 south two road, Xindu Satellite Town Industrial Park, Sichuan, Chengdu Patentee after: Sichuan Kelun Pharmaceutical Co.,Ltd. Patentee after: SICHUAN KELUN PHARMACEUTICAL RESEARCH INSTITUTE Co.,Ltd. Address before: 610500 south two road, Xindu Satellite Town Industrial Park, Sichuan, Chengdu Patentee before: Sichuan Kelun Pharmaceutical Co.,Ltd. Patentee before: Sichuan Kelun Pharmaceutical Research Co.,Ltd. |
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Commission number: 4W100491 Conclusion of examination: The patent rights continued to be valid on the basis of the modified claim 1-9, which was amended by the patent holder on 2011 01, 25. Decision date of declaring invalidation: 20110301 Decision number of declaring invalidation: 16107 Denomination of invention: Polyenic phosphatide acylcholine freeze-dried powder injecta medicine Granted publication date: 20070509 Patentee: Sichuan Kelun Pharmaceutical Co.,Ltd.|SICHUAN KELUN PHARMACEUTICAL RESEARCH INSTITUTE Co.,Ltd. |