CN101278921B - Triopisetron Hydrochloride microcapsule and method for preparing injection - Google Patents
Triopisetron Hydrochloride microcapsule and method for preparing injection Download PDFInfo
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- CN101278921B CN101278921B CN2008101104233A CN200810110423A CN101278921B CN 101278921 B CN101278921 B CN 101278921B CN 2008101104233 A CN2008101104233 A CN 2008101104233A CN 200810110423 A CN200810110423 A CN 200810110423A CN 101278921 B CN101278921 B CN 101278921B
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- soz
- navoban
- microcapsule
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- injection
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- 239000003094 microcapsule Substances 0.000 title claims abstract description 53
- 239000007924 injection Substances 0.000 title claims abstract description 27
- 238000002347 injection Methods 0.000 title claims abstract description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 23
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 46
- 239000000839 emulsion Substances 0.000 claims abstract description 26
- 239000000243 solution Substances 0.000 claims abstract description 23
- 108010010803 Gelatin Proteins 0.000 claims abstract description 20
- 229920000159 gelatin Polymers 0.000 claims abstract description 20
- 239000008273 gelatin Substances 0.000 claims abstract description 20
- 235000019322 gelatine Nutrition 0.000 claims abstract description 20
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 229920002307 Dextran Polymers 0.000 claims abstract description 10
- 239000007762 w/o emulsion Substances 0.000 claims abstract description 9
- 230000005686 electrostatic field Effects 0.000 claims abstract description 7
- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 claims description 92
- 229960003688 tropisetron Drugs 0.000 claims description 92
- 238000007596 consolidation process Methods 0.000 claims description 23
- 239000007788 liquid Substances 0.000 claims description 23
- 239000000843 powder Substances 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 14
- 229920001503 Glucan Polymers 0.000 claims description 12
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 12
- 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 9
- 102000002322 Egg Proteins Human genes 0.000 claims description 9
- 108010000912 Egg Proteins Proteins 0.000 claims description 9
- 241000287828 Gallus gallus Species 0.000 claims description 9
- 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 9
- 239000000787 lecithin Substances 0.000 claims description 9
- 235000010445 lecithin Nutrition 0.000 claims description 9
- 229940067606 lecithin Drugs 0.000 claims description 9
- 210000004681 ovum Anatomy 0.000 claims description 9
- 239000008215 water for injection Substances 0.000 claims description 9
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol 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 claims description 8
- 239000008103 glucose Substances 0.000 claims description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 6
- 229920000136 polysorbate Polymers 0.000 claims description 6
- 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 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 229940083466 soybean lecithin Drugs 0.000 claims description 5
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class 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 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 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 4
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- -1 polyoxyethylene Polymers 0.000 claims description 4
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 3
- 235000010469 Glycine max Nutrition 0.000 claims description 3
- 238000012856 packing Methods 0.000 claims description 3
- 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 description 3
- 150000003904 phospholipids Chemical class 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 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 2
- 239000004471 Glycine Substances 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
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 21
- 206010047700 Vomiting Diseases 0.000 abstract description 3
- 238000004108 freeze drying Methods 0.000 abstract description 3
- 229960003674 tropisetron hydrochloride Drugs 0.000 abstract 5
- XIEGSJAEZIGKSA-LUNMCBQDSA-N tropisetron hydrochloride Chemical compound Cl.C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 XIEGSJAEZIGKSA-LUNMCBQDSA-N 0.000 abstract 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229940090044 injection Drugs 0.000 description 16
- 238000012360 testing method Methods 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000005684 electric field Effects 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 229940044519 poloxamer 188 Drugs 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 102000035037 5-HT3 receptors Human genes 0.000 description 1
- 108091005477 5-HT3 receptors Proteins 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 210000003818 area postrema Anatomy 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention provides a tropisetron hydrochloride freeze-dry preparation for treating emesis, containing tropisetron hydrochloride, gelatin, dextran, oleophilic emulsifier, hydrophilic emulsifier and freeze-dry supporting agent. The invention also relates to a preparation method of the tropisetron hydrochloride freeze-dry preparation, containing the following steps: (1) the tropisetron hydrochloride is added into injection water and completely dissolved; (2) the gelatin and the oleophilic emulsifier are added in solution prepared in step (1) to prepare water-in-oil emulsion; (3) dextran solution and the hydrophilic emulsifier are added in the solution prepared in step (2) to prepare water-in-oil-in-water double emulsion; (4) the prepared double emulsion is dropped by bolus injection into strong base solidified liquor in a high-voltage electrostatic field by an orifice; after solidifying, a microcapsule is filtered and washed by water or PH regulator to lead PH to be 5-7; (5) the freeze-dry supporting agent is dissolved in the injection water and mixed with the microcapsule evenly; after subpackage and freeze drying, the tropisetron hydrochloride freeze-dry preparation is obtained.
Description
Technical field
The invention provides a kind of hydrochloride for injection tropisetron microcapsule, a kind of Navoban (Soz) freeze-dried powder and preparation method thereof also is provided.Belong to field of medicaments.
Background technology
Navoban (Soz) is that a kind of peripheral nervous potent, high selectivity former and central nervous system's 5-hydroxy tryptamine 3 (5-HT3) receptor are competed antagonist.Operation or some material comprise that some chemotherapeutic can excite the class pheochromocyte of internal organs mucosa to discharge 5-hydroxy tryptamine under stimulating, thereby bring out the vomiting reflex that the companion feels sick.This product mainly suppresses vomiting reflex by optionally blocking the former presynaptic 5-HT3 of peripheral nervous receptor, and in addition, its antiemetic effect also may be relevant by vagal stimulation that the direct blocking-up to maincenter 5-HT3 receptor suppresses area postrema with it.
Navoban (Soz) is unstable in aqueous solution, is hydrolyzed separation easily, produces insoluble visible foreign matters, influences drug quality, lessens the curative effect, so the suitable lyophilized preparation of making.Commercially available lyophilized preparation all is that Navoban (Soz) and holder are dissolved in water at present, and lyophilization makes.It is solvent that lyophilized formulations is wanted water in use, also can cause Navoban (Soz) to be hydrolyzed separation, and the back clarity of redissolving is poor.This just need work out a kind of when redissolving, and still can keep enough Navoban (Soz) lyophilized formulations of stability, to satisfy needs clinically.
Summary of the invention
For overcoming above-mentioned prior art defective, the object of the present invention is to provide the hydrochloride for injection tropisetron microcapsule that has enough stability in a kind of aqueous solution.
Technical solution of the present invention is as follows:
The invention provides a kind of hydrochloride for injection tropisetron microcapsule, form by Navoban (Soz) and adjuvant, it is characterized in that described adjuvant contains gelatin, glucosan and emulsifying agent, wherein, according to listed as parts by weight, 1 part of Navoban (Soz), 2～6 parts in gelatin, 1～4 part of glucosan, 0.5～5 part of emulsifying agent.
Wherein, above-mentioned described hydrochloride for injection tropisetron microcapsule, wherein, described emulsifying agent comprises oleophilic emulsifier and hydrophilic emulsifying agent; Calculate oleophilic emulsifier in the preferred described emulsifying agent by weight: hydrophilic emulsifying agent is 1: 0.5～3.
Wherein, above-mentioned described hydrochloride for injection tropisetron microcapsule, wherein, described oleophilic emulsifier is selected from one or more in span, cholesterol, soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline, the synthetic phospholipid; Described hydrophilic emulsifying agent is selected from one or more in tween, poloxamer, Myrj 45, the polyoxyethylene hydrogenated Oleum Ricini.
Wherein, hydrochloride for injection tropisetron microcapsule of the present invention is to make by the method that comprises following steps:
(1) Navoban (Soz) is added in the water for injection, fully dissolving;
(2) in step (1) gained solution, add gelatin and oleophilic emulsifier, be prepared into water-in-oil emulsion;
(3) in step (2) gained emulsion, add dextran solution and hydrophilic emulsifying agent, be prepared into the W/O/W double emulsion;
(4) step (3) gained double emulsion is injected highly basic consolidation liquid in the high-voltage electrostatic field by orifice, make microcapsule.
As one of preferred embodiment of the invention, above-mentioned described hydrochloride for injection tropisetron microcapsule, wherein said oleophilic emulsifier is an Ovum Gallus domesticus Flavus lecithin, described hydrophilic emulsifying agent is a tween.
The above-mentioned described hydrochloride for injection tropisetron microcapsule of the present invention, wherein said highly basic consolidation liquid is selected from sodium hydroxide consolidation liquid, potassium hydroxide consolidation liquid, Sodium ethylate consolidation liquid or tert-butyl group sodium consolidation liquid; As preferably, the concentration of described highly basic consolidation liquid is 2mol/L-6mol/L.More preferably described consolidation liquid is the sodium hydroxide solution of 2mol/L-6mol/L.
The above-mentioned described hydrochloride for injection tropisetron microcapsule of the present invention, wherein said microcapsule diameter is 50 μ m～600 μ m, is preferably 50 μ m～100 μ m.
As another goal of the invention of the present invention, a kind of method for preparing above-mentioned described hydrochloride for injection tropisetron microcapsule also is provided, it is characterized in that comprising following steps:
(1) Navoban (Soz) is added in the water for injection, fully dissolving;
(2) in step (1) gained solution, add gelatin and oleophilic emulsifier, be prepared into water-in-oil emulsion;
(3) in step (2) gained emulsion, add dextran solution and hydrophilic emulsifying agent, be prepared into the W/O/W double emulsion;
(4) step (3) gained double emulsion is injected highly basic consolidation liquid in the high-voltage electrostatic field by orifice, make microcapsule.
As another goal of the invention of the present invention, a kind of Navoban (Soz) freeze-dried powder also is provided, with the Navoban (Soz) is effective ingredient, it is characterized in that being made up of Navoban (Soz) microcapsule and frozen-dried supporting agent, wherein said Navoban (Soz) microcapsule is above-mentioned described hydrochloride for injection tropisetron microcapsule.
Wherein, above-mentioned described Navoban (Soz) freeze-dried powder, wherein said frozen-dried supporting agent is selected from one or more in mannitol, lactose, glucose, sucrose, glucosan, polyvinylpyrrolidone, glycine, xylitol or the sorbitol, and preferred described frozen-dried supporting agent is mannitol or glucose.
As one of concrete scheme of the present invention, described Navoban (Soz) freeze-dried powder, each amounts of components is:
Navoban (Soz) 2～5g
Gelatin 6～20g
Glucosan 5～8g
Oleophilic emulsifier 1～7g
Hydrophilic emulsifying agent 1～7g
Frozen-dried supporting agent 50～300g
As one of preferred version of the present invention, wherein said Navoban (Soz) freeze-dried powder is characterized in that it being to be made by following method:
(1) Navoban (Soz) is added in the water for injection, fully dissolving;
(2) in step (1) gained solution, add gelatin and oleophilic emulsifier, be prepared into water-in-oil emulsion;
(3) in step (2) gained emulsion, add dextran solution and hydrophilic emulsifying agent, be prepared into the W/O/W double emulsion;
(4) step (3) gained double emulsion is injected the highly basic consolidation liquid that splashes in the high-voltage electrostatic field by orifice, leaches microcapsule, with the gained microcapsule with water rinse or contain the pH regulator agent solution to be washed till pH be 5～7;
(5) frozen-dried supporting agent is dissolved in water for injection, and step (4) gained microcapsule mix homogeneously, the packing postlyophilization gets the Navoban (Soz) freeze-dried powder.
Oleophilic emulsifier of the present invention is used to prepare water-in-oil emulsion, can select any one pharmaceutically acceptable oleophilic emulsifier for use, for example can select for use but be not limited in span, cholesterol, soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline, the synthetic phospholipid one or more.The present invention preferably uses Ovum Gallus domesticus Flavus lecithin.
Hydrophilic emulsifying agent of the present invention is used to prepare the W/O/W double emulsion, can select any one pharmaceutically acceptable hydrophilic emulsifying agent for use, for example can select for use but be not limited in tween, poloxamer, Myrj 45, the polyoxyethylene hydrogenated Oleum Ricini one or more.The present invention preferably uses tween.
The Navoban (Soz) microcapsule has the effect of slow release and target administration.Wherein microcapsule diameter directly influence the release rate of drugs of wrapping and medicine absorption in vivo position.As preferred implementation of the present invention, after improving the stability of Navoban (Soz) in aqueous solution, can also improve the drug effect of described hydrochloride for injection tropisetron microcapsule by the microcapsule for preparing certain particle diameter.The microcapsule diameter of hydrochloride for injection tropisetron microcapsule of the present invention is preferably 50 μ m～600 μ m, more preferably 50 μ m～100 μ m.
PH regulator agent described in the above-mentioned described method can be acidic materials, for example can select mineral acid or organic acid for use.Wherein said mineral acid for example is selected from one or more in hydrochloric acid, phosphoric acid, acetic acid, the boric acid; Described organic acid is selected from citric acid, malic acid, succinic acid, one or more in maleic acid, Fumaric acid, tartaric acid, succinic acid, the cholic acid.
In the preparation hydrochloride for injection tropisetron microcapsule method of the present invention, prepare water-in-oil emulsion and W/O/W double emulsion and can adopt this area method commonly used, for example: mechanical mixing method, high pressure homogenization method or ultrasonic method.
Highly basic consolidation liquid of the present invention can use sodium hydroxide consolidation liquid, potassium hydroxide consolidation liquid, Sodium ethylate consolidation liquid or tert-butyl group sodium consolidation liquid, and the concentration of described highly basic consolidation liquid is 2mol/L-6mol/L.The present invention preferably uses the sodium hydroxide consolidation liquid, and further preferred working concentration is the sodium hydroxide consolidation liquid of 2mol/L-6mol/L.
In order to make the Navoban (Soz) microcapsule have excellent mechanical intensity and drug release rate, need being controlled hardening time.Too short meeting hardening time causes embedding rate to descend, and hardening time is long more, and the rigidity of microcapsule is big more, and the swellbility of microcapsule is more little, and crosslinking degree is also big more simultaneously, and reduce the microchannel in the microcapsule, and the rate of release of medicine slows down.In preparation method provided by the present invention, be 10min-60min, more preferably 20min-40min the hardening time of Navoban (Soz) microcapsule.
The method that the present invention prepares described Navoban (Soz) lyophilized formulations is the common technology in present technique field, can determine suitable freeze drying process parameter by routine test.
The present invention adopts orifice+high-pressure electrostatic legal system to be equipped with the Navoban (Soz) microcapsule.The present invention all is not particularly limited the distance between electric field intensity, syringe and the highly basic consolidation liquid and the fltting speed of double emulsion.As preferably, described electric field intensity can remain on and be not less than 2.2kv; The fltting speed of described double emulsion is 5ml/min-20ml/min.In order better to solidify the Navoban (Soz) microcapsule, improve solidified homogeneity, in injecting double emulsion and solidification process, can stir consolidation liquid, mixing speed is 1000r/min-2000r/min.
Technique effect below by test explanation Navoban (Soz) lyophilized formulations of the present invention.
Test one, quality stability test
Navoban (Soz) lyophilized formulations that embodiment 1-6 in the specific embodiment is prepared and commercially available Navoban (Soz) injection and lyophilized injectable powder are under 60 ℃ of temperature, humidity 75% condition, carry out stable accelerated test, investigate the variation of each quality detecting index, result of the test is as shown in table 1.
Stable accelerated test under 60 ℃ of table 1 temperature, humidity 75% condition
By above data result as can be seen, the Navoban (Soz) lyophilized formulations and the commercially available related preparations of the present invention's preparation are compared, and pH is stable, Navoban (Soz) content height, and its related substances is low simultaneously, and the back visible foreign matters that redissolves is few.Therefore, Navoban (Soz) lyophilized formulations provided by the present invention is higher than commercially available Navoban (Soz) preparation stability, better quality.
Test two, compatibility test
Navoban (Soz) lyophilized formulations that embodiment 1-6 in the specific embodiment is prepared and listing injectable powder carry out the compatibility test with the sodium chloride injection of 5% glucose injection and 0.9% respectively, detect each leading indicator after 8 hours.The result: the sample compatibility pH value of solution value of the present invention's preparation changes little, and visible foreign matters is up to specification; And the compatibility solution of listing injectable powder has a spot of floccule to generate, and visible foreign matters is obviously defective, may be that Navoban (Soz) hydrolysis in aqueous solution causes, and produces insoluble foreign body.This explanation liposome microencapsulation principal agent Navoban (Soz) has greatly improved its stability in water, has guaranteed normal drug safety.
Test three, safety testing
1. the undue toxicity checks: according to the undue toxicity's inspection technique among the version pharmacopeia appendix XI in 2005, the Navoban (Soz) lyophilized formulations of embodiment of the invention 1-6 preparation is diluted to certain density need testing solution with sodium chloride solution, injects in the mice body of Pass Test requirement.Result of the test shows that mice did not all have the phenomena of mortality in 48 hours, illustrate that this product undue toxicity is up to specification.
2. heat source check: check that according to the heat resource method among 2005 editions pharmacopeia appendix XI the result is also up to specification.
Therefore, Navoban (Soz) lyophilized formulations provided by the present invention has greatly improved the stability in aqueous solution.Navoban (Soz) wraps in the microcapsule, can stablize, discharge slowly, has improved the bioavailability of Navoban (Soz).It is simple that the method for the described Navoban (Soz) lyophilized formulations of preparation provided by the present invention has technology, reaction condition gentleness, even, the narrowly distributing of making particle diameter, the advantage that yield is high, and selected adjuvant is all biodegradable, and good biocompatibility has no side effect.
The specific embodiment
The invention will be further described below in conjunction with embodiment.
Embodiment 1:
Navoban (Soz) 2g
Gelatin 6g
Glucosan 5g
Soybean lecithin 1.1g
Tween 80 1.5g
Mannitol 50g
Preparation technology
(1) the 2g Navoban (Soz) is added in the water for injection, fully dissolving;
(2) in step (1) gained solution, add 6g gelatin and 1.1g soybean lecithin, be prepared into water-in-oil emulsion with mechanical mixing method;
(3) in step (2) gained emulsion, add 2.5% dextran solution 200ml and 1.5g Tween 80, be prepared into the W/O/W double emulsion with mechanical mixing method;
(4) step (3) gained double emulsion is injected the 2mol/L sodium hydroxide consolidation liquid that splashes in the high-voltage electrostatic field by orifice, voltage of electric field is for being 2.2kv, the speed of injecting is 15ml/min, solidify the 20min after-filtration and go out microcapsule, stir the highly basic firming agent to solidifying end after injecting double emulsion, mixing speed is 1500r/min, wash with water microcapsule to pH be 5.2;
(5) 50g mannitol is dissolved in water for injection, and step (4) gained microcapsule mix homogeneously, the packing postlyophilization gets the Navoban (Soz) freeze-dried powder.
Embodiment 2:
Navoban (Soz) 5g
Gelatin 20g
Dextran 8 g
Ovum Gallus domesticus Flavus lecithin 6.1g
Poloxamer 188 7.0g
Glucose 300g
Preparation technology makes the Navoban (Soz) freeze-dried powder with embodiment 1.
Embodiment 3:
Navoban (Soz) 3g
Gelatin 10g
Glucosan 5g
Cholesterol 2.7g
Poloxamer 188 3.6g
Glucose 120g
Preparation technology makes the Navoban (Soz) freeze-dried powder with embodiment 1.
Embodiment 4:
Navoban (Soz) 4g
Gelatin 15g
Glucosan 7g
Ovum Gallus domesticus Flavus lecithin 4.5g
Tween 80 5.3g
Glucose 210g
Preparation technology makes the Navoban (Soz) freeze-dried powder with embodiment 1.
Embodiment 5:
Navoban (Soz) 2g
Gelatin 6g
Glucosan 5g
Span 1g
Poloxamer 1g
Glucose 50g
Preparation technology makes the Navoban (Soz) freeze-dried powder with embodiment 1.
Embodiment 6:
Navoban (Soz) 5g
Gelatin 20g
Dextran 8 g
Ovum Gallus domesticus Flavus lecithin 7g
Polyoxyethylene hydrogenated Oleum Ricini 7g
Mannitol 300g
Preparation technology makes the Navoban (Soz) freeze-dried powder with embodiment 1.
The present invention is described according to preferred embodiment.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (11)
1. hydrochloride for injection tropisetron microcapsule, form by Navoban (Soz) and adjuvant, it is characterized in that described adjuvant is made up of gelatin, glucosan and emulsifying agent, wherein, according to listed as parts by weight, 1 part of Navoban (Soz), 2～6 parts in gelatin, 1～4 part of glucosan, 0.5～5 part of emulsifying agent, wherein said emulsifying agent comprises oleophilic emulsifier and hydrophilic emulsifying agent.
2. hydrochloride for injection tropisetron microcapsule according to claim 1, wherein, calculate oleophilic emulsifier in the described emulsifying agent by weight: hydrophilic emulsifying agent is 1: 0.5～3.
3. hydrochloride for injection tropisetron microcapsule according to claim 1 and 2, wherein, described oleophilic emulsifier is selected from one or more in span, cholesterol, soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline, the synthetic phospholipid; Described hydrophilic emulsifying agent is selected from one or more in tween, poloxamer, Myrj 45, the polyoxyethylene hydrogenated Oleum Ricini.
4. according to each described hydrochloride for injection tropisetron microcapsule of claim 1-3, it is to make by the method that comprises following steps:
(1) Navoban (Soz) is added in the water for injection, fully dissolving;
(2) in step (1) gained solution, add gelatin and oleophilic emulsifier, be prepared into water-in-oil emulsion;
(3) in step (2) gained emulsion, add dextran solution and hydrophilic emulsifying agent, be prepared into the W/O/W double emulsion;
(4) step (3) gained double emulsion is injected highly basic consolidation liquid in the high-voltage electrostatic field by orifice, make microcapsule.
5. Navoban (Soz) freeze-dried powder, with the Navoban (Soz) is effective ingredient, it is characterized in that being made up of Navoban (Soz) microcapsule and frozen-dried supporting agent, wherein said Navoban (Soz) microcapsule is each described hydrochloride for injection tropisetron microcapsule of aforesaid right requirement 1-4.
6. Navoban (Soz) freeze-dried powder according to claim 5, wherein said frozen-dried supporting agent is selected from one or more in mannitol, lactose, glucose, sucrose, glucosan, polyvinylpyrrolidone, glycine, xylitol or the sorbitol.
7. Navoban (Soz) freeze-dried powder according to claim 6, wherein said frozen-dried supporting agent are mannitol or glucose.
8. Navoban (Soz) freeze-dried powder according to claim 5 is characterized in that: each amounts of components is:
Navoban (Soz) 2～5g
Gelatin 6～20g
Glucosan 5～8g
Oleophilic emulsifier 1～7g
Hydrophilic emulsifying agent 1～7g
Frozen-dried supporting agent 50～300g.
9. according to each described Navoban (Soz) freeze-dried powder of claim 5-8, it is characterized in that it being to make by following method:
(1) Navoban (Soz) is added in the water for injection, fully dissolving;
(2) in step (1) gained solution, add gelatin and oleophilic emulsifier, be prepared into water-in-oil emulsion;
(3) in step (2) gained emulsion, add dextran solution and hydrophilic emulsifying agent, be prepared into the W/O/W double emulsion;
(4) step (3) gained double emulsion is injected the highly basic consolidation liquid that splashes in the high-voltage electrostatic field by orifice, leaches microcapsule, with the gained microcapsule with water rinse or contain the pH regulator agent solution to be washed till pH be 5～7;
(5) frozen-dried supporting agent is dissolved in water for injection, and step (4) gained microcapsule mix homogeneously, the packing postlyophilization gets the Navoban (Soz) freeze-dried powder.
10. hydrochloride for injection tropisetron freeze-dried powder according to claim 9, wherein said oleophilic emulsifier is an Ovum Gallus domesticus Flavus lecithin, described hydrophilic emulsifying agent is a tween.
11. hydrochloride for injection tropisetron freeze-dried powder according to claim 9 is characterized in that: described Navoban (Soz) microcapsule diameter is 50 μ m～600 μ m.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2008101104233A CN101278921B (en) | 2008-06-03 | 2008-06-03 | Triopisetron Hydrochloride microcapsule and method for preparing injection |
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| CN2008101104233A CN101278921B (en) | 2008-06-03 | 2008-06-03 | Triopisetron Hydrochloride microcapsule and method for preparing injection |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1165478A (en) * | 1994-11-09 | 1997-11-19 | 俄亥俄州州立大学研究基金会 | Formation of pellets |
| CN1287877A (en) * | 1999-07-27 | 2001-03-21 | 株式会社资生堂 | Micro-capsule and its prepn. method |
| WO2006006595A1 (en) * | 2004-07-12 | 2006-01-19 | Teikokumedix Co., Ltd. | Medicinal composition for oral use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1165478A (en) * | 1994-11-09 | 1997-11-19 | 俄亥俄州州立大学研究基金会 | Formation of pellets |
| CN1287877A (en) * | 1999-07-27 | 2001-03-21 | 株式会社资生堂 | Micro-capsule and its prepn. method |
| WO2006006595A1 (en) * | 2004-07-12 | 2006-01-19 | Teikokumedix Co., Ltd. | Medicinal composition for oral use |
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