注射用促肝细胞生长素及其冻干工艺的研究
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摘要
本文以80mg／瓶注射用促肝细胞生长素为研究对象，通过处方筛选和工艺优化，获得最佳处方和冻干工艺曲线。
首先，选择赋形剂多元醇类的甘露醇和多糖类的右旋糖酐作为辅料，按照不同的用量，组合成8种处方进行冷冻干燥试生产，采用二因素三水平的满因子分析法，通过处方调整，确定甘露醇160mg／瓶、右旋糖酐40mg／瓶为最佳处方，解决了冻干制剂在性状、水分(≤1.5％)、溶解性(≤6s)和含量稳定性(95.0～110.0％)等方面的不足，提高了产品质量。
其次，研究冻干曲线和成品质量之间的关系，按照冻干曲线(时间)为18、24、30、36、42、48小时进行冷冻干燥试生产，通过对制成的冻干品进行测试分析，确定冻干曲线(时间)36小时为最佳冻干曲线，达到了既保证产品质量又节约能耗、降低生产成本的目的。
再次，借助显微成像和X-衍射分析技术研究促肝细胞生长素原药、辅料及冻干粉针剂的结构与性状，以揭示其相关性。
最后，进行稳定性考察，通过加速稳定性试验和含量变化分析，进一步验证大规格注射用促肝细胞生长素研究中处方筛选和工艺优化的可靠性。
In this paper, the object of studying is that of hepatocytegrowth-promoting factor for injection(80mg/bottle),we achieve thebest recipe and freezen curved-line by optimization of recipe andtechnique.
The first, selecting Mannitol of polyhydric and Dextran ofpolysaccharide as subsidiary material, In accordance with differentusing quantities, making up eight recipes, freeze-drying test is madewith eight recipes differently. By adjusting recipe, to select themethod of two factors three levels. The best recipe determined is thatof Mannitol(160mg/bottle) and Dextran(40mg/bottle), Solving theproblem of description、moisture(≤1.5%)、solution(≤6s)、stability(95.0～110.0%) etc., The quality of preparation has beenimproved.
Next, studying the relations of freezen curved-line and the qualityof products, According to the freezen time 18、24、30、36、42、48 hours,freeze-dried products is experimented. By testing the freeze-driedproducts and analysing, The best freezen curved-line(time) is 36 hours.Not only the quality of produce is good, but also energy is economized,and producing costs is reduced.
A second time, the optical micrography and the X-ray diffractionanalysis were utilized in the study of the characteristics andconfiguration of the bulk drug、the adjuvant and freeze-dried powerto reveal their correlations.
Finally,by studying on stability in the accelerate test andanalysing on variations of contents, Further, verify the reliabilityof results that study on optimization of recipe and technique ofhepatocyte growth-promoting factor for injection.
首先，选择赋形剂多元醇类的甘露醇和多糖类的右旋糖酐作为辅料，按照不同的用量，组合成8种处方进行冷冻干燥试生产，采用二因素三水平的满因子分析法，通过处方调整，确定甘露醇160mg／瓶、右旋糖酐40mg／瓶为最佳处方，解决了冻干制剂在性状、水分(≤1.5％)、溶解性(≤6s)和含量稳定性(95.0～110.0％)等方面的不足，提高了产品质量。
其次，研究冻干曲线和成品质量之间的关系，按照冻干曲线(时间)为18、24、30、36、42、48小时进行冷冻干燥试生产，通过对制成的冻干品进行测试分析，确定冻干曲线(时间)36小时为最佳冻干曲线，达到了既保证产品质量又节约能耗、降低生产成本的目的。
再次，借助显微成像和X-衍射分析技术研究促肝细胞生长素原药、辅料及冻干粉针剂的结构与性状，以揭示其相关性。
最后，进行稳定性考察，通过加速稳定性试验和含量变化分析，进一步验证大规格注射用促肝细胞生长素研究中处方筛选和工艺优化的可靠性。
In this paper, the object of studying is that of hepatocytegrowth-promoting factor for injection(80mg/bottle),we achieve thebest recipe and freezen curved-line by optimization of recipe andtechnique.
The first, selecting Mannitol of polyhydric and Dextran ofpolysaccharide as subsidiary material, In accordance with differentusing quantities, making up eight recipes, freeze-drying test is madewith eight recipes differently. By adjusting recipe, to select themethod of two factors three levels. The best recipe determined is thatof Mannitol(160mg/bottle) and Dextran(40mg/bottle), Solving theproblem of description、moisture(≤1.5%)、solution(≤6s)、stability(95.0～110.0%) etc., The quality of preparation has beenimproved.
Next, studying the relations of freezen curved-line and the qualityof products, According to the freezen time 18、24、30、36、42、48 hours,freeze-dried products is experimented. By testing the freeze-driedproducts and analysing, The best freezen curved-line(time) is 36 hours.Not only the quality of produce is good, but also energy is economized,and producing costs is reduced.
A second time, the optical micrography and the X-ray diffractionanalysis were utilized in the study of the characteristics andconfiguration of the bulk drug、the adjuvant and freeze-dried powerto reveal their correlations.
Finally,by studying on stability in the accelerate test andanalysing on variations of contents, Further, verify the reliabilityof results that study on optimization of recipe and technique ofhepatocyte growth-promoting factor for injection.
引文
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[2] 赵鹤臬，林秀试．冷冻干燥技术[M]．武汉：华中理工大学出版社，1996．7．
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[7] Sandall OC, king CJ. TheRelationship Between Transport Properties ang Freeze Drying of Poultry Mcat. A.L. Ch.E.J 1967, 13: 428.
[8] Dyre DE, Sunderlanf JE. Heat and Mass Transfer Mechanisms in Sublimation Dehydration. ASME, Transaction, Journal of Heat transfer, 1968, 12:379.
[9] Litchield RT, Laips AI. Absorption-sublimation Model for a Freeze Dryer. Chemical Emgineering Science, 1979, 34: 1085.
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[15] RAghu K Cavatur, N.Murti Vemuri, Abira Pyne, et al..Crystallization behavior of mannitol in frozen aqueous solu-tions[J].Pharm. Res., 2002,19(6):894-900.
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[32] Dawson PJ, Hockley DJ. Scanning electron microscopy of freeze-dried preparations: relationship of morphology to freeze-drying parameters[J]. Dev Biol Stand. 1992, 74:185-92.
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[34] Yoshioka S, Aso Y, Kojima S. Determination of molecular mobility of lyophilized bovine serum albumin and γ-globulin by solid-state ~1H NMR and relation to aggregation-susceptibility[J]. Pharm Res. 1996, 13:926-930.
[35] Cavatur RK, Suryanarayanan R. Characterization of frozen aqueous solutions by low temperature X-ray powder diffractometry. Pharm Res[J]. 1998, 15(2): 194-9.
[36] 陈新谦，金有豫．新编药物学[M]．第15版．北京：人民卫生出版社，2003．471．
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[40] 孙长宇，余祖江，江河清．促肝细胞生长素联合胸腺肽、苦参碱治疗慢性重型乙型肝炎60例[J]．新乡医学院学报，2003，20(1)49-50．
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[2] 赵鹤臬，林秀试．冷冻干燥技术[M]．武汉：华中理工大学出版社，1996．7．
[3] 徐成海，等．真空低温技术与设备[M]．北京：冶金工业出版社，1995．4．
[4] 张兆祥，晏继之，徐成海，等．真空冷冻干燥与空调保鲜[M]．北京：中国民航出版社，1996．7．
[5] 高福成，刘志胜，李修渠．冻干食品[M]．北京：中国轻工业出版社，1998，5．
[6] 余善鸣，百杰，马国庆．果疏保鲜与冷冻干燥技术[M]．哈尔滨：黑龙江科学技术出版社，1999．2．
[7] Sandall OC, king CJ. TheRelationship Between Transport Properties ang Freeze Drying of Poultry Mcat. A.L. Ch.E.J 1967, 13: 428.
[8] Dyre DE, Sunderlanf JE. Heat and Mass Transfer Mechanisms in Sublimation Dehydration. ASME, Transaction, Journal of Heat transfer, 1968, 12:379.
[9] Litchield RT, Laips AI. Absorption-sublimation Model for a Freeze Dryer. Chemical Emgineering Science, 1979, 34: 1085.
[10] May JC, Reyl, Freeze-drying/lyophilization of pharmaceutical and biological products. New York: Marcel Dekker, 1999.
[11] 元英进，赵广荣，冯霞，等．现代制药工艺学[M]．第15版．北京：化学工业出版社，2004．316-317．
[12] 徐成海，彭润玲，刘军，等译．冷冻干燥[M]．原著第二版．北京：化学工业出版社，2005．283-284．
[13] Ken-ichi I, Shigeo K. Freeze-concentration separates protein and polymer excipients into different amorphous phase[J]. Pharm. Res, 2000, 17(10): 1316-1322.
[14] Zheng XM, Gary PM, Christopher M. Effects of molecular weight of polyvinylpyrrodoneon on the glass transfer and crystallization of co-lyophilized sucrose[J]. Int.J. Pharm.,2001, 218:63-73.
[15] RAghu K Cavatur, N.Murti Vemuri, Abira Pyne, et al..Crystallization behavior of mannitol in frozen aqueous solu-tions[J].Pharm. Res., 2002,19(6):894-900.
[16] Abira P, Rahul S, Raj S. Crystallization of mannitol blew Tg' during freeze-drying in binary and ternary aqueous[J]. Pharm. Res., 2002,19(6):901-908.
[17] Evgenyi YS, Tiffany DJ, Liuquan C, et al.. Thermophysical properties of pharmaceutically compatible buffers at sub-zero temperatures: Implications for Freeze-Drying[J]. Pharm. Res., 2002, 19(2):195-201.
[18] 刘占杰，华泽钊，陶乐仁，等．不同保护剂浓度和不同降温速率对脂质体玻璃化转变温度的影响[J]．低温工程，2000，6：1-5．
[19] Ch Korber, MW Scheiwe, P Boutron, et al..The influence of hydroxyethyl starch on ice formation in aqueous solutions[J].Cryobiology, 1982, 19: 478-492.
[20] M Kresin, G Rau. The glass transition of hydroxyethyl starch[J]. Cryo-Letters, 1992, 13:371-378.
[21] Liapis AI, Pikal MJ, Bruttini R. Research and development needs and opportunities in freeze drying[J]. Drying Technol, 1996, 14(6):1265-1300.
[22] Mellor JD. freeze-drying process with cyclic vacuum pressure. Brit Pat, No. 1083244,1967.
[23] Arakava T, Prestrelski SJ, Kenney WC, et al. Factors affecting short-term and long-term stabilities of proteins. Adv Drug Deliv Rev, 2001, 46(1-3): 307-326.
[24] 平其能．现代药剂学[M]．北京：中国医药科技出版社，1998．222-229．
[25] Searles JA, Carpenter JF, Randolph TW. The ice nucleation temperature determines the primary drying rate of lyophilization for samples frozen on a temperature-controlled shelf[J]. J Pharm. Sci, 2001, 90 (7) 860-871.
[26] 徐成海，张世伟，关奎之．真空干燥[M]．北京：化学工业出版社，2005．173．
[27] 比勤荪、戴惠天、六茜元，生物药物的研究与开发[J]．中国药事，2000，14(2)：114-116
[28] 王普善，王宇梅，世界生物药品工业现状与展望[J]．精细与专用化学品，2003，5：8-9
[29] Craig DQ, Barsnes M, Royall PG, Kett VL. An evaluation of the use of modulated temperature DSC as a means of assessing the relaxation behaviour of amorphous lactose[J]. Pharm Res, 2000, 17: 696-700.
[30] Knopp SA, Chongprasert S, Nail SL. The relationship between the TMDSC curve of frozen sucrose solutions and collapse during freeze-drying[J]. J Therm Anal Calorim, 1998, 54: 659-672.
[31] Cosman MD, Toner M, Kandel J, et al. An integrated cryomicroscopy system[J]. Cryo-Lett. 1989,10: 17-38.
[32] Dawson PJ, Hockley DJ. Scanning electron microscopy of freeze-dried preparations: relationship of morphology to freeze-drying parameters[J]. Dev Biol Stand. 1992, 74:185-92.
[33] Hsu CC, Walsh AJ, Nguyen HM, et al. Design and application o.f a low-temperature peltier-cooling microscope stage. J Pharmaceutical Sciences[J]. 1996, 85: 70-74.
[34] Yoshioka S, Aso Y, Kojima S. Determination of molecular mobility of lyophilized bovine serum albumin and γ-globulin by solid-state ~1H NMR and relation to aggregation-susceptibility[J]. Pharm Res. 1996, 13:926-930.
[35] Cavatur RK, Suryanarayanan R. Characterization of frozen aqueous solutions by low temperature X-ray powder diffractometry. Pharm Res[J]. 1998, 15(2): 194-9.
[36] 陈新谦，金有豫．新编药物学[M]．第15版．北京：人民卫生出版社，2003．471．
[37] 苏金良．果糖二磷酸钠联合促肝细胞生长素治疗重度肝炎52例疗效分析[J]．中国血液流变学杂志，2003，13(4)389-390．
[38] 朱宇佳．促肝细胞生长素治疗慢性重型肝炎的临床疗效观察[J]．广西医学，2003，25(8)1508-1509．
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