胸腺五肽肺部吸入粉雾剂的研制及其药效学研究
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摘要
胸腺五肽(Thymopentin, Tp5)是胸腺中分离出来的胸腺生成素(Thymopoietin)的免疫活性中心,是一个五肽片段,具有与胸腺生成素相同的全部生理功能,即具有双向调节免疫系统的功能。主要用于治疗恶性肿瘤、慢性乙型肝炎、慢性丙型肝炎和病毒性肝炎合并胆道感染、多种耐药性结核抗药性瘤型麻风、败血症并发症等,还可治疗更年期综合征、糖尿病自身免疫功能紊乱性疾病、年老体弱免疫功能低下等。
开发安全、有效、生物利用度高的蛋白质和肽类药物的非注射给药系统是目前制剂学的研究热点之一。本研究以胸腺五肽为模型药物,系统地研究了胸腺五肽肺部吸入粉雾剂的制备处方和工艺,考察了不同的制备方法对胸腺五肽吸入粉雾剂体外生物活性的影响,并对不同剂量的粉雾剂在大鼠体内的药效学进行了初步研究。
肺部吸入粉雾剂的评价指标包括堆密度、休止角、排空率、雾化特性等。本文的第一部分以模糊数学原理,将四个不同量纲的指标统一为一个无量纲的复合评价指标,以此指标作为吸入粉雾剂物理性能评价的依据,避免了各指标的不同标准对载体系统筛选的影响。同时,建立了HPLC法测定制剂中胸腺五肽的含量以及每批粉雾剂胶囊的含量均匀度,并对胸腺五肽进行了制剂前稳定性考察。
本文第二部分重点对吸入粉雾剂的制备处方和工艺进行了研究。喷雾干燥技术是常用的微粉化技术之一,根据吸入粉雾剂的特点,本文设计了相应的处方和工艺,利用复合评价指标对载体系统进行了筛选,并设计了正交实验考察了工艺因素对产品收率和性状的影响;喷雾冷冻干燥技术是新兴的微粉化技术,避免了喷雾干燥过程中的高温可能造成的药物活性损失,实验中处方筛选参考了前述喷雾干燥法的试验结果,根据复合指标的得分对喷雾冷冻干燥的载体系统进行了评价,并以喷雾速度和溶液浓度为考察因素,确定了最佳制备工艺;应用超临界流体技术对胸腺五肽进行微粉化研究,考察了温度、压力、溶液浓度、溶液流速及超临界流体的伴流速等对微粉制备和粒径的影响,制备吸入粉雾剂后对相关指标进行了测定,均符合中国药典2000版标准。
Thymopentin (Tp5) is synthesized as an effective part of thymopoietin, which has the ability to take part in the immunological adjustment. It can play a very important role in the treatment of malignant cancer, several kinds of hepatitis and some other infection syndrome. Generally it is given as an injection.Studies on non-injective drug delivery system of polypeptide have been paid much attention to recently. Dry powder inhalations (DPIs) are regarded as useful vector for pulmonary delivery of polypeptides. On the basis of the fuzzy system theory, a complex factor was constructed to unite the dumping ratio, aerosolizing property, bulk density and repose angel to evaluate the qualities of Tp5 DPIs. Meanwhile, the HPLC method was utilized to determine the Tp5 in the DPIs.Studies of the composition and preparation of Tp5 DPIs were emphases of this dissertation. A spray drying method was designed to make the Tp5 DPIs. The formulae were selected according to the complex factor which was constructed in the first part of this dissertation. The manufacture process was selected according to the recovery and the characteristics of the product. For spray-freeze drying method, the ideal preparation conditions were evaluated in the pump spraying speed, the concentration of Tp5 solution and the volume of the solution. Besides, supercritical fluids technology, which was firstly used to powder Tp5, was also studied to make Tp5 DPIs. The preparation process including temperature, pressure, concentration and flow rate of the solution, the co-flow rate of SCF were studied according to the properties of DPIs, and the results were in accordance with the CHP (2000).To detect the biological activity of Tp5 DPIs in vitro, CCK-8 tests were employed. The results showed that Tp5 DPIs had the same biological activity as Tp5 did. The results indicated that carriers without Tp5 had no obvious effect as Tp5 did.Pharmacodynamics study in vivo was executed by giving the Wistar rats Tp5 DPIs periodically, which were injected with immunosuppressant (Cyclophosphamide,
开发安全、有效、生物利用度高的蛋白质和肽类药物的非注射给药系统是目前制剂学的研究热点之一。本研究以胸腺五肽为模型药物,系统地研究了胸腺五肽肺部吸入粉雾剂的制备处方和工艺,考察了不同的制备方法对胸腺五肽吸入粉雾剂体外生物活性的影响,并对不同剂量的粉雾剂在大鼠体内的药效学进行了初步研究。
肺部吸入粉雾剂的评价指标包括堆密度、休止角、排空率、雾化特性等。本文的第一部分以模糊数学原理,将四个不同量纲的指标统一为一个无量纲的复合评价指标,以此指标作为吸入粉雾剂物理性能评价的依据,避免了各指标的不同标准对载体系统筛选的影响。同时,建立了HPLC法测定制剂中胸腺五肽的含量以及每批粉雾剂胶囊的含量均匀度,并对胸腺五肽进行了制剂前稳定性考察。
本文第二部分重点对吸入粉雾剂的制备处方和工艺进行了研究。喷雾干燥技术是常用的微粉化技术之一,根据吸入粉雾剂的特点,本文设计了相应的处方和工艺,利用复合评价指标对载体系统进行了筛选,并设计了正交实验考察了工艺因素对产品收率和性状的影响;喷雾冷冻干燥技术是新兴的微粉化技术,避免了喷雾干燥过程中的高温可能造成的药物活性损失,实验中处方筛选参考了前述喷雾干燥法的试验结果,根据复合指标的得分对喷雾冷冻干燥的载体系统进行了评价,并以喷雾速度和溶液浓度为考察因素,确定了最佳制备工艺;应用超临界流体技术对胸腺五肽进行微粉化研究,考察了温度、压力、溶液浓度、溶液流速及超临界流体的伴流速等对微粉制备和粒径的影响,制备吸入粉雾剂后对相关指标进行了测定,均符合中国药典2000版标准。
Thymopentin (Tp5) is synthesized as an effective part of thymopoietin, which has the ability to take part in the immunological adjustment. It can play a very important role in the treatment of malignant cancer, several kinds of hepatitis and some other infection syndrome. Generally it is given as an injection.Studies on non-injective drug delivery system of polypeptide have been paid much attention to recently. Dry powder inhalations (DPIs) are regarded as useful vector for pulmonary delivery of polypeptides. On the basis of the fuzzy system theory, a complex factor was constructed to unite the dumping ratio, aerosolizing property, bulk density and repose angel to evaluate the qualities of Tp5 DPIs. Meanwhile, the HPLC method was utilized to determine the Tp5 in the DPIs.Studies of the composition and preparation of Tp5 DPIs were emphases of this dissertation. A spray drying method was designed to make the Tp5 DPIs. The formulae were selected according to the complex factor which was constructed in the first part of this dissertation. The manufacture process was selected according to the recovery and the characteristics of the product. For spray-freeze drying method, the ideal preparation conditions were evaluated in the pump spraying speed, the concentration of Tp5 solution and the volume of the solution. Besides, supercritical fluids technology, which was firstly used to powder Tp5, was also studied to make Tp5 DPIs. The preparation process including temperature, pressure, concentration and flow rate of the solution, the co-flow rate of SCF were studied according to the properties of DPIs, and the results were in accordance with the CHP (2000).To detect the biological activity of Tp5 DPIs in vitro, CCK-8 tests were employed. The results showed that Tp5 DPIs had the same biological activity as Tp5 did. The results indicated that carriers without Tp5 had no obvious effect as Tp5 did.Pharmacodynamics study in vivo was executed by giving the Wistar rats Tp5 DPIs periodically, which were injected with immunosuppressant (Cyclophosphamide,
引文
[1] 朱祥林,王军.注射用胸腺五肽.中国新药杂志.1999,8(8):547.
[2] 盛家琦,贾杰,胡晓愚.胸腺五肽的研究与应用.厂矿医药卫生.1999,15(2):68-70.
[3] 王玲,魏浩,韦萍等.固相合成胸腺五肽的研究进展.化工进展.2003,2:153-156
[4] 王凤山,蔡祖花,张天民.1999年我国生化药物的研究进展.中国药学杂志,2000,35(4):223
[5] 张天民,王凤山.2001年我国生化药物的研究进展.中国药学杂志,2002,37(7):487
[6] 卢岳青,贡联兵,佟东宁.3485例应用胸腺五肽预防SARS的疗效分析.中华临床医药,2004,5(3):109-110.
[7] 吴德政,刘琴棣等.胸腺五肽在肿瘤化疗中的免疫调节作用.中国新药杂志,1999,8(5):321
[8] 丛玉隆,孙带,陈宝梁,主编.当代血液分析技术与临床.人民卫生出版社,1997
[9] 张章平,雷自重,陈绪元等.注射用胸腺五肽对肿瘤化疗病人的免疫增强作用.重庆医科大学学报.2001,26(3):299-301.
[10] 马欣,张如敏,詹丽.胸腺五肽对老年肿瘤病人T细胞亚群的影响.传染病信息,2001,14(1):42
[11] 杨国玲,王勤,王珠银.胸腺五肽固相合成及其对人血液若干生化指标的影响.甘肃科学学报,1994,6(1):36
[12] 付清泉,左斌海,李天全.几类生物活性肽的研究进展.航天医学与医学工程,2002,15(3):227
[13] 熊莲洁,陈西敬,朱家壁.蛋白质和肽类药物肺部给药新剂型——吸入粉雾剂.药学进展.2001,25(4):224-227.
[14] 曾衍霖.蛋白质及多肽类药物的药剂学研究进展.中国新药杂志.1997,6(1):13-18.
[2] 盛家琦,贾杰,胡晓愚.胸腺五肽的研究与应用.厂矿医药卫生.1999,15(2):68-70.
[3] 王玲,魏浩,韦萍等.固相合成胸腺五肽的研究进展.化工进展.2003,2:153-156
[4] 王凤山,蔡祖花,张天民.1999年我国生化药物的研究进展.中国药学杂志,2000,35(4):223
[5] 张天民,王凤山.2001年我国生化药物的研究进展.中国药学杂志,2002,37(7):487
[6] 卢岳青,贡联兵,佟东宁.3485例应用胸腺五肽预防SARS的疗效分析.中华临床医药,2004,5(3):109-110.
[7] 吴德政,刘琴棣等.胸腺五肽在肿瘤化疗中的免疫调节作用.中国新药杂志,1999,8(5):321
[8] 丛玉隆,孙带,陈宝梁,主编.当代血液分析技术与临床.人民卫生出版社,1997
[9] 张章平,雷自重,陈绪元等.注射用胸腺五肽对肿瘤化疗病人的免疫增强作用.重庆医科大学学报.2001,26(3):299-301.
[10] 马欣,张如敏,詹丽.胸腺五肽对老年肿瘤病人T细胞亚群的影响.传染病信息,2001,14(1):42
[11] 杨国玲,王勤,王珠银.胸腺五肽固相合成及其对人血液若干生化指标的影响.甘肃科学学报,1994,6(1):36
[12] 付清泉,左斌海,李天全.几类生物活性肽的研究进展.航天医学与医学工程,2002,15(3):227
[13] 熊莲洁,陈西敬,朱家壁.蛋白质和肽类药物肺部给药新剂型——吸入粉雾剂.药学进展.2001,25(4):224-227.
[14] 曾衍霖.蛋白质及多肽类药物的药剂学研究进展.中国新药杂志.1997,6(1):13-18.