复合川芎嗪温敏原位凝胶抗腹腔粘连的实验研究
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摘要
本论文对术后腹腔粘连的防治进展及中医药在这一领域的独特优势进行了系统的文献检索，并对当前新型药物剂型——微乳及原位凝胶进行综述。在前期实验研究的基础上以鸡胚尿囊膜法观察川芎嗪对血管生成的影响，结合腹腔粘连形成的生理病理学特点，将传统中医外治法引入腹腔内，并思辨地将中药单体有效成分—盐酸川芎嗪—微乳化、原位凝胶化，研制具有缓释、温敏成胶、机械屏障等特性作用的盐酸川芎嗪微乳、原位凝胶。为此进行了微乳、原位凝胶制备，原位凝胶降解性和相容性实验及盐酸川芎嗪微乳、原位凝胶有效性验证等基础研究。
盐酸川芎嗪对血管生长的影响血管新生的过程贯穿于创伤修复的三个阶段—炎症阶段、增殖阶段、降解塑型阶段，特别是在前两个阶段尤以血管内皮细胞的大量增殖，血管新生为特点。鸡胚尿囊膜法观察发现：川芎嗪对血管生成有明显的抑制作用。
微乳制备研究采用加水滴定法制备盐酸川芎嗪微乳，应用单因子法进行多次实验配比筛选微乳处方构成，以伪三元相图法结合稳定性考察筛选处方，同时采用多种方法对微乳类型进行判断，最终优选盐酸川芎嗪微乳处方为：OP乳化剂，丙三醇助乳化剂，油酸乙酯为油相，盐酸川芎嗪溶液滴定浓度为50mg／mL。
原位凝胶制备研究制备Poloxamer 407的不同浓度溶液，分别测定其相转变温度、绘制黏度—温度曲线及37℃条件下体外释放度测定，实验发现40％P-407原位凝胶与辅料2～3％甲基纤维素(MC)结合使盐酸川芎嗪的体外释放度明显延长，最符合本实验要求。
生物降解性和相容性研究在pH=7．4的磷酸缓冲液中加入溶菌酶模拟腹腔环境进行40％P407原位凝胶体外降解试验，并在小鼠体内进行相容性试验，结果提示：72h降解57．4％，120h降解65．2％。腹腔内均未见到大网膜包裹，且局部无渗液、无明显水肿，说明原位凝胶在腹腔内不会出现明显排异反应，与腹腔内组织相容性良好，基本符合腹腔内使用条件。
微乳、原位凝胶药效学研究将SD大鼠造模后随机分成生理盐水；盐酸川芎嗪；空白微乳：盐酸川芎嗪微乳高、中、低剂量；空白原位凝胶、盐酸川芎嗪原位凝胶高、中、低剂量组。腹腔给药，于术后22d处死，进行腹膜粘连评分及免疫组化SABC统计分析。结果提示：盐酸川芎嗪低剂量原位凝胶效果最佳。
This article made systemic literature retrieval on prevention and cure of peritoneal adhesion and the unique superiority of Chinese Medicine in this field. And also, it summarized on the new type of pharmaceutical dosage forms: microemulsion and situ-gel. Combining with the physiopathology characteristic of peritoneal adhesion formation, we brought in the traditional Chinese medicine and external treatment into abdominal cavity. We prepared microemulsion and situ-gel of Ligustrazine Hydrochloride, a traditional Chinese drug monomer effective constituent, developed Ligustrazine Hydrochloride microemulsion and situ-gel with delayed release, temperature sensitive and machinery barricade characteristics. For that, we did the preparation of microemulsion and situ-gel, the degradation and compatibility experiments of situ-gel, the efficacy experiment of microemulsion and situ-gel.
Microemulsion preparation: Ligustrazine Hydrochloride microemulsion was prepared in titrimetric method with water. The formation was optimized in single-factor experiments, ternary phase diagram and stability investigation. The type of microemulsion was judged in several methods. HPLC method was employed in Ligustrazine Hydrochloride content determination. At the same time, the loaded-drug, stability and clarity of microemulsion were investigated. The optimized formation of Ligustrazine Hydrochloride microemulsion were OP as the emulsifier, glycerol as the co-emulsifier and ethyl oleate as oil, the concentration of Ligustrazine Hydrochloride was 50mg/mL.
Situ-gel preparation: The solution of Poloxamer 407 in different concentrations was prepared. We determined the phase variation temperature, drew the viscosity-temperature curve and determined the drug release in 37℃in vitro. It showed that the P-407 situ-gel in 40% prolonged the drug release in vitro obviously, which was consistent with experiment request.
The study of biological degradation and compatibility: We added lysozyme into phosphate buffer in pH 7.4 to determine the degradation of situ-gel in vitro. And also, the compatibility test was conducted in vivo with SD rats. It showed that: the preparation degradation was 45.1% in 60h and 74.2% in 120h. Greater omentum was not found in abdominal cavity. There was no part effusion and obvious edema. It suggested that situ-gel would not show up rejection obviously in abdominal cavity, had good histocompatibility and was consistent with the working condition in abdominal cavity.
Pharmacodynamic action of microemulsion and situ-gel: Divide the SD rats into ten groups randomly after mode-make: sodium chloride group, Ligustrazine Hydrochloride group, blank microemulsion group, Ligustrazine Hydrochloride microemulsion in high doss group, and also in middle and low doss group, blank situ-gel group, Ligustrazine Hydrochloride situ-gel in high doss group, and also in middle and low dose group. The preparations were used in abdominal cavity. All the rats were killed 22 days after operation. Peritoneal adhesion score and immunity SABC statistical analysis were undertaken. It showed that Ligustrazine Hydrochloride situ-gel in low doss possessed the best effect.
盐酸川芎嗪对血管生长的影响血管新生的过程贯穿于创伤修复的三个阶段—炎症阶段、增殖阶段、降解塑型阶段，特别是在前两个阶段尤以血管内皮细胞的大量增殖，血管新生为特点。鸡胚尿囊膜法观察发现：川芎嗪对血管生成有明显的抑制作用。
微乳制备研究采用加水滴定法制备盐酸川芎嗪微乳，应用单因子法进行多次实验配比筛选微乳处方构成，以伪三元相图法结合稳定性考察筛选处方，同时采用多种方法对微乳类型进行判断，最终优选盐酸川芎嗪微乳处方为：OP乳化剂，丙三醇助乳化剂，油酸乙酯为油相，盐酸川芎嗪溶液滴定浓度为50mg／mL。
原位凝胶制备研究制备Poloxamer 407的不同浓度溶液，分别测定其相转变温度、绘制黏度—温度曲线及37℃条件下体外释放度测定，实验发现40％P-407原位凝胶与辅料2～3％甲基纤维素(MC)结合使盐酸川芎嗪的体外释放度明显延长，最符合本实验要求。
生物降解性和相容性研究在pH=7．4的磷酸缓冲液中加入溶菌酶模拟腹腔环境进行40％P407原位凝胶体外降解试验，并在小鼠体内进行相容性试验，结果提示：72h降解57．4％，120h降解65．2％。腹腔内均未见到大网膜包裹，且局部无渗液、无明显水肿，说明原位凝胶在腹腔内不会出现明显排异反应，与腹腔内组织相容性良好，基本符合腹腔内使用条件。
微乳、原位凝胶药效学研究将SD大鼠造模后随机分成生理盐水；盐酸川芎嗪；空白微乳：盐酸川芎嗪微乳高、中、低剂量；空白原位凝胶、盐酸川芎嗪原位凝胶高、中、低剂量组。腹腔给药，于术后22d处死，进行腹膜粘连评分及免疫组化SABC统计分析。结果提示：盐酸川芎嗪低剂量原位凝胶效果最佳。
This article made systemic literature retrieval on prevention and cure of peritoneal adhesion and the unique superiority of Chinese Medicine in this field. And also, it summarized on the new type of pharmaceutical dosage forms: microemulsion and situ-gel. Combining with the physiopathology characteristic of peritoneal adhesion formation, we brought in the traditional Chinese medicine and external treatment into abdominal cavity. We prepared microemulsion and situ-gel of Ligustrazine Hydrochloride, a traditional Chinese drug monomer effective constituent, developed Ligustrazine Hydrochloride microemulsion and situ-gel with delayed release, temperature sensitive and machinery barricade characteristics. For that, we did the preparation of microemulsion and situ-gel, the degradation and compatibility experiments of situ-gel, the efficacy experiment of microemulsion and situ-gel.
Microemulsion preparation: Ligustrazine Hydrochloride microemulsion was prepared in titrimetric method with water. The formation was optimized in single-factor experiments, ternary phase diagram and stability investigation. The type of microemulsion was judged in several methods. HPLC method was employed in Ligustrazine Hydrochloride content determination. At the same time, the loaded-drug, stability and clarity of microemulsion were investigated. The optimized formation of Ligustrazine Hydrochloride microemulsion were OP as the emulsifier, glycerol as the co-emulsifier and ethyl oleate as oil, the concentration of Ligustrazine Hydrochloride was 50mg/mL.
Situ-gel preparation: The solution of Poloxamer 407 in different concentrations was prepared. We determined the phase variation temperature, drew the viscosity-temperature curve and determined the drug release in 37℃in vitro. It showed that the P-407 situ-gel in 40% prolonged the drug release in vitro obviously, which was consistent with experiment request.
The study of biological degradation and compatibility: We added lysozyme into phosphate buffer in pH 7.4 to determine the degradation of situ-gel in vitro. And also, the compatibility test was conducted in vivo with SD rats. It showed that: the preparation degradation was 45.1% in 60h and 74.2% in 120h. Greater omentum was not found in abdominal cavity. There was no part effusion and obvious edema. It suggested that situ-gel would not show up rejection obviously in abdominal cavity, had good histocompatibility and was consistent with the working condition in abdominal cavity.
Pharmacodynamic action of microemulsion and situ-gel: Divide the SD rats into ten groups randomly after mode-make: sodium chloride group, Ligustrazine Hydrochloride group, blank microemulsion group, Ligustrazine Hydrochloride microemulsion in high doss group, and also in middle and low doss group, blank situ-gel group, Ligustrazine Hydrochloride situ-gel in high doss group, and also in middle and low dose group. The preparations were used in abdominal cavity. All the rats were killed 22 days after operation. Peritoneal adhesion score and immunity SABC statistical analysis were undertaken. It showed that Ligustrazine Hydrochloride situ-gel in low doss possessed the best effect.
引文
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[6]王学清，齐宪荣，刘明辉．盐酸丁卡因脂质体凝胶剂的制备与释放度的测定．中国现代应用药学杂志．2003，20(1)：37-40．
[7]冯怡，谢树华，史芝英，徐莲英．不同基质小儿哮喘直肠凝胶剂的释放度比较．中成药．2000。22(7)：461-464．
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[1]杨惊宁，严冬等．新型药物剂型—微乳．中国医学工程．2005，13(4)：378-381．
[2]陆彬，张正全．用三角相图法研究药用微乳的形成条件．药学学报．2001，36(1)：58—62．
[3]辛寅昌等．非离子型表面活性剂的W/O型微乳液的渗滤现象[J]．化学学报．1996，54：132—139．
[4]张菊花等．阴离子表面活性剂微乳体系电导行为及活化能．北京石油化工学院学报．2004，12(1)：19-21．
[5]张蜀，谭载友，陈济民，李帼姬，陈绍斌．盐酸多西环素注入用缓释凝胶的体外释放度研究．中国新药杂志．2003，12(9)：731-734．
[6]王学清，齐宪荣，刘明辉．盐酸丁卡因脂质体凝胶剂的制备与释放度的测定．中国现代应用药学杂志．2003，20(1)：37-40．
[7]冯怡，谢树华，史芝英，徐莲英．不同基质小儿哮喘直肠凝胶剂的释放度比较．中成药．2000。22(7)：461-464．
[1]刘志东，丁平田，李佳玮，等依诺沙星眼用缓释凝胶剂的体外研究[J]．中国约学杂志，2004，39(11)，：834
[2]Desai SD, Blanehard J. In vitro evaluation of Plumnie F127. based controlled-release ocular delivery systems for pilocarpine[J]. J Pharm Sci , 1998,87(2): 226
[3]王成伟，唐星，王晓梅，等温度敏感性壬苯醇醚阴道用缓释凝胶的制备与评价[J]．中国新药杂志2006，15(4)：280
[1]殷以华，秦东珍，杨亚江．用作盲肠位点药物传载的交联凝胶的体外降解[J]．约学学报Acta Pharmaceutica Sinica 200l，3(6 11)：863—867
[2]曹宗顺，卢凤琦，王风山．壳聚糖膜的降解性研究[J]．生物医学工程杂志，1995，12(4)：364-366．
[1]王胜虎，毛少华．川芎嗪注射液治疗粘连性肠梗阻疗效观察[J]．中国中西医结合外科杂志，2002，7(8)：275—276．
[2]Nair SK, Bhal IK, Aurora Al. Role of proteolytic enzymes in the prevention of post-operative intra-peritoneal adhesions . Arch Surg ,1974,108:849.
[3]Bo Risberg Adhesions. Preventive Strategies[J]Eur J Surg (Suppl),1997,577:32.
[4]Lena Holmdahl, Bo Risberg, David E. Beck, et al. Adhesions: Pathogenesis and Prevention- Panel Discussion and Summary[J]Eur J Surg(Suppl) ,1997 ,577:56.
[5]张忠涛，腹部手术后腹腔粘连形成的病理生理及预防[J]，国外医学外科分册，1995．143—145．
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