马钱子凝胶膏的研制及对大鼠骨癌痛疗效观察

发布时间：2018-07-23 12:30

【摘要】：马钱子是常用有毒中药,其临床疗效卓越,通络止痛、散结消肿之功尤为显著。但口服治疗剂量与中毒剂量接近,极大地限制了其临床上安全有效应用。近年来,随着中药经皮给药系统研究的不断深入和发展,越来越多的中药和天然药物采用此种剂型开发成用量明确、持久有效,不良反应少的新产品。为此,本文详细开展了马钱子凝胶膏的系统研究,以期为含马钱子制剂临床安全有效应用提供支撑。主要围绕马钱子的化学成分、药理毒理的现代研究进展和中药经皮给药制剂技术的沿革以及现代研究进行了文献综述。为后期开展马钱子凝胶膏的研制奠定了理论基础。论文首先在单因素考察的基础上采用Box-Behnken响应面法优化了马钱子凝胶膏基质处方,以初黏力为评价指标,对凝胶膏剂处方进行优选。对关键因素通过Box-Behnken响应面法进行优化,采用多元线性回归与二项式进行方程拟合,预测出最佳工艺方案。结果表明聚乙烯吡咯烷酮、聚丙烯酸钠、甘羟铝对凝胶膏剂的性能影响显著,二项式方程复相关系数R2为0.8883,最佳配比为聚丙烯酸钠为3.0g,聚乙烯吡咯烷酮为2.0g,甘羟铝为0.5g。对透皮促渗剂氮酮、薄荷醇、吐温-80进行筛选,结果表明3%氮酮优于后两者,可以达到较好的透皮效果。对马钱子凝胶膏中试制备工艺进行了初步考察。结果表明,混浆时间工艺最佳参数为30min,涂布初、中、后期涂布均匀。马钱子碱和士的宁从提取物至成品的转移率分别为83.33%、83.27%,说明工艺可行。对其中试产品质量控制方法进行了初步研究。经测定马钱子凝胶膏的含膏量为21 士1.5g/100cm2;黏附力考察了初黏力,结果为能黏住11号钢球;马钱子凝胶膏放置于倾斜角为60°的钢板上24小时,膏面无流淌现象;赋形性符合药典要求;含量测定结果为马钱子碱含量0.19mg/cm2,士的宁含量为0.11mg/cm2。对马钱子凝胶膏进行了初步安全性评价。分别考察了马钱子凝胶膏急性毒性、对家兔皮肤单次、多次刺激的影响以及对豚鼠皮肤过敏性的影响。试验表明马钱子凝胶膏无急性毒性作用,无刺激性,无皮肤过敏性。对马钱子凝胶膏对骨癌痛疗效进行了评价。复制了了大鼠骨癌痛模型,基于此,考察了马钱子凝胶膏60mg/kg、120mg/kg、240mg/kg三个剂量对大鼠骨癌痛的疗效。最终通过测定各组大鼠对机械刺激的反应潜伏期的变化来测定马钱子凝胶膏其缓解癌痛的情况。外用马钱子凝胶膏后,第14d及16d给药高剂量组240mg/kg与模型组骨癌痛模型大鼠缩足反射时间之间有显著性差异(P0.01),表明马钱子凝胶膏在一定程度上缓解了骨癌痛模型大鼠的痛觉过敏反应。
[Abstract]:Semen strychni is a common toxic Chinese medicine, its clinical efficacy is excellent, Tongluo pain, Sanjie detumescence is particularly significant. However, the dose of oral therapy is close to the dose of poisoning, which greatly limits its safe and effective clinical application. In recent years, with the development of transdermal drug delivery system of Chinese medicine, more and more traditional Chinese medicine and natural drugs are used to develop new products with definite dosage, lasting effectiveness and less adverse reactions. Therefore, the systematic study of brucine gel ointment was carried out in order to provide support for the safe and effective application of brucine preparation. This paper reviews the chemical constituents, pharmacological toxicology, the development of traditional Chinese medicine (TCM) transdermal drug delivery technology and the modern research on the chemical constituents and pharmacological toxicology of semen strychni. It laid a theoretical foundation for the later development of brucine gel paste. Firstly, on the basis of single factor investigation, Box-Behnken response surface method was used to optimize the formulation of brucine gel paste matrix, and the initial viscosity was taken as the evaluation index to optimize the formulation of gel paste. The key factors are optimized by Box-Behnken response surface method, and the best process scheme is predicted by fitting the equation with multivariate linear regression and binomial equation. The results showed that polyvinylpyrrolidone, sodium polyacrylate and aluminum glycolate had significant effects on the properties of the gel paste. The binomial equation complex correlation coefficient R2 was 0.8883, the optimum ratio was 3.0 g for sodium polyacrylate, 2.0 g for polyvinylpyrrolidone and 0.5 g for aluminum glycolate. The results showed that 3% azone was superior to the latter, and the transdermal effect was better than that of Tween-80. The results showed that the transdermal permeation agents of azone, menthol and Tween-80 were better than those of the latter. The pilot-scale preparation of brucine gel paste was preliminarily investigated. The results show that the optimum parameters of mixing time are 30 min, and the initial, middle and late coating is uniform. The transfer rates of brucine and strychnine from extract to finished product were 83.33 and 83.27, respectively, indicating that the process was feasible. The quality control method of pilot products was studied. The paste content of brucine gel paste was determined to be 21 + 1.5 g / 100 cm ~ (2). The initial adhesion force was investigated, and the result was that it could stick to No. 11 steel ball, and the brucine gel paste was placed on the steel plate with an angle of 60 掳for 24 hours, and there was no flowing phenomenon on the surface of the paste. The content of brucine was 0.19 mg / cm ~ (2) and strychnine was 0.11 mg / cm ~ (2). The safety of brucine gel ointment was evaluated. The acute toxicity of brucine gel ointment, the effects of single and multiple irritation on rabbit skin and the effect on skin hypersensitivity of guinea pigs were investigated. The results showed that strychnine gel ointment had no acute toxicity, no irritation and no skin allergy. The curative effect of brucine gel ointment on bone cancer pain was evaluated. The pain model of bone cancer in rats was established. Based on this, the therapeutic effects of brucine gel ointment 60 mg / kg ~ (120 mg / kg) ~ (120 mg / kg) ~ (240 mg / kg) on bone cancer pain in rats were investigated. Finally, the effect of strychnine gel ointment on relieving cancer pain was determined by measuring the latency of response to mechanical stimulation in each group. After topical application of brucine gel cream, There was a significant difference in reflex time between the high dose group (14 d and 16 d) and the model group (P0.01), which indicated that strychnine gel ointment alleviated the hyperalgesia in the model rats with bone cancer pain to some extent.
【学位授予单位】：南京中医药大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R283.6;R285.5

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