利多卡因微乳凝胶外用制剂的制备及药效学评价

发布时间：2018-02-22 23:49

本文关键词： 利多卡因微乳凝胶剂伪三元相图经皮渗透镇痛　出处：《浙江大学》2014年硕士论文　论文类型：学位论文

【摘要】：目的：探讨利多卡因微乳凝胶外用制剂的制备方法,进行了体外评价,并通过初步药效学研究考察微乳凝胶制剂的镇痛作用,进一步对其皮肤刺激性进行考察,以期为开发一种新型利多卡因局部给药制剂奠定实验基础。方法：1、建立利多卡因的HPLC色谱分析法,并对利多卡因的有关理化性质进行了研究。2、以油酸乙酯为油相,吐温-80为表面活性剂,无水乙醇为助表面活性剂,通过绘制伪三元相图确定最佳Km值,用水滴定的方法制备利多卡因微乳。通过经皮渗透实验确定微乳载药量,并对最佳微乳处方进行体外释放实验。采用透射电子显微镜和激光粒度仪观测其形态,粒径大小及分布,并对微乳的稳定性进行初步考察。3、通过体外经皮渗透实验,筛选凝胶骨架和用量,采用直接溶胀法制备利多卡因微乳凝胶,并对最佳微乳凝胶处方进行体外释放试验、理化性质考察和初步稳定性研究。4、采用经典的镇痛实验,考察利多卡因微乳凝胶剂的镇痛作用,并进一步对其皮肤刺激性进行研究。结果：1、建立了灵敏度高、专属性强、重现性和准确性均良好,且操作简便的HPLC色谱法,用于测定利多卡因。利多卡因的理化性质表明利多卡因是制备经皮给药制剂的适宜药物。2、利多卡因微乳的最优处方为：利多卡因含量为2%,油酸乙酯为4%,吐温-80为15%,无水乙醇为9%,去离子水为70%。采用最优处方制得的利多卡因微乳体外释放性能良好,微乳大小均在40nm左右,透射电镜观察微乳液滴均呈圆球形,稳定性考察结果表明微乳制剂较稳定。3、通过筛选确定凝胶基质为卡波姆940,利多卡因微乳凝胶剂的最优处方为：卡波姆940为0.5%,利多卡因含量为2%,油酸乙酯为4%,吐温-80为15%,无水乙醇为9%,去离子水为69.5%。最优微乳凝胶处方制得的制剂体外释放行为接近零级释放,理化性质及稳定性初步考察结果表明制剂理化性质及稳定性均良好。4、镇痛实验表明,低、中、高剂量的微乳凝胶均能剂量依赖性地提高小鼠痛阈值,并且在相同给药量下,中、高剂量的微乳凝胶在给药45min和60min时与空白对照组、2%利多卡因凝胶组、2%利多卡因溶液组相比较具有显著性差异(P0.05),这些结果表明中、高剂量的微乳凝胶的镇痛效果较凝胶好。皮肤刺激性实验结果表明,高剂量的微乳对正常完整皮肤有轻度刺激性,高剂量的微乳凝胶对正常完整皮肤没有刺激性,但高剂量的微乳及微乳凝胶对破损皮肤均有轻度刺激性,这表明利多卡因微乳凝胶有更好的安全性。结论：利多卡因微乳凝胶剂制备工艺简单,易于涂布,粒径较小且分布均匀,表现出较好的局麻镇痛作用和良好的安全性,具有很好的临床应用前景。
[Abstract]:Objective: to study the preparation method of lidocaine microemulsion gel for external use and evaluate in vitro the analgesic effect and skin irritation of lidocaine microemulsion gel. Methods HPLC chromatographic analysis of lidocaine was established, and the physical and chemical properties of lidocaine were studied. 2. Ethyl oleate was used as oil phase. Tween-80 was used as surfactant and anhydrous ethanol as cosurfactant. The best km value was determined by drawing pseudo-ternary phase diagram. Lidocaine microemulsion was prepared by water titration. The morphology, particle size and distribution of microemulsion were observed by transmission electron microscope and laser particle size analyzer, and the stability of microemulsion was preliminarily investigated. The gel skeleton and dosage were screened, and lidocaine microemulsion gel was prepared by direct swelling method. The release test in vitro, physicochemical properties and preliminary stability of lidocaine microemulsion gel were carried out, and the classical analgesic experiment was used. The analgesic effect of lidocaine microemulsion was investigated, and the skin irritation of lidocaine was further studied. Results HPLC chromatography was established with high sensitivity, strong specificity, good reproducibility and accuracy, and simple operation. The physicochemical properties of lidocaine and lidocaine showed that lidocaine was an appropriate drug for the preparation of transdermal drug preparation. The optimum formulation of lidocaine microemulsion was as follows: the content of lidocaine was 2, ethyl oleate was 4x4 and Tween-80 was the best. The absolute ethanol is 9 and the deionized water is 70. The lidocaine microemulsion prepared with the best prescription has good release performance in vitro. The size of microemulsion was about 40 nm, and the droplets of microemulsion were spherical by transmission electron microscope. The results of stability test showed that the microemulsion preparation was more stable .3. the gel matrix was determined to be Carbomer 940, lidocaine microemulsion gel was determined as follows: carbomer 940 was 0.5, lidocaine content was 2, ethyl oleate was 4 and Tween was determined. -80 is 15, anhydrous ethanol is 9 and deionized water is 69.5. The in vitro release behavior of the best microemulsion gel formulation is close to zero. The physical and chemical properties and stability of the preparation were all good. The analgesic experiment showed that the low, medium and high doses of microemulsion gel could increase the pain threshold of mice in a dose-dependent manner, and at the same dosage, the dose of microemulsion gel could increase the pain threshold of mice in a dose-dependent manner. The high dose microemulsion gel was significantly different from the 2% lidocaine solution group in the control group at 45min and 60min. These results indicated that, in the control group, there was no significant difference between the control group and the control group (P 0.05), and the results showed that there was no significant difference between the 2% lidocaine gel group and the 2% lidocaine solution group. The analgesic effect of high dose microemulsion gel was better than that of gel. The results of skin irritation experiment showed that high dose microemulsion had mild irritation on normal intact skin, and high dose microemulsion gel had no irritation on normal intact skin. However, high dose microemulsion and microemulsion gel had slight irritation to damaged skin, which indicated that lidocaine microemulsion gel had better safety. Conclusion: the preparation process of lidocaine microemulsion gel is simple and easy to be coated. The particle size is small and the distribution is uniform, showing good analgesic effect and safety of local anesthesia, and has a good clinical application prospect.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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