本文關(guān)鍵詞： 利多卡因 微乳 凝膠劑 偽三元相圖 經(jīng)皮滲透 鎮(zhèn)痛　出處：《浙江大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：目的：探討利多卡因微乳凝膠外用制劑的制備方法,進(jìn)行了體外評(píng)價(jià),并通過初步藥效學(xué)研究考察微乳凝膠制劑的鎮(zhèn)痛作用,進(jìn)一步對(duì)其皮膚刺激性進(jìn)行考察,以期為開發(fā)一種新型利多卡因局部給藥制劑奠定實(shí)驗(yàn)基礎(chǔ)。方法：1、建立利多卡因的HPLC色譜分析法,并對(duì)利多卡因的有關(guān)理化性質(zhì)進(jìn)行了研究。2、以油酸乙酯為油相,吐溫-80為表面活性劑,無水乙醇為助表面活性劑,通過繪制偽三元相圖確定最佳Km值,用水滴定的方法制備利多卡因微乳。通過經(jīng)皮滲透實(shí)驗(yàn)確定微乳載藥量,并對(duì)最佳微乳處方進(jìn)行體外釋放實(shí)驗(yàn)。采用透射電子顯微鏡和激光粒度儀觀測其形態(tài),粒徑大小及分布,并對(duì)微乳的穩(wěn)定性進(jìn)行初步考察。3、通過體外經(jīng)皮滲透實(shí)驗(yàn),篩選凝膠骨架和用量,采用直接溶脹法制備利多卡因微乳凝膠,并對(duì)最佳微乳凝膠處方進(jìn)行體外釋放試驗(yàn)、理化性質(zhì)考察和初步穩(wěn)定性研究。4、采用經(jīng)典的鎮(zhèn)痛實(shí)驗(yàn),考察利多卡因微乳凝膠劑的鎮(zhèn)痛作用,并進(jìn)一步對(duì)其皮膚刺激性進(jìn)行研究。結(jié)果：1、建立了靈敏度高、專屬性強(qiáng)、重現(xiàn)性和準(zhǔn)確性均良好,且操作簡便的HPLC色譜法,用于測定利多卡因。利多卡因的理化性質(zhì)表明利多卡因是制備經(jīng)皮給藥制劑的適宜藥物。2、利多卡因微乳的最優(yōu)處方為：利多卡因含量為2%,油酸乙酯為4%,吐溫-80為15%,無水乙醇為9%,去離子水為70%。采用最優(yōu)處方制得的利多卡因微乳體外釋放性能良好,微乳大小均在40nm左右,透射電鏡觀察微乳液滴均呈圓球形,穩(wěn)定性考察結(jié)果表明微乳制劑較穩(wěn)定。3、通過篩選確定凝膠基質(zhì)為卡波姆940,利多卡因微乳凝膠劑的最優(yōu)處方為：卡波姆940為0.5%,利多卡因含量為2%,油酸乙酯為4%,吐溫-80為15%,無水乙醇為9%,去離子水為69.5%。最優(yōu)微乳凝膠處方制得的制劑體外釋放行為接近零級(jí)釋放,理化性質(zhì)及穩(wěn)定性初步考察結(jié)果表明制劑理化性質(zhì)及穩(wěn)定性均良好。4、鎮(zhèn)痛實(shí)驗(yàn)表明,低、中、高劑量的微乳凝膠均能劑量依賴性地提高小鼠痛閾值,并且在相同給藥量下,中、高劑量的微乳凝膠在給藥45min和60min時(shí)與空白對(duì)照組、2%利多卡因凝膠組、2%利多卡因溶液組相比較具有顯著性差異(P0.05),這些結(jié)果表明中、高劑量的微乳凝膠的鎮(zhèn)痛效果較凝膠好。皮膚刺激性實(shí)驗(yàn)結(jié)果表明,高劑量的微乳對(duì)正常完整皮膚有輕度刺激性,高劑量的微乳凝膠對(duì)正常完整皮膚沒有刺激性,但高劑量的微乳及微乳凝膠對(duì)破損皮膚均有輕度刺激性,這表明利多卡因微乳凝膠有更好的安全性。結(jié)論：利多卡因微乳凝膠劑制備工藝簡單,易于涂布,粒徑較小且分布均勻,表現(xiàn)出較好的局麻鎮(zhèn)痛作用和良好的安全性,具有很好的臨床應(yīng)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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R943

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本文編號(hào)：1525617