本文選題：辣椒堿 + Box-Becken設(shè)計(jì)��； 參考：《浙江大學(xué)》2017年碩士論文

【摘要】：目的：本研究擬構(gòu)建辣椒堿納米脂質(zhì)載體局部給藥系統(tǒng),通過(guò)單因素分析以及Box-Becken設(shè)計(jì)優(yōu)化處方,以期提高辣椒堿的透皮量,能夠產(chǎn)生鎮(zhèn)痛、抗炎作用,同時(shí)減少辣椒堿局部應(yīng)用的皮膚刺激性。方法：1.通過(guò)單因素分析篩選影響辣椒堿納米脂質(zhì)載體包封率和粒徑的處方因素；2.利用Box-Becken設(shè)計(jì)分析不同處方因素對(duì)響應(yīng)值的影響,模擬得到優(yōu)化處方,對(duì)合成的辣椒堿納米脂質(zhì)載體進(jìn)行物理化學(xué)性質(zhì)表征并考察體外釋放情況；3.通過(guò)體外細(xì)胞實(shí)驗(yàn),考察辣椒堿游離藥物和辣椒堿納米脂質(zhì)載體對(duì)皮膚細(xì)胞的毒性；4.通過(guò)體外經(jīng)皮滲透實(shí)驗(yàn),考察辣椒堿制劑的透皮效果和不同皮層內(nèi)辣椒堿的滯留量；考察納米脂質(zhì)載體促進(jìn)藥物透皮的深度和主要途徑；5.采用熱板法考察辣椒堿制劑對(duì)ICR小鼠的鎮(zhèn)痛作用；采用角叉菜膠大鼠足趾腫脹模型考察辣椒堿制劑的抗炎作用,并探究其抗炎機(jī)制；6.考察不同濃度辣椒堿制劑的皮膚刺激性；7.通過(guò)篩選適宜凍干保護(hù)劑,制備辣椒堿納米脂質(zhì)載體凍干粉劑。結(jié)果：利用Box-Becken設(shè)計(jì)優(yōu)化處方,考察固液脂質(zhì)比例、脂質(zhì)投入量和表面活性劑使用量對(duì)包封率和粒徑的綜合影響,得到最優(yōu)處方為：脂質(zhì)總質(zhì)量為0.86g,其中固體脂質(zhì)占58%；表面活性劑用量為3.6%。制備得到的辣椒堿納米脂質(zhì)載體溶液呈乳白色且?guī)в腥楣?粒徑均一,約為119nm,形態(tài)圓整,包封率為91.6%且在體外釋放48h過(guò)程中具有良好的緩釋效果。MTT實(shí)驗(yàn)和細(xì)胞周期實(shí)驗(yàn)證明納米脂質(zhì)載體能夠降低辣椒堿對(duì)皮膚細(xì)胞的毒性,增加使用的安全性。體外24 h經(jīng)皮滲透實(shí)驗(yàn)后,辣椒堿納米脂質(zhì)載體及其凝膠的單位面積累積透過(guò)量分別為29.7μg.cm-2和25.6μg. cm-2,較辣椒堿市售軟膏組和辣椒堿溶液組的17.9 μg. cm-2和2.2 μg. cm-2顯著提高；辣椒堿納米脂質(zhì)載體及其凝膠的透皮速率較辣椒堿溶液組分別提高14.4倍和12.2倍,表明納米脂質(zhì)載體能夠顯著提高辣椒堿的透皮效率。通過(guò)檢測(cè)辣椒堿的皮內(nèi)滯留量證明納米脂質(zhì)載體能夠顯著增加辣椒堿在表皮和真皮中的滯留。利用細(xì)胞膜綠色熒光探針(3,3'-dioctadecyloxacarbocyanine perchlorate, Dio)代替辣椒堿進(jìn)行藥物透皮深度和主要透皮途徑的考察,結(jié)果發(fā)現(xiàn)Dio溶液組大約滲透至150μm皮膚深度,而Dio納米脂質(zhì)載體凝膠組和Dio納米脂質(zhì)載體組可滲透至皮膚內(nèi)約210μm和260μm,結(jié)合皮膚切片觀察結(jié)果表明納米脂質(zhì)載體主要是通過(guò)毛囊附屬器途徑促進(jìn)藥物透皮,增加藥物的透皮深度。體內(nèi)實(shí)驗(yàn)結(jié)果表明辣椒堿納米脂質(zhì)載體具有鎮(zhèn)痛作用且呈劑量依賴性并可以通過(guò)抑制PGE2信號(hào)通路產(chǎn)生抗炎作用。皮膚刺激性實(shí)驗(yàn)結(jié)果顯示納米脂質(zhì)載體能夠減輕辣椒堿的刺激性。利用篩選得到的凍干保護(hù)劑：2%蔗糖+2%葡萄糖制備辣椒堿納米脂質(zhì)載體凍干粉劑,發(fā)現(xiàn)其具有較好的復(fù)溶性且復(fù)溶后納米粒形態(tài)并未發(fā)生明顯變化。結(jié)論：經(jīng)Box-Becken設(shè)計(jì)優(yōu)化處方后制備得到的辣椒堿納米脂質(zhì)載體溶液及其凝膠具有良好的體外透皮效果,能夠在體內(nèi)產(chǎn)生鎮(zhèn)痛和抗炎作用的同時(shí)減少辣椒堿的刺激性。
[Abstract]:Objective: to construct the local drug delivery system of capsaicin nano lipid carrier, and optimize the prescription by single factor analysis and Box-Becken design in order to improve the transdermal volume of capsaicin, to produce analgesic and anti inflammatory effects, and to reduce the skin irritation of capsaicin local application. Method: 1. screening of peppers by single factor analysis. The formulation factors of encapsulation efficiency and particle size of alkali nano lipid carrier were analyzed. 2. Box-Becken was used to analyze the effect of different prescription factors on the response value. The optimized prescription was simulated. The physicochemical properties of capsaicin nanoparticles were characterized and released in vitro. 3. through in vitro cell experiments, capsaicin dissociation was investigated. The toxicity of drugs and capsaicin nanoparticles on skin cells; 4. through the skin penetration test in vitro, the transdermal effect of capsaicin preparation and the retention of capsaicin in different cortex were investigated, and the depth and main ways of promoting drug penetration by nano lipid carriers were investigated. 5. the hot plate method was used to investigate the town of capsaicin on ICR mice. Pain effect; using the rat toe swelling model of carrageenin to investigate the anti-inflammatory effect of capsaicin and explore its anti-inflammatory mechanism; 6. to investigate the skin irritation of capsaicin in different concentrations; 7. to prepare capsaicin nano liposome freeze-dried powder by screening suitable freeze-drying protective agent. Results: the optimized prescription of Box-Becken was designed by using the formula. The optimum prescription of lipid ratio, lipid input and use of surfactant on encapsulation efficiency and particle size was obtained: the total mass of lipid was 0.86g, in which the solid lipid accounted for 58%, and the capsaicin nano lipid carrier prepared by the dosage of surfactant was milk white with milk light, and the particle size was uniform. About 119nm, round and round, the encapsulation rate is 91.6% and has good release effect during the release of 48h in vitro..MTT experiment and cell cycle experiment prove that nano lipid carrier can reduce the toxicity of capsaicin to skin cells and increase the safety of use. After 24 h transdermal permeation test, capsaicin nano lipid carrier and its gel The cumulative overdose of the unit area was 29.7 mu g.cm-2 and 25.6 g. cm-2 respectively. The 17.9 Mu g. cm-2 and 2.2 u g. cm-2 of capsaicin group and capsaicin solution group were significantly improved, and the transdermal rate of capsaicin nanoparticles and its gel were 14.4 and 12.2 times higher than that of capsaicin solution group respectively. The transdermal efficiency of capsaicin is improved. The retention of capsaicin in the epidermis and dermis can be significantly increased by detecting the intradermal retention of capsaicin. The penetration depth and main transdermal pathway of the drug using the cell membrane green fluorescent probe (3,3'-dioctadecyloxacarbocyanine perchlorate, Dio) instead of rimperine The results showed that the Dio solution group penetrated to the skin depth of about 150 mu m, and the Dio nano lipid carrier gel group and the Dio nano lipid carrier group permeated into the skin about 210 mu m and 260 micron m. The results of skin slice observation showed that the nano lipid carrier was mainly through the hair follicle accessory pathway to promote the drug transdermal and to increase the drug transdermal delivery. The results of in vivo experiments showed that capsaicin nanoparticles had analgesic and dose-dependent effects and could inhibit the anti-inflammatory effect by inhibiting the PGE2 signaling pathway. Skin irritation results showed that nano lipid carriers could reduce capsaicin irritation. The screened lyophilized protective agent, 2% sucrose +2% glucose, was used. The lyophilized powder of capsaicin nano lipid carrier was prepared. It was found that it had good resolubility and the morphology of the nanoparticles did not change obviously. Conclusion: the capsaicin nano lipid carrier solution and its gel prepared after the optimized formulation of Box-Becken and its gel have good external transdermal effect and can produce analgesic and analgesic effects in the body. The anti inflammatory effect reduces the irritation of capsaicin.
【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】：2017
【分類號(hào)】：R943

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