【作者】 殷丹；

【导师】 李三鸣；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2006， 硕士

【摘要】 氟比洛芬(FP)是一新型非甾体类抗炎镇痛药，临床上主要用于治疗风湿性类风湿关节炎、骨关节炎和外伤疼痛。FP与其它非甾体抗炎药相类似，口服时易引起胃痛、胃不适、恶心、腹泻等不良反应，严重者可导致消化道出血和胃溃疡。本文利用脂质体包封FP进行皮肤局部给药，既有效地将FP渗透进入局部深层组织，同时又避免了较高的血药浓度，这对于减少FP副作用，增加疗效都有着很大的意义。考虑到脂质体的稳定性较差和液体用药的不便，最终把FP做成脂质体凝胶剂。 建立了紫外分光光度法用于FP的处方前研究。FP的pK_a为5.53，FP在水相中的溶解度及表观油水分配系数均与水相的pH值有关，pH值越大，其溶解度越大，表观油水分配系数越小。 采用乙醇注入法制备FP脂质体，以包封率为指标，采用正交设计优化得到最佳处方为0.5％FP+4％PC+0.5％CHOL+0.04％V_E+PBS7.4(17mM)。同时建立了包封率的测定方法，采用微型柱离心法和透析法分离脂质体和游离药物，HPLC法测定包封于脂质体中FP的量，两种方法测得平均粒径为181.8nm的FP脂质体的包封率分别为46.7％、41.6％。 采用Franz扩散池法考察了FP脂质体体外透皮的影响因素。结果表明，脂质体粒径越小，FP皮肤透过量越大；开放式给药能显著促进FP的经皮吸收；脂质体的双分子层结构对促进药物的经皮渗透性是必要的；胆固醇影响脂质体膜的柔韧性，随着脂质体成分中胆固醇的量的增大，FP累计透过量减少；脂质体所荷电性对FP的经皮吸收无影响；3％Azone预处理皮肤能显著提高FP的渗透性。 在以上研究工作的基础上，根据文献报道，选用卡波姆作为凝胶剂的基质，通过正交设计对FP脂质体凝胶剂的处方进行了优化筛选，得到最佳处方组成为3％Azone+5％PG+1.0％C—940。体外实验表明，FP脂质体凝胶剂在透皮量、透皮速率和皮内滞留量上均较普通凝胶制剂存在明显的优势。 对制备的FP脂质体凝胶进行了含量测定和稳定性初步考察。结果表明，制备的凝胶含量均匀，在3个月的加速试验和6个月的室温留样试验中稳定性良好。 考察了FP脂质体凝胶剂的皮肤刺激性和抗炎镇痛作用。药效学试验结果表明，该制剂无刺激性，并具有良好的抗炎镇痛作用。更多还原

【Abstract】 Flurbiprofen (FP) is a new nonsteroidal anti-inflammatory drug (NSAID) which is widely used in the treatments of rheumatic arthritis, rheumatoid arthritis, osteoarthritis and traumatic pain in clinics. However, like other NSAIDs, it may bring adverse effects (e.g. gastralgia nausea and diarrhoea) on gastrointestinal tract when orally administrated. Even bleeding and ulceration often occur. Therefore, liposome was selected to carry FP into local deeper tissues and avoid high plasma concentration. It is important to minimize the side effects of oral FP and increase curative effect. Taking into the consideration of poor stability of liposome and the inconvenience of liquid administration, FP liposome gel was finally prepared.UV spectrophotometry was used for the investigation of the pharmaceutical preformulation of FP. The ionization constant was determined as 5.42. The solubility and oil/water partition coefficient of FP were correlated with the pH value of aqueous media. With the increasing value of pH, the solubility of FP increased, while the oil/water partition coefficient decreased.FP liposomes were prepared by Ethanol Injection method. The optimized formulation of FP liposomes was 0.5% FP+4% PC+0.5% CHOL+0.04% V_E+PBS7.4(17mM) which optimized by orthogonal design.The Minicolumn Centrifugation method and Dialysis method were used to separate the free FP from liposomes, and the concentration of FP in liposomes was determined by HPLC method. The entrapment efficiency(EE) of FP liposomes with mean particle size of 181.8 nm were 46.7%and 41.6% for Minicolumn Centrifugation method and Dialysis method respectively.The transdermal delivery of FP liposomes across rat skin was studied by modified Franz diffusion cells in vitro. The results showed that comparing to larger ones, liposomes with small particle size enhanced permeation of FP into the skin. When donor compartment was under nonocclusive situations, the cumulative amount was higher than that of occlusive ones. The bilayer structure of liposomes was necessary to promote the permeation of FP. Pre-treating the rat skin with 3% azone could increase the cumulative amount of FP, on the contrary, the increasing amount of cholesterol would decrease it. The charge of FP liposomes had no effect on the permeation of FP.On the basis of the studies mentioned above and the some reported literatures, carpobol was更多还原