Anderson K E, Eliot L A, Stevenson B R, Rogers J A
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Pharm Res. 2001 Mar;18(3):316-22. doi: 10.1023/a:1011002913601.
To demonstrate utility of folic acid-coated liposomes for enhancing the delivery of a poorly absorbed glycopeptide, vancomycin. via the oral route.
Liposomes prepared as dehydration-rehydration vesicles (DRVs) containing vancomycin were optimized for encapsulation efficiency and stability. A folic acid-poly(ethylene oxide)-cholesterol construct was synthesized for adsorption at DRV surfaces. Liposomes were characterized by differential scanning calorimetry (DSC) and assessed in vitro in the Caco-2 cell model and in vivo in male Sprague-Dawley rats. Non-compartmental pharmacokinetic analysis of vancomycin was conducted after intravenous and oral administration of solution or liposome-encapsulated vancomycin with or without 0.05 mole ratio FA-PEO-Chol adsorbed at liposome surfaces.
Optimal loading of vancomycin (32%) was achieved in DRVs of DSPC:Chol:DCP, 3:1:0.25 mole ratio (m.r.) after liposome extrusion. Liposomes released less than 40% of the entrapped drug after 2 hours incubation in simulated gastrointestinal (GI) fluid and simulated intestinal fluid containing a 10 mM bile salt cocktail. Incorporation of FA-PEO-Chol in liposomes increased drug leakage by 20% but resulted in a 5.7-fold increase in Caco-2 cell uptake of vancomycin. Liposomal delivery significantly increased the area under the curve of oral vancomycin resulting in a mean 3.9-fold and 12.5-fold increase in relative bioavailability for uncoated and FA-PEO-Chol-coated liposomes, respectively, compared with an oral solution.
The design of FA-PEO-Chol-coated liposomes resulted in a dramatic increase in the oral delivery of a moderate-size glycopeptide in the rat compared with uncoated liposomes or oral solution. It is speculated that the cause of the observed effect was due to binding of liposome-surface folic acid to receptors in the GI tract with subsequent receptor-mediated endocytosis of entrapped vancomycin by enterocytes.
证明叶酸包被的脂质体可用于增强口服吸收不良的糖肽万古霉素的递送。
将含有万古霉素的脱水再水化囊泡（DRV）制备的脂质体进行优化，以提高包封效率和稳定性。合成了叶酸 - 聚环氧乙烷 - 胆固醇构建体，用于吸附在DRV表面。通过差示扫描量热法（DSC）对脂质体进行表征，并在Caco - 2细胞模型中进行体外评估，以及在雄性Sprague - Dawley大鼠中进行体内评估。在静脉内和口服给予溶液或脂质体包封的万古霉素后，进行非房室药代动力学分析，脂质体表面吸附或未吸附0.05摩尔比的FA - PEO - Chol。
在DSPC:Chol:DCP摩尔比为3:1:0.25的DRV中，通过脂质体挤压后，万古霉素的最佳载药量达到32%。在含有10 mM胆盐混合物的模拟胃肠（GI）液和模拟肠液中孵育2小时后，脂质体释放的包封药物少于40%。在脂质体中加入FA - PEO - Chol会使药物泄漏增加20%，但导致Caco - 2细胞对万古霉素的摄取增加了5.7倍。脂质体递送显著增加了口服万古霉素的曲线下面积，与口服溶液相比，未包被和FA - PEO - Chol包被的脂质体的相对生物利用度分别平均增加了3.9倍和12.5倍。
与未包被的脂质体或口服溶液相比，FA - PEO - Chol包被的脂质体的设计使大鼠体内中等大小糖肽的口服递送显著增加。据推测，观察到的效果的原因是脂质体表面的叶酸与胃肠道中的受体结合，随后被肠细胞通过受体介导的内吞作用摄取包封的万古霉素。
