Maestrelli Francesca, González-Rodríguez Maria Luisa, Rabasco Antonio Maria, Mura Paola
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
Int J Pharm. 2006 Apr 7;312(1-2):53-60. doi: 10.1016/j.ijpharm.2005.12.047. Epub 2006 Feb 15.
The combined approach of cyclodextrin complexation and entrapment in liposomes was investigated in order to develop an effective topical formulation of ketoprofen. Equimolar complex of drug and hydroxypropyl-beta-cyclodextrin (HPbetaCyd) was added at different concentrations to the aqueous phase of liposomes consisting of phosphatidylcholine and cholesterol (60%/40%, w/w). Liposomes were prepared with different techniques, such as thin layer evaporation, freezing and thawing, extrusion through microporous membrane, and reverse phase evaporation method, obtaining, respectively, multi-lamellar vesicles (MLV), frozen and thawed MLV (FATMLV), small uni-lamellar vesicles (SUV) and large uni-lamellar vesicles (LUV). Size and morphology of the different types of liposomes were investigated by light scattering analysis, transmission electron microscopy, and confocal laser scanning microscopy, whereas drug entrapment efficiency was determined by dialysis experiments. Cyclodextrin complexation improved drug solubilization and allowed a strong improvement of its entrapment into the aqueous liposomal phase. Liposome preparation method and operating conditions clearly affected both liposome size and drug loading capacity. Encapsulation efficiency increased with increasing the complex concentration up to 10 mM, and was in the order MLV>LUV>SUV. An opposite behaviour was observed for FATMLV, probably due to the freezing phase required by such a preparation method, which reduced the complex solubility. Moreover, it was not possible to use higher complex concentrations, due to the destabilizing effect of cyclodextrins toward the liposomal membrane. Permeability studies of drug-HPbetaCyd complexes, directly in solution or incorporated in liposomes, performed across artificial membranes simulating the skin behaviour, highlighted, as expected, a prolonged release effect of liposomal formulations. Furthermore, the drug permeation rate depended on the vesicle characteristics and varied in the order: SUV>MLV=FATMLV>LUV. Therefore, the most suitable liposome preparation method can be suitably selected on the basis of drug encapsulation efficiency and/or desired drug release rate.
为了开发一种有效的酮洛芬局部用制剂，研究了环糊精包合与脂质体包封相结合的方法。将药物与羟丙基-β-环糊精（HPβCyd）的等摩尔复合物以不同浓度添加到由磷脂酰胆碱和胆固醇（60%/40%，w/w）组成的脂质体水相中。采用不同技术制备脂质体，如薄膜蒸发法、冻融法、微孔膜挤压法和反相蒸发法，分别得到多层囊泡（MLV）、冻融多层囊泡（FATMLV）、小单层囊泡（SUV）和大单层囊泡（LUV）。通过光散射分析、透射电子显微镜和共聚焦激光扫描显微镜研究了不同类型脂质体的大小和形态，而通过透析实验测定了药物包封效率。环糊精包合提高了药物的溶解度，并使其在脂质体水相中的包封率显著提高。脂质体制备方法和操作条件明显影响脂质体大小和药物载量。包封效率随复合物浓度增加至10 mM而提高，且顺序为MLV>LUV>SUV。对于FATMLV观察到相反的行为，可能是由于这种制备方法所需的冷冻阶段降低了复合物的溶解度。此外，由于环糊精对脂质体膜的去稳定作用，不可能使用更高的复合物浓度。在模拟皮肤行为的人工膜上进行的药物-HPβCyd复合物（直接在溶液中或包封在脂质体中）的渗透性研究，正如预期的那样，突出了脂质体制剂的缓释效果。此外，药物渗透速率取决于囊泡特性，顺序为：SUV>MLV=FATMLV>LUV。因此，可以根据药物包封效率和/或所需药物释放速率适当地选择最合适的脂质体制备方法。
