Barichello José Mario, Handa Hiroshi, Kisyuku Masatoshi, Shibata Taiki, Ishida Tatsuhiro, Kiwada Hiroshi
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan.
J Control Release. 2006 Sep 28;115(1):94-102. doi: 10.1016/j.jconrel.2006.07.008. Epub 2006 Jul 13.
In order to investigate the effect of liposomal drugs on skin delivery, it was postulated that the process of liposomalization might lead the drug to an overpredicted solubility state which has far-reaching implications for drug skin permeation and accumulation. In this regard, conventional (CL) and flexible liposomes (FL) were prepared by the lipid film hydration method and the particles were downsized by sonication using hydrocortisone (HC) as a poorly water soluble model drug. The solutions derived from the whole CL and FL suspensions eluted on a Sephadex G-50 column (SG-50) demonstrated that most part of HC not only resides solely in the water phase but also it might exist in an improved solubility state. The results of the in vitro study using rat abdominal skin and occlusive application indicated that HC penetrated and accumulated much better solely than when associated with CL or FL. In regard to the penetration of the non-entrapped HC associated to liposomes bilayer fragments, a very small amount of phospholipids in the non-liposomal part eluted on SG-50 was found that could not justify by itself the penetration of HC associated to liposome bilayer fragments. It was proposed that all the steps of the liposomes preparation process might contribute for the increased HC solubility state, but definitively the presence of phospholipids played a crucial role on improving the HC solubility in the absence of sodium cholate. In comparison with commercially available ointments, the non-entrapped HC solution derived from the whole CL suspension eluted on SG-50 showed a higher concentration of HC accumulated and more uniformly distributed as well in the epidermis and dermis compartments. In addition, the thermodynamic activity of the non-entrapped HC solutions maintaining a driving force of the drug across the skin barrier pointed out that the level of HC solubility achieved during liposome preparation has far-reaching implication for drug skin permeation and accumulation in the experimental conditions used. The findings also indicated that the non-entrapped drug solutions obtained on the process of liposomalization could be useful on transdermal drug delivery systems, particularly for improving the permeation and accumulation capacity of poorly soluble drugs.
为了研究脂质体药物对皮肤给药的影响，有人推测脂质体化过程可能会使药物处于预测溶解度过高的状态，这对药物的皮肤渗透和蓄积具有深远影响。在这方面，采用脂质膜水化法制备了常规脂质体（CL）和柔性脂质体（FL），并以水溶性差的氢化可的松（HC）为模型药物，通过超声处理使颗粒尺寸减小。从整个CL和FL悬浮液中洗脱得到的溶液在葡聚糖G-50柱（SG-50）上进行分析，结果表明大部分HC不仅单独存在于水相中，而且可能以溶解度提高的状态存在。使用大鼠腹部皮肤并采用封闭敷用的体外研究结果表明，HC单独渗透和蓄积的效果比与CL或FL结合时要好得多。关于与脂质体双层片段相关的未包封HC的渗透，发现SG-50上洗脱的非脂质体部分中极少量的磷脂本身无法解释与脂质体双层片段相关的HC的渗透情况。有人提出，脂质体制备过程的所有步骤可能都有助于提高HC的溶解度状态，但毫无疑问，在没有胆酸钠的情况下，磷脂的存在对提高HC的溶解度起着关键作用。与市售软膏相比，从整个CL悬浮液中洗脱得到的未包封HC溶液在SG-50上显示出在表皮和真皮层中积累的HC浓度更高且分布更均匀。此外，未包封HC溶液的热力学活性保持了药物穿过皮肤屏障的驱动力，这表明在脂质体制备过程中达到的HC溶解度水平对实验条件下的药物皮肤渗透和蓄积具有深远影响。研究结果还表明，在脂质体化过程中获得的未包封药物溶液可用于透皮给药系统，特别是用于提高难溶性药物的渗透和蓄积能力。
