背景:Vemurafenib(VEM)是用于治疗皮肤黑色素瘤的许可药物,仅在市场上以大剂量(1920mg/天)的口服片剂提供。高剂量的一个原因是维罗非尼的口服生物利用度低。方法:基于征服和汞程序预测VEM-脂质复合物(DLC),并使用脂质(磷脂酰乙醇胺)使用溶剂蒸发法制备。对DLC进行表征(FT-IR,拉曼光谱,DSC,TGA,P-XRD,和FESEM)以确认络合。用DLC制备固体油中纳米分散体(DLC-SON),离体,以及与我们最近制备的常规SON(VEM-SON)和DLC对照相比的体内评估。结果:征服和汞预测了VEM和磷脂酰乙醇胺(PE)之间分子间氢键的可用性。DLC的所有表征测试确保药物与PE的络合。离体研究表明,DLC-SON中的药物具有比DLC对照显著(P<0.05)更高的皮肤渗透,但比常规SON具有更低的药物渗透,但其具有比其他更高的皮肤沉积%(P<0.05)。与常规SON和纯VEM相比,制备的DLC-SON的半最大抑制浓度(IC50)显著高(P<0.05)。使用共聚焦激光扫描显微镜(在大鼠上)的体内渗透结果表明,常规SON和DLC-SON均可穿过SC并渗入真皮和表皮,但与常规SON相比,DLC-SON在真皮中24小时后具有更高的亮度/灰度值。结论:使用PE作为脂质并包封在SON中制备的用于VEM的新型脂质复合物显示出更高的抗癌活性和局部渗透以及持续递送和在真皮中的良好保留时间,所述真皮以足够的浓度定位药物以消除早期诊断的皮肤黑色素瘤。
Background: Vemurafenib (VEM) was a licensed drug for the treatment of skin melanoma and is available only in the market as oral tablets prescribed in huge doses (1920 mg/day). One reason for the high dose is vemurafenib\'s low oral bioavailability. Methods: VEM-lipid complex (DLC) was predicted based on Conquest and Mercury programs and prepared using the solvent evaporation method using the lipid (phosphatidylethanolamine). DLC was subjected to characterization (FT-IR, Raman spectroscopy, DSC, TGA, P-XRD, and FESEM) to confirm complexation. DLC was used to prepare solid in oil nanodispersion (DLC-
SON) and subjected to in vitro, ex vivo, and in vivo evaluation in comparison to our recently prepared conventional
SON (VEM-
SON) and DLC-control. Results: Conquest and Mercury predict the availability of intermolecular hydrogen bonding between VEM and phosphatidylethanolamine (PE). All characterization tests of DLC ensure the complexation of the drug with PE. Ex vivo studies showed that the drug in DLC-SON has significantly (P<0.05) higher skin permeation than DLC-control but lower drug permeation than conventional SON but it has a higher % skin deposition (P<0.05) than others. The half-maximal inhibitory concentration (IC50) of the prepared DLC-SON is significantly high (P<0.05) in comparison to the conventional
SON and pure VEM. In vivo permeation using confocal laser scanning microscopy (on the rat) results indicated that both conventional SON and DLC-
SON can cross the SC and infiltrate the dermis and epidermis but DLC-
SON has a higher luminance/gray value after 24 h in the dermis in comparison to the conventional
SON. Conclusion: The novel lipid complex for VEM prepared using PE as a lipid and enclosed in SON showed higher anticancer activity and topical permeation as well as sustained delivery and good retention time in the dermis that localize the drug in a sufficient concentration to eliminate early diagnosed skin melanoma.