In vitro evaluation of cutaneous penetration of acyclovir from semisolid commercial formulations and relation with its effective antiviral concentration

ABSTRACT The evaluation of drug permeation/penetration of semisolid formulations into animal skin can be useful to supplement the pharmaceutical equivalence. This paper describes the in vitro assessment of acyclovir (ACV) into porcine skin from commercial formulations with etermination of drug concentration in different layers of cutaneous tissue to correlate with effective antiviral concentration in order to improve the equivalence decision. Studies were conducted using Franz cells and porcine skin. Selected pharmaceutical creams containing ACV had identical (reference and generic) and different (similar) excipients. A software program was employed for the simulation of antiviral effectiveness in the skin. Regarding ACV skin penetration, the first batch of the generic product showed a significant difference from reference and similar products, while in the second batch all products demonstrated equivalent drug penetration in the skin. Simulation studies suggest that formulations analysed exhibit a pharmacological effect even when in contact with Herpes simplex strains of high IC50 (inhibitory concentration required to reduce viral replication by 50%). According to results, it can be assumed that the in vitro cutaneous permeation/penetration study does not supply sensitivity information regarding small alterations of ACV semisolid formulations due to the variability inherent to the method, although it can be relevant to pharmaceutical equivalence studies in the development of semisolid products.摘要：对半固体制剂经动物皮肤的药物透皮/渗透（drug permeation/penetration）行为进行评估，可用于补充药学等效性评价工作。本文针对市售阿昔洛韦（acyclovir, ACV）制剂开展体外猪皮肤透皮评价，通过测定皮肤不同组织层中的药物浓度，关联其有效抗病毒浓度，以优化药学等效性的判定标准。本研究采用Franz扩散池（Franz cells）与猪皮肤开展实验，所选用的含阿昔洛韦乳膏制剂分为两类：一类为参比制剂与仿制药（二者药用辅料一致），另一类为药用辅料存在差异的相似制剂。本研究借助软件模拟皮肤内的抗病毒药效。针对阿昔洛韦皮肤渗透行为的分析结果显示：首批仿制药的皮肤渗透水平与参比制剂及相似制剂存在显著差异，而第二批所有制剂的皮肤药物渗透水平均表现出等效性。药效模拟研究表明，即便接触半最大抑制浓度（IC50, inhibitory concentration required to reduce viral replication by 50%）较高的单纯疱疹（Herpes simplex）毒株，本次研究所分析的制剂仍可发挥药理学效应。综合上述结果可知，尽管体外皮肤透皮/渗透研究对半固体制剂开发过程中的药学等效性评价具有参考价值，但由于该方法固有的变异性，其无法为阿昔洛韦半固体制剂的微小变更提供足够的灵敏度信息。