Leal Leila Bastos, Cordery Sarah F, Delgado-Charro M Begoña, Bunge Annette L, Guy Richard H
Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco, CEP: 50740-520, Recife-PE, Brazil.
Pharm Res. 2017 Apr;34(4):730-737. doi: 10.1007/s11095-017-2099-1. Epub 2017 Jan 17.
To examine whether in vitro and ex vivo measurements of topical drug product performance correlate with in vivo outcomes, such that more efficient experimental approaches can be reliably and reproducibly used to establish (in)equivalence between formulations for skin application.
In vitro drug release through artificial membranes, and drug penetration into porcine skin ex vivo, were compared with published human in vivo studies. Two betamethasone valerate (BMV) formulations, and three marketed econazole nitrate (EN) creams were assessed.
For BMV, the stratum corneum (SC) uptake of drug in 6 h closely matched data observed in vivo in humans, and distinguished between inequivalent formulations. SC uptake of EN from the 3 creams mirrored the in vivo equivalence in man (both clinically and via similar tape-stripping experiments). However, EN clearance from SC ex vivo did not parallel that in vivo, presumably due to the absence of a functioning microcirculation. In vitro release of BMV from the different formulations did not overlap with either ex vivo or in vivo tape-stripping data whereas, for EN, a good correlation was observed. No measurable permeation of either BMV or EN was detected in a 6-h in vitro skin penetration experiment.
In vitro and ex vivo methods for topical bioequivalence determination can show correlation with in vivo outcomes. However, these surrogates have understandable limitations. A "one-size-fits-all" approach for topical bioequivalence evaluation may not always be successful, therefore, and the judicious use of complementary methods may prove a more effective and reliable strategy.
研究局部用药品性能的体外和离体测量结果是否与体内结果相关，以便能够可靠且可重复地使用更高效的实验方法来确定皮肤用制剂之间的（不）等效性。
将通过人工膜的体外药物释放以及药物离体渗透进入猪皮肤的情况与已发表的人体体内研究进行比较。评估了两种戊酸倍他米松（BMV）制剂以及三种市售硝酸益康唑（EN）乳膏。
对于BMV，6小时内药物在角质层（SC）中的摄取与人体体内观察到的数据紧密匹配，并且能够区分不等效的制剂。3种乳膏中EN在SC中的摄取反映了人体体内的等效性（临床观察以及通过类似的胶带剥离实验）。然而，EN从SC的离体清除情况与体内情况不平行，推测是由于缺乏有效的微循环。不同制剂中BMV的体外释放与离体或体内胶带剥离数据均无重叠，而对于EN，则观察到良好的相关性。在6小时的体外皮肤渗透实验中未检测到BMV或EN的可测量渗透。
用于局部生物等效性测定的体外和离体方法可以显示与体内结果的相关性。然而，这些替代方法存在可理解的局限性。因此，局部生物等效性评估的“一刀切”方法可能并不总是成功的，明智地使用互补方法可能是一种更有效且可靠的策略。
