Almirall Hermal, R&D Dermatology, Scholtzstrasse 3, 21465, Reinbek, Germany.
RaDes GmbH, Schnackenburgallee 114, 22525, Hamburg, Germany.
AAPS PharmSciTech. 2019 Jan 24;20(2):89. doi: 10.1208/s12249-019-1305-3.
The Skin Parallel Artificial Membrane Permeability Assay (PAMPA) is a 96-well plate-based skin model with an artificial membrane containing free fatty acid, cholesterol, and synthetic ceramide analogs to mimic the stratum corneum (SC) barrier. The current study evaluates the compatibility of lipophilic solvents/penetration enhancer, topical emulsions containing different emulsifier systems, and organic acceptor media additives with the artificial membrane of the assay. Additionally, different assay setups (standard setup: donor in bottom plate versus modified setup: donor in top plate) were compared. Methylparaben (MP), ethylparaben (EP), and propylparaben (PP) were used as model permeants and internal standards for proper assay execution. The permeation order of the parabens (MP > EP > PP) remained the same with different lipophilic solvents, and the ranking of lipophilic solvents was comparable under standard and modified conditions (isopropyl myristate, IPM > dimethyl isosorbide, DMI ≥ propylene glycol, PG > diisopropyl adipate, DIPA). Pre-incubation of the Skin PAMPA plates with IPM, DIPA, and DMI, as well as with formulations that contain non-ionic emulsifiers, and acceptor solutions containing DMSO or EtOH (≤ 50%) for 4 h did not increase the percentage of permeated parabens in the main experiment, suggesting that those compounds do not make the artificial membrane more permeable. High-resolution mass spectrometry confirmed that acceptor solutions with ≤ 50% DMSO or EtOH do not extract stearic acid, cholesterol, and certramides at standard assay conditions. Hence, if certain constraints are considered, the Skin PAMPA model can be used as a pre-screening tool for topical formulation selection.
皮肤平行人工膜渗透测定法（PAMPA）是一种基于 96 孔板的皮肤模型，其人工膜含有游离脂肪酸、胆固醇和合成神经酰胺类似物，以模拟角质层（SC）屏障。本研究评估了亲脂性溶剂/渗透增强剂、含有不同乳化剂系统的局部乳液以及有机接受剂介质添加剂与测定法人工膜的相容性。此外，还比较了不同的测定设置（标准设置：供体在底板上与改良设置：供体在顶板上）。对羟基苯甲酸甲酯（MP）、对羟基苯甲酸乙酯（EP）和对羟基苯甲酸丙酯（PP）被用作模型渗透物和适当测定执行的内标。不同亲脂性溶剂中对羟基苯甲酸酯的渗透顺序（MP > EP > PP）保持不变，标准和改良条件下亲脂性溶剂的排序相似（肉豆蔻异丙酯、IPM > 二甲基异山梨醇、DMI≥丙二醇、PG > 二异丙基癸二酸酯、DIPA）。在主实验中，将 Skin PAMPA 板用 IPM、DIPA 和 DMI 预孵育 4 小时，以及用含有非离子乳化剂的制剂和含有 DMSO 或 EtOH（≤50%）的接受溶液预孵育 4 小时，并不会增加透皮的对羟基苯甲酸酯的百分比，这表明这些化合物不会使人工膜更具渗透性。高分辨率质谱证实，在标准测定条件下，含有≤50%DMSO 或 EtOH 的接受溶液不会提取硬脂酸、胆固醇和神经酰胺。因此，如果考虑某些限制条件，皮肤 PAMPA 模型可以用作局部制剂选择的初步筛选工具。
