Department of Pharmacy, the Second Affiliated Hospital, Harbin Medical University (Key Laboratory of medications research, college of Heilongjiang Province), 148 Baojian Road, Harbin, 150086, People's Republic of China.
Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, 150086, People's Republic of China.
AAPS PharmSciTech. 2021 Apr 6;22(3):125. doi: 10.1208/s12249-021-01989-w.
The main objective of the study was to prepare the microemulsions containing adapalene (MEs-Ap) to enhance epidermal penetration, dermal retention, and local bioavailability compared with the commercial preparation. The optimal formulations were selected by solubility experiments, pseudo-ternary phase diagram, and percutaneous permeation experiments and the physiochemical properties were also investigated. Then, the study of permeability, retention, safety, pharmacodynamics, and pharmacokinetics in the skin for MEs-Ap compared with the commercial preparation were researched. The optimized formulation was developed as follows: the ratio of AP, isopropyl myristate, polyoxyethylene hydrogenated castor oil, ethanol, and water was 0.01:1:1.25:3.75:4 (w/w). The globule size and average viscosity of the optimized MEs-Ap were 99.34 nm and 1.7 mPa·s, respectively, which was oil-in-water microemulsion without serious irritation or allergy for skin. The J, Q, and Q of MEs-Ap (0.81 ± 0.19 μg/cm/h, 24.73 ± 4.24 μg/cm, 2.08 ± 0.18 μg/cm) were apparently higher than Differin® (0.022 ± 0.009 μg/cm/h, 0.536 ± 0.103 μg/cm, and 0.523 ± 0.130 μg/cm) respectively. The local bioavailability study showed that the AUC of the MEs-Ap in the dermal (19.6 ± 1.22 μg/cm) was significantly improved comparing to Differin® (13.9 ± 1.73 μg/cm) (p < 0.01). The pharmacodynamics study showed that the therapeutic effect of MEs-Ap was better than that of Differin® in the acne model of rabbit auricle. These results suggested that the MEs-Ap could be considered as a having higher epidermal penetrability, dermal retention, local bioavailability, efficacy, and safety topical preparations for acne. Graphical abstract.
本研究的主要目的是制备载有他扎罗汀（MEs-Ap）的微乳，以增强与市售制剂相比的表皮穿透性、真皮滞留性和局部生物利用度。通过溶解度实验、伪三元相图和透皮渗透实验选择最佳配方，并研究其物理化学性质。然后，研究了 MEs-Ap 与市售制剂相比在皮肤中的渗透性、滞留性、安全性、药效学和药代动力学。优化的制剂如下开发：AP、肉豆蔻酸异丙酯、聚氧乙烯氢化蓖麻油、乙醇和水的比例为 0.01:1:1.25:3.75:4（w/w）。优化的 MEs-Ap 的粒径和平均粘度分别为 99.34nm 和 1.7mPa·s，为油包水乳剂，对皮肤无严重刺激或过敏。MEs-Ap 的 J、Q 和 Q 值（0.81±0.19μg/cm/h、24.73±4.24μg/cm、2.08±0.18μg/cm）明显高于达芙文®（0.022±0.009μg/cm/h、0.536±0.103μg/cm、0.523±0.130μg/cm）。局部生物利用度研究表明，与达芙文®相比，MEs-Ap 在真皮中的 AUC（19.6±1.22μg/cm）明显提高（p<0.01）。药效学研究表明，在兔耳粉刺模型中，MEs-Ap 的治疗效果优于达芙文®。这些结果表明，MEs-Ap 可作为一种具有更高表皮穿透性、真皮滞留性、局部生物利用度、疗效和安全性的痤疮外用制剂。
