TAK-441是一种强效的刺激子途径抑制剂（IC50为4.4 nM），用于治疗基底细胞癌，对于具有耐甲曾丙抑制剂的Smoothened受体D473H突变体具有活性。本研究的目的是利用D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）开发基于胶束的TAK-441制剂，并研究其皮肤传递和生物分布。采用溶剂蒸发法制备胶束，将TAK-441纳入到TPGS胶束中，使其水溶性增加约40倍。最佳配方为3％ HPMC水凝胶，其中含有TAK-441负载的TPGS胶束，在4°C贮存6个月后，保持了初始TAK-441含量的约92％（2.5 mgTAK-441/g）。使用人体皮肤进行有限剂量实验表明，与非胶束对照制剂相比，该配方在12小时后导致TAK-441在皮肤中沉积量显著增加（分别为0.40±0.11µg/cm2和0.05±0.02µg/cm2），但未观察到经皮渗透。皮肤生物分布特征表明，TAK-441主要递送至有活力的表皮和上表皮。从HPMC水凝胶制剂中释放的TAK-441表皮浓度是IC50的数千倍，几乎没有经皮渗透，从而降低体内系统性副作用的风险。版权所有©2023作者。由Elsevier B.V.出版。保留所有权利。

TAK-441 is a potent inhibitor of the hedgehog pathway (IC50 4.4 nM) developed for the treatment of basal cell carcinoma that is active against the vismodegib-resistant Smoothened receptor D473H mutant. The objective of this study was to develop a micelle-based formulation of TAK-441 using D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and to investigate its cutaneous delivery and biodistribution. The micelles were prepared using solvent evaporation and incorporation of TAK-441 in the TPGS micelles increased aqueous solubility ∼40-fold. The optimal formulation, a 3% HPMC hydrogel of TAK-441 loaded TPGS micelles, retained ∼92% of the initial TAK-441 content (2.5 mgTAK-441/g) after storage at 4 °C for 6 months. Finite dose experiments using human skin demonstrated that this formulation resulted in significantly greater cutaneous deposition of TAK-441 after 12 h than a non-micelle control formulation, (0.40 ± 0.11 µg/cm2 and 0.05 ± 0.02 µg/cm2, respectively) - no transdermal permeation was observed. The cutaneous biodistribution profile demonstrated that TAK-441 was predominantly delivered to the viable epidermis and upper dermis. Delivery from the HPMC hydrogel formulation resulted in TAK-441 epidermal concentrations that were several thousand-fold higher than the IC50, with almost negligible transdermal permeation, thereby decreasing the risk of systemic side effects in vivo.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.