School of Pharmaceutical Sciences, University of Geneva, CMU, 1 rue Michel-Servet, 1211, Geneva 4, Switzerland; Institute of Pharmaceutical Sciences Western Switzerland, University of Geneva, Geneva, Switzerland.
Takeda Pharmaceuticals, Drug Delivery Technologies Search and Evaluation, 40 Landsdowne St, Cambridge MA 02139, United States.
Int J Pharm. 2023 Sep 25;644:123349. doi: 10.1016/j.ijpharm.2023.123349. Epub 2023 Aug 24.
TAK-441 is a potent inhibitor of the hedgehog pathway (IC 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 mg/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/cm and 0.05 ± 0.02 µg/cm, 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 IC, with almost negligible transdermal permeation, thereby decreasing the risk of systemic side effects in vivo.
TAK-441 是一种有效的 Hedgehog 通路抑制剂（IC4.4 nM），用于治疗基底细胞癌，对 vismodegib 耐药的 Smoothened 受体 D473H 突变体有效。本研究的目的是使用 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）开发 TAK-441 的胶束制剂，并研究其经皮传递和体内分布。采用溶剂蒸发法制备胶束，将 TAK-441 包载于 TPGS 胶束中，其水溶解度增加了约 40 倍。优化后的制剂为 3% HPMC 水凝胶载 TAK-441 的 TPGS 胶束，在 4°C 下储存 6 个月后，仍保留初始 TAK-441 含量（2.5 mg/g）的约 92%。使用人体皮肤进行的有限剂量实验表明，与非胶束对照制剂相比，该制剂在 12 小时后可显著增加 TAK-441 的皮肤沉积量（分别为 0.40±0.11 µg/cm 和 0.05±0.02 µg/cm），但未观察到透皮渗透。皮肤分布曲线表明，TAK-441 主要递送至有活力的表皮和上真皮。从 HPMC 水凝胶制剂中释放 TAK-441 可使表皮中的 TAK-441 浓度比 IC 高数千倍，几乎没有透皮渗透，从而降低了体内全身副作用的风险。
