Polymeric micelles for cutaneous delivery of the hedgehog pathway inhibitor TAK-441: Formulation development and cutaneous biodistribution in porcine and human skin

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-alpha-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 similar to 40-fold. The optimal formulation, a 3% HPMC hydrogel of TAK-441 loaded TPGS micelles, retained similar to 92% of the initial TAK-441 content (2.5 mg(TAK-441)/g) after storage at 4 degrees 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 mu g/cm(2) and 0.05 +/- 0.02 mu g/cm(2), 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.

Automated summary

This study developed a micelle-based formulation of TAK-441 using TPGS, which significantly increased the aqueous solubility of TAK-441. Experimental results showed that this formulation resulted in greater cutaneous deposition of TAK-441 compared to a non-micelle control formulation, with negligible transdermal permeation, thereby reducing the risk of systemic side effects in vivo.