A finasteride patch for the treatment of androgenetic alopecia: A study of promoting permeability strategy using synthetic novel O-acylmenthols combined with ion-pair

Abstract

Currently, finasteride (FIN) is approved to treat androgenetic alopecia only orally, and the application of FIN in transdermal drug delivery system (TDDS) has introduced a new approach for treating the disease. This study was aimed to develop a FIN transdermal patch for the treatment of androgenetic alopecia（AGA） by combing ion-pair and O-acylmenthols (AM) as chemical permeation enhancers (CPEs). The formulation of patch was optimized though single-factor investigation and Box-Behnken design. The pharmacokinetics and androgenetic alopecia pharmacodynamics of the patch were evaluated. Additionally, the permeability enhancement mechanisms of ion-pair and AMs were explored at both the patch and skin levels. The effects of ion-pair and AMs on the patch were characterized by rheology study, FTIR, and molecular docking, and the effects on the skin were assessed through ATR-FTIR, Raman study, DSC, CLSM and molecular dynamics. The finalized formulation of FIN patches was consisted of 5 % (w/w) synthetic FIN-CA (Citric Acid), 6 % MT-C6 as CPEs, 25-AAOH as a pressure-sensitive adhesive (PSA), with a patch thickness of 80 ± 5 μm. The final Q24 h is 78.22 ± 5.18 μg/cm2. Based on the high FIN permeability, the pharmacokinetic analysis revealed that the FIN patch group exhibited a slower absorption rate (tmax = 7.3 ± 2.7 h), lower peak plasma concentration and slower metabolic rate (t1/2 = 6.2 ± 0.8 h, MRT0-t = 26.0 ± 7.8 h) compared to the oral group. Moreover, the FIN patch also demonstrated the same effect as the oral group in promoting hair growth in AGA mice. The results indicated that both FIN-CA and AMs could enhance the fluidity of the PSA and weaken the interaction between FIN-CA and PSA, thereby promoting the release of the FIN from the patch. The interaction sites on the skin for ion-pair and the four AMs were found in the stratum corneum (SC) of the skin, disrupting the tight arrangement of stratum corneum lipids. This study serves as a reference for the multi-pathway administration of FIN and the combination of ion-pair with AMs to enhance drug permeation.