School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
Int J Pharm. 2024 Dec 5;666:124802. doi: 10.1016/j.ijpharm.2024.124802. Epub 2024 Oct 4.
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 Q is 78.22 ± 5.18 μg/cm. Based on the high FIN permeability, the pharmacokinetic analysis revealed that the FIN patch group exhibited a slower absorption rate (t = 7.3 ± 2.7 h), lower peak plasma concentration and slower metabolic rate (t = 6.2 ± 0.8 h, MRT = 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.
目前，非那雄胺（FIN）仅被批准用于口服治疗雄激素性脱发，而将 FIN 应用于透皮给药系统（TDDS）为治疗该疾病提供了一种新方法。本研究旨在通过离子对和 O-酰基薄荷醇（AM）作为化学渗透增强剂（CPE）来开发一种用于治疗雄激素性脱发（AGA）的 FIN 透皮贴剂。通过单因素考察和 Box-Behnken 设计优化了贴剂的配方。评估了贴剂的药代动力学和 AGA 药效学。此外，还在贴剂和皮肤两个层面上探讨了离子对和 AM 对渗透的增强机制。通过流变学研究、FTIR 和分子对接研究了离子对和 AM 对贴剂的影响，通过 ATR-FTIR、拉曼研究、DSC、CLSM 和分子动力学研究了其对皮肤的影响。FIN 贴剂的最终配方由 5%（w/w）合成的 FIN-CA（柠檬酸）、6% MT-C6 作为 CPEs、25-AAOH 作为压敏胶（PSA）组成，贴剂厚度为 80±5μm。最终的 Q 值为 78.22±5.18μg/cm。基于 FIN 的高渗透性，药代动力学分析表明，与口服组相比，FIN 贴剂组表现出较慢的吸收速率（t=7.3±2.7h）、较低的峰血浆浓度和较慢的代谢速率（t=6.2±0.8h，MRT=26.0±7.8h）。此外，FIN 贴剂在促进 AGA 小鼠毛发生长方面也表现出与口服组相同的效果。结果表明，FIN-CA 和 AMs 均可增强 PSA 的流动性，并削弱 FIN-CA 与 PSA 之间的相互作用，从而促进 FIN 从贴剂中的释放。在皮肤的角质层（SC）中发现了离子对和四种 AMs 的作用部位，破坏了角质层脂质的紧密排列。本研究为 FIN 的多途径给药和离子对与 AMs 联合增强药物渗透提供了参考。
