用于治疗雄激素性脱发的非那雄胺贴片：利用合成的新型 O-酰基薄荷醇结合离子对促进渗透性策略的研究。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics Pub Date : 2024-10-04 DOI:10.1016/j.ijpharm.2024.124802

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引用次数: 0

摘要

目前，非那雄胺（FIN）仅被批准用于口服治疗雄激素性脱发，而将非那雄胺应用于透皮给药系统（TDDS）则为治疗该疾病提供了一种新方法。本研究的目的是通过离子对和OPO的结合，开发一种治疗雄激素性脱发（AGA）的FIN透皮贴片。将离子对和O-酰基薄荷醇（AM）结合起来作为化学渗透促进剂（CPE）。通过单因素考察和盒-贝肯设计对贴片配方进行了优化。对贴片的药代动力学和雄激素性脱发的药效学进行了评估。此外，还从贴片和皮肤两个层面探讨了离子对和 AMs 的渗透性增强机制。离子对和 AMs 对贴片的影响通过流变学研究、傅立叶变换红外光谱和分子对接进行了表征，对皮肤的影响则通过 ATR-傅立叶变换红外光谱、拉曼研究、DSC、CLSM 和分子动力学进行了评估。FIN 贴片的最终配方由 5 %（重量比）合成 FIN-CA（柠檬酸）、6 % MT-C6 作为 CPE、25-AAOH 作为压敏胶（PSA）组成，贴片厚度为 80 ± 5 μm。最终的 Q24 h 值为 78.22 ± 5.18 μg/cm2。基于 FIN 的高渗透性，药代动力学分析表明，与口服组相比，FIN 贴片组的吸收速率较慢（tmax = 7.3 ± 2.7 h），血浆峰浓度较低，代谢速率较慢（t1/2 = 6.2 ± 0.8 h，MRT0-t = 26.0 ± 7.8 h）。此外，FIN 贴片在促进 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 都能增强 PSA 的流动性，削弱 FIN-CA 和 PSA 之间的相互作用，从而促进 FIN 从贴片中释放出来。离子对和四种 AMs 在皮肤上的相互作用位点位于皮肤的角质层（SC），破坏了角质层脂质的紧密排列。这项研究为 FIN 的多途径给药以及将离子对与 AMs 结合以增强药物渗透性提供了参考。

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

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_{24 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 (t_max = 7.3 ± 2.7 h), lower peak plasma concentration and slower metabolic rate (t_1/2 = 6.2 ± 0.8 h, MRT_0-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.

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来源期刊

International Journal of Pharmaceutics 医学-药学

CiteScore

10.70

自引率

8.60%

发文量

951

审稿时长

72 days

期刊介绍： The International Journal of Pharmaceutics is the third most cited journal in the "Pharmacy & Pharmacology" category out of 366 journals, being the true home for pharmaceutical scientists concerned with the physical, chemical and biological properties of devices and delivery systems for drugs, vaccines and biologicals, including their design, manufacture and evaluation. This includes evaluation of the properties of drugs, excipients such as surfactants and polymers and novel materials. The journal has special sections on pharmaceutical nanotechnology and personalized medicines, and publishes research papers, reviews, commentaries and letters to the editor as well as special issues.