Dissolving microneedle patches for transdermal delivery of paroxetine: <i>in-vitro, ex-vivo</i> studies and its PBPK modeling

Paroxetine HCl (PRX-HCl), an antidepressant, has poor water solubility and low oral bioavailability with 50% being metabolized in the liver. The oral formulations have multiple side effects. The present work aimed to develop dissolving microneedle patches (MNPs) of PRX-HCl to resolve low bioavailability and side effect issues while achieving enhanced transdermal delivery. Three silicone templates of varying dimensions were used to fabricate 27 blank and nine PRX-HCl MNPs with PVP and PVA through mold casting method. MNPs were evaluated for physicochemical properties, <i>in-vitro release, and ex-vivo permeation</i>. The optimized MNP was further analyzed for FTIR, DSC, skin penetration, <i>in-silico</i> PBPK modeling, and stability. MNPs from the optimized formulation successfully created microchannels in rat skin, demonstrated higher permeation than control MNPs with a flux of 146.18 ± 13.42 µg/cm²/h, presented a decrease in lag phase and an increase in drug plasma C_max and AUC compared to PAXIL CR 12.5 mg oral, and showed higher stability in the room and refrigerator conditions. The prepared MNPs were stable and can deliver PRX-HCl sufficiently across skin barrier with enhanced bioavailability compared to oral administration at similar doses and thus be a better alternative to already available delivery systems for PRX-HCl.

盐酸帕罗西汀（Paroxetine HCl, PRX-HCl）是一种抗抑郁药，存在水溶性差、口服生物利用度低的问题，且约50%的药物会在肝脏中被代谢。其口服制剂存在多种不良反应。本研究旨在开发盐酸帕罗西汀的可溶性微针贴片（dissolving microneedle patches, MNPs），以解决生物利用度不足与不良反应问题，同时实现经皮递送效率的提升。

本研究采用三种不同尺寸的硅模板，通过模铸法（mold casting method）以聚乙烯吡咯烷酮（PVP）和聚乙烯醇（PVA）为载体材料，制备了27组空白微针与9组载盐酸帕罗西汀微针。对所得微针的理化性质、体外释放与离体透皮渗透性能进行了表征评价。

对优化后的最优处方微针贴片，进一步开展了傅里叶变换红外光谱（FTIR）、差示扫描量热法（DSC）、皮肤渗透实验、计算机模拟（in-silico）生理药代动力学（PBPK）建模以及稳定性考察。

结果显示，优化处方制备的微针贴片可在大鼠皮肤中成功形成微通道，透皮渗透通量达146.18±13.42 µg/cm²/h，优于对照微针；与12.5mg帕罗西汀控释口服制剂（PAXIL CR）相比，其透皮滞后时间缩短，血浆药物峰浓度（C_max）与药时曲线下面积（AUC）均显著提升；且在室温及冷藏储存条件下均表现出更优的稳定性。

所制备的可溶性微针贴片稳定性良好，在等效给药剂量下，较口服给药可有效突破皮肤屏障递送盐酸帕罗西汀，显著提升药物生物利用度，有望成为盐酸帕罗西汀现有递送系统的更优替代方案。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于开发一种用于透皮递送抗抑郁药帕罗西汀的溶解微针贴片，旨在解决其口服给药时生物利用度低和副作用多的问题。研究通过体外和离体实验评估了微针贴片的物理化学性质、药物释放和渗透性能，并利用PBPK建模优化了配方，结果显示该贴片能有效穿透皮肤屏障，提高药物生物利用度，且稳定性良好。