Transdermal Drug Delivery of Rizatriptan Using Microneedles Array Patch: Preparation, Characterization and Ex-vivo/In-Vivo Study

Given the extensive first pass metabolism of rizatriptan in oral administration and its delayed absorption during a migraine attack as a result of gastric stasis, focus has been on transdermal delivery. The main purpose of this study is to prepare and assess transdermal formulation of rizatriptan, loaded on hydrogel microneedles delivery system, to avoid first pass metabolism and also improve its percutaneous permeation rate. Rizatriptan hydrogel microneedles were prepared using micromolding method and evaluated in terms of mechanical strength, encapsulation efficiency, permeation and in-vivo skin absorption. Different formulations of rizatriptan microneedles (F1-F5) were successfully prepared using different concentrations of carboxymethyl cellulose and gelatin type A. Rizatriptan hydrogel microneedles demonstrated favorable mechanical properties, demonstrating its mechanical strength to withstand insertion forces, thereby enhancing its skin insertion ability. In permeation study the percent cumulative drug released after 24 hours ranged between 93.1-100% which means that microneedles were able to deliver the drug effectively. For in-vivo study, F3 formulation was selected due to its superior characteristics over other formulations as it exhibited the highest swelling capacity, demonstrated favorable mechanical properties. Furthermore, F3 showcased the most controlled drug release over a 24-hour period. Relative bioavailability of F3 microneedles was 179.59% compared to oral administration based on the AUC_0-24. The observed AUC_0-24 in F3 microneedles was statistically significant and 1.80 times greater than that in oral administration. The higher rizatriptan level in the microneedle demonstrated adequate drug permeability through the rat skin, suggesting the potential of microneedles for enhanced therapeutic effectiveness.鉴于利扎曲普坦（rizatriptan）口服给药时存在显著首过代谢，且偏头痛发作时因胃排空延迟导致其吸收延缓，现有研究多聚焦于经皮给药途径。本研究的核心目的为制备并评估负载于水凝胶微针给药系统的利扎曲普坦经皮制剂，以规避首过代谢并提升其经皮渗透速率。本研究采用微模压法制备利扎曲普坦水凝胶微针，并从机械强度、包封率、渗透性能及体内皮肤吸收等方面对其进行评价。通过调整羧甲基纤维素与A型明胶的浓度比例，本研究成功制备了5组利扎曲普坦微针制剂（F1~F5）。利扎曲普坦水凝胶微针展现出良好的机械性能，可承受穿刺外力，进而提升皮肤穿刺能力。渗透实验结果显示，24小时累计药物释放率介于93.1%~100%之间，表明该微针可实现药物的有效递送。体内实验中，因F3制剂具备最高的溶胀能力与良好的机械性能，综合表现优于其余组别，故被选为最优制剂。此外，F3制剂在24小时内展现出最平稳的药物控释效果。以AUC₀₋₂₄（药时曲线下面积0~24小时）为评价指标，F3微针相对于口服给药的相对生物利用度为179.59%。F3微针组的AUC₀₋₂₄具有统计学意义，较口服给药组升高1.80倍。微针制剂中更高的利扎曲普坦暴露量表明其可通过大鼠皮肤实现良好的药物渗透，提示该微针系统具备提升治疗效果的应用潜力。