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 AUC0-24. The observed AUC0-24 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的首过代谢（first pass metabolism），且偏头痛发作时因胃潴留导致其吸收延迟，目前研究焦点已转向经皮给药（transdermal delivery）途径。本研究的核心目的为制备并评估负载于水凝胶微针（hydrogel microneedles）给药系统的利扎曲普坦经皮制剂，以规避首过代谢，同时提升其经皮渗透速率。本研究采用微模压法（micromolding method）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四个维度对其进行评价。通过调整羧甲基纤维素（carboxymethyl cellulose）与A型明胶（gelatin type A）的浓度比例，本研究成功制备了5组不同配方的利扎曲普坦微针（F1-F5）。利扎曲普坦水凝胶微针展现出优异的机械性能，可承受穿刺所需的外力，从而提升其皮肤穿刺能力。渗透性能实验结果显示，24小时内药物累计释放率为93.1%~100%，表明该微针可有效递送药物。体内实验中，由于F3配方展现出最高的溶胀能力与优异的机械性能，其综合性能优于其余4组配方，故被选为最优制剂。此外，F3在24小时内展现出最稳定的药物控释效果。以药时曲线下面积0~24小时（AUC₀₋₂₄）为评价指标，F3微针的相对生物利用度较口服给药组提升至179.59%。实验测得F3微针组的AUC₀₋₂₄具有统计学意义，较口服给药组高出1.80倍。微针制剂中较高的利扎曲普坦浓度证明其可通过大鼠皮肤实现良好的药物渗透，提示微针给药系统有望提升利扎曲普坦的治疗效果。