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的首过代谢效应，且偏头痛发作时因胃潴留导致药物吸收延迟，研究者们将研究焦点转向经皮给药途径。本研究的核心目的为制备并评估负载于水凝胶微针（hydrogel microneedles）递送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（micromolding method）制备利扎曲普坦水凝胶微针，并从机械强度、包封率（encapsulation efficiency）、渗透性能及体内皮肤吸收特性四个维度进行评价。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，成功制备了5组不同配方的利扎曲普坦微针（编号F1至F5）。所制备的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，进而提升皮肤穿刺能力。渗透实验结果显示，24小时内的累积药物释放百分率介于93.1%至100%之间，表明该微针可实现高效的药物递送。体内实验中，因F3配方具备最优的综合性能——其溶胀能力（swelling capacity）最高且机械性能优异，故被选为最优制剂。此外，F3配方可实现长达24小时的平稳控释。基于AUC₀₋₂₄（药时曲线下面积，Area Under the Curve）计算，F3微针的相对生物利用度为179.59%，相较于口服给药组显著提升。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。微针制剂中更高的利扎曲普坦水平证实其可通过大鼠皮肤实现良好的药物渗透，提示该微针递送系统具备提升治疗效果的应用潜力。