Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Labeled Compounds Department, Hot Labs Center, Egyptian Atomic Energy Authority, Cairo, 13759, Egypt.
Drug Deliv Transl Res. 2023 Dec;13(12):3059-3076. doi: 10.1007/s13346-023-01373-0. Epub 2023 Jun 5.
Zolmitriptan (ZT) is a potent second generation triptan, commonly administered to alleviate migraine attacks. ZT suffers various limitations; massive hepatic first pass metabolism, P-gp efflux transporters susceptibility, and limited (≈40%) oral bioavailability. Transdermal route of administration could be explored to enhance its bioavailability. A 2.3 full factorial design was constructed to developed twenty-four ZT loaded terpesomes via thin film hydration technique. The influence of drug: phosphatidylcholine ratio, terpene type, terpene concentration and sodium deoxycholate concentration on the characterization of the developed ZT-loaded terpesomes was assessed. Particle size (PS), zeta potential (ZP), ZT entrapment efficiency (EE%), drug loading (DL%) and drug released percentages after 6 h (Q) were the selected dependent variables. Further morphological, crystallinity, and in-vivo histopathological studies were conducted for the optimum terpesomes (T6). Tc-ZT and Tc-ZT-T6 gel were radio-formulated for in-vivo biodistribution studies in mice following transdermal application of Tc-ZT-T6 gel, relative to Tc-ZT oral solution. T6 terpesomes [comprising ZT and phosphatidylcholine (1:15), cineole (1% w/v) and sodium deoxycholate (0.1% w/v)] were optimum with respect to spherical PS (290.2 nm), ZP (-48.9 mV), EE% (83%), DL% (3.9%) and Q (92.2%) with desirability value of 0.85. The safety of the developed T6 terpesomes was verified by the in-vivo histopathological studies. Tc-ZT-T6 gel showed maximum brain concentration (5 ± 0.1%ID/ g) with highest brain to blood ratio of 1.92 ± 0.1 at 4 h post transdermal application. Significant improvement of ZT brain relative bioavailability (529%) and high brain targeting efficiency (315%) were revealed with Tc-ZT-T6 gel, which confirmed successful ZT delivery to the brain. Terpesomes could be safe, successful systems capable of improving ZT bioavailability with high brain targeting efficiency.
佐米曲普坦（ZT）是一种强效的第二代曲普坦类药物，常用于缓解偏头痛发作。ZT 存在多种局限性，如肝首过代谢巨大、P-糖蛋白外排转运体易感性和有限的（约 40%）口服生物利用度。透皮给药途径可用于提高其生物利用度。本研究采用薄膜水化技术制备了 24 种负载 ZT 的萜类囊泡，构建了 2.3 全因子设计。评估了药物：磷脂酰胆碱比、萜烯类型、萜烯浓度和脱氧胆酸钠浓度对所制备的 ZT 负载萜类囊泡的特性的影响。选择粒径（PS）、Zeta 电位（ZP）、ZT 包封效率（EE%）、药物载量（DL%）和 6 h 后药物释放百分比（Q）作为依赖变量。进一步对最佳萜类囊泡（T6）进行形态学、结晶度和体内组织病理学研究。Tc-ZT 和 Tc-ZT-T6 凝胶经放射性标记后，用于小鼠经皮应用 Tc-ZT-T6 凝胶后的体内分布研究，与 Tc-ZT 口服溶液相比。T6 萜类囊泡[包含 ZT 和磷脂酰胆碱（1:15）、桉油精（1%w/v）和脱氧胆酸钠（0.1%w/v）]在 PS（290.2nm）、ZP（-48.9mV）、EE%（83%）、DL%（3.9%）和 Q（92.2%）方面具有最佳球形PS（290.2nm）、ZP（-48.9mV）、EE%（83%）、DL%（3.9%）和 Q（92.2%），其理想值为 0.85。通过体内组织病理学研究验证了所制备的 T6 萜类囊泡的安全性。Tc-ZT-T6 凝胶在经皮给药后 4 小时内显示出最大的脑浓度（5±0.1%ID/g）和最高的脑血比 1.92±0.1。与 Tc-ZT 口服溶液相比，Tc-ZT-T6 凝胶显著提高了 ZT 的脑相对生物利用度（529%）和高脑靶向效率（315%），证实了 ZT 成功递送到大脑。萜类囊泡可能是安全、成功的系统，能够提高 ZT 的生物利用度，并具有高脑靶向效率。
