Casanova Yaquelyn, Negro Sofía, Slowing Karla, García-García Luis, Fernández-Carballido Ana, Rahmani Mahdieh, Barcia Emilia
Department of Pharmaceutics and Food Technology, School of Pharmacy, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain.
Institute of Industrial Pharmacy, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain.
Pharmaceutics. 2022 May 17;14(5):1080. doi: 10.3390/pharmaceutics14051080.
To date there is no cure for Parkinson's disease (PD), a devastating neurodegenerative disorder with levodopa being the cornerstone of its treatment. In early PD, levodopa provides a smooth clinical response, but after long-term therapy many patients develop motor complications. Tolcapone (TC) is an effective adjunct in the treatment of PD but has a short elimination half-life. In our work, two new controlled delivery systems of TC consisting of biodegradable PLGA 502 (poly (D,L-lactide-co-glycolide acid) microparticles (MPs) and nanoparticles (NPs) were developed and characterized. Formulations MP-TC4 and NP-TC3 were selected for animal testing. Formulation MP-TC4, prepared with 120 mg TC and 400 mg PLGA 502, exhibited a mean encapsulation efficiency (EE) of 85.13%, and zero-order in vitro release of TC for 30 days, with around 95% of the drug released at this time. Formulation NP-TC3, prepared with 10 mg of TC and 50 mg of PLGA 502, exhibited mean EE of 56.69%, particle size of 182 nm, and controlled the release of TC for 8 days. Daily i.p. (intraperitoneal) doses of rotenone (RT, 2 mg/kg) were given to Wistar rats to induce neurodegeneration. Once established, animals received TC in saline (3 mg/kg/day) or encapsulated within formulations MP-TC4 (amount of MPs equivalent to 3 mg/kg/day TC every 14 days) and NP-TC3 (amount of NPs equivalent to 3 mg/kg/day TC every 3 days). Brain analyses of Nissl-staining, GFAP (glial fibrillary acidic protein), and TH (tyrosine hydroxylase) immunohistochemistry as well as behavioral testing (catalepsy, akinesia, swim test) showed that the best formulation was NP-TC3, which was able to revert PD-like symptoms of neurodegeneration in the animal model assayed.
帕金森病（PD）是一种具有破坏性的神经退行性疾病，至今仍无法治愈，左旋多巴是其治疗的基石。在早期帕金森病中，左旋多巴能产生平稳的临床反应，但长期治疗后，许多患者会出现运动并发症。托卡朋（TC）是治疗帕金森病的一种有效辅助药物，但消除半衰期较短。在我们的研究中，开发并表征了两种由可生物降解的聚（D，L-丙交酯-共-乙交酯）502（PLGA 502）制成的托卡朋新型控释系统，即微粒（MPs）和纳米颗粒（NPs）。选择制剂MP-TC4和NP-TC3进行动物试验。用120 mg托卡朋和400 mg PLGA 502制备的制剂MP-TC4，平均包封率（EE）为85.13%，托卡朋在体外呈零级释放30天，此时约95%的药物被释放。用10 mg托卡朋和50 mg PLGA 502制备的制剂NP-TC3，平均包封率为56.69%，粒径为182 nm，托卡朋的释放控制在8天。每天给Wistar大鼠腹腔注射鱼藤酮（RT，2 mg/kg）以诱导神经退行性变。一旦模型建立，动物接受生理盐水溶解的托卡朋（3 mg/kg/天）或包裹在制剂MP-TC4（每14天给予相当于3 mg/kg/天托卡朋量的微粒）和NP-TC3（每3天给予相当于3 mg/kg/天托卡朋量的纳米颗粒）中。对尼氏染色、胶质纤维酸性蛋白（GFAP）和酪氨酸羟化酶（TH）免疫组化进行脑分析以及行为测试（僵住症、运动不能、游泳试验）表明，最佳制剂是NP-TC3，它能够逆转所检测动物模型中类似帕金森病的神经退行性变症状。
