Department of Drug Sciences, Division of Pharmaceutical Technology, University of G. D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
Mol Pharm. 2011 Dec 5;8(6):2408-15. doi: 10.1021/mp200337h. Epub 2011 Nov 1.
During chronic treatment with L-dopa (LD), Parkinsonian patients often experience uncontrolled motor complications due to fluctuations of the plasmatic levels of LD that result in pulsatile dopaminergic stimulation. To overcome these plasmatic fluctuations, a novel prodrug of LD, L-dopa-α-lipoic acid (LD-LA), has been proposed as a tool for achieving continuous dopaminergic stimulation. Due to slower susceptibility toward enzymatic conversion by LD-degrading enzymes (such as catechol-O-methyltransferase and monoamine oxidase), the plasma half-life of this prodrug is longer than that of LD. Moreover, the higher lipophilicity of LD-LA over LD promotes its delivery to the CNS, where the resulting levels of dopamine (DA) are kept high for a longer time than after equimolar administration of LD. To further reduce fluctuations in plasma levels of LD, LD-LA has been entrapped into biodegradable polymeric microspheres to be used as a depot system with the aim to prevent prodrug degradation and to obtain a sustained release of the intact compound. In the present work, a formulation of LD-LA loaded microspheres (characterized for drug loading, size, morphology, thermal properties, and in vitro prodrug release) has been administered subcutaneously to rats, and the resulting levels of LD and DA in plasma and striatal tissue, respectively, have been monitored. A good correlation between the in vitro release kinetics and the time range during which the formulation alters the LD/DA tissue levels in vivo was observed, suggesting that the polymeric microsphere matrix protects the loaded prodrug from chemical and enzymatic degradation and controls its release. Interestingly, LD-LA microspheres provided sustained levels of DA neurotransmitter in the striatum nucleus for up to 4 days after a single administration. In conclusion, a polymeric microsphere formulation of LD-LA is an attractive medicine for treating Parkinson's disease (PD) symptoms, avoiding motor complications.
在慢性左旋多巴（L-dopa，LD）治疗期间，由于 LD 血浆水平的波动导致脉冲式多巴胺刺激，帕金森病患者经常出现不受控制的运动并发症。为了克服这些血浆波动，已经提出了 LD 的一种新型前药，即左旋多巴-α-硫辛酸（LD-LA），作为实现持续多巴胺刺激的工具。由于 LD 降解酶（如儿茶酚-O-甲基转移酶和单胺氧化酶）对这种前药的酶转化敏感性较低，因此其血浆半衰期比 LD 长。此外，LD-LA 相对于 LD 的较高亲脂性促进其递送至中枢神经系统，其中多巴胺（DA）的水平在长时间内保持较高，而不是在给予等摩尔 LD 后。为了进一步降低 LD 血浆水平的波动，已经将 LD-LA 包埋在可生物降解的聚合物微球中，用作储存系统，以防止前药降解并获得完整化合物的持续释放。在本工作中，已将 LD-LA 载药微球的制剂（其特征在于药物载量、大小、形态、热性能和体外前药释放）皮下给予大鼠，并分别监测血浆和纹状体组织中 LD 和 DA 的水平。观察到体外释放动力学与制剂在体内改变 LD/DA 组织水平的时间范围之间具有良好的相关性，这表明聚合物微球基质可以保护载药前药免受化学和酶降解，并控制其释放。有趣的是，LD-LA 微球在单次给药后 4 天内持续提供纹状体核中的 DA 神经递质水平。总之，LD-LA 的聚合物微球制剂是一种有吸引力的治疗帕金森病（PD）症状的药物，可以避免运动并发症。
