Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India.
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India.
Eur J Pharm Sci. 2019 Mar 15;130:200-214. doi: 10.1016/j.ejps.2019.02.002. Epub 2019 Feb 4.
Curcumin (cur) is a well known plant flavonoid with pleiotropic pharmacological activities. However, due to its poor bioavailability those therapeutic benefits are still out of reach for patient community. The main aim of our study was to prepare sustained release cur microparticles (CuMPs) with Poly (lactic-co-glycolic acid) (PLGA), an FDA approved biodegradable polymer and to assess their pharmacological potential in multiple low doses streptozotocin (MLD-STZ) induced type 1 diabetes mellitus (T1DM). CuMPs were formulated and characterized for size (12.71 ± 4.20 μm) and encapsulation efficiency (85.10 ± 2.33%) with 28% drug loading. In vitro release and in vivo pharmacokinetics studies showed promising results of sustained release of cur from CuMPs. With this here we report a strategy that single administration of CuMPs may fill the therapeutic window that is missing from free drug repeated administration and low bioavailability of cur. Moving forward with this concept, we compared the therapeutic effects of CuMPs (equivalent to 7.5 mg/kg cur with free cur orally (100 mg/kg) and intraperitoneally (7.5 mg/kg) administered daily in MLD-STZ challenged animals). CuMPs exhibited superior effects compared to daily administration free drug given either orally or i.p. in terms of lowering the blood glucose levels, improved glucose clearance as evident from results of i.p. glucose tolerance test (IPGTT). Interestingly, we observed a remarkable reduction in diabetes incidence in CuMPs groups (only one out of six animals i.e. 16.6%). Moreover, plasma and tissue levels of insulin indicated superior effect of CuMPs. In addition, immunohistochemical analysis of insulin in pancreatic β-cells further confirmed the improved therapeutic benefit with significant increase in insulin signal with CuMPs. Amelioration of oxidative stress and inflammation of CuMPs was observed as the molecular mechanism behind the observed superior pharmacological effects with CuMPs. Cumulatively, our sustained release CuMPs formulation may serve as a bridge in overcoming the poor pharmacokinetics issues associated with cur and may hasten the clinical translation of cur.
姜黄素（cur）是一种众所周知的植物类黄酮，具有多种药理学活性。然而，由于其生物利用度差，这些治疗益处仍然无法惠及患者群体。我们研究的主要目的是用聚（乳酸-共-乙醇酸）（PLGA）制备姜黄素的缓释微球（CuMPs），PLGA 是一种经过 FDA 批准的可生物降解聚合物，并评估其在多次低剂量链脲佐菌素（MLD-STZ）诱导的 1 型糖尿病（T1DM）中的药理潜力。CuMPs 的粒径为 12.71±4.20μm，包封效率为 85.10±2.33%，载药量为 28%。体外释放和体内药代动力学研究显示出 CuMPs 从姜黄素中持续释放的有希望的结果。在此，我们报告了一种策略，即单次给予 CuMPs 可能填补游离药物重复给药和姜黄素生物利用度低所缺失的治疗窗口。在此概念的基础上，我们比较了 CuMPs（相当于口服 100mg/kg 姜黄素（100mg/kg）和腹腔内 7.5mg/kg 姜黄素）和每日 MLD-STZ 挑战动物中腹腔内给药的游离药物的治疗效果。与每日给予游离药物相比，CuMPs 在降低血糖水平方面表现出更好的效果，从腹腔葡萄糖耐量试验（IPGTT）的结果可以明显看出葡萄糖清除率得到改善。有趣的是，我们观察到 CuMPs 组糖尿病发病率显著降低（仅 6 只动物中有 1 只，即 16.6%）。此外，血浆和组织中的胰岛素水平表明 CuMPs 的效果更好。此外，胰腺β细胞中胰岛素的免疫组织化学分析进一步证实了 CuMPs 的治疗益处，胰岛素信号显著增加。CuMPs 改善氧化应激和炎症的作用被认为是观察到的 CuMPs 具有优越的药理作用的分子机制。总之，我们的姜黄素缓释微球制剂可能有助于克服与姜黄素相关的药代动力学问题，并可能加速姜黄素的临床转化。
