Avendaño-Godoy Javier, Miranda Arnoldo, Mennickent Sigrid, Gómez-Gaete Carolina
Departamento de Farmacia, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile.
Escuela de Química y Farmacia, Facultad de Medicina y Ciencia, Universidad San Sebastián, Concepción, Chile.
J Pharm Sci. 2023 Dec;112(12):3175-3184. doi: 10.1016/j.xphs.2023.08.011. Epub 2023 Aug 16.
Rivastigmine is an acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) inhibitor drug approved by the US Food and Drug Administration (FDA) for the treatment of mild to moderate dementia of Alzheimer's type. However, its first-pass metabolism and gastrointestinal side effects negatively affect the tolerability and efficacy of oral therapy. These adverse effects could be avoided with the use of a sustained -release formulation as an intramuscular (IM) administration system. The objective of this work was to develop polylactic co-glycolic acid (PLGA) microparticles for the sustained release of rivastigmine and to evaluate its stability during storage, tissue tolerance, in vitro release, and in vivo pharmacokinetics after its IM administration. The microparticles were made by the solvent evaporation emulsion method. A series of formulation parameters (the type of polymer used, the amount of polymer used, the initial amount of rivastigmine, and the volume of PVA 0.1% w/v) were studied to achieve an encapsulation efficiency (EE) and a rivastigmine load of 54.8 ± 0.9% and 3.3 ± 0.1%, respectively. The microparticles, whose size was 56.1 ± 2.8 μm, had a spherical shape and a smooth surface. FT-IR analysis showed that there is no chemical interaction between rivastigmine and the polymer. PLGA microparticles maintain rivastigmine retained and stable under normal (5 ± 3 °C) and accelerated storage (25 ± 2 °C and 60 ± 5 % RH) conditions for at least 6 months. The microparticles behaved as a sustained release system both in vitro and in vivo compared to non-encapsulated rivastigmine. The IM administration of the formulation in rats did not produce significant tissue damage. However, it is necessary to reproduce the experiments with multiple doses to rule out a negative effect in terms of tolerability in chronic treatment. To the best of our knowledge, this study is the only one that has obtained the sustained release of rivastigmine from PLGA microparticles after IM administration in an in vivo model.
卡巴拉汀是一种乙酰胆碱酯酶（AchE）和丁酰胆碱酯酶（BchE）抑制剂药物，已获美国食品药品监督管理局（FDA）批准用于治疗轻度至中度阿尔茨海默病型痴呆。然而，其首过代谢和胃肠道副作用对口服治疗的耐受性和疗效产生负面影响。使用缓释制剂作为肌肉注射（IM）给药系统可避免这些不良反应。本研究的目的是开发用于卡巴拉汀缓释的聚乳酸-乙醇酸共聚物（PLGA）微粒，并评估其在储存期间的稳定性、组织耐受性、体外释放以及肌肉注射后的体内药代动力学。微粒通过溶剂蒸发乳液法制备。研究了一系列制剂参数（所用聚合物的类型、聚合物用量、卡巴拉汀的初始用量以及0.1% w/v聚乙烯醇（PVA）的体积），以分别实现54.8±0.9%的包封率（EE）和3.3±0.1%的卡巴拉汀载药量。微粒尺寸为56.1±2.8μm，呈球形且表面光滑。傅里叶变换红外光谱（FT-IR）分析表明卡巴拉汀与聚合物之间不存在化学相互作用。PLGA微粒在正常（5±3°C）和加速储存（25±2°C和60±5%相对湿度）条件下，卡巴拉汀至少6个月保持保留且稳定。与未包封的卡巴拉汀相比，微粒在体外和体内均表现为缓释系统。该制剂在大鼠体内肌肉注射未产生明显的组织损伤。然而，有必要用多剂量重复实验以排除慢性治疗中耐受性方面的负面影响。据我们所知，本研究是唯一一项在体内模型中肌肉注射后从PLGA微粒获得卡巴拉汀缓释效果的研究。
