Mathematical modeling of drug release from bioerodible microparticles: effect of gamma-irradiation
Mathematical modeling of drug release from bioerodible microparticles: effect of gamma-irradiation
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DOI：
10.1016/s0939-6411(03)00104-8
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发表时间：
2003-09-01
影响因子：
4.9
通讯作者：
Benoit, JP
中科院分区：
文献类型：
--
作者：
Faisant, N;Siepmann, J;Benoit, JP
用于受控药物递送系统的生物可蚀性聚合物，例如聚（乳酸-共-乙醇酸）（PLGA）在γ-辐照期间经历辐射降解。尽管有相当大的实际重要性，但只有很少的知识是可用的结果，这种灭菌方法对所产生的药物释放模式，以定量的方式。本研究的主要目的是：（i）监测不同γ-辐射剂量对无药物和载药的基于PLGA的微粒的物理化学性质的影响;（ii）使用适当的数学模型分析所获得的实验结果;（iii）进一步了解发生的物理和化学现象;（iv）观察不同剂量的γ-辐射对载药微粒的物理化学性质的影响。和（iv）以定量的方式将所施加的γ-辐射剂量与所得到的药物释放速率相关联。采用水包油溶剂萃取法制备负载5-氟尿嘧啶的基于PLGA的微粒，并暴露于0至33 kGy范围内的γ辐射剂量。采用体积排阻色谱法、差示扫描量热法、扫描电镜、粒径分析、实际载药量测定和体外释药动力学等方法研究了γ射线照射剂量对微粒理化性质的影响。两个数学模型-一个简化的和一个更全面的-被用来分析实验结果。简化的模型认为药物扩散的基础上菲克的第二定律的球形几何形状和Higuchi一样的伪稳态方法。复杂的模型结合蒙特卡罗模拟（描述聚合物侵蚀）与偏微分方程量化药物扩散与时间，位置和方向依赖的扩散率。有趣的是，可以建立γ射线照射剂量与微粒内初始药物扩散率之间的指数关系。基于这一知识，这两个模型被用来预测所得到的药物释放动力学的γ-照射剂量的函数。重要的是，理论预测得到了实验结果的证实。(C)2003 Elsevier B. V.保留所有权利。
Bioerodible polymers used in controlled drug delivery systems, such as poly(lactic-co-glycolic acid) (PLGA) undergo radiolytic degradation during gamma-irradiation. In spite of the considerable practical importance, yet only little knowledge is available on the consequences of this sterilization method on the resulting drug release patterns in a quantitative way. The major objectives of the present study were: (i) to monitor the effects of different gamma-irradiation doses on the physicochemical properties of drug-free and drug-loaded, PLGA-based microparticles: (ii) to analyze the obtained experimental results using adequate mathematical models; (iii) to get further insight into the occurring physical and chemical phenomena; and (iv) to relate the applied gamma-irradiation dose in a quantitative way to the resulting drug release rate. 5-Fluorouracil-loaded, PLGA-based microparticles were prepared with an oil-in-water solvent extraction method and exposed to gamma-irradiation doses ranging from 0 to 33 kGy. Size exclusion chromatography, differential scanning calorimetry, scanning electron microscopy, particle size analysis, determination of the actual drug loading and in vitro drug release kinetics were used to study the effects of the gamma-irradiation dose on the physicochemical properties of the microparticles. Two mathematical models-a simplified and a more comprehensive one-were used to analyze the experimental results. The simplified model considers drug diffusion based on Fick's second law for spherical geometry and a Higuchi-like pseudo-steady-state approach. The complex model combines Monte Carlo simulations (describing polymer erosion) with partial differential equations quantifying drug diffusion with time-, position- and direction-dependent diffusivities. Interestingly, exponential relationships between the gamma-irradiation dose and the initial drug diffusivity within the microparticles could be established. Based on this knowledge both models were used to predict the resulting drug release kinetics as a function of the gamma-irradiation dose. Importantly, the theoretical predictions were confirmed by experimental results. (C) 2003 Elsevier B.V. All rights reserved.