聚乳酸微球载体的结构与控释性能关系及模型
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摘要
可生物降解聚合物微球作为一种新的药物载体系统,在药物的控制释放领域得到了广泛的研究和应用。微球载体能够克服现有药物制剂的一些弊端,利用自身的微小粒径和药物的高度分散,改善难溶性药物的水溶性和溶出速率,提高药物的生物利用率。然而就目前的开发手段来说,微球载体的开发主要还是依赖于重复的实验和尝试的途径。仅从宏观操作条件对微球释放性能影响的表观现象入手,难以从本质上掌握其基本规律。本文从实验和数学模拟两种途径着手,将质量平衡、传质和动力学等化学工程的理论应用到分散的结构体系中,结合微观的作用机理和宏观的传质现象来综合研究微球的结构性质关系,为药物载体的研究和开发提供理论依据。
首先,以难溶性药物硝苯地平作为模型药物,以不同单体比例的聚乳酸及其共聚物作为载体材料,采用O/W乳化溶剂蒸发法制备了硝苯地平的微球载体。分析了聚合物类型、浓度、药物的初始含量等对微球的粒度分布、结构形态、包载效率等性质的影响趋势,评价了不同结构微球的释放性能。另外,基于相容性的观点,从药物与聚合物的分子间相互作用、药物和聚合物的存在形态以及宏观的释放速率曲线等多个不同层次上综合研究了药物的释放动力学,分析和探讨了影响微球性能的内在的作用机理。
对描述药物释放的几种常用的理论模型,探讨了其适用性和局限性。根据硝苯地平这类难溶性药物的特点,分析了其在聚合物微球中释放的传质机理。分别针对微球内液相与固相中药物动态质量平衡,综合考虑了药物的扩散、有限溶解速率的限制、固态药物溶解的移动边界以及微球的粒度分布等因素,提出了一种新的溶解扩散模型,并通过线法对偏微分方程组的模型进行了数值求解。根据模型考察了不同的结构性质和模型参数对释放速率曲线的影响,同时计算了不同情况下微球内固、液相中药物浓度的变化规律,描述了影响药物释放速率的传质过程。与基于Fick第二定律的扩散模型和Higuchi模型的对比说明,本文所提出的模型具有很好的通用性,能够完整地描述不同溶解性质的药物的整个释放过程,前两种模型可看作溶解扩散模型在假定无限溶解速率或溶解度下的特例。最后,使用溶解扩散模型对体外实验的释放数据进行分析,研究了微球的结构性质对模型参数的影响趋势,微球的微观结构性质的影响隐含在模型传质系数的变化中。通过对不同结构微球的释放速率和模型参数的比较,并结合微球的性质表征和相容性分析,揭示了微球结构和释放性能关系的基本规律。为探索如何改善和控制药物的释放性能提供了基础。
Biodegradable polymeric microspheres, as a new type of controlled drug delivery system, have advantages of controlled release of active drug molecules over prolonged time to target sites, easiness of administration, favorable biocompatibility, and good degradability. In consideration of hydrophobic nature, some drug composites are encapsulated in polymeric microspheres at highly dispersed amorphous state to improve solubility and bioavailability. Structure-property relationships of the microsphere system are investigated in this work from both of microscopic mechanism and macroscopic mass transfer phenomena with experiments and modeling. Nifedipine, a calcium antagonist for treatment of hypertension, was studied as a model hydrophobic ingredient for drug entrapment and release. An oil-in-water solvent evaporation method was used to prepare polymer microspheres with controlled size. Fundamental mechanism of drug release was investigated from three aspects: interaction between molecules of drugs and polymers, morphology and dispersion of drugs, and in vitro release experimental findings. Taking consideration of effects of diffusion, finite dissolution rate, and moving front of dissolution, a new model is developed for quantitative description of the release patterns. Finally, integrated with pharmacokinetics, the release model was extended to in vivo process to evaluate drug concentration levels in the plasma.Nifedipine loaded microspheres were prepared using biodegradable polymers poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA). Microspheres size, entrapment efficiency, morphology, and release profiles were characterized by DLS, SEM, DSC, FTIR and in vitro release tests. Particle size was controlled with interfacial tension and viscosity of polymer and surfactant (PVA) concentrations. Diameters of microspheres vary from 1μm to 10μm. A broad range of drug release profiles were achieved. Due to large surface area, drug leakage is found in small particles, as a result of diffusion to continuous phase during fabrication. Compromise has to be made between high entrapment efficiency and small size. For all the microspheres, nifedipine was found to be totally amorphous in the polymer, which suggested that the drug is well dispersed in the matrix.
首先,以难溶性药物硝苯地平作为模型药物,以不同单体比例的聚乳酸及其共聚物作为载体材料,采用O/W乳化溶剂蒸发法制备了硝苯地平的微球载体。分析了聚合物类型、浓度、药物的初始含量等对微球的粒度分布、结构形态、包载效率等性质的影响趋势,评价了不同结构微球的释放性能。另外,基于相容性的观点,从药物与聚合物的分子间相互作用、药物和聚合物的存在形态以及宏观的释放速率曲线等多个不同层次上综合研究了药物的释放动力学,分析和探讨了影响微球性能的内在的作用机理。
对描述药物释放的几种常用的理论模型,探讨了其适用性和局限性。根据硝苯地平这类难溶性药物的特点,分析了其在聚合物微球中释放的传质机理。分别针对微球内液相与固相中药物动态质量平衡,综合考虑了药物的扩散、有限溶解速率的限制、固态药物溶解的移动边界以及微球的粒度分布等因素,提出了一种新的溶解扩散模型,并通过线法对偏微分方程组的模型进行了数值求解。根据模型考察了不同的结构性质和模型参数对释放速率曲线的影响,同时计算了不同情况下微球内固、液相中药物浓度的变化规律,描述了影响药物释放速率的传质过程。与基于Fick第二定律的扩散模型和Higuchi模型的对比说明,本文所提出的模型具有很好的通用性,能够完整地描述不同溶解性质的药物的整个释放过程,前两种模型可看作溶解扩散模型在假定无限溶解速率或溶解度下的特例。最后,使用溶解扩散模型对体外实验的释放数据进行分析,研究了微球的结构性质对模型参数的影响趋势,微球的微观结构性质的影响隐含在模型传质系数的变化中。通过对不同结构微球的释放速率和模型参数的比较,并结合微球的性质表征和相容性分析,揭示了微球结构和释放性能关系的基本规律。为探索如何改善和控制药物的释放性能提供了基础。
Biodegradable polymeric microspheres, as a new type of controlled drug delivery system, have advantages of controlled release of active drug molecules over prolonged time to target sites, easiness of administration, favorable biocompatibility, and good degradability. In consideration of hydrophobic nature, some drug composites are encapsulated in polymeric microspheres at highly dispersed amorphous state to improve solubility and bioavailability. Structure-property relationships of the microsphere system are investigated in this work from both of microscopic mechanism and macroscopic mass transfer phenomena with experiments and modeling. Nifedipine, a calcium antagonist for treatment of hypertension, was studied as a model hydrophobic ingredient for drug entrapment and release. An oil-in-water solvent evaporation method was used to prepare polymer microspheres with controlled size. Fundamental mechanism of drug release was investigated from three aspects: interaction between molecules of drugs and polymers, morphology and dispersion of drugs, and in vitro release experimental findings. Taking consideration of effects of diffusion, finite dissolution rate, and moving front of dissolution, a new model is developed for quantitative description of the release patterns. Finally, integrated with pharmacokinetics, the release model was extended to in vivo process to evaluate drug concentration levels in the plasma.Nifedipine loaded microspheres were prepared using biodegradable polymers poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA). Microspheres size, entrapment efficiency, morphology, and release profiles were characterized by DLS, SEM, DSC, FTIR and in vitro release tests. Particle size was controlled with interfacial tension and viscosity of polymer and surfactant (PVA) concentrations. Diameters of microspheres vary from 1μm to 10μm. A broad range of drug release profiles were achieved. Due to large surface area, drug leakage is found in small particles, as a result of diffusion to continuous phase during fabrication. Compromise has to be made between high entrapment efficiency and small size. For all the microspheres, nifedipine was found to be totally amorphous in the polymer, which suggested that the drug is well dispersed in the matrix.
引文
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