摘要
本文分别以聚乳酸(PLA)和胶原(Col)改性聚乳酸(PLA-co-Col)为基体材料,采用溶剂浸提/冷冻干燥技术,结合相分离法,制备了PLA及PLA-co-Col的储存式载体,并通过正交设计实验,对主要工艺参数进行了筛选和优化,探讨了载体制备的原理与工艺,采用红外光谱仪、XRD衍射仪、MicroTester材料试验机、重量法及扫描电子显微镜和三维视频显微镜对材料进行了表征。IR和XRD进一步证实了PLA与Col间发生了化学反应而存在着化学相互作用,形成了PLA-co-Col材料;重量法测定的孔率在68%～88%之间,相对密度分布在0.58～1.07 g/cm~3之间,对孔率影响最大的因素是体积/质量比,冷冻成型温度与时间对孔率影响不大;力学弯曲实验显示材料的弹性模量可以达到139.77 MPa,可以满足作为载体的力学性能要求。SEM结果显示载体横断面呈现出一种规则的径向延伸、由内壁和外壁同时向中间层发展的多孔结构,孔结构连通,平均孔径在40μm以下可控,孔径大小受体积/质量比和冷冻成型温度影响。
正交实验结果表明,冷冻成型时间是三个影响因素中的最次要因素,结合释药曲线结果,得出最佳工艺:体积/质量比(V_(1,4-dioxan)/m_(PLA))为10%,冷冻成型温度为-70℃以及冷冻成型时间为1h。
在体外模拟生理环境,测试材料的降解失重率;以HCl-LVFX为模型药物,36.5℃恒温水浴,PBS液为释药环境的条件下,用紫外-可见光光度计法,研究了体积/质量比、冷冻成型温度及时间、载药量、物理添加β-TCP颗粒和PLA-co-Col改性对载体的释药性能的影响;并根据载体自身特点,结合已有数学与理论模型,建立的模型形式简单、实用,能够描述生物降解高分子载体中药物释放各阶段,揭示了储存式PLA-co-Col/β-TCP药物载体结构和释放性能关系的一些基本规律。
In this paper,using polylactic acid(PLA) and collagen(Col) modified polylactic acid(PLA-co-Col) as matrix material,the principle and process of drug-carrier preparation were studied.Using solvent extraction/freeze-drying technology, combined with phase separation,through orthogonal experimental design to screen and optimize the main technical parameters,principle and fabrication process were discussed,and its performances were characterized by infrared spectroscopy(IR), X-ray diffraction instrument(XRD),MicroTester material testing machine, gravimetric method,scanning electron microscope(SEM) and three-dimensional video microscope.IR and XRD further confirmed a chemical reaction had taken place between PLA and Col,and the existence of chemical bonds,and obtained the PLA-co-Col composite materials.Porosity tested by gravimetric method was between 68%and 88%,volume/mass ratio(V_(1.4-dioxane)/m_(PLA)) played a leading role on porosity and frozen molding temperature and time had little effect on porosity. Mechanical bending experiments showed that the elastic modulus of material can reach to 139.77 MPa,enough to meet the requirements of the mechanical as a drug carrier material.SEM results showed that the cross-sectional displayed a kind of ruled, stretching the inner wall and outer wall to the middle layer,radial extension porous structure.The pore was a kind of connected structure,average pore size below 40μm.
Orthogonal experiment result showed frozen forming time was the most minor factors in the three factors.Combining the results of drug release curve,The optimum process choice was 10%(volume/mass ratio),-70℃(frozen molding temperature)and 1 hour(frozen molding time).
Weight loss rate of carriers was tested in vitro simulation biological environment. Using HCl-LVFX as a model drug,UV-visible spectrophotometric method,PBS solution as the release environment,studied the drug-carrier release performance with different volume/mass ratio,frozen molding temperature and time and drug loading dosage.Effects of physical addition and chemical modified were also discussed.In accordance with its own characteristics,combined with mathematical and theoretical models,the model has established a simple,practical drug release model and can described the features of various stages in this biodegradable polymer drug delivery carrier.Revealed the basic laws of the relationship between the structure and the release performance.
引文
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