【作者】 陈畅；

【导师】 李志义；

【作者基本信息】 大连理工大学 ， 化工过程机械， 2012， 博士

【摘要】 药物-聚合物微粒可供多途径给药,是极有发展前景的新型给药系统,可以通过控制载药微粒的粒径,达到靶向给药的目的。微粒制备的传统方法和新型方法(超临界流体技术)都可简称为一步法。本文将超临界反溶剂(SAS)过程和超临界渗透(SSI)过程相结合,建立了两步法制备载药微粒的方法,它克服了传统方法制备载药微粒有机溶剂残留和粒径较大,粒径分布较宽等缺点,弥补了超临界快速膨胀(RESS)过程和SAS及其衍生技术在原料选择上的局限性和产量较低的不足,既可用于脂溶性药物复合微粒的制备,也可用于水溶性药物复合微粒的制备。所制备的产品形态取决于聚合物基体的制备过程(SAS过程)与后续的载药过程(SSI过程)无关,两步法将微粒粒径控制与载药控制分开,从而更好的控制载药微粒的形貌和载药量。本论文针对两步法的工艺基础进行了研究：应用SAS过程制备聚乳酸(PLLA)微粒,为两步法提供载药基体；通过研究水溶性药物(5-Fu)载药微粒的SSI过程制备工艺,给出了SSI过程中各因素对产物的影响规律；通过SSI过程相平衡实验和理论分析为SSI过程提供基础工艺数据。本论文的主要研究工作及结论如下：应用SAS过程,成功的制备了PLLA基体微粒。应用正交实验和单因素实验分别研究了温度、压力、溶液浓度、溶液流速和夹带剂含量对微粒形态、粒径及粒径分布的影响规律,确定了最佳工艺条件。通过调节过程参数,达到控制微粒粒径的目的,为SSI过程提供了载药基体。建立了SSI过程制备载药微粒的实验装置,以5-Fu作为药物模型,以制得的PLLA微粒作为药物载体,进行载药微粒的制备。研究了卸压速率、压力、温度、夹带剂含量对载药微粒的形貌、载药量以及药物释放性能的影响。结果表明：应用SSI过程,成功的制备了溶解性较差的药物5-Fu和PLLA的复合微粒,通过调节过程参数,达到控制微粒载药量的目的。通过夹带剂的添加,有效地改善了微粒制备和载药过程的效果。与无夹带剂的SAS过程相比,加入夹带剂后,微粒的粒径明显减小,粒径分布明显变窄；与无夹带剂的SSI过程相比,加入夹带剂后,提高了药物在SCF中的溶解度和在聚合物中的分配系数,有效地提高了微粒的载药量。通过对SSI过程相平衡特性研究,分析了“药物-超临界流体”和“药物-超临界流体-聚合物”的相平衡问题。分别对药物在SCF中的溶解度和药物在PLLA中的分配系数进行了测定。采用改进的静态法取样方式对药物在SCF中的溶解度进行测定,分析和总结了压力、温度、夹带剂等因素对溶解度的影响趋势和规律；利用Chrastil模型和Mendez-Santiago and Teja模型对溶解度进行关联。结果表明,改进静态法较适用于对溶解度较低的固体物质在SCF中的溶解度的测定。借助于所建立的关联计算式和测试方法,可对SSI过程的相平衡特性进行定量描述。应用SAS过程和SSI过程相结合两步法工艺,可成功制备载药微粒。通过分别控制两个独立过程的过程参数,可达到既能控制微粒形貌又能控制载药量的目的。更多还原

【Abstract】 The drug-loaded polymer microparticle can be used for multiple adminstration and has a great potential in the pharmaceutical field. The targeted drug-delivery function can be realized by controlling the particle size of microparticles. The conventional preparation methods and new preparation methods (the supercritical fluid techniques) of the drug-loaded microparticles can be called one-step method.A two-step method combining supercritical antisolvent (SAS) process and supercritical solvent impregnation (SSI) process has been proposed. This method can overcome the disadvantages of the conventional methods such as residual organic solvents, large particle size and wide particle size distribution, and it also makes up the deficiencies in the limitation to the raw materials selection and the lower yield of the final product of RESS process, SAS process and its derivative processes.It is suitable for the preparation of lipid-soluble as well as water-soluble drug-loaded microparticles.The morphology of drug-loaded microparticles is determined by SAS process and has nothing to do with SSI process.Owing to the particle size control having no relation to the drug loading control by two-step method, the morphology and drug loading can be controlled better separately.This dissertation focuses on the study of the technological foundation of the two-step method. The PLLA polymer-based microparticle of the two-step method has been prepared by SAS process. Then, the water-soluble drug loaded microparticle has been prepared by SSI process and the effects of the factors have been studied. The experiment and theory of phase equilibrium of SSI process have been studied to obtain the basic process data. The main research work and achievements are as follows:PLLA microparticles have been successfully prepared by SAS process.The effects of the molar percentage of cosolvent, temperature, pressure, flow rate, and concentration of the solution on the morphology, particle size and particle size distribution have been studied by the single-factor experiment, and the optimum process conditions are obtained by the orthogonal experiment. The particle size of microparticles can be controlled by the adjustment of process parameters.The experiment apparatus of SSI process are established.With the5-Fu as model drug and the PLLA microparticles as matrix,5-Fu-PLLA drug-loaded microparticle has been prepared.The effects of process parameters (depressurizing rate, pressure, temperature, and concentration of the cosolvent) on the morphology, drug loading and release property of microparticles have been studied. The results show that the poorly water-soluble drug of5-Fu loaded PLLA microparticles can be successfully prepared by SSI process.The drug loading can be controlled by the adjustment of process parameters.The microparticle preparation process and drug-loaded process can be improved effectively with the cosolvent added.The microparticles prepared by SAS process with cosolvent have smaller particle size and narrower particle size distribution than those prepared without cosolvent. In SSI process, the reason of drug loading increase may be that the addition of cosolvent can increase the solubility of drug in SCF and the partition coefficient of drug in PLLA.The characteristics of phase equilibrium of drug/SCF and drug/SCF/polymer by SSI process have been analyzed.The solubility of drug in SCF (measured by static method with modified sampling method) and the partition coefficient of drug in PLLA are measured respectively. The effects of temperature, pressure and concentration of the cosolvent on the characteristics have been analyzed. The experimental data has been correlated by Chrastil model and Mendez-Santiago and Teja model.The results show that the modified static method can successfully measure the solubility of solid with low solubility in SCF.The phase equilibrium characteristics can be quantitatively described by the experimental techniques developed in this study and the correlation models.The drug-loaded microparticles can be successfully prepared by the two-step method combining SAS process and SSI process.The two-step method can adjust and control the morphology and drug loading of microparticles by the adjustment of process parameters in two different processes respectively.更多还原