A Fundamental Study On The Preparation Of Drug-loaded Polymer Microparticles By The Supercritical Fluid Technology

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.