Structure-Property Relationship And Mesoscale Simulation Of Drug-loaded Solid Lipid Microparticles

With proper drug delivery system (DDS), sustained and controlled drug release could be realized, which improves drug efficiency and reduces its side effect. Solid lipid microparticles (SLM) are micro-size DDS made from lipids with high melting point as matrixes. They are characteristic of good biocompatibility and controlling drug release effectively. SLM are complex multi-phase system. The operation conditions and their composition impose effect on their properties by means of altering their microstructures. In this thesis, the relationship between SLM microstructures and their properties is investigated, and influences of composition and operation conditions on their microstructures are analyzed. SLM microstrucure and properties could be optimized by controlling operation conditions and composition. During the process, Experimental characterization, theoretical analysis, and mesoscale simulation are integratively used to study the microstructures-property relationship of SLM.A nonsteroidal anti-inflammatory drug, ibuprofen, is chosen as the model drug. Ibuprofen-loaded SLM are prepared with high shear homogenization technique. Effects of operation conditions on SLM mean diameter, volume distribution, drug entrapment efficiency, as well as SLM microstructures are investigated, and optimized operation conditions are obtained. The entrapment efficiency of ibuprofen in SLM varies with different carrier materials. The reasons lie in two aspects, the compatibility between drug and carrier materials, and the crystal modification of SLM. The stability of SLM with different stabilizers is investigated and the stabilization mechanism is also analyzed. The optimized formulation of ibuprofen-loaded SLM is obtained by further investigating the effect of stabilizer content and initial drug content on the performance of SLM. The release performance of ibuprofen-loaded SLM is investigated in simulated gastrointestinal medium without enzymes. The influences of carrier materials, stabilizers, and particle sizes on SLM release performance are also studied.The microstructures of SLM are further investigated with Dissipative Particle Dynamics (DPD) simulation, and are related with their properties. Drug distributions in SLM matrixes of different carrier materials are simulated and their effect on SLM release performance are studied. Stabilizer distribution on SLM surface is also simulated, and the corresponding SLM stability is investigated. SLM properties can be predicted with DPD simulation results. DPD simulations show clear microscopic pictures which are difficult to be displayed by experiments, and is proved to be very useful in investigating the microstructures of micro-size DDS.Based on the experimental preparation, DPD simulations as well as the theoretical analysis, heuristics for SLM formulation design and factors that should be considered in carrier material and stabilizer selection are proposed. Afterwards, clozapine is chosen as another model drug. Clozapine-loaded SLM are designed and produced according to the proposed heuristics. Clozapine entrapment efficiency in SLM of different carrier materials and SLM stability with different stabilizers are qualitatively predicted from the simulated results and theoretic analysis. The corresponding experiments are carried out and the results agree well with those of the prediction. SLM are developed with the proposed heuristics, which can significantly reduce the trial-and-error experiments, and speed up the development of DDS.In this thesis, theoretical analysis, experimental preparation & characterization and mesoscale simulation are integratively used to investigate the structure-property relationship of SLM as a case study. A systematic approach for the rational design of structured products is proposed and practised.