固体脂质微颗粒载药体系结构与性能关系的探索和介观模拟研究
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摘要
对药物传输系统(Drug delivery system, DDS)的合理设计能够实现对药物的控释和缓释,从而提高药物的疗效、降低其毒副作用。固体脂质微颗粒(Solid Lipid Microparticles, SLM)以熔点较高的脂质材料为载体,是生物相容性好、能有效控制药物释放的一种微尺寸药物传输系统。SLM是结构复杂的多相体系,其配方组成以及制备工艺过程决定了SLM的微观结构进而影响着它的最终性能。本研究考察SLM配方组成和制备工艺条件对体系微观结构的影响,通过改变配方组成和制备工艺条件来调控SLM的微观结构,达到对SLM性能的优化设计。在研究过程中综合应用了实验表征、理论分析以及计算机模拟的手段对SLM不同层次的微、介观结构进行表征和分析。
以非甾类抗炎药物布洛芬为模型药物,采用高剪应力乳均法制备了SLM。考察了制备工艺条件对SLM平均粒径、粒度分布和药物包封率的影响趋势,以及在此过程中SLM微观结构的变化,并优化了SLM的制备工艺条件。针对布洛芬在不同载体SLM中的包封效果不同,从药物和载体的相容性以及载体晶体构型两方面分析了原因。考察了不同稳定剂对SLM的稳定效果,分析了稳定剂的稳定机理。探讨了稳定剂的用量和布洛芬初始含量对SLM平均粒径及药物包封率的影响,并得到了布洛芬SLM的优化配方。最后考察了布洛芬SLM在模拟胃肠道环境中的释放性能,并分析了载体材料和稳定剂种类以及SLM粒径对其释放性能的影响。
利用DPD介观模拟方法进一步探讨了SLM的微观结构并与其性能关联。模拟了布洛芬在不同载体SLM中的分布状况,并和SLM的缓释性能相关联。对稳定剂在SLM表面的分布状况进行了模拟,并分析其对SLM稳定性的影响。DPD介观模拟结果能够直观地展现通过实验难以观察到的现象和过程,可以根据模拟结果定性地预测SLM的性能。是研究微颗粒载药体系微观结构的有效手段。
根据实验研究、介观模拟以及理论分析的结果,提出了SLM载药体系的配方设计规则,阐述了在进行载体材料和稳定剂选择时所要考虑的因素和遵循的原则。利用提出的设计规则,以氯氮平为另一种模型药物进行SLM的配方设计和制备。根据介观模拟和理论分析,预测了不同载体对氯氮平的包载效果以及不同稳定剂对SLM的稳定效果,并进行了相关实验,实验结果较好地吻合了理论预测。利用提出的SLM载药体系的配方设计规则辅助进行SLM的设计和制备,能够减少研究过程中盲目的实验探索,加快SLM的研究和开发进程。
本文通过理论分析、实验探索和计算机介观模拟三者相结合的研究手段,运用“结构-性能”关系模型和分析方法,以固体脂质微颗粒载药体系为研究案例,尝试和开辟了对复杂配方结构化产品进行优化设计的系统化方法。
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.
以非甾类抗炎药物布洛芬为模型药物,采用高剪应力乳均法制备了SLM。考察了制备工艺条件对SLM平均粒径、粒度分布和药物包封率的影响趋势,以及在此过程中SLM微观结构的变化,并优化了SLM的制备工艺条件。针对布洛芬在不同载体SLM中的包封效果不同,从药物和载体的相容性以及载体晶体构型两方面分析了原因。考察了不同稳定剂对SLM的稳定效果,分析了稳定剂的稳定机理。探讨了稳定剂的用量和布洛芬初始含量对SLM平均粒径及药物包封率的影响,并得到了布洛芬SLM的优化配方。最后考察了布洛芬SLM在模拟胃肠道环境中的释放性能,并分析了载体材料和稳定剂种类以及SLM粒径对其释放性能的影响。
利用DPD介观模拟方法进一步探讨了SLM的微观结构并与其性能关联。模拟了布洛芬在不同载体SLM中的分布状况,并和SLM的缓释性能相关联。对稳定剂在SLM表面的分布状况进行了模拟,并分析其对SLM稳定性的影响。DPD介观模拟结果能够直观地展现通过实验难以观察到的现象和过程,可以根据模拟结果定性地预测SLM的性能。是研究微颗粒载药体系微观结构的有效手段。
根据实验研究、介观模拟以及理论分析的结果,提出了SLM载药体系的配方设计规则,阐述了在进行载体材料和稳定剂选择时所要考虑的因素和遵循的原则。利用提出的设计规则,以氯氮平为另一种模型药物进行SLM的配方设计和制备。根据介观模拟和理论分析,预测了不同载体对氯氮平的包载效果以及不同稳定剂对SLM的稳定效果,并进行了相关实验,实验结果较好地吻合了理论预测。利用提出的SLM载药体系的配方设计规则辅助进行SLM的设计和制备,能够减少研究过程中盲目的实验探索,加快SLM的研究和开发进程。
本文通过理论分析、实验探索和计算机介观模拟三者相结合的研究手段,运用“结构-性能”关系模型和分析方法,以固体脂质微颗粒载药体系为研究案例,尝试和开辟了对复杂配方结构化产品进行优化设计的系统化方法。
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.
引文
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