Prediction of dexamethasone release from PLGA microspheres prepared with polymer blends using a design of experiment approach.
Prediction of dexamethasone release from PLGA microspheres prepared with polymer blends using a design of experiment approach.
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DOI：
10.1016/j.ijpharm.2015.08.089
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发表时间：
2015-11-10
影响因子：
5.8
通讯作者：
Burgess DJ
中科院分区：
文献类型：
--
作者：
Gu B;Burgess DJ
聚（乳酸-共-乙醇酸）（PLGA）微球的疏水性药物释放通常表现出三阶段特征，即突释阶段，随后是迟滞阶段和二次释放阶段。高突释可能与不良反应相关，并且在长滞后期期间无法确保制剂的功效。因此，长效微球产品的开发需要优化所有药物释放阶段。本研究的目的是研究低分子量和高分子量聚合物的共混物是否可用于减少突释并消除/最小化迟滞期。使用单一乳液溶剂蒸发法使用两种PLGA聚合物（PLGA 5050（25 KDa）和PLGA 9010（113 KDa））的共混物制备微球。应用中心复合设计方法研究制剂组成对这些微球释放地塞米松的影响。利用从该实验研究设计获得的数学模型来产生具有最大化微球药物负载和减少突释的设计空间。具体地，当使用80%PLGA 9010和90 mg地塞米松的组合物时，可以实现接近15%的载药量和小于10%的突释。为了更好地描述滞后期，基于地塞米松从PLGA微球/PVA水凝胶复合涂层的释放生成热图。使用热图，选择具有最小滞后期的优化制剂。微球的粒径/粒径分布，热性能和形态进行了表征。粒径被证明与聚合物浓度和两种聚合物的比例有关，但与地塞米松浓度无关。
Hydrophobic drug release from poly (lactic-co-glycolic acid) (PLGA) microspheres typically exhibits a tri-phasic profile with a burst release phase followed by a lag phase and a secondary release phase. High burst release can be associated with adverse effects and the efficacy of the formulation cannot be ensured during a long lag phase. Accordingly, the development of a long-acting microsphere product requires optimization of all drug release phases. The purpose of the current study was to investigate whether a blend of low and high molecular weight polymers can be used to reduce the burst release and eliminate/minimize the lag phase. A single emulsion solvent evaporation method was used to prepare microspheres using blends of two PLGA polymers (PLGA5050 (25KDa) and PLGA9010 (113KDa)). A central composite design approach was applied to investigate the effect of formulation composition on dexamethasone release from these microspheres. Mathematical models obtained from this design of experiments study were utilized to generate a design space with maximized microsphere drug loading and reduced burst release. Specifically, a drug loading close to 15% can be achieved and a burst release less than 10% when a composition of 80% PLGA9010 and 90 mg of dexamethasone is used. In order to better describe the lag phase, a heat map was generated based on dexamethasone release from the PLGA microsphere/PVA hydrogel composite coatings. Using the heat map an optimized formulation with minimum lag phase was selected. The microspheres were also characterized for particle size/size distribution, thermal properties and morphology. The particle size was demonstrated to be related to the polymer concentration and the ratio of the two polymers but not to the dexamethasone concentration.