Effect of Particle Size on Drug Loading and Release Kinetics of Gefitinib-Loaded PLGA Microspheres
Effect of Particle Size on Drug Loading and Release Kinetics of Gefitinib-Loaded PLGA Microspheres
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DOI：
10.1021/acs.molpharmaceut.6b00896
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发表时间：
2017-02-01
影响因子：
4.9
通讯作者：
Kok, Robbert J.
中科院分区：
文献类型：
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作者：
Chen, Weiluan;Palazzo, Amelia;Kok, Robbert J.
聚合物微球作为药物洗脱剂得到了广泛的应用。通常，载药聚合物微球通过水包油乳化制备，其产生具有宽尺寸分布的产物。本研究的目的是研究不同粒径的载药微球的性质，以描绘粒径是否决定载药效率和释放曲线。使用水包油溶剂蒸发法制备负载吉非替尼的PLGA基微球，并进行湿筛分以分别获得5 +/-1，32 +/-4，70 +/-3和130 +/-7 μ m的明确尺寸级分。未分级微球的平均载药量为6.3 +/-0.4%w/w，而对于最小至最大微粒，筛分级分的载药量范围为2.4 +/- 0.3至7.6 +/-0.9%w/w。X射线衍射（XRD）和差示扫描量热法（DSC）分析表明，吉非替尼无定形分散在PLGA基质中，PLGA的T-g无明显变化，表明由于形成嵌入PLGA的小药物颗粒，药物和聚合物之间不存在直接的分子相互作用。在体外药物释放进行了研究与微球包埋在葡聚糖水凝胶，以避免其聚集在孵育条件。小于50 μ m的微球表现出快速的基于扩散的释放，当颗粒尚未降解时，在2天内达到完全释放。然而，较大的微球显示出S形释放模式，持续三个月，其中扩散（早期阶段）以及颗粒侵蚀（后期阶段）控制药物释放。扫描电子显微镜（SEM）和聚合物降解数据显示，较大的微球比较小的微球降解更快，这与微粒核心内酸化后的自催化PLGA降解一致。结果表明，不同粒径的载药微球具有不同的载药量和释药动力学。因此，通过分级来控制微粒尺寸是获得良好限定的和可再现的持续释放储库的重要决定因素。
Polymeric microspheres have gained widespread application as drug eluting depots. Typically, drug-loaded polymeric microspheres are prepared by oil-in-water emulsification which yields a product with a broad size distribution. The aim of the present study was to investigate the properties of different size-fractions of drug-loaded microspheres, in order to delineate whether particle size governs drug loading efficiency and release profile. Gefitinib-loaded PLGA-based microspheres were prepared using an oil-in-water solvent evaporation method and wet-sieved to obtain well-defined size fractions of 5 +/- 1, 32 +/- 4, 70 +/- 3, and 130 +/- 7 mu m, respectively. The average drug loading of unfractionated microspheres was 6.3 +/- 0.4% w/w, while drug loading of sieved fractions ranged from 2.4 +/- 0.3 to 7.6 +/- 0.9% w/w for smallest to largest microparticles. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis demonstrated that gefitinib was amorphously dispersed in the PLGA matrix, with no apparent shift in the T-g of PLGA indicating the absence of direct molecular interactions of the drug and polymer due to the formation of small drug particles embedded in PLGA. In vitro drug release was studied with microspheres embedded in dextran hydrogels to avoid their aggregation during the incubation conditions. Microspheres smaller than 50 m showed rapid diffusion-based release reaching completion within 2 days when particles have not degraded yet. Larger microspheres, however, showed a sigmoidal release pattern that continued for three months in which diffusion (early stage) as well as particle erosion (later stage) governed drug release. Scanning electron microscopy (SEM) and polymer degradation data showed that larger microspheres degraded faster than smaller ones, which is in line with autocatalytic PLGA degradation upon acidification within the core of microparticles. In conclusion, we showed that different size-fractions of drug-loaded microspheres showed quite distinct drug loading and release kinetics. Control of microparticle size by fractionation is therefore an important determinant for obtaining well-defined and reproducible sustained release depots.