粒径对吉非替尼载药PLGA微球载药量和释放动力学的影响,Molecular Pharmaceutics

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粒径对吉非替尼载药PLGA微球载药量和释放动力学的影响
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2016-12-27 00:00:00 , DOI: 10.1021/acs.molpharmaceut.6b00896
Weiluan Chen ₁ , Amelia Palazzo ₁ , Wim E. Hennink ₁ , Robbert J. Kok ₁

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聚合物微球已作为药物洗脱库获得了广泛的应用。通常，通过水包油乳化来制备载有药物的聚合物微球，其产生具有宽尺寸分布的产品。本研究的目的是研究载药微球的不同大小级分的性质，以便确定粒径是否决定着载药效率和释放曲线。使用水包油溶剂蒸发法制备载有吉非替尼的PLGA基微球，并进行湿筛，以分别获得5±1、32±4、70±3和130±7μm的明确定义的粒径分数。未分级的微球的平均载药量为6.3±0.4％w / w，而筛分级分的载药量范围从2.4±0.3到7.6±0.9％w / w（从最小到最大）。Ť_克PLGA的指示不存在药物和聚合物的直接分子相互作用由于嵌入在PLGA小药物粒子的形成。体外用微球包埋在葡聚糖水凝胶中研究了药物释放，以避免它们在温育条件下聚集。当颗粒尚未降解时，小于50μm的微球显示出基于扩散的快速释放，并在2天内完成。然而，较大的微球显示出S型释放模式，这种模式持续了三个月，其中扩散（早期）和颗粒侵蚀（后期）决定了药物的释放。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得更快，这与在微粒核心内酸化时自催化PLGA降解相符。总之，我们表明载药微球的不同大小分数显示出截然不同的载药和释放动力学。

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Effect of Particle Size on Drug Loading and Release Kinetics of Gefitinib-Loaded PLGA Microspheres

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 μm, 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 μm 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.

更新日期：2016-12-27

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