Effect of fabrication parameters on morphology and drug loading of polymer particles for rosiglitazone delivery.
Effect of fabrication parameters on morphology and drug loading of polymer particles for rosiglitazone delivery.
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DOI：
10.1016/j.jddst.2021.102672
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发表时间：
2021-07
影响因子：
5
通讯作者：
Gower RM
中科院分区：
文献类型：
--
作者：
Spetz MR;Isely C;Gower RM
在过去的几十年里，药物封装的聚合物颗粒已经被研究作为局部递送的长效疗法。生产此类颗粒最常用的方法是水浸油溶剂萃取技术。利用该技术，我们制备了包封小分子降糖药罗格列酮的聚丙交酯-羟基乙酸酯（PLG）微颗粒。我们研究了调制制备参数，包括有机溶剂的选择、聚合物的浓度、均质和离心速度对颗粒形态和载药量的影响。此外，我们还研究了空气-水界面面积与萃取液体积的比值，这是一个以前未研究过的制备参数，以及它在使用二氯甲烷作为有机溶剂时对罗格列酮负载的影响。在测试条件下，通过增加该比例，药物载量可以增加5倍，这可以通过简单地选择更大的提取容器来实现。通过将有机溶剂从二氯甲烷改为乙酸乙酯，我们生产的颗粒罗格列酮的负载提高了60%。有趣的是，用乙酸乙酯制成的颗粒在光镜下呈现相暗，表明存在内部孔隙。通过增加乳化液中有机相的比例，消除了乳化液的异常形态，但不改变载药量。作为颗粒开发的最后一步，我们通过证明装载罗格列酮的颗粒增强脂肪细胞脂质储存和脂联素分泌，确定了罗格列酮在整个包封过程及其随后从颗粒中释放的过程中保持稳定。综上所述，在该系统中，萃取液和有机溶剂的气-水界面面积与体积比都是最大限度地提高罗格列酮在PLG微粒中的负载的关键参数。这项关于制造参数如何影响药物负载和颗粒形态的研究可能有助于其他研究将小分子封装在聚合物颗粒中以实现控释应用。
For the past several decades, drug-encapsulated polymer particles have been investigated as locally-delivered, long-acting therapies. The most common method of producing such particles is the oil in water solvent extraction technique. Using this technique, we produced poly(lactide-co-glycolide) (PLG) microparticles encapsulating rosiglitazone, a small molecule anti-diabetic drug. We investigated the impact of modulating fabrication parameters, including choice of organic solvent, concentration of polymer, and speed of homogenization and centrifugation on particle morphology and drug loading. Additionally, we studied the ratio of air-water-interface area to the extraction bath volume, a previously unstudied fabrication parameter, and its impact on rosiglitazone loading when using dichloromethane as the organic solvent. Under the conditions tested, drug loading can be increased 5-fold by increasing this ratio, which may be achieved by simply selecting a larger extraction vessel. By changing the organic solvent from dichloromethane to ethyl acetate, we produced particles with 60% higher rosiglitazone loading. Interestingly, the particles made with ethyl acetate appeared phase dark under light microscopy suggesting the presence of internal pores. By increasing the proportion of organic phase in the emulsion we eliminated the aberrant morphology but did not alter drug loading. As a final step in the development of the particles, we established that rosiglitazone remained stable throughout the encapsulation process and its subsequent release from particles by demonstrating that rosiglitazone loaded particles enhanced adipocyte lipid storage and adiponectin secretion. Taken together, for this system, air-water-interface area to volume ratio of the extraction bath and organic solvent both arose as key parameters in maximizing rosiglitazone loading in PLG microparticles. This study of how fabrication parameters impact drug loading and particle morphology may be useful in other investigations to encapsulate small molecules in polymer particles for controlled release applications.
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