Ramazani F, Hiemstra C, Steendam R, Kazazi-Hyseni F, Van Nostrum C F, Storm G, Kiessling F, Lammers T, Hennink W E, Kok R J
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands; Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen, Germany.
InnoCore Pharmaceuticals, Groningen, The Netherlands.
Eur J Pharm Biopharm. 2015 Sep;95(Pt B):368-77. doi: 10.1016/j.ejpb.2015.02.011. Epub 2015 Feb 19.
Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks several angiogenesis related pathways. The aim of this study was to develop sunitinib-loaded polymeric microspheres that can be used as intravitreal formulation for the treatment of ocular diseases. A series of novel multi-block copolymers composed of amorphous blocks of poly-(D,L-lactide) (PDLLA) and polyethylene glycol (PEG) and of semi-crystalline poly-(L-lactide) (PLLA) blocks were synthesized. Sunitinib-loaded microspheres were prepared by a single emulsion method using dichloromethane as volatile solvent and DMSO as co-solvent. SEM images showed that the prepared microspheres (∼ 30 μm) were spherical with a non-porous surface. Sunitinib-loaded microspheres were studied for their degradation and in-vitro release behavior. It was found that increasing the percentage of amorphous soft blocks from 10% to 30% accelerated the degradation of the multi-block copolymers. Sunitinib microspheres released their cargo for a period of at least 210 days by a combination of diffusion and polymer erosion. The initial burst (release in 24h) and release rate could be tailored by controlling the PEG-content of the multi-block copolymers. Sunitinib-loaded microspheres suppressed angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These microspheres therefore hold promise for long-term suppression of ocular neovascularization.
舒尼替尼是一种多靶点受体酪氨酸激酶（RTK）抑制剂，可阻断多种与血管生成相关的途径。本研究的目的是开发负载舒尼替尼的聚合物微球，用作玻璃体内制剂来治疗眼部疾病。合成了一系列由聚（D，L-丙交酯）（PDLLA）和聚乙二醇（PEG）的无定形嵌段以及半结晶聚（L-丙交酯）（PLLA）嵌段组成的新型多嵌段共聚物。以二氯甲烷为挥发性溶剂、二甲基亚砜为共溶剂，通过单乳液法制备了负载舒尼替尼的微球。扫描电子显微镜图像显示，制备的微球（约30μm）呈球形，表面无孔。对负载舒尼替尼的微球的降解和体外释放行为进行了研究。发现将无定形软嵌段的百分比从10%增加到30%可加速多嵌段共聚物的降解。舒尼替尼微球通过扩散和聚合物侵蚀的组合方式释放其药物至少210天。通过控制多嵌段共聚物的PEG含量，可以调整初始突释（24小时内释放）和释放速率。在鸡胚绒毛尿囊膜（CAM）试验中，负载舒尼替尼的微球可抑制血管生成。因此，这些微球有望长期抑制眼部新生血管形成。
