Peira Elena, Chindamo Giulia, Chirio Daniela, Sapino Simona, Oliaro-Bosso Simonetta, Rebba Erica, Ivanchenko Pavlo, Gallarate Marina
Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy.
Department of Chemistry and Interdepartmental Nanostructured Interfaces and Surfaces (NIS) Centre, University of Turin, 10125 Turin, Italy.
Pharmaceutics. 2021 Feb 13;13(2):258. doi: 10.3390/pharmaceutics13020258.
Bevacizumab (BVZ), a recombinant humanized monoclonal antibody, has recently been proposed as a topical application in the treatment of anterior segment neovascularization; however, as there are some disadvantages in the administration of common eye-drops, ophthalmic topical drug delivery systems are under study to improve the precorneal residence time, reducing the frequency of administration. In this work, oil-in-water and water-in-oil BVZ-loaded microemulsions are developed, able to increase their viscosity, either by the formation of a liquid-crystalline structure upon aqueous dilution, thanks to the presence of Epikuron 200 and polysorbate 80, or by body-temperature-induced jellification for the presence of Pluronic F127 aqueous solution as an external phase. In oil-in-water microemulsion, hydrophobic ion pairs of BVZ were also prepared, and their incorporation was determined by release studies. Microemulsions were characterized for rheological behavior, corneal opacity, in vitro corneal permeation, and adhesion properties. The studied microemulsions were able to incorporate BVZ (from 1.25 to 1.6 mg/mL), which maintained dose-dependent activity on retinal pigment epithelial ARPE-19 cell lines. BVZ loaded in microemulsions permeated the excised cornea easier (0.76-1.56% BVZ diffused, 4-20% BVZ accumulated) than BVZ commercial solution (0.4% BVZ diffused, 5% accumulated) and only a mild irritation effect on the excised cornea was observed. The good adhesion properties as well the increased viscosity after application, under conditions that mimic the corneal environment (from 1 × 10 to more than 100 × 10 mPa·s), might prolong precorneal residence time, proving these systems could be excellent topical BVZ release systems.
贝伐单抗（BVZ）是一种重组人源化单克隆抗体，最近有人提议将其局部应用于眼前段新生血管的治疗；然而，由于普通眼药水给药存在一些缺点，目前正在研究眼科局部给药系统，以延长药物在角膜前的停留时间，减少给药频率。在这项研究中，开发了水包油型和油包水型载有BVZ的微乳剂，它们能够通过以下两种方式增加其粘度：一是由于存在Epikuron 200和聚山梨酯80，在用水稀释时形成液晶结构；二是由于外部相为Pluronic F127水溶液，在体温诱导下发生胶凝。在水包油型微乳剂中，还制备了BVZ的疏水离子对，并通过释放研究确定了它们的掺入情况。对微乳剂的流变行为、角膜混浊度、体外角膜渗透和粘附性能进行了表征。所研究的微乳剂能够包载BVZ（浓度为1.25至1.6 mg/mL），并且在视网膜色素上皮ARPE - 19细胞系上保持剂量依赖性活性。与BVZ商业溶液（0.4%的BVZ扩散，5%的BVZ积累）相比，载于微乳剂中的BVZ更容易透过离体角膜（0.76 - 1.56%的BVZ扩散，4 - 20%的BVZ积累），并且仅观察到对离体角膜有轻微的刺激作用。在模拟角膜环境的条件下（从1×10到超过100×10 mPa·s），良好的粘附性能以及应用后增加的粘度可能会延长角膜前的停留时间，证明这些系统可能是优秀的局部BVZ释放系统。
