Prospective insulin-based ophthalmic delivery systems for the treatment of dry eye syndrome and corneal injuries
Prospective insulin-based ophthalmic delivery systems for the treatment of dry eye syndrome and corneal injuries
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DOI：
10.1016/j.ejpb.2019.04.014
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发表时间：
2019-07-01
影响因子：
4.9
通讯作者：
Lopez, Renata F., V
中科院分区：
文献类型：
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作者：
Cruz-Cazarim, Estael L. C.;Cazarim, Maurilio S.;Lopez, Renata F., V
胰岛素(INS)受体在眼表(OS)和泪腺(LG)的存在，以及干眼综合征(DES)和糖尿病患者角膜病变的高患病率表明，INS与OS动态平衡和伤口愈合有关。本研究旨在开发INS局部给药给药系统，以提高INS的局部生物利用度，并评价给药系统对糖尿病大鼠(DM)DES的影响(n=05/组)。制备了含或不含INS的壳聚糖微球(MP)、壳聚糖/泊洛沙姆凝胶(GELMP)和凝胶(GELMP)。给糖尿病大鼠(DM)滴眼15d，测定泪液体积、角膜细胞形态和角膜厚度，并与INS水分散体(DISPINS)进行比较。所有给药系统的pH值约为6，渗透压适合局部应用，且Zeta电位为正。无论加入或不加入INS，MPS的粒径均接近4微米，球形，INS包封率为77+/-6%。DISP-INS和GELMP-INS制剂产生的泪液分泌量明显高于不含INS的制剂，与健康动物相似。角膜表面印迹细胞学检查显示，使用INS给药系统和不使用DISP-INS的处理几乎使细胞形态正常化。与凝胶-INS和MP-INS治疗组相比，GELMP-INS治疗组LG和眼球中的INS增加了2.5%，而DISP-INS治疗在治疗结束后没有在眼睛中留下药物的痕迹。含有INS的凝胶和GELMP也能使角膜上皮厚度正常化。总之，GELMP-INS使泪液容量、角膜厚度、受保护的角膜细胞形态正常化，并提高了INS的眼生物利用度，使其成为DES和角膜病变的一种有前景的治疗策略。
The presence of insulin (INS) receptors on the ocular surface (OS) and lacrimal gland (LG), and the high prevalence of dry eye syndrome (DES) and corneal lesions in diabetic patients suggest that INS is relevant for OS homeostasis and wound healing. The study aims at developing delivery systems for the topical administration of INS to the OS in order to improve INS local bioavailability and evaluate the influence of the delivery systems on DES in diabetic rats (DM) (n = 05/group). Chitosan microparticles (MP), chitosan/poloxamer gel (GEL) and MP-loaded GEL (GELMP), with or without INS were developed. Formulations were instilled into the eyes of diabetic rats (DM) for 15 days and the tear fluid volume, corneal cells morphology and cornea thickness were assessed and compared with an aqueous dispersion of INS (DISP-INS). All delivery systems had pH of about 6, osmolality suitable for topical application and positive zeta potential. The MPs with or without INS had sizes close to 4 mu m, spherical morphology and INS encapsulation efficiency of 77 +/- 6%. DISP-INS and GELMP-INS formulations produced tear secretion amounts significantly higher than those receiving formulations containing no INS and similar to healthy animals. Cornea surface impression cytology showed that treatment with INS-delivery systems and not DISP-INS almost normalized cells morphology. Treatment with GELMP-INS increased INS by 2.5 in the LG and eyeball as compared to the groups treated with GEL-INS and MP-INS, while treatment with DISP-INS left no traces of drug in the eye after treatment termination. GEL and GELMP containing INS were also able to normalize the thickness of the corneal epithelia. In conclusion, GELMP-INS normalized tear fluid volume, corneal thickness, protected corneal cells morphology and increased ocular bioavailability of INS, making it a promising treatment strategy for DES and corneal lesions.