基于粘膜粘附聚合物的眼用微球提高更昔洛韦的眼内生物利用度：在Wistar大鼠中的研发与模拟过程

Improved intraocular bioavailability of ganciclovir by mucoadhesive polymer based ocular microspheres: development and simulation process in Wistar rats.

作者信息

Kapanigowda Usha Ganganahalli, Nagaraja Sree Harsha, Ramaiah Balakeshwa, Boggarapu Prakash Rao

机构信息

Department of Pharmaceutical Technology, Karnataka College of Pharmacy, #33/2, Tirumenahalli, Hegde Nagar Main Road, Bengaluru, 560064, , Karnataka, India.

Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, 31982, Saudi Arabia.

出版信息

Daru. 2015 Oct 24;23:49. doi: 10.1186/s40199-015-0132-7.

DOI:10.1186/s40199-015-0132-7

PMID:26497653

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4620023/

Abstract

BACKGROUND

The poor ocular bioavailability of the conventional eye drops is due to lack of corneal permeability, nasolacrimal drainage and metabolic degradation. To overcome this issue, drug encapsulated in mucoadhesive polymer based ocular microspheres have the advantages of improved drug stability, easy administration in liquid form, diffuse rapidly and better ocular tissue internalization.

METHODS

The ganciclovir chitosan microspheres (GCM) were prepared by modified water-in-oil emulsification method. The formulation was optimized and characterized by investigating in vitro release study, release kinetics, XRD and microspheres stability. Ocular irritancy, in vivo ocular pharmacokinetic parameters and histopathology study was evaluated in Wistar rats. The use of pharmacokinetic/pharmacodynamic indices and simulation process was carried out to further ensure clinical applicability of the formulation.

RESULTS

The in vitro release study showed initial burst (nearly 50 %) in first few minutes and followed Fickian (R(2) = 0.9234, n-value = 0.2329) type of diffusion release mechanism. The XRD and stability studies showed favorable results. The Wistar rat eyes treated with GCM showed significant increase in ganciclovir AUC (~4.99-fold) and Cmax (2.69-fold) in aqueous humor compared to ganciclovir solution and delay in Tmax. The Cmax/MIC90, AUC0-24/MIC90, AUC above MIC90 and T above MIC90 were significantly higher in GCM group. The aqueous humor concentration-time profile of ganciclovir in GCM and ganciclovir solution was simulated with every 28.1 and 12.8 h, respectively. The simulated concentration-time profile shows that in duration of 75 h, the ganciclovir solution require six ocular instillations compared to three ocular instillations of the GCM formulation. The photomicrograph of GCM and ganciclovir solution treated rat retina showed normal organization and cytoarchitecture.

CONCLUSIONS

Correlating with in vitro data, the formulation showed sustained drug release along with improved intraocular bioavailability of ganciclovir in Wistar rats.

摘要

背景

传统眼药水的眼部生物利用度较差，这是由于缺乏角膜通透性、鼻泪引流以及代谢降解。为克服这一问题，包裹在基于粘膜粘附聚合物的眼部微球中的药物具有提高药物稳定性、易于以液体形式给药、快速扩散以及更好的眼部组织内化等优点。

方法

采用改良的油包水乳化法制备更昔洛韦壳聚糖微球（GCM）。通过体外释放研究、释放动力学、X射线衍射（XRD）和微球稳定性研究对制剂进行优化和表征。在Wistar大鼠中评估眼部刺激性、体内眼部药代动力学参数和组织病理学研究。使用药代动力学/药效学指标和模拟过程进一步确保制剂的临床适用性。

结果

体外释放研究显示在最初几分钟内有初始突释（近50%），随后遵循菲克（Fickian）型（R(2) = 0.9234，n值 = 0.2329）扩散释放机制。XRD和稳定性研究显示出良好的结果。与更昔洛韦溶液相比，用GCM处理的Wistar大鼠眼睛房水中更昔洛韦的药时曲线下面积（AUC）显著增加（约4.99倍），峰浓度（Cmax）增加（2.69倍），达峰时间（Tmax）延迟。GCM组的Cmax/MIC90、AUC0-24/MIC90、高于MIC90的AUC以及高于MIC90的时间（T）均显著更高。分别以每28.1小时和12.8小时模拟了GCM和更昔洛韦溶液中更昔洛韦的房水浓度-时间曲线。模拟的浓度-时间曲线表明，在75小时的持续时间内，更昔洛韦溶液需要滴眼6次，而GCM制剂需要滴眼3次。GCM和更昔洛韦溶液处理的大鼠视网膜的显微照片显示组织结构和细胞结构正常。