Colloids and Surfaces B: Biointerfaces 130 (2015) 23–30 Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces j o ur nal ho me pa ge: www.elsevier.com/locate/colsurfb Zero order delivery of itraconazole via polymeric micelles incorporated in situ ocular gel for the management of fungal keratitis Munmun Jaiswal, Manish Kumar ∗ , Kamla Pathak Department of Pharmaceutics, Rajiv Academy for Pharmacy, National Highway #2, P.O. Chhattikara, Mathura 281001, Uttar Pradesh, India a r t i c l e i n f o Article history: Received 15 November 2014 Received in revised form 9 March 2015 Accepted 30 March 2015 Available online 6 April 2015 Keywords: Itraconazole Polymeric micelles In situ gel Ex vivo transcorneal permeation In vitro corneal hydration Histology a b s t r a c t The aim of this article is to investigate the role of amphiphilic block copolymer-based polymeric micelles of itraconazole for the management of fungal keratitis to overcome the limitations of the conventional dosage form. The polymeric micelles were made using pluronics above critical micelle concentration. Itraconazole-loaded polymeric micelles prepared by rotary evaporation method were characterized and the optimized micellar formulation (M5) was selected on the basis of least micelle size (79.99 nm), max- imum entrapment efficiency (91.32% ± 1.73%) and in vitro permeation (90.28% ± 0.31%) in 8 h, that best fitted zero-order kinetics. M5 was developed as pH sensitive in situ gel and characterized for various parameters. The optimized in situ gel (F5) proved to be superior in its ex vivo transcorneal permeation when compared with Itral ® eye drop and pure drug suspension, exhibiting 41.45% ± 0.87% permeation with zero-order kinetics (r 2 = 0.994) across goat cornea. Transmission electron microscopy revealed spherical polymeric micelles entrapped in the gel matrix. A spectrum of tests revealed hydration capabil- ity, non-irritancy, and histologically safe gel formulation that had appropriate handling characteristics. Conclusively, a controlled release pH-sensitive ocular formulation capable of carrying drug to the anterior segment of the eye via topical delivery was successfully developed for the treatment of fungal keratitis. © 2015 Published by Elsevier B.V. 1. Introduction Keratitis is the inflammation of cornea characterized by corneal edema, cellular infiltration, and cilliary congestion, and can be both infectious and non-infectious. The occurrence of keratitis varies depending on the cause of infection, which can be bacterial, fun- gal, or viral. Out of these, the fungal infection is the most common. The fungi more commonly responsible for mycotic corneal ulcers are Aspergillus flavus, A. fumigatus, A. niger, Candida, and Fusa- rium [1]. The fungus can invade into the stromal tissue through a defect in the epithelial sheet, after which it invades into corneal stroma and multiplies, with subsequent tissue necrosis and trigg- ers a host inflammatory response. Unfortunately, these organisms may penetrate through an intact Descemet’s membrane and enter the anterior chamber. Therefore, eradication of these pathogens becomes more difficult to treat [2]. The antifungal agents avail- able for treatment of fungal keratitis are generally associated with poor corneal penetration, stromal permeability, and poor clinical outcomes [3]. ∗ Corresponding author. Tel.: +91 9719021160. E-mail address: manishsingh170180@gmail.com (M. Kumar). Itraconazole used for the management of fungal keratitis is a synthetic triazole agent and has pronounced antifungal activity against Aspergillus, Curvularia, and Candida species. Com- mercially available as Itral ® eye drops (Jawa Pharmaceuticals, Gurgaon, India) is applied hourly and is precipitated in the corneal tissue after topical administration [4]. The formulation is also associated with poor corneal penetration and visual disturbances, lacrimation, tear dilution, nasolacrimal drainage, and tear turnover. Hence, it was aimed to investigate an amphiphilic block copolymer-based polymeric micellar ocular delivery system with superior corneal penetration to combat fun- gal invasion in the anterior chamber of eye devoid of irritation issues. Amphiphilic block copolymers have the affinity to self-assemble into micelles above the critical micelle concentration to form nano-sized (10–100 nm) carrier with a core–shell structure. The hydrophobic core surrounded by hydrophilic shell offers entrap- ment of hydrophobic drug that serves as drug reservoir while hydrophilic shell forms steric barrier to micelles aggregation and ensures micelle solubility in aqueous environment [5]. The poly- meric micellar delivery system of itraconazole is expected to improve corneal permeability and control its release at the target site. http://dx.doi.org/10.1016/j.colsurfb.2015.03.059 0927-7765/© 2015 Published by Elsevier B.V.