Abstract
A stable topical ophthalmic cyclosporine A (CsA) formulation with good tolerance and high efficacy is still a desire in pharmaceutics and clinics. This article describes the preparation of CsA containing nanomicelles using a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVCL-PVA-PEG) graft copolymer. Both the polymer itself and the CsA nanomicelles were evaluated for cytotoxicity and ocular irritation. The in vitro uptake and intracellular fate of nanomicelles were characterized. In vivo cornea permeation test performed with 0.5 mg/mL CsA containing nanomicelles, and compared with a commercially available CsA (10 mg/mL) oil-based ophthalmic solution. The CsA nanomicelle ophthalmic solution was simple to prepare and remained storage stable. PVCL-PVA-PEG had no cytotoxicity as its monomer solution, and as its micelle solution (IC50(48 h) = 14.02 mg/mL). CsA nanomicelles also had excellent ocular tolerance in rabbits. The use of nanomicelles significantly improved in vitro cellular uptake, apparently by an energy dependent intracellular endocytosis pathway that involved early endosomes, late endosomes, lysosomes, and ER. In vivo permeation showed that 0.5 mg/mL CsA nanomicelles delivered high levels of CsA into the cornea, when compared to the oil-based 10 mg/mL CsA ophthalmic solution. These findings indicated PVCL-PVA-PEG nanomicelles could be a promising topical delivery system for ocular administration of CsA.
Highlights
A stable topical ophthalmic cyclosporine A (CsA) formulation with good tolerance and high efficacy is still a desire in pharmaceutics and clinics
Transmission electron microscope (TEM) analysis showed that the micelles were spherical or quasi-circular and homogenous, and no aggregates were present
The particle size obtained by photo-correlation spectroscopy was the same as the size visualized by TEM
Summary
A stable topical ophthalmic cyclosporine A (CsA) formulation with good tolerance and high efficacy is still a desire in pharmaceutics and clinics. In vivo permeation showed that 0.5 mg/mL CsA nanomicelles delivered high levels of CsA into the cornea, when compared to the oil-based 10 mg/mL CsA ophthalmic solution These findings indicated PVCL-PVAPEG nanomicelles could be a promising topical delivery system for ocular administration of CsA. Various attempts have been made to attain this goal of developing ophthalmic formulations of CsA, including the use of a cyclodextrin inclusion complex[5,6], colloidal carriers (liposomes, nanoparticles, nanoemulsions, nanomicelles, and solid lipid nanoparticles)[4,7,8,9,10,11,12], hydrogels[10], and collagen shields[13] Some of these systems have been shown to improve a number of the unfavorable physicochemical properties associated with CsA by enhancing its ocular availability and improving tolerance; none of these topical systems has yet reached the market. The present study examined the use of polyvinyl caprolactam-polyvinyl acetate-polyethylene
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