title: A method for enhancing the ocular penetration of eye drops using nanoparticles of hydrolyzable dye.
abstract: This report describes a method for enhancing the ocular penetration of eye drops using nanoparticles of hydrolyzable dye, which is similar to a prodrug approach. The entry of eye drops into the ocular globe is restricted predominantly by corneal barrier functions. The barrier functions are epithelial tight junctions as well as a physicochemical property consisting of the opposite characteristics of a lipophilic epithelium and a hydrophilic stroma. We found that using a formulation of nanoparticles of hydrolyzable dye (with particles of 200 nm in diameter on average) attained a greater than tenfold higher (about 50-fold) ocular penetration than that of micron-sized particles. The nanoparticles were prepared by a carrier-free technique; i.e., the reprecipitation method. Confocal laser fluorescence microscopy showed that dyes originating from the nanoparticles surmounted the corneal epithelium barrier, which has tight junctions, and achieved deeper penetration into the cornea. The high penetration rate of the dyes into the cornea was attributed to the size of particles (i.e., nanoparticles) and a transformation of dye polarity from lipophilic to hydrophilic in in vivo hydrolysis reactions. We concluded that utilizing in vivo hydrolysis reactions to alter the physicochemical nature of nanoparticles consisting of hydrolyzable compounds was an effective approach for enhancing the ocular penetration of eye drops.
authors.affiliation: Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Sendai 980-8574, Japan. koichi.baba@ophthal.med.osaka-u.ac.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Baba
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Akira
authors.initials: A
authors.lastname: Kubota
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kasai
authors.forename: Shunji
authors.initials: S
authors.lastname: Yokokura
authors.forename: Hachiro
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Kohji
authors.initials: K
authors.lastname: Nishida
mesh_terms: D000818:Animals; D004339:Drug Compounding; D019573:Epithelium, Corneal / Q000378:metabolism*; D005452:Fluoresceins / Q000737:chemistry / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000737:chemistry / Q000494:pharmacology; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010316:Particle Size; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013499:Surface Properties
chemical_list: D005452:Fluoresceins; D005456:Fluorescent Dyes; D009883:Ophthalmic Solutions; C018506:diacetylfluorescein