PII: S0301-5629(02)00515-X ● Original Contribution OCULAR DRUG DELIVERY USING 20-kHz ULTRASOUND VESNA ZDERIC,* † SHAHRAM VAEZY,* † ROY W. MARTIN* † and JOHN I. CLARK ‡ *Department of Bioengineering, † Center for Industrial and Medical Ultrasound, Applied Physics Laboratory and ‡ Department of Biological Structure, University of Washington, Seattle, WA, USA (Received 3 September 2001; in final form 13 March 2002) Abstract—The cornea is a major pathway for drug delivery to diseased eye structures. We have investigated the application of 1-s bursts of 20-kHz ultrasound, at I SAPA of 14 W/cm 2 (I SATA of 2 W/cm 2 ), for enhancement of corneal permeability to glaucoma drugs of different lipophilicity (atenolol, carteolol, timolol and betaxolol). The permeability of rabbit cornea increased by 2.6 times for atenolol, 2.8 for carteolol, 1.9 for timolol and 4.4 times for betaxolol (all p-values < 0.05), after 60 min of ultrasound (US) exposure in vitro. The differences between the treatment and control experiments were statistically significant after 10 to 30 min of US exposure for all four drugs. US application appeared to produce epithelial disorganization and structural changes in the corneal stroma. Further studies are needed to determine the optimal US parameters for a safe and effective treatment. (E-mail: vesna@u.washington.edu) © 2002 World Federation for Ultrasound in Medicine & Biology. Key Words: Ultrasound, Drug delivery, Eye, Sonophoresis, Phonophoresis. INTRODUCTION Efficient drug delivery into the eye is a significant clin- ical problem (Sasaki et al. 1999). The internal structures of the eye are protected by different barriers that make it difficult to achieve a sufficient drug concentration in diseased ocular structures. The blood-aqueous barrier, a selectively permeable barrier between the capillary bed in the processes of the ciliary body and the aqueous humor in the anterior chamber of the eye, prevents sys- temically administered drugs from entering into the aqueous humor. The blood-retina barrier prevents drugs from entering into the extravascular space of the retina and into the vitreous body (Raviola 1977). Topically applied drugs are rapidly washed from the eye surface due to rinsing by tears, and absorbed into the systemic circulation, increasing the chance of systemic adverse effects (Schoenwald 1990). Most of the drugs that pen- etrate the sclera (white of the eye) are carried away by the blood circulation before diffusion to the intraocular structures takes place (Sasaki et al. 1999). The cornea is considered a major pathway for pen- etration of topically applied drugs (Doane et al. 1978). It is an avascular structure consisting of three primary layers: epithelium, stroma and endothelium. The epithe- lium is the dominant barrier for hydrophilic drugs, and the stroma is the main barrier for lipophilic drugs (Ke et al. 1999). The barrier properties of the cornea have been shown to be modified by the application of physical methods such as iontophoresis, application of electrical current, and sonophoresis, application of ultrasound (US) (Cherkasov et al. 1974; Filippenko and Tretiak 1989; Gvarishvili and Dushin 1999). Sonophoresis at frequen- cies of 470 to 880 kHz and intensities of 0.2 to 0.3 W/cm 2 applied for 5 min in a continuous mode produced up to a 10 times increase in the corneal permeability in a rabbit model, in vivo (Nuritdinov 1981; Tsok et al. 1990). The mechanism of action was thought to be cavitation- induced corneal epithelium damage that healed in 6 h (Nuritdinov 1981). The objective of our work was to determine if 20-kHz ultrasound, which was shown to be effective in transdermal drug delivery (Mitragotri et al. 1996), can increase the corneal permeability for glaucoma drugs of different lipophilicity. The experiments were performed in a rabbit model, in vitro, using a vertical diffusion cell. MATERIALS AND METHODS Rabbit eyes were obtained within 30 min of eutha- nasia. The rabbits were previously anesthetized, and a protective ointment (Artificial tear ointment, Phoenix Pharmaceutical, St. Joseph, MO) was applied in 90% of Address correspondence to: Vesna Zderic, Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, 1013 NE 40th St., Seattle, WA 98105 USA. E-mail: vesna@u.washington.edu Ultrasound in Med. & Biol., Vol. 28, No. 6, pp. 823– 829, 2002 Copyright © 2002 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/02/$–see front matter 823