ABSTRACTExisting ocular drug delivery systems are fairly primitive and inefficient, but the stage is set for the rational design of newer and significantly improved systems. The focus of this review is on recent developments in topical ocular drug delivery systems relative to their success in overcoming the constraints imposed by the eye and to the improvements that have yet to be made. In addition, this review attempts to place in perspective the importance of pharmacokinetic modeling, ocular drug pharmacokinetic and bioavailability studies, and choice of animal models in the design and evaluation of these delivery systems. Five future challenges are perceived to confront the field. These are: (a) The extent to which the protective mechanisms of the eye can be safely altered to facilitate drug absorption, (b) Delivery of drugs to the posterior portion of the eye from topical dosing, (c) Topical delivery of macromolecular drugs including those derived from biotechnology, (d) Improved technology which will permit non-invasive monitoring of ocular drug movement, and (e) Predictive animal models in all phases of ocular drug evaluation.The design of ocular drug delivery systems is undergoing a gradual transition from an empirical to a rational base. This is partly due to a better understanding of the constraints on drug disposition in the eye and partly due to improved approaches in animal and clinical assessment of ocular drugs and drug delivery systems. Undoubtedly, interest in the broad area of ocular drug delivery has increased in recent years due to an increased understanding of a number of ocular physiological processes and pathological conditions, including aqueous humor dynamics, inflammation, corneal wound healing, and cataractogenesis, with a parallel increase in the number of drugs and drug candidates that have a beneficial effect in these conditions. Some of these compounds are rather potent and, at the same time, possess unfavorable aqueous solubility, stability, and lipophilicity characteristics. The inevitable result is that the formulation of these compounds for optimal topical delivery to the eye is increasingly challenging, much more so for the posterior than for the anterior portion of the eye. Coincidentally, the design of ocular drug delivery systems is becoming more sophisticated, partly due to a better understanding of the constraints in ocular drug disposition and partly due to the availability of polymers with a wide range of properties including biodegradability and bioadhesiveness.A number of recent reviews (1-5) have provided excellent background information on corneal drug transport mechanisms, ocular drug bioavailability, and ocular drug pharmacokinetics. Although a portion of each of these reviews also deals with the subject of ocular drug delivery, either directly or indirectly, a comprehensive current review of this subject does not appear to be available in the literature, hence the purpose of this article. Specifically, this paper will first review and describe (a) the constraints in topical ocular drug delivery, (b) mechanisms and constraints of ocular drug absorption, and (c) mathematics and modelling of ocular drug disposition in order to set the stage for understanding (a) the approaches that can be taken to optimize ocular drug delivery, (b) the suitability of rabbits as an animal model to evaluate ocular drug delivery systems, and (c) new challenges in ocular drug delivery system design.To provide a framework for subsequent discussions, it is useful to describe typical boundaries that are encountered in topical drug application. It is common to see approximately 1% or less of an applied dose absorbed across the cornea to reach anterior segment tissues of the eye. This, therefore, is an extremely inefficient process that also signals a substantial systemic drug load. Obviously, subsequent movement of this absorbed drug to the posterior segment of the eye will occur for only a tiny fraction of that which is in the anterior segment. In addition to the fraction of dose absorbed, the issue of residence time in the living eye is also important. Typically, an instilled aqueous solution will be eliminated from the precorneal area within 90 seconds. All things considered, improving the fraction of dose absorbed, achieving relatively high drug concentrations in the posterior segment, and maintaining drug in the front of the eye for several hours to several days are considerable challenges in ocular drug delivery.