The ocular globe can be divided into anterior and posterior segments (Fig. 1). The anterior segment consists of external cornea, conjunctiva, aqueous humor, iris-ciliary body and lens. The cornea and the lens consisting of avascular and transparent structures, these structures obtain most of the necessary nutrients from aqueous humor. The cornea also partially depends on the tear fluid for essential nutrients like amino acids
Figure 1 Structure of the human eye.
and vitamins. The iris-ciliary body and conjunctiva are highly vascular tissues. The aqueous humor is a dynamic watery fluid that is continuously secreted by ciliary body and drained out by trabecular meshwork returning to blood stream through schlemm's canal. It maintains a pressure that imparts the convex shape to the front of the globe.
The posterior chamber primarily consists of outer sclera, choroid, retina and the vitreous humor. The sclera is an avascular tissue and acts as outer protective layer. Underneath the sclera is a highly vascular choroid which supplies nutrients to both outer sclera and inner retina. The innermost layer is retina which is primarily responsible for image formation and the thus the vision. The blood-retinal barrier is comprised of retinal pigment epithelium and the endothelium of retinal blood vessels. Unlike the aqueous humor, vitreous humor is a clear watery viscous fluid which is replaced at a very slow rate. The primary purpose of the vitreous humor is to provide a cushioned support for the rest of ocular structures, as well as a clear unobstructed path of light to the retina.
The ocular tissues most prone to microbial infections are the cornea, the conjunctiva and the iris-ciliary body in the anterior chamber, and the retina in the posterior chamber. To treat ocular infections in the anterior chamber, topical delivery of anti infectives is the most preferred. However, nasolacrimal drainage, tear dilution, conjunctiva absorption, and the outer cornea are the big barriers to topical delivery. Less than 5% of drug reaches the intra ocular tissues after topical administration. The cornea consists of an outer corneal epithelium, the middle stroma and the innermost corneal endothelium. The corneal epithelium is composed of 5-6 layer of columnar epithelial cells with tight junctions presenting a barrier to the hydrophilic compounds, followed by the stroma, which contains more than 90% water and hence acts as a barrier to hydrophobic compounds (1). Hence a drug molecule should posses an optimal hydrophilic-lipophilic balance to permeate across the cornea. The nasolacrimal drianage can be reduced by increasing the residence time of the drug on the cornea which can be achieved by various formulation approaches like liposomes (2), nano-particles (3-5), and other colloidal carriers like microemulsions etc. (5). Oral and systemic administrations have been attempted where the drug molecules need to cross the blood aqueous barrier. This barrier is formed by the non-pigmented layer of the ciliary epithelium and the endothelium of the iridial vessels. It regulates mostly the inward movement of the compounds from blood into the eye (6,7).
Drug delivery to the posterior segment is a significant challenge as the topical delivery may not generate therapeutic concentrations to treat infections. The blood retinal barrier has tight junctions formed by retinal pigment epithelium and endothelium of retinal blood vessels (7). These cells form the tight junctions that can restrict the entry of drug molecules into the posterior chamber after oral or systemic administration. The retina itself is also a big barrier to hydrophilic molecules like ganciclovir and also for macrmolecules (8). Hence high doses are required in the systemic circulation to achieve therapeutic concentrations in retina, which may lead to serious systemic side effects. Intravitreal injection is currently a common mode of drug administration to the posterior chamber. However, this method is associated with retinal detachment, vitreal haemorrahage and cataract (6). Moreover, the frequency of injections depends on the vitreal half life of the drug. Other than systemic and intravitreal routes, periocular routes (subconjunctival, subtenon, and retrobulbular) have also been investigated for drug delivery to the posterior segment. The periocular route is much safer and less invasive than the intravitreal injection. As all these modes involve drug diffusion across the sclera it would be more appropriate to develop transscleral delivery systems. The large surface area of human sclera provides significant avenue for elevated amounts of drug diffusion. Regional differences in the thickness of sclera can further be exploited for designing an optimum delivery system (9). The main mechanism of drug diffusion across sclera is passive diffusion across the aqueous pore pathway. But, diffusion across sclera may not always lead to increased concentrations inside the retina, as molecules still have to cross the highly vascular choroid which can drain a significant fraction of drug into the systemic circulation. Hence the success of this approach depends on whether the choroidal blood supply can limit drug permeation into retina.
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