Ocular Barriers To Various Routes Of Administration

Drug delivery to the posterior segment of the eye is of high clinical significance in treating various ocular disorders, i.e., endophthalmitis, viral retinitis, proliferative vitreoretinopathy, uveitis, etc. The problem of administering potent drugs to the posterior segment of the eye, which is a relatively closed and well-defined compartment, may be approached in different ways. The most common and patient-acceptable route is the topical instillation of drugs. Many studies have shown that approximately 5% or less of the topically applied dose is absorbed across the cornea, which forms the major barrier to drug penetration to anterior segment tissues. Amounts of drug absorbed into the posterior segment of the eye will only be a minute fraction of the amounts achieved in the anterior segment. The main constraints afforded by the eye upon topical delivery are the protective mechanisms, which include solution drainage, lacrimation, diversion of exogenous chemicals into the systemic circulation via conjunctiva, and a highly selective corneal barrier to exclude these compounds from the eye (29). In addition, there is a finite limit to the size of the dose that can be applied and tolerated by the cul-de-sac (usually 7-10 mL) and the contact time of the drug with the absorptive surfaces of the eye. The drugs usually disappear in about 5-10 minutes in rabbits and 1-2 minutes in humans following topical instillation (30,31) and at an even faster rate at the pH where most of the ophthalmic drugs are formulated (32).

Intraocular drug concentrations achieved after systemic administration depend primarily on the ocular blood circulation. With most drugs, very low intraocular concentrations were achieved after systemic administration, due mainly to the presence of blood-aqueous barrier, which restricts substances from entering into the aqueous humor, and blood-retinal barrier, which prevents the drugs entering into the vitreous chamber (33-37). Higher levels are generally found in the aqueous humor compared to vitreous, as the blood-aqueous barrier is known to be leakier than the blood-retinal barrier.

Subconjunctival administration of drugs can also generate elevated intraocular concentrations compared to topical and systemic administration, with minimal systemic adverse effects. The aqueous and vitreous concentrations of various drugs have been determined after subconjunctival administration (38-41). Even in this case the intraocular concentrations achieved were found to be only a fraction of the dose administered, as conjunctival epithelium constitutes a relatively tight barrier. The sclera does not offer a very tight barrier to the penetration of even relatively large molecular weight drugs (42).

The only possible way to achieve therapeutic concentrations in the posterior segment of the eye was found to be the intravitreal administration (43-51). This route of administration has become the recommended therapy for the treatment of endophthalmitis and cytomegalovirus retinitis. Drugs injected into the vitreous may be eliminated by two routes. Drugs eliminated by diffusion into the posterior chamber with subsequent removal by normal egress of fluid from the anterior chamber (52,53) generally exhibit half-lives within a range of 20-30 hours (53). The second route is through the retina via penetration of the blood-retinal barrier (52,53). Drugs eliminated by this route usually exhibit half-lives in the range of 5-10 hour (53).

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