Noncorneal Routes In Ocular Drug Delivery

Ahmed and Patton (5) proposed a schematic for the pathways for the intraocular penetration of topically applied drugs, as shown in Figure 2. Modeling of the intraocular penetration routes and implication on ocular pharmacokinetics and pharmacodynamics was recently reviewed by Worakul and Robinson (14).

Although several investigators had reported a minor route of intraocular drug entry via the sclera and the conjunctiva (1-3), Bito and Baroody were the first to present evidence that this noncorneal route may, at least under some circumstances, be more important than the corneal route (4). They showed that after topical 3H-PGF2a application, the choroid, anterior sclera, and the ciliary body contained higher drug concentrations than the aqueous, indicating that the drug was entering the eye by some route other than through the cornea.

Figure 2 Intraocular penetration routes.

Over the past two decades there have been several investigations to further examine the conjunctival/scleral pathway for intraocular entry of drugs. The preferred method has been to mechanically block the cornea from the conjunctiva and sclera in situ with the use of a cylindrical well and introducing a drug solution either inside or outside the well. Hence, the disappearance of drug from the reservoir as well as the appearance of drug in intraocular tissues can be determined to compare the rate and extent of drug penetration via the corneal versus the conjunctival/scleral pathway. This method was employed by Schoenwald et al. (15) to study the ocular penetration pathway for methazolamide analogs, 6-carboxyfluorescein and rhodamine. The conjunctival/scleral route of entry produced higher iris/ ciliary body concentrations for all compounds except for the lipophilic rhodamine. Confocal microscopy results suggested that drug gained entry into the ciliary body through uptake into the blood vessels of the sclera. The clinical implication of the scleral/conjunctival pathway may be important for antiglaucoma drugs where a quicker route to the iris-ciliary body via the blood vessels may result in a faster onset of action. Sasaki et al. (11) used the in situ technique to show that while the p-blocker tilisolol entered the aqueous humor primarily via the corneal route, the access to the vitreous body was four times more effective through the sclera than through the cornea. The application of tilisolol in the conjunctiva or the sclera also showed a high concentration in plasma whereas corneal application produced no systemic levels.

The physicochemical drug properties important to noncorneal penetration of topically applied drugs appear to be lipophilicity and molecular size. Using a series of p-blockers Sasaki et al. (16) showed that the permeability of penetrants is strongly dependent on lipophilicity for the cornea but less so for the conjunctiva and the sclera (Fig. 3). Chien et al. (10) studied a2-adrenergic agents of varying lipophilicity and observed that the conjuncti-val/scleral pathway was the predominant route for delivery of least lipophi-lic molecule, p-aminoclonidine. The investigators also reported evidence of lateral diffusion of drug from the conjunctiva to the cornea. Pech et al. (18) evaluated a series of amphiphilic timolol prodrugs and observed that the transcleral absorption was the highest with the longest aliphatic chain pro-drugs, which also had the most amphiphilic/lipophilic character. Hence, the in vitro studies suggest that solute lipophilicity is less important for non-corneal drug penetration than it is for transcorneal drug penetration. However, the effect of lipophilicity on the extent of noncorneal penetration

Figure 3 Relationship between logarithmic values of the octanol/water partition coefficient (PC) and permeability coefficient (Kp). (0) Cornea; (A) conjunctiva; (□) sclera; (*) scraped cornea.

of topically applied drugs in vivo may be difficult to predict from in vitro studies alone. This requires information on the permeability of the drug across the conjunctiva, sclera, and ocular blood vessels, as well as drug binding to ocular tissues. A suitable predictive model that accounts for all these factors is not yet available.

There is also strong evidence that the noncorneal route may be the preferred pathway for intraocular entry of large, polar molecules that have poor corneal permeability. Ahmed and Patton (5,6) used corneal blocking techniques to demonstrate that the noncorneal pathway was the primary route of intraocular entry for inulin, a molecule that was poorly absorbed across the cornea (Table 2). The permeability of large molecules in conjunctiva and sclera is typically higher than in the cornea, suggesting that the noncorneal route may contribute more to the intraocular absorption of large molecules than the corneal route. The permeability of the sclera and conjunctiva will be discussed later in the chapter.

Table 2 Concentration of Inulin in Various Ocular Tissues 20 Minutes Following the Topical Instillation of 25 mL of a 0.65% Inulin Solution, in the Presence and Absence of Corneal Access

Concentration (mg/g)

Table 2 Concentration of Inulin in Various Ocular Tissues 20 Minutes Following the Topical Instillation of 25 mL of a 0.65% Inulin Solution, in the Presence and Absence of Corneal Access

Concentration (mg/g)

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