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Source: Adapted from Refs. 8, 9.

Source: Adapted from Refs. 8, 9.

classical sequence of events involves drug instillation, dilution in tear fluid, diffusion through mucin layer, corneal penetration (epithelium, stroma, endothelium), and transfer from cornea to aqueous humor. Following absorption, drug distributes to the site of action (e.g., iris-ciliary body). Parallel absorption via the conjunctiva/sclera provides an additional pathway to eye tissues but, for most drugs, is minor compared with corneal absorption. Also, nonproductive, competing, and parallel pathways (e.g., nasolacrimal drainage or systemic absorption via the conjunctiva) work to carry drug away from the eye and limit the time allowed for the absorption process. Moreover, in some species, such as the rabbit, nonproductive absorption into the nictitating membrane can occur. Figure 1 presents a summary of these precorneal events, along with a relatively simplified view of the kinetics in the cornea, aqueous humor, and anterior segment.

a. Corneal Penetration. Drug absorption through the cornea into the eye is dependent to a large degree upon a drug's physicochemical properties, such as octanol-water partition coefficient, molecular weight, solubility, and ionization state. In addition, corneal penetration is layer (corneal epithelium, stroma, and endothelium) selective. Schoenwald and Ward demonstrated a parabolic relationship between log corneal

Dose

Dose

' Instilled su lut Um drainage

K|0„ * Conjunctival absorption

• Tear turnover

^ * Drug protein binding

■ Nictitating membrane absorption

• Drug Metabolism

' Instilled su lut Um drainage

Figure 1 Model showing precorneal and intraocular events following topical ocular administration of a drug. (Adapted from Ref. 2.)

permeability coefficients and log octanol-water coefficients of various steroids (10) (see Fig. 2). The optimum log octanol-water coefficient was 2.9. Schoenwald and Huang showed a correlation between octanol-water partitioning of beta-blocking agents and their corneal permeabilities using excised rabbit corneas (11). Over a fourfold logarithmic range, the best fit was also a parabolic curve. In a refinement of this parabolic relationship, Huang et al. demonstrated in vitro a sigmoidal relationship between permeabiilty coefficient and distribution coefficient (12) (see Fig. 3). In this study, the endothelium offered little resistance and the stroma posed even less. Lipophilic drugs penetrated the cornea more rapidly; however, the hydrophilic stroma was rate limiting for these compounds. Maren et al. studied 11 sulfonamide carbonic anhydrase inhibitors (CAIs) of varied physicochemical characteristics with respect to transcorneal permeability and reduction of intraocular flow (13). In isolated rabbit cornea with a constantly applied drug concentration, the first-order rate constants ranged from 0.1-40 x 10~3 h-1, nearly proportional to lipid solubility, with water-insoluble drugs tending to have higher rate constants.

For most drugs, the multicell layered corneal epithelium presents the greatest barrier to penetration, primarily due to its cellular membranes.

Figure 2 Log-log plot of corneal permeability coefficient (pH 7.65) versus distribution coefficient (pH 7.65). Observed data (*) and predicted curve (—) are presented. (Replotted from Ref. 10.)

Log Partition Coefficient

Figure 2 Log-log plot of corneal permeability coefficient (pH 7.65) versus distribution coefficient (pH 7.65). Observed data (*) and predicted curve (—) are presented. (Replotted from Ref. 10.)

Stroma and particularly endothelium offer little resistance, except for highly lipophilic drugs. In fact, these two layers are often lumped together, along with aqueous humor, as a single compartment for purposes of pharmaco-kinetic modeling. The influence of the epithelium is most clearly demonstrated by studying corneal penetration following removal of the epithelium. Cox et al. showed in rabbits that when the epithelium was intact, no 14C-dexamethasone was detected in cornea or aqueous humor following topical ocular administration (14,15), while detectable levels were observed after removal of the corneal epithelium. Chien et al. studied the relationship between corneal epithelial integrity and prodrug lipophilicity with corneal penetration of a homologous series of timolol prodrugs (16). Deepithelization of the corneal in vitro did not affect corneal permeability of O-acetyl, propionyl, or butryl timolol but reduced penetration of the other prodrugs. In contrast, deepithelization in vivo only reduced timolol aqueous humor concentrations derived from O-propionyl and octanoyl esters. Therefore, factors other than the corneal epithelium may play a role in penetration.

Log Distribution Coefficient (Octanol-Buffer)

Figure 3 Log-log plot of corneal permeability coefficient versus distribution coefficient (octanol-Sorensen's buffer, pH 7.65). Intact corneal data (*) and computergenerated, model-derived curve (—) are presented. (Replotted from Ref. 12.)

Corneal penetration is also affected by the composition of the drug formulation. Whether a formulation is a solution, suspension, contains a buffer, viscosilating agent, or penetration enhancer, can influence absorption. Burstein and Anderson have reviewed corneal penetration and ocular bioavailability of drugs relative to optimizing formulations for typical ocular use (1). They evaluated the effects of preservatives, vehicles, adjunct agents, and anatomy and developed model systems for selecting the best formulations for preclinical and clinical use. Vehicle pH was one important factor considered. Adjusting the pH so that the drug was mostly in the unionized form greatly enhanced corneal penetration. Furthermore, it was concluded that buffering capacity, which keeps drug mainly in the ionized form, should be minimized to allow for adequate neutralization by tear film.

Other formulation components have been examined for their effect on absorption. Madhu et al. studied the influence of benzalkonium chloride (BAC)/EDTA on ocular bioavailability of ketorolac tromethamine follow ing topical ocular instillation onto normal and deepithelialized rabbit corneas in vitro and in vivo (17). BAC/EDTA caused a statistically significant increase in the ocular bioavailability of ketorolac through deepithelialized cornea but not intact cornea in vitro and in vivo. Jani et al. demonstrated that inclusion of ion exchange resins in an ophthalmic formulation of betax-olol increased the ocular bioavailabilty of betaxolol twofold (18). Hyaluronic acid, which can adhere to the corneal surface, is also capable of prolonging precorneal residence time (19).

b. Noncorneal, Ocular (Productive) Absorption. In addition to the classical corneal pathway, there is a competing and parallel route of absorption via the conjunctiva and sclera, the so-called conjunctival/scleral pathway. For most drugs this is a minor absorption pathway compared to the corneal route, but for a few compounds its contribution is significant. Ahmed and Patton investigated corneal versus noncorneal penetration of topically applied drugs in the eye (20,21). They demonstrated that noncorneal absorption can contribute significantly to intraocular penetration. A "productive" noncorneal route involving penetration through the conjunctiva and underlying sclera was described. Drug can therefore bypass the anterior chamber and distribute directly to the uveal tract and vitreous. This route was shown to be particularly important for drugs with low corneal permeability, such as inulin. In a separate study, Ahmed et al. evaluated in vitro the barrier properties of the conjunctiva, sclera, and cornea (22). Diffusion characteristics of various drugs were studied. Scleral permeability was significantly higher than that in cornea, and permeability coefficients of the ^-blockers ranked as follows: propranolol > penbutolol > timolol > nadolol for cornea, and penbutolol > propranolol > timolol > nadolol for the sclera. Resistance was higher in cornea versus conjunctiva for inulin but similar in the case of timolol. Chien et al. studied the ocular penetration pathways of three a2-adrenergic agents in rabbits both in vitro and in vivo (23). The predominant pathway for absorption was the corneal route, with the exception of p-aminoclonidine, the least lipophilic, which utilized the conjunctival/scleral pathway. The results suggest that the pathway of absorption may be influenced in part by lipophilicity and that hydrophilic compounds may prefer the conjuncti-val/scleral route.

Some investigators have employed a dosing cylinder affixed to the cornea to study corneal and noncorneal absorption. Drug is applied within the cylinder for corneal dosing and outside the cylinder for noncorneal (conjunctival/scleral) dosing. In a study by Schoenwald et al., the conjunc-tival/scleral pathway yielded higher iris-ciliary body concentrations for all compounds evaluated with the exception of lipophilic rhodamine B (24).

Romanelli et al. demonstrated the absorption of topical ocular bendazac into the retina/choroid via the conjunctival/scleral pathway (25). Absorption by way of this extracorneal route was influenced by physico-chemical features and not by vehicle, while the transcorneal route was affected by vehicle.

c. Noncorneal, Nonproductive Absorption and Precorneal Drainage. Routes that lead to the removal of drug from the precorneal area and do not result in direct ocular uptake are referred to as nonproductive absorption pathways. These noncorneal pathways, which are in parallel with corneal absorption, include conjunctival uptake and drainage via the nasolacrimal duct. Both lead to systemic absorption by way of conjunctival blood vessels in the former case or via the nasal mucosa and gastrointestinal tract in the latter case. As discussed previously, the conjunctiva can absorb drug and, via the sclera, deliver drug to the eye; however, blood vessels within the conjunctiva can also lead to systemic absorption.

Nonproductive, noncorneal absorption and drainage loss greatly impact the precorneal residence time and the time for ocular absorption. Drainage, in particular, is very rapid and generally limits ocular contact at the site of absorption to about 3-10 minutes (8). However, the lag time—the time for drug to traverse the cornea and appear in the aqueous humor—is sufficiently long to extend time to maximal concentration in the aqueous to between 20 and 60 minutes for most drugs (8). Due to rapid loss of drug from the precorneal region, less than 10%, and more typically less than 12%, of a topical dose is absorbed into the eye. At the same time, systemic absorption can be as high as 100%, indicating that most of the drug dose is unavailable for efficacy. For example, Ling and Combs showed that the ocular bioavailability of topical ocular ketorolac was 4% in anesthetized rabbits, while systemic absorption was complete (26). Ocular tissue levels were about 13-fold higher than those in plasma, and peak concentrations were achieved by 1 hour in both aqueous humor and plasma postdose. Tang-Liu et al. showed that topical ocular levobunolol was rapidly absorbed, with an ocular bioavailability of 2.5% and systemic bioavailability of 46% (27). Patton and Robinson have investigated the contribution of tear turnover, instilled solution drainage, and nonproductive absorption to precorneal loss of drug (28). Instilled solution drainage was shown to be the predominant factor in precorneal loss, while the influence of tear turnover was minor. It was concluded that noncorneal, nonproductive loss was potentially significant due to the large surface area of noncorneal tissue; however, its role was minimal compared to drainage. Ocular (aqueous humor) and systemic bioavailabilities for various drugs are presented in Table 2.

Table 2 Ocular and Systemic Bioavailabilities (Percent of Dose) Following Topical Ocular Administration

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