Physicochemical Properties

Lipophilic drugs permeate the corneal epithelium via the transcellular pathway while hydrophilic molecules utilize the paracellular route; the latter process involves passive or altered diffusion through intercellular spaces. Passive diffusion along a concentration gradient, which is largely influenced by various physicochemical properties, is the main corneal permeation mechanism for most topically applied drugs.

Drug lipophilicity is the most important property for corneal permeation, and both parabolic (Schoenwald and Ward, 1978; Chien et al., 1991) and sigmoidal (Wang et al., 1991) curves have been used to describe their relationship. The optimum apparent partition coefficient (Papp; octanol/pH 7.4 buffer) for corneal drug absorption is in the range of 100-1000 (log Papp 2-3) (Schoenwald and Ward, 1978; Schoenwald and Huang, 1983), indicating that the absorption of moderately lipophilic compounds is favoured. In the case of prodrugs, it is more complicated to estimate the optimal Papp value for corneal permeability because their corneal permeability depends on the lipophilicity of both the prodrug and parent drug and also on the conversion rate of prodrug to the parent drug in vivo.

Aqueous solubility is another important physicochemical property for efficacious ophthalmic delivery. The surface of the eye is constantly being cleaned and moistened by the aqueous tear fluid. Thus, it is difficult for drug molecules to be absorbed by the corneal epithelium without being soluble in the tear film. In addition, the water solubility of the drug must also be sufficient to enable the formulation of aqueous eyedrops. The dilemma here is that an ideal ophthalmic drug should simultaneously be both water-soluble and lipid soluble, but only a few molecules are known to fulfill these criteria.

In addition to the lipophilicity and aqueous solubility of a drug, molecular size (Liaw and Robinson, 1992), charge (Liaw et al., 1992), and degree of ionization (Maren and Jankowska, 1985; Brechue and Maren, 1993) also affect corneal penetration. Tear fluid has a limited buffering capacity (Carney and Hill, 1979). Thus, pH and buffering capacity of the instilled eyedrops affect the pH of tear fluid and, consequently, drug ionization in the precorneal area. The non-ionized form of a drug usually permeates the cornea more easily than does the ionized form, so both the pH and buffering capacity of instilled eyedrops can have a significant effect on ophthalmic drug absorption.

Drugs developed for ophthalmic use should have good chemical stability to allow formulation into topical ready-to-use aqueous eyedrops, which is the most practical and commonly used administration route for treatment of ophthalmic diseases. This is often challenging in the development of ophthalmic prodrugs that are intended to be rapidly converted to active drug after absorption. Therefore, only those prodrugs that show good chemical stability combined with high enough enzymatic lability can be easily developed without resorting to multivial reconstitutable products.

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