Source: Adapted from Ref. 24.

Source: Adapted from Ref. 24.

anhydrase inhibitors ethoxzolamide and methazolamide and concluded that the permeability was six times greater in the sclera than in the cornea for the less lipophilic methazolamide but similar for the more lipophilic ethoxzola-mide.

2. Conjunctiva

Unlike the sclera, the conjunctiva shares an important attribute with the cornea in that both contain an outer lining of stratified squamous epithelium continuous with each other at the corneoscleral limbus. However, the cornea is avascular while the conjunctival epithelium overlies a loose, highly vascular connective tissue, the substantia propria.

Characteristic of any epithelial tissue, both paracellular and transcel-lular transport is possible across the conjunctiva. In both the cornea and the conjunctiva, lipophilic drugs prefer the transcellular route, while the para-cellular route is preferred by hydrophilic drugs (36). The ratio of the permeability coefficients of a series of p-adrenergic blockers in the cornea and those in the conjunctiva exhibited a sigmoidal correlation with log partition coefficient, as shown in Figure 5 (51). This indicates that while the conjunctiva is leakier than the cornea, the differential permeability of the conjunctiva to the cornea is higher for hydrophilic compounds than for lipophilic compounds. The data presented in Table 5, which shows that the permeability of peptides in conjunctiva is higher than in the cornea, support this conclusion (52,53).

Several authors have studied the effect of molecular size on conjunctival permeability. Horibe et al. (31) characterized the conjunctival permeability to polar solutes ranging from 182 to 167,000 daltons in molecular weight and concluded that solutes up to 40 kDa traverse the conjunctival epithelial barrier primarily by restricted diffusion through equivalent pores of 5.5 nm. Polar solutes of greater than 70 kDa may cross the barrier primarily via nondiffusional pathways, such as nonspecific endocytosis. Huang et al. (27) and Kahn et al. (28) also studied the solute size effect on conjunctival penetration. They estimated the limiting size of solutes that can pass the conjunctival barrier by paracellular transport at between 20 and 40 kDa. Hamalainen et al. (29) reported that the conjunctival epithelia in the rabbit have 2 times larger pores and 16 times higher pore density than the cornea. They estimated that intercellular space in the cornea is 0.3 x 10~3 mm2, whereas it is 7 x 10~3 mm2 in rabbit conjunctiva. Finally, there is some evidence that human conjunctiva may be more permeable to hydrophilic solutes than rabbit conjunctiva (32)

Figure 5 Permeability coefficient ratio (cornea/conjunctiva) as a function of the log partition coefficient
Table 5 Permeability Ratio of Peptides Across Ocular Membranes in Rabbit


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