Cornea drug permeability

There is growing evidence implicating Na+-dependent solute transporters and intracellular as well as extracellular Ca2+ in the physiological regulation of the paracellular pathway [81,203,204], Such modulation of paracellular permeability is especially important for drugs such as peptides and oligonucleotides that exhibit poor permeability characteristics across both the cornea and the conjunctiva [150,152,154,155], In addition, ion transporters such as Cl and Ca2+ channels have been implicated in macromolecular transport (see Sections IV.B.2 and IV.B.4). In the following discussion, some key ion transport processes and their possible roles in solute transport across epithelial tissues are summarized. 

The effects of D-glucose observed in vivo are not well reproduced in vitro. Madara [203] reported that cytoskeletal contraction and enhanced paracellular permeability were observed only in an in situ perfusion preparation and not in an isolated tissue preparation. Although its in vivo effect was not tested, 25 mM D-glucose, an effective concentration in the jejunum [47], failed to enhance the in vitro transport of sotalol (log PC = -0.62), atenolol (log PC = 0.16), or nadolol (log PC = 0.93) across the isolated conjunctiva [213], For a similar reason and possibly due to the absence of a Na+-glucose cotransporter in the cornea, 25 mM D-glucose was ineffective in increasing the corneal transport of these three drugs. 

Swan, K.C. and White, N.G. (1972). Corneal permeability (1) factors affecting penetration of drugs into the cornea. Amer. J. Ophthalmol. 25 1043-1058. 

This approach consists of transiently increasing the permeability characteristics of the cornea by appropriate substances, known as penetration enhancers or absorption promoters. It bears a strict analogy to techniques aimed at facilitating drug penetration through the skin and other epithelia such as the buccal, nasal, intestinal, or rectal. 

Loftssona et al. [98] found that with increases in the concentration of HP-(3-CD, the flux of a hydrophobic drug arachidonylethanolamide increased. Later, Tirucherai and Mitra [99] found that HP-(3-CD could also enhance the corneal permeation of the lipophilic drug ganciclovir dibutyrate (acyl ester prodrug of ganciclovir). Aktas [100] also found that addition of HP-(3-CD to the simple aqueous solution of pilocarpine nitrate increased the permeation of pilocarpine nitrate by four times in an in vitro permeability study using isolated rabbit cornea. 

In addition to the corneal route, topically applied ocular drugs may be absorbed via a noncorneal absorption route that involves drug transport across the bulbar conjunctiva and underlying sclera into the uveal tract and vitreous humor.65 The intercellular spaces of the conjunctival epithelium are wider than those of the corneal epithelium. As a result, the conjunctiva has higher permeability than the cornea to agents such as mannitol, inulin, and FITC-dextran.86 The penetration of peptides, however, is limited by enzymatic degradation.87 The limit of molecular size for conjunctival penetration is between 20,000 and 40,000 Da. Vitreous can act as an aqueous and unstirred diffusion barrier to drug permeation.64... 

In general, however, hypotonic solutions are well tolerated in the eye and can lead to better corneal absorption of the drug due to a concentration effect on the formulation and increased permeability of the cornea (both by virtue of uptake of water from the formulation by the corneal tissue). 

Figure 9.37 Influence of drug lipophilicily (log P) on the permeabilily coefficients (P pp) of beta-blockers across (a) the conjunctiva and (b) the cornea of the pigmented rabbit. Plot (c) shows the influence of log P on the ratio of the corneal (C) and conjunctival (J) permeability coefficients.

---