Theoretical corneal permeation model for ionizable drugs.

Abstract

The primary route into the eye for many drugs is transcorneal permeation. A better understanding of the mechanisms involved in transcorneal permeation could lead to improvements in drug dosage forms or the development of drug delivery devices which enhance the ocular bioavailability of drugs. A corneal permeation model has been developed which can be used to study the mechanisms involved in corneal permeation. The model uses five compartments in series to simulate the tear film, epithelium, stroma, endothelium and aqueous humour. These tissues were assumed to be adequately represented by plane sheet barriers of physiological thickness. The tear film was assumed to be perfectly mixed and the stroma completely stagnant. Due to inadequate knowledge of the hydrodynamics of the aqueous humour, both stagnant and perfectly mixed extremes were studied. The four routes of drug loss which were considered the most significant and therefore included in the model were lacrimal drainage, conjunctival absorption, aqueous drainage and iris-ciliary body absorption. The equilibrium that can exist between the ionic and non-ionic forms of a drug was found to be an important step in the mechanism of transcorneal permeation. Including the equilibrium condition in the model resulted in aqueous humour drug levels that were over 50 times higher than the levels predicted by a model which did not use the equilibrium mechanism. A relationship between the lipophilicity of each of the two drug forms and its permeability in each layer of the cornea was used in the model. The model was used to predict aqueous humour drug concentrations resulting from a constant release of timolol into the tear film or from the application of timolol, levobunolol and pilocarpine eyedrops. The model produced transient aqueous humour drug levels that closely followed experimental in vivo data from literature. Using the model, it was also possible to predict the amount of instilled drug that is lost through each of the four elimination routes of the eye.