Corneal barrier

A simple estimate of the diffusion coefficients can be approximated from examining the effects of molecular size on transport through a continuum for which there is an energy cost of displacing solvent. Since the molecular weight dependence of the diffusion coefficients for polymers obeys a power law equation [206], a similar form was chosen for the corneal barriers. That is, the molecular weight (M) dependence of the diffusion coefficients was written as ... 

After topical administration of an ophthalmic drug solution, the drug has to cross a succession of anatomical barriers before reaching the systemic circulation. These barriers (as shown in Figure 25.1) can be commonly classified as precorneal and corneal barriers [3]. 

Limited corneal area and poor corneal permeability (Figure 25.1) are the main corneal barriers that are responsible for the poor bioavailability of drugs applied topically as eye drops. 

An area where CDs have a significant therapeutic benefit is in the solubilization of drugs intended for ophthalmic use. Corneal permeability favors moderately lipophilic drugs. These compounds often have a low aqueous solubility. Thus, the CDs are being extensively exploited for their usefulness in increasing the solubility of insoluble and poorly soluble drugs and keeping them at the corneal barrier. 

Figure 12.1 Microscopic structure and characteristics of the corneal barrier...

Commonly used methodological variations to improve the sensitivity and accuracy of describing damage in these tests are inspection of the eyes with a slit lamp and instillation of the eyes with a vital dye (very commonly, fluorescein) as an indicator of increases in permeability of the corneal barrier. 

As previously mentioned, systemic delivery is limited because of the isolation of ocular tissues from the systemic circulation thus, topical delivery is often the preferred administration route owing to ease of access and patient compliance, particularly when treating infections of the anterior segment such as keratitis sicca, conjunctivitis, or blepharitis and diseases such as glaucoma or uveitis that require the drug to be diffused across the corneal barrier [19,20]. However, drainage, lacrimation and tear dilution, tear turnover, conjunctival absorption, and the corneal epithelium all limit corneal drug penetration [21,22]. 

Exposure to UVB radiation has a profound effect on the corneal endothelium. Following exposure to UV radiation, the cornea swells, the extent and duration of which is directly related to the magnitude and duration of the exposure (Riley etal., 1987). At very high in vivo exposures, these authors reported a decrease in ascorbate concentration and an increase in protein content, which they suggested resulted from a breakdown of the blood-aqueous barrier. They concluded that UV radiation may cause or promote changes in the endothelium associated with ageing. 

Basic hydrodynamic phenomena govern the duration of exposure of corneal and conjunctival membranes to the therapeutic agents. Rapid clearance provides a temporal barrier to drug delivery. 

One of the key parameters for correlating molecular structure and chemical properties with bioavailability has been transcorneal flux or, alternatively, the corneal permeability coefficient. The epithelium has been modeled as a lipid barrier (possibly with a limited number of aqueous pores that, for this physical model, serve as the equivalent of the extracellular space in a more physiological description) and the stroma as an aqueous barrier (Fig. 11). The endothelium is very thin and porous compared with the epithelium [189] and often has been ignored in the analysis, although mathematically it can be included as part of the lipid barrier. Diffusion through bilayer membranes of various structures has been modeled for some time [202] and adapted to ophthalmic applications more recently [203,204]. For a series of molecules of similar size, it was shown that the permeability increases with octa-nol/water distribution (or partition) coefficient until a plateau is reached. Modeling of this type of data has led to the earlier statement that drugs need to be both... 

Another method of delivery of drug to the anterior segment of the eye that has proved successful is prodrug administration [144]. Since the corneal surface presents an effective lipoidal barrier, especially to hydrophilic compounds, it seems reasonable that a prodrug that is more lipophilic than the parent drug will be more successful in penetrating this barrier. 

While the lactate-H+ symporter and the K+/H+ exchanger are involved in acidification of the cell, the Na+/H+ exchanger present in the basal cells exports protons out of the cell in exchange for Na+ [139]. It was observed that removal of Na+ from the Ringer s solution decreased intracellular pH by 0.5 unit in basal cells, possibly due to inhibition of the Na+/H+ exchanger. As the basal cells are the precursors for the superficial cells of the corneal epithelium, it is quite likely that similar exchange processes are also present in the superficial layer, the principal barrier to ion and drug transport [99,103],... 

RL Shih, VHL Lee. (1990). Rate limiting barrier to the penetration of ocular hypotensive beta-blockers across the corneal epithelium in the pigmented rabbit. J Ocular Pharmacol 6 329-336. 

HS Huang, RD Schoenwald, JL Lach. (1983). Corneal penetration behavior of betablocking agents. II Assessment of barrier contributions. J Pharm Sci 72 1272-1279. 

P. Calvo, J. L. Vila-Jato, and M. J. Alonso, Corneal penetration of 14C-indomethacin-loaded nanocapsules, in Methods to Overcome Biological Barriers in Drug Delivery, Kuopio, Finland, 1993, Kuopio University, Department of Pharmaceutical Technology, p. 93. 

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