Ionization and pH

The majority of drugs are ionizable, but for a drug to pass the lipid barriers of the epithelium and endothelium, it needs to be hydrophobic, which generally means unionized. The ionized form prefers the trans-stromal route since this is primarily hydrophilic. After an ophthalmic formulation is instilled into the eye, it is mixed with the tears present in the conjunctival sac and with the precorneal tear film. The pH of the mixture is mainly determined by the pH of the instilled solution as the tear film is of small volume with low buffering capacity. Since the pH can so easily be influenced by the delivery vehicle, it can be exploited to optimize absorption. For example, pilocarpine, a weak base, is administered in a vehicle of low pH, in which it is ionized. In this form it can be absorbed before the tear film secretion returns the local pH to physiological levels. Adjustment of the vehicle buffer capacity allows some measure of control over the duration of the pH disturbance.

Figure 11.8 Transcorneal penetration into the aqueous humour. The losses are significant and it usual for less than 5% of the instilled dose to penetrate into the intraocular tissues following a 25 ul drop.

Figure 11.8 Transcorneal penetration into the aqueous humour. The losses are significant and it usual for less than 5% of the instilled dose to penetrate into the intraocular tissues following a 25 ul drop.

Protein binding

Estimates of the total protein content of tears range from 0.6 to 2% w/v, the major fractions consisting of albumin, globulin and lysozyme. Drugs bound to the protein in the tear fluid may not permeate the cornea due to the additional bulk of the protein molecule; also binding of drugs to protein in conjunctival tissues competes for the drug available for corneal absorption (Figure 11.8). Binding increases in certain disease states, particularly inflammatory conditions, due to higher secretion of proteins in tissue exudate.

If two drugs have to be applied to the same eye, an interval of five to ten minutes should elapse between administration of each drug. If the second drug is applied too soon after the first, it may displace the first drug, which will then be rapidly cleared, thereby reducing its effect.

Pigmentation and drug effects

There have been only a limited number of studies carried out in this area, but these suggest that the intraocular distribution of drugs vary with levels of eye pigmentation. For example, a ten-fold increase in pilocarpine deposition in the iris-ciliary body of the pigmented rabbit eye is found when compared with albinos, although the pilocarpine concentration in the aqueous humor was indistinguishable between the two4. Pilocarpine is metabolised by tissue

Figure 11.9 Losses during disposition into the eye. The precorneal losses are significant; binding and clearance processes further reduce the concentration of applied drug to the interior tissues

Figure 11.9 Losses during disposition into the eye. The precorneal losses are significant; binding and clearance processes further reduce the concentration of applied drug to the interior tissues esterases and esterase activity is highest in the iris and ciliary body, followed by the cornea and aqueous5. In the pigmented eyes, the pharmacological effect was reduced owing to a higher amount of esterase activity in the cornea and iris-ciliary body.

Drug distribution in the eye

The amount of drug reaching the anterior chamber of the eye is determined by the net result of two competing processes,

1. the rate of drug loss from the precorneal area.

2. the rate of drug uptake by the cornea

Once the drug penetrates the cornea and enters the aqueous humor, it is distributed to all the internal tissues of the eye. The anterior chamber is in contact with the cornea, iris, ciliary body, lens and vitreous humor. The drug is rapidly distributed to these tissues and concentrations mirror those of the aqueous humor. Deeper into the intraocular tissues, the concentration is reduced by aqueous humor turnover and non-specific binding as illustrated in Figure 11.9.

Drug penetration through the sclera and conjunctiva

The sclera could constitute an important penetration route for some drugs, particularly those with low corneal permeation. Drugs may diffuse across the sclera by three possible pathways:-

1. through perivascular spaces

2. through the aqueous media of gel-like mucopolysaccharides

3. across the scleral collagen fibrils.

An in vitro study using isolated corneal and scleral membranes of the rabbit has shown that scleral permeability was significantly higher than the respective corneal permeability for many hydrophilic compounds6. The ratio of permeability coefficient of sclera to that of cornea was reported 1.2-5.7 for some blockers and 4.6 for inulin. The permeability coefficients were in the order propranolol > penbutolol > timolol > nadolol for the cornea and penbutolol > propranolol > timolol > nadolol for the sclera. It was suggested that the mechanism for scleral permeation was diffusion across the intercellular aqueous media, as in the case of the structurally similar corneal stroma. This mechanism alone however, cannot explain the substantially higher permeability of penbutolol and propranolol compared with the other compounds of similar molecular weight. A partitioning mechanism may account for these observations. The conjunctival/scleral route has also been reported to be the predominant pathway for the delivery of p-aminoclonidine to the ciliary body7.

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