Topical Chemical Drug Delivery Systems

In addition to the physical ways of controlling drug release it is possible to control the release rate by chemical reaction. This principle is utilized in prodrugs - compounds that are inactive themselves, but release the parent compound in a chemical reaction, usually enzyme-catalysed hydrolysis. Often prodrugs are esters and esterase activity in the route of drug penetration, or later, is required for activity. In addition to esters, other types of ocular prodrugs have been developed (Lee and Li, 1989).

Ocular prodrugs are usually more lipophilic than the parent compound. Consequently, they show improved corneal absorption. The cornea contains esterases mostly in the epithelium, where hydrolysis of topically applied prodrugs takes place (Lee etal., 1982). Esterases are present also in the corneal stroma and iris-ciliary body and thus they may also have a role in the release of the parent compound. Ocular absorption of epinephrine (Anderson, 1980), timolol (Chang etal., 1987, 1988), and pilocarpine (Mosher etal., 1987; Suhonen etal., 1991) has been improved using the prodrug technique.

Ocular pharmacokinetics of prodrugs is very complex. Although several excellent comparative studies on the general performance of the prodrugs have been undertaken, there are no quantitative modelling studies on ocular prodrugs. The rate and extent at which the parent drug is formed from the prodrug depends on the ability of the prodrug to reach the enzymes, the time that the prodrug is in contact with the enzymes in the cornea, and finally the susceptibility of the prodrug structure to enzymatic hydrolysis (Lee and Li, 1989). The amount of prodrug that is absorbed by the cornea determines the drug bioavailability, if the prodrug is quantitatively converted to the parent drug in the eye. Peak drug concentration in aqueous humour is determined by the input rate and elimination (Chang et al., 1987; Lee and Li, 1989). Here, input rate is determined by the rate of parent drug formation from the prodrug and thus it can be controlled by proper chemical design. Because enzyme-catalysed reactions are saturable, the rate of drug cleavage from the prodrug may be dose-dependent and the ocular pharmacokinetics may become non-linear. Dose-dependent kinetic behaviour of the ocular prodrugs has not been demonstrated but, in principle, it is possible. At the level of enzyme saturation ocular drug delivery could be impaired owing to incomplete prodrug hydrolysis in the eye.

Prodrug technique also offers possibilities of prolonging drug activity in the eye. Prolonged activity is possible if the prodrug is well absorbed into the cornea and the parent drug is released slowly from the prodrug. For example, prolonged miotic activity of lipophilic pilocarpine diester prodrugs was demonstrated by Mosher etal. (1987). Using prodrug technology it is possible to change the rate of hydrolysis by orders of magnitude by changing the ester moieties (Chang etal., 1987; Jarvinen et al., 1991). Thus, it is a powerful technique for controlling drug release, but intact prodrug must be retained long enough in the regions of enzymatic activity in the eye (Lee etal., 1982). If the retention in the eye is not long enough to allow drug release from the prodrug, bioavailability may be decreased and no substantial prolongation of drug activity is achieved. Lipophilic drugs with stroma-controlled corneal permeation have longer retention in the corneal epithelium - the main site of prodrug hydrolysis (Suhonen etal., 1991). Conversion of the lipophilic prodrug to less lipophilic intermediates and/or parent drug accelerates the rate of corneal transport (Chien etal., 1991; Suhonen etal., 1991). Thus, it is possible to control the input rate of the drug to the intraocular receptors by changing the rate of hydrolysis and lipophilicity of the prodrug. However, a prerequisite of this is adequate retention of the prodrug in the vicinity of the enzymes in the cornea and iris/ciliary body (Mosher, 1986; Lee and Li, 1989).

Smaller drug doses can be used in prodrug eyedrops because the ocular bioavailability can be increased several-fold (e.g. timolol and adrenaline) (Anderson, 1980; Chang etal., 1987, 1988). Fortunately, the systemic absorption of the drugs does not increase in the same proportion as ocular absorption. Consequently, prodrug technology has been shown to be an efficient way of decreasing the systemic absorption of timolol and adrenaline (Anderson, 1980; Lee and Robinson, 1986; Chang etal., 1987). This follows because the systemic bioavailabilities of timolol and adrenaline are 70% and 50%, respectively, and these values cannot be increased several-fold like ocular absorption.

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