Subconjunctival drug administration

Antibiotics (Barza etal., 1981) and steroids (McCartney etal., 1965) are examples of drugs which are sometimes administered as subconjunctival injections in order to achieve higher drug concentrations in the eye. The volume administered subconjunctival^ is usually 0.5-1.0 ml and after injection a bleb is formed on the ocular surface. Increased ocular absorption of subconjunctival drugs, compared with topically administered drugs, has been demonstrated in several studies (Maurice and Mishima, 1984).

The reasons for increased ocular absorption and the pharmacokinetics of subconjunctival injections have long been studied and discussed but the picture is not yet clear. There are several possibilities for the increased ocular penetration (Fig. 2). Subconjunctival^ injected drug may leach from the injection bleb to the lacrimal fluid and thereafter it may absorb trans-corneally into the eye (Conrad and Robinson, 1980). Bioavailability is increased because the retention time of subconjunctival depot is longer than retention of eyedrops on the ocular surface. Another possibility is the direct penetration through sclera to the anterior uvea (McCartney etal., 1965). There are studies supporting both views. For example, Conrad and Robinson (1980) have shown in a quantitative and mechanistic study that pilocarpine is absorbed by the rabbit eye mainly via the cornea after subconjunctival injection. In contrast, McCartney etal. (1965) have demonstrated scleral penetration of hydrocortisone into the rabbit eye after subconjunctival injection.

The importance of different routes of drug absorption after subconjunctival injection is probably dependent on the physicochemical properties of the drug and the vehicle. Because polar and large molecules do not penetrate well through the cornea (Huang etal., 1983; Wang etal., 1991) they probably do not penetrate corneally even after solution leaching from the subconjunctival depot. For hydrophilic molecules the scleral route may dominate over the corneal route but for more lipophilic molecules leaching from the subconjunctival space and subsequent corneal penetration is the most probable route of ocular absorption. These views are supported by the study of Ahmed and Patton (1985). In their study, inulin (a hydrophilic substance with a molecular weight of 5000) was absorbed after constant topical ocular exposure mainly through conjunctiva and sclera to the iris-ciliary body. In contrast, the smaller and more lipophilic timolol was absorbed mainly transcorneally into the eye. Unfortunately, no one has yet quantitatively and systematically compared ocular absorption of different molecules after subconjunctival injections to demonstrate the possible dependence of the penetration route on the physicochemical properties of the drug.

DRUG IN DOSAGE FORM

RELEASE

DISSOLUTION

REGURGITATION

DOSAGE FORM IN LACRIMAL FLUID

DRAINAGE

RELEASE

RELEASED DRUG

REGURGITATION

RELEASED DRUG IN

LACRIMAL FLUID

SCLERAL PENETRATION INTO THE EYE

SYSTEMIC ABSORPTION

CORNEAL PENETRATION

DRAINAGE

Fig. 2 Ocular pharmacokinetics after subconjunctival injection.

Although at least part of the injected solution may remain in the injection bleb for hours (Conrad and Robinson, 1980) this does not necessarily imply drug retention at the injection site. Subconjunctival^ injected drug is usually absorbed rapidly by blood and therefore the drug concentration in the bleb decreases rapidly (Maurice and Mishima, 1984). This happens both in humans and in rabbits (Maurice and Mishima, 1984). For example, pilocarpine concentration decreased in the subconjunctival space of rabbits to 1/100 in 1 h despite a sizeable bleb (Conrad and Robinson, 1980). Furthermore, Maurice and Ota (1978) have shown that a subconjunctival^ injected concentration of [125I] iodopyracet decreased tenfold in 30min in rabbits. In order to increase ocular absorption and prolong the duration of action different subconjunctival prolonged action medications have been tested.

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