Intravitreal Drug Delivery Systems

Rapid drug elimination from the vitreous humour is a major kinetic difficulty in intravitreal drug administration. Injection of antiproliferative agents (in proliferative vitreoretinopathy) or antibiotics (in endophthalmitis) may cause retinal toxicity that is associated with the peak drug concentrations (Niesman, 1992). The peak drug concentrations and subsequent toxicity can be decreased by administering the drugs in controlled release systems. Polymeric inserts (Smith etal., 1990), liposomes (Barza etal., 1987; Liu etal., 1989a), and biodegradable microparticles (Moritera etal., 1991) have been used for this purpose.

Liposomes are the most commonly studied prolonged action dosage form for intravitreal administration (Lee etal., 1985). The pharmacokinetics of the intravitreal liposomal drug are presented schematically in Fig. 3. The role of drug release depends on the drug: in the case of antimicrobials only the released fraction is efficacious, while liposomal drug serves as a depot. Consequently, both the efficacy and retinal toxicity of liposomal amphotericin B was decreased compared with the solution (Liu etal., 1989a). This may be due to the fact that after administration only a part of the drug in the vitreous humour is free. Both antimicrobial efficacy and retinal toxicity are related to the free drug concentration and not to the total drug in the vitreous humour. Nevertheless, total drug concentrations (encapsulated plus free) are usually determined from the vitreous humour after liposomal administration. Typically, the half-life of free drug is shorter than that of liposomal drug and, consequently, the elimination and release kinetics of liposomes are the rate-determining factors in the system. Barza etal. (1987) determined the half-life of the liposomes in the vitreous humour as 9-20 days, depending on the composition; e.g. the half-life of gentamicin in the vitreous humour is 1 day. Addition of cholesterol to liposomes increases

DOSAGE FORM IN VITREOUS

RELEASED DRUG IN VITREOUS

->. POSTERIOR ELIMINATION

DOSAGE FORM IN VITREOUS

ANTERIOR ELIMINATION TO AQUEOUS HUMOUR

Fig. 3 Ocular pharmacokinetics of intravitreal sustained release medications.

the drug retention in the vitreous humour, probably because the release rate is decreased (Barza etal., 1987).

In the case of antimetabolites, liposomes can be used to target drug to proliferating cells (Stern etal., 1987). The cells may endocytose liposomes and in this way more efficient intracellular drug delivery and drug potency are achieved. Liposomal antimetabolites, e.g. 5-fluorouracil and cytara-bine, have reduced retinal toxicity compared with the drug in solution (Stern etal., 1987; Liu etal., 1989b). If the liposomes are endocytosed by the target cells the free drug concentration is not a crucial factor. Three ways of drug elimination from vitreous humour are then possible: elimination of free drug, liposomal drug, and the cells with internalized liposomes (Fig. 3).

After intravitreal liposome injection the concentration of the free drug in the vitreous humour is determined by the drug release from the liposomes and the elimination of the released drug (Fig. 3). Thus, for drugs with high vitreal clearance a faster drug release rate is required to sustain the concentrations at adequate levels. In vitrectomized eyes and for drugs capable of elimination via both the anterior and posterior routes (Maurice and Mishima, 1984) rapid release is required to maintain therapeutic free drug concentrations in the vitreous humour.

Another way to achieve prolonged action for intravitreal drug is to incorporate the drug in biodegradable polylactide-co-glycolide microparticles (Moritera etal., 1991). The microparticles have a mean diameter of 50/im and therefore cannot be endocytosed (Fig. 3). The microparticles are cleared from the normal eye by 48 ± 5.2 days, but in vitrectomized rabbit eyes the mean retention is 14 ± 2.4 days.

Recently, polymer matrices have been tested as a prolonged action dosage form for intravitreal drug administration. For example, ganciclovir intravit-really administered in sutured ethylene vinyl acetate (EVA) and polyvinyl alcohol polymer matrices resulted in drug levels above the ID 100 (inhibitory dose for 100% of the viruses) of cytomegalovirus for 50 days (Smith etal., 1990). This approach may be useful in the treatment of cytomegalovirus infections that are a common problem in the eyes of acquired immune deficiency syndrome (AIDS) patients.

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