Intravitreal crystalline drug delivery for intraocular proliferation diseases.

Direct delivery of drug to the posterior segment by intravitreal injection or intravitreal implant has demonstrated advantages in treating acute or chronic vitreoretinal diseases. Contrasted with systemic drug administration, local intravitreal drug administration bypasses the blood–ocular barriers, allowing higher intraocular drug levels and avoiding many of the side effects associated with systemic therapy. We have developed and reported a crystalline lipid prodrug intraocular delivery system.1 We demonstrated that the crystalline lipid prodrugs of ganciclovir (HDP-P-GCV) and cyclic cidofovir (HDP-cCDV) provided longer duration of antiviral effect than the unmodified compounds in a rabbit HSV retinitis model after a single intravitreal injection.1,2 Compared with intravitreal surgical implants, this delivery system involves only a simple intravitreal injection that can be easily performed in an office setting without the complications associated with surgical placement or replacement of intravitreal implants.3 We propose that this intravitreal drug-delivery system may be applicable to certain other compounds for the purpose of developing long-lasting drugs for inhibition of intraocular proliferation and angiogenesis. In this report, we extended this work to an area of unmet medical need; long-acting antiproliferative intraocular drug treatment. We chose to target proliferative vitreoretinopathy (PVR) associated with trauma and/or retinal detachment as well as proliferation associated with age-related macular degeneration (ARMD). PVR is the most common cause of poor visual outcomes in association with retinal detachment4,5 and ocular trauma. despite extensive advances in vitreoretinal surgical technique.6–8 Pharmacologic interventions have shown limited success with the use of one-time intraoperative treatments with antiproliferative agents such as daunomycin and a combination of 5-fluorouracil and heparin.9,10 In both ocular trauma and retinal detachment, an intravitreal injection of a long-acting nontoxic agent to prevent proliferation and all the attendant disastrous consequences of such proliferation would be of major benefit. ARMD and choroidal neovascularization (CNV) in particular are the leading causes of irreversible visual loss in the Western world.11,12 The primary pathologic process in CNV associated with ARMD includes a subretinal proliferative neovascular response in the macula. Over time, proliferation results in a fibrous disciform scar causing permanent loss of central vision and legal blindness. Currently available treatments for CNV include thermal photocoagulation for extrafoveal CNV,13,14 and intravitreal injection of antiangiogenesis agents for subfoveal CNV.15,16 These antiangiogenesis treatments require frequent intravitreal injections (8–12 times per year), although the vision can be maintained during the study period with repeated administration.17,18 A long-acting, intravitreal antiproliferation treatment could reduce the necessity for frequent intravitreal injections, and the crystalline lipid prodrugs of antiproliferation may be synergistic with these angiogenesis treatments by reducing scarring and angiogenesis.19 In the present study, we modified the antiproliferative nucleoside analogues arabinofuranosylguanine (AraG) and 2′-deoxy-5-fluorouridine (5-F-2dUrd) by covalent attachment of an alkoxyalkyl phospholipid residue to obtain three lipophilic prodrugs: hexadecyloxypropyl arabinofuranosylguanine 5′-monophosphate (HDP-P-AraG), hexadecyloxypropyl 5-fluoro-2′-deoxyuridine 5′-monophosphate (HDP-P-5F-2dUrd), and hexadecyloxypropyl 5-fluoro-2′-deoxyuridine 3′,5′-cyclic monophosphate (HDP-cP-5-F-2dUrd). These compounds were intravitreally injected into animal eyes, and the intravitreal properties as well as preliminary efficacy were evaluated.