Influence of Dosage Form on the Intravitreal Pharmacokinetics of Diclofenac

Anti-inflammatory corticosteroids are being used in the clinical settings for the treatment of age-related macular degeneration (AMD) and diabetic macular edema, which are common causes of vision loss in the United States.1–4 However, due to the high prevalence of side effects associated with the use of corticosteroids,4,5 there is a need to identify other anti-inflammatory agents with a better safety profile. Recent studies have demonstrated the usefulness of nonsteroidal anti-inflammatory drugs (NSAIDs) as an alternative.6–8 NSAIDs are potent cyclooxygenase (COX) inhibitors and anti-inflammatory agents, with potential antiproliferative and antiangiogenic effects as well.9 Also, NSAIDs are not associated with cataract formation or elevated intraocular pressure,10 the main side effects of intravitreal corticosteroids. Since topical administration of NSAIDs does not deliver appreciable drug quantities to the posterior segment,11 intravitreal administration of NSAIDs remains a viable option for treating posterior segment disease. However, repeated intravitreal injections entail a risk of retinal detachment and endophthalmitis. A possible alternative to frequent injections of drug solutions is the development of sustained release systems or molecules with prolonged half-lives to reduce injection-related complications, provide enhanced duration of drug effects, and reduce any high-peak-concentration–related side effects encountered with the solution form of the drug. Diclofenac, an NSAID, exerts its action by inhibition of both the COX and lipoxygenase pathways.12 Although diclofenac has been used topically in the treatment of inflammatory conditions, recent focus has been on intravitreal delivery (Baranano DE et al. IOVS 2008;49:ARVO E-Abstract 5606).13 Diclofenac sodium was found to be safe and nontoxic up to a dose of 0.3 mg after intravitreal administration. Since diclofenac sodium is a low-molecular-weight drug (MWt: 318.13), when in solution, as is the case with its commercial ophthalmic formulations, it is predicted to disappear rapidly from the vitreous humor, with a short half life of 2.87 hours.14 To maintain safe levels of diclofenac for prolonged periods in the eye, slow-release drug delivery systems such as nanoparticles,15,16 microparticles,9 or implants17 may be useful. Alternatively, the use of a suspension or less soluble form of the drug may be useful in prolonging intravitreal drug delivery. For instance, intravitreal triamcinolone acetonide drug suspension is known to sustain drug levels up to 8 months.18 Keeping the earlier success of triamcinolone acetonide suspension in mind, the objective of this study was to prepare and assess intravitreal drug delivery from a suspension dosage form of diclofenac acid and compare it with diclofenac solution. A pigmented rabbit model was used in this study, because human eyes are pigmented19 and the drug elimination from the vitreous14 and delivery to the back of the eye can be influenced by eye pigmentation.20 Furthermore, pharmacokinetic models were developed in this study to explain the delivery of diclofenac to tissues of the posterior segment from solution and suspension dosage forms.