In vitro in vivo correlation of dexamethasone TIPS particles

Abstract

Purpose : Corticosteroids are often administered to the posterior segment of the eye via intravitreal (IVT) injections. However, due to their short half-life (t_1/2) of 3-7 hours, repeated injections are necessary to maintain a therapeutic dose over intermediate time periods (e.g. 1-2 weeks). There has been much effort to extend the ocular residence time of steroids and other drugs by formulating them into polymeric implants and devices to achieve a prolonged and sustained release profile. We have designed dexamethasone poly-DL-lactide-co-glycolide (PLGA) microparticles to provide sustained release after IVT administration and to predict their in vivo t_1/2 using an in vitro ocular dissolution model (PK-Eye).

Methods : Dexamethasone-loaded (0.2 mg) PLGA microparticles were fabricated using a thermally induced phase separation (TIPS) and lyophilisation method. The release profile of the TIPS microparticles was evaluated using the proprietary PK-Eye, a two-compartment model that simulates aqueous outflow to estimate drug clearance time from the ocular posterior cavity. Drug release was investigated in both PBS with pH 7.4 and simulated vitreous, which mimic vitrectomised and non-vitrectomised eyes respectively.

Results : Dexamethasone TIPS microparticles were successfully developed and shown to provide sustained in vitro drug release. The particles showed an in vitro t_1/2 of 1.0 ± 0.1 days in PBS and 9.6 ± 0.3 days in simulated vitreous. In vivo t_1/2 was then predicted using in vitro drug release and retinal permeability data. Predicted in vivo t_1/2 was determined to be 48 hours, almost 9 times longer than that reported for dexamethasone suspension. This approach was validated with in vitro drug profiles and published in vivo data for triamcinolone acetonide and dexamethasone suspensions. In vitro in vivo correlations (IVIVC) for intraocular clearance times were successfully achieved using this approach.

Conclusions : Dexamethasone-PLGA TIPS microparticles provide sustained drug delivery of intermediate duration which is useful for acute ocular conditions of the posterior segment. Integrating drug permeation across the retinal choroid sclera (RCS) pathway with anterior aqueous outflow from the PK-Eye allows the in vivo drug clearance of suspensions and implants from the vitreous compartment to be predicted.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.