(T1130-08-44) Dexamethasone Intravitreal Implants: Manufacture, Characterization, and Elucidation of Drug Release Mechanisms

Purpose: Ozurdex^® (dexamethasone intravitreal implant) is a long-acting, biodegradable implant containing dexamethasone and poly(lactic-co-glycolic acid) (PLGA) indicated for treatment of macular edema and noninfectious uveitis (1). The rod-shaped implant slowly releases dexamethasone from a PLGA matrix over the course of several months.  In this study, dexamethasone intravitreal implants similar to Ozurdex were manufactured and studied to elucidate the mechanisms of controlled drug release.

Methods: Dexamethasone intravitreal implants with an average diameter of 459 μm (± 5 μm S.D., N=1474) were prepared with the following composition: 60% micronized dexamethasone, 30% Resomer RG 502 H (50:50 PLGA, acid-terminated), and 10% Resomer RG 502 (50:50 PLGA, ester-terminated).  A two-step hot melt extrusion process was performed with a Haake MiniLab extruder fitted with co-rotating screws.  The melt was pushed through a heated, cylindrical die and reduced to the target diameter via a dual-wheel puller and integrated laser micrometer (Figure 1).  Internal and external morphology of the implant was characterized using X-ray micro-computed tomography (microCT), polarized light microscopy (PLM), and scanning electron microscopy (SEM).  In vitro release testing in saline was performed at 37°C to evaluate drug release over several weeks (2).  Whole implants were consumed throughout the dissolution process for characterization of PLGA molecular weight by gel permeation chromatography (GPC), implant water content, and total mass loss.

Results: Careful control of the extruder feeding process at 8-10 g/hr was required to produce implants with consistent diameter.  The two-step extrusion process was necessary to first densify the material and produce granules for consistent feeding during the second extrusion and implant shaping process.  A mean residence time of approximately 33 minutes was measured using a tracer dye during the second extrusion.  X-ray microCT imaging revealed dexamethasone intravitreal implants have a porosity of 12-14% by volume due to numerous internal voids with an average diameter of 3 μm (Figure 2).  SEM showed intimate mixing of drug and PLGA occurred during the melt extrusion process.  PLM indicated that the dexamethasone remains crystalline throughout the implant matrix.  The implants exhibit a tri-phasic release profile common to many PLGA-based formulations: burst release, a lag phase, followed by release to completion (3).  Minimal burst release on Day 1 ( < 2%) and a one-week lag phase were observed prior to complete release of dexamethasone in the third phase.  A 57% drop in PLGA molecular weight along with a 10% (w/w) increase in water content was observed after one-week, despite only 10% drug release.  Throughout the in vitro dissolution study, total implant mass loss correlated closely with dexamethasone release (Figure 3).

Conclusion: Dexamethasone intravitreal implants produced using a two-stage extrusion process exhibited considerable internal porosity and a tri-phasic release profile comparable to Ozurdex®.  Drug release is largely dictated by implant structure and significant hydrolytic reduction in PLGA molecular weight during the first seven days in normal saline.

References: (1) Ozurdex [package insert]. Madison, NJ: Allergan; 2020.
(2) Bhagat R, Zhang J, Farooq S, Li XY. Comparison of the release profile and pharmacokinetics of intact and fragmented dexamethasone intravitreal implants in rabbit eyes. J Ocul Pharmacol Ther. 2014;30(10):854-8.
(3) Tamani F, Bassand C, Hamoudi MC, Danede F, Willart JF, Siepmann F, et al. Mechanistic explanation of the (up to) 3 release phases of PLGA microparticles: Diprophylline dispersions. Int J Pharm. 2019;572:118819.

Acknowledgments: This work was supported by the Broad Agency Announcement (BAA) Contract # 75F40120C00198 from the U.S. Food and Drug Administration (FDA). The content reflects the views of the authors and should not be construed to present FDA’s views or policies.

Illustration of second extrusion and shaping process used to prepare dexamethasone intravitreal implants.



Overlay of drug release and total mass loss from dexamethasone intravitreal implants during in vitro release testing in normal saline.



X-ray microCT cross-section of Ozurdex® and the reverse-engineered dexamethasone intravitreal implant produced using the method described above (see Figure 1). Dark spots represent voids.