(W1130-06-35) Innovative Multilayer VitalDose® EVA Implants for Controlled and Sustained Release of Goserelin Acetate

Purpose: Ethylene Vinyl Acetate (EVA) copolymers have a long commercial history of use in drug-eluting subcutaneous implants. To achieve successful long-term delivery, it is desirable to produce implants with a high drug load. However, high drug loading in a monolithic implant often results in high initial burst release and a faster-than-desired overall drug release rate. To resolve these issues and tune release, multilayer implants can be. In this study we investigated the release of goserelin acetate, a peptide used in the treatment of prostate and breast cancer, from both monolithic and multilayer EVA implants.

Methods: Hot-Melt Extrusion: Hot-melt extrusion was used  to fabricate rod-shaped implants composed of goserelin acetate (GA) and Ethylene Vinyl Acetate (EVA). The implants consisted of 40 wt.% EVA and 60 wt.% GA. EVA was cryogenically ground and blended with GA powder. The resultant powder blend was fed into an 11 mm twin-screw extruder and extruded at 65°C. The extrudate pieces underwent secondary processing via vacuum compression molding (MeltPrep VCM) to form 2mm diameter x 1cm long cylindrical implants. A subset of these monolithic implants were used without further modification. Membranes were attached to the reminder of these implants by thermal bonding to produce two membrane implant formulations, multilayer A and multilayer B. In Vitro Drug Release: Monolithic and multilayer implants (n = 3 per formulation) were immersed in 25 mL of phosphate-buffered saline (PBS) solution with a pH of 7.4 and 0.02% (w/v) sodium azide to perform in vitro drug elution testing. After being placed in an incubator at a temperature of 37°C, the media and implant were subjected to gentle agitation on a 100 rpm oscillating table. The elution media was periodically replaced with fresh buffer, and the concentration of GA in the media was determined using (HPLC). Drug release from the implant was followed for over 200 days. Elution media at selected timepoints was further characterized with HPLC-Mass Spectroscopy to detect and identify GA degradants.

Results: At a drug loading of 60 wt.%, the application of membranes in multilayer samples effectively controlled the overall drug release compared to monolayer rods. The monolithic implants exhibited a faster release of goserelin acetate (GA), depleting in 35 days; the average daily release rate over this time period was approximately 470 µg per day. In contrast, the multilayer designs exhibited sustained drug release over the full 217 days of the experiment. Implants with multilayer A demonstrated a release rate of 130 µg per day over the first 90 days, and an average release rate of approximately 70 µg per day averaged over the full study. The multilayer B design showed a significantly slower release, resulting in 10 µg per day over the full length of the study.  GA was not degraded by extrusion, and exhibited excellent stability over the first 90 days of the study. After 90 days we detected a small quantity of an impurity with a molar mass 57 Da less than that of GA in the elution media.

Conclusion: Our results demonstrate the successful incorporation of goserelin acetate at high loading via the hot-melt extrusion process into VitalDose® EVA. Using membranes to slow down drug release kinetics, we were able to tune drug release rates over an approximately 500-fold range, and achieve release profiles with essentially no initial burst release. Implants in this study achieved the target therapeutic dose with good drug stability for at least 90 days.