(M1030-01-06) Release Tunability of Exemestane from EVA Implants

Purpose: Polymeric drug delivery implants provide long-acting drug release that can improve patient compliance for chronic disease treatments or other treatments that require sustained drug release. Aromatase inhibitors are a class of drugs used in post-menopausal women to reduce the risk of breast cancer as well as to treat hormone receptor-positive breast cancer. Long-term usage of the drug is, generally, required as adjuvant treatment to lower the risk of breast cancer recurrence. The long-acting polymeric implant therefore offers the promise of both patient compliance and convenience by virtue of the sustained release drug profile from the implant product. In this work, we explore the possibility of developing Ethylene Vinyl Acetate (EVA) based implants of a model Aromatase inhibitor drug – Exemestane. The release tunability to achieve long-term Exemestane release from EVA matrix was explored by application of EVA membranes on core matrix implants.

Methods: Cryogenically ground EVA at different vinyl acetate (VA) levels was hot melt extruded with Exemestane at two (2) different drug loading levels (10% and 60% w/w). Hot Melt Extrusion (HME) was performed using an 11 mm twin-screw extruder. Multilayer samples to control drug release were then prepared by further re-processing of extruded rod samples via Vacuum Compression Molding (VCM) to yield discs (2 cm x 0.1 cm). These discs were then coated with membranes of EVA (28% VA) to yield final dimensions of 2 cm x 0.15 cm. Each disc was further cut into four quadrants and open edges of each quadrant were sealed with EVA (40% VA content). During the extrusion and VCM, process temperatures were maintained at ≤ 100°C. The multilayer quadrant disc samples and controls, i.e. extruded rods and monolayer discs, were subjected to drug release in phosphate buffered saline (PBS) in incubators constantly shaking at 100 RPM and maintained at 37°C. Elution buffer was replaced at every sample pull point. All samples were analyzed via HPLC. Samples analyzed were either duplicated or triplicated and no individual sample deviated more than 35% from the average. Only average values are reported.

Results: At any drug loading, application of membranes in multilayer samples controlled the overall drug release when compared to monolayer samples (disc or rod). At the end of the study, surface area normalized cumulative release was found to be mg/cm² as compared to 1.17 mg/cm² for 60% drug loaded monolayer and multilayer discs respectively (see Fig. 1). Also, for the same drug loading, i.e. 60 %, initial burst for monolayer disc was 0.4 mg/cm² and 0.17 mg/cm² for monolayer and multilayer samples, respectively. A similar trend followed for 10% loaded samples as well. Also, release prediction using the Higuchi model showed that even the monolayer 60% drug loaded disc samples were capable of releasing drug up to ~ 4 years.

Conclusion: Our results show tunability of results by application of EVA membranes on a core EVA matrix. HME/VCM can therefore be used to tune the Exemestane drug release to provide a sustained release drug profile. This has the potential to improve patient compliance as multiyear implants can be developed via the HME/ VCM technique.

Fig. 1 Release of Exemestane (at 10 or 60% loading) from EVA implants with either 28% or 40% nominal VA content.