Antiretroviral (ARV) effectiveness for HIV pre-exposure prophylaxis (PrEP) is proven, but hinges on correct and consistent use. User compliance and therapeutic effectiveness can be improved by long acting drug delivery systems. Here we describe a thin-film polymer device (TFPD) as a biodegradable subcutaneous implant for PrEP. A thin-film polycaprolactone (PCL) membrane controls drug release from a reservoir, and release rates and device size are tunable, a key feature for an implant in the early stages of pre-clinical development. We have explored release of ARVs from various classes and will present data pertaining to development of a device to deliver Tenofovir Alafenimide Fumarate (TAF).
Devices were fabricated as a hollow rod with an open end using a wire-heat sealing apparatus and solvent cast PCL films. TAF was loaded into the reservoir with or without formulation excipients. Devices were sealed and incubated in PBS, pH7.4 at 37˚C. For release rates we measured TAF concentration in release media over time. Sink conditions were maintained by regularly replacing the media. Relationships between release rate and device parameters were evaluated using devices with 10-30µm thick membranes and 50-320 mm2 surface areas. TAF chemical stability in the TFPD reservoir was evaluated by RP-HPLC.
Based on published data for oral TAF, subcutaneous constant-rate release for HIV PrEP is estimated at < 2.8mg/day. To achieve membrane controlled release, TAF required additional formulation excipients such as PEG300 or hydroxypropyl-ß-cyclodextrin. The size and shape of the TFPD are tunable, achieving release rates ranging from 0.5-4.4 mg/day in devices no larger than a contraceptive implant.
A proportional relationship between membrane area and release rate was demonstrated. An inverse relationship between membrane thickness and release rate was observed for membranes between 10-15µm, with no further impact on release for membranes > 15µm. Prototype devices demonstrated linear release at 1.2mg/day for up to 90 days and at 2.2mg/day for up to 60 days. We achieved reproducibility in device design and performance with < 10% variability between replicate devices (Figure 1). TAF remained chemically stable in the device reservoir with < 3% change in purity at 50 days
We developed a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape and release rate of the device are tunable over a > 8-fold range. This system is being further evaluated in vivo.