A Tunable, Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant Delivering Tenofovir Alafenamide Fumarate for HIV Pre-exposure Prophylaxis

Abstract

Purpose: The effectiveness of Tenofovir based 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.

Methods: A thin-film polycaprolactone (PCL) membrane controls drug release from a reservoir. To achieve membrane controlled release, TAF requires a formulation excipient such as PEG300 to increase the dissolution rate and reservoir solubility. Short-term In vitro release studies are used to develop an empirical design model, which is applied to the production of in vitro prototype devices demonstrating up to 90-days of linear release and TAF chemical stability.

Results: The size and shape of the TFPD are tunable, achieving release rates ranging from 0.5 to 4.4 mg/day in devices no larger than a contraceptive implant. Based on published data for oral TAF, subcutaneous constant-rate release for HIV PrEP is estimated at <2.8 mg/day. Prototype devices demonstrated linear release at 1.2 mg/day for up to 90 days and at 2.2 mg/day for up to 60 days.

Conclusions: We present 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.

Keywords: HIV pre-exposure prophylaxis; antiretroviral; biodegradable implant; membrane controlled release; polycaprolactone; tenofovir alafenamide fumarate.

Figure 1

Linear release rate of TAF from PCL reservoir device has a non-linear dependence on surface area. This is not characteristic of membrane controlled release. Release rates are normalized for membrane thickness and each data point represents an individual device.

Figure 2

(A) Cumulative release profile of TAF from PCL TFPDs loaded with TAF-PEG300 (2:1 w/w ratio). All devices have 8.5μm thick membrane. Each series represents an average of triplicate devices with error bars representing 1 standard deviation. Average values are only calculated for time points while all devices retain solid TAF in device reservoir and release profile is linear. (B) TAF linear release rates taken from the data shown in (A) scale linearly with membrane surface area. Error bars represent 1 standard deviation.

Figure 3

Reference source not found.: (A) Cumulative release profile of TAF from PCL TFPDs loaded with TAF-PEG300 (2:1 w/w ratio). Each series represents average of triplicate devices with error bars representing 1 standard deviation. Average values are only calculated for time points while all devices retain solid TAF in device reservoir and release profile is linear. All devices are 2–2.5mm diameter × 40mm long rods (294 mm² +/− 26 surface area). (B) TAF linear release rates taken from the data shown in (A) and from prototype devices in [Figure 6]. Error bars represent 1 standard deviation.

Figure 4

Reference source not found.: Surface area normalized release rates for TAF from PCL TFPD (8.5 μm membrane) with a range of w/w ratios of TAF to PEG300. No statistically significant difference in release rates (p=0.16).

Figure 5. TAF Thin Film Polycaprolactone Device Prototypes

(A) 2.5mm diameter, 40mm long prototypes loaded with 230mg 1:1 TAF:PEG300 (w/w). (B) 0.6mm diameter, 20mm long prototype loaded with 26mg 1:1 TAF:PEG300 (w/w).

Figure 6. TAF TFPD Prototypes

(A) Device parameters and predicted release rates for TAF TFPD prototype devices. Each group consists of n=3 devices and measurements represent average values +/− 1 standard deviation. (B) Cumulative release profiles for prototype device groups. Prototype devices are loaded with a 1:1 TAF:PEG300 (w/w) formulation. Release profile is linear (solid data points) until device nears depletion (outlined data points). Linear regression determines average release rate for each prototype group (mg/day). (C) Purity of TAF remaining in device reservoir after incubation under physiological conditions (PBS pH 7.4, 37°C).