(T0930-08-50) Polymer Coated Solid Injectable Dispersions for Long-Acting Delivery of Tenofovir Alafenamide

Purpose: This research was aimed at developing a method for long-acting delivery of the prodrug tenofovir alafenamide (TAF) based on a novel solid injectable dispersion (SID) modality.  TAF is a nucleoside reverse transcriptase inhibitor (NRTI) approved for use against human immunodeficiency virus (HIV) as both a pre-exposure prophylaxis (PrEP) and as part of a co-antiretroviral therapy (cART) for managing active HIV infections. Developing a long acting (LA) form of the drug would enable both LA-PrEP and LA-cART for many patients. The primary benefit of this is to improve patient adherence and patient choice when selecting treatment regimen. More reliable, controlled dosing would improve patient quality of life and work towards the goal of ending the HIV epidemic.

Methods: Solid drug nanoparticles (SDNs) were prepared containing 70 wt% TAF stabilised by polyvinyl alcohol (PVA) (9-10k Mw, 30 wt%) or poly lactic-co-glycolic acid (PLGA) (75:25 L:G, 20 wt%) and PVA (10 wt%). Materials were prepared via an emulsion templated freeze-drying methodology. TAF and PLGA dissolved into dichloromethane (DCM) were added to an aqueous PVA solution. The biphasic mixture was sonicated to form an emulsion followed immediately by flash freezing in liquid nitrogen. The frozen samples were placed in a freeze dryer for 48 hrs. Freeze dried materials were characterised by dynamic light scattering following dispersion in water at 1 mg/mL w.r.t. TAF. Formulations were also characterised by high performance liquid chromatography (HPLC), powder x-ray diffraction (pXRD) and scanning electron microscopy-energy dispersive x-ray (SEM-EDX) analysis. SIDs (2 mm diameter ~8 mm length) were prepared by vacuum compression moulding (VCM) at 86°C or 70 °C for PVA and PLGA based materials respectively. An illustration of the VCM equipment is shown in Figure 1. Heating was performed for 6 minutes under -1 bar vacuum and cooling was performed over 5 minutes. A similar method was used to attach 2x2 mm cylinders of polycaprolactone (PCL) to the ends of the SIDs. VCM heating at 60 °C for 10 minutes, 5 minutes cooling time, -0.5 bar pressure. To reduce the rate of TAF dissolution from the SIDs, coatings were applied to SIDs by means of airbrushing. A 50 mg/mL solution of polycaprolactone (PCL) and polyethylene glycol (PEG) dissolved in DCM was sprayed and leftto dry on the surface of the samples; multiple coats were applied to form an opaque film. Rapid equilibrium dialysis (RED) was used to assess the in vitro release of TAF (via HPLC) from the SIDs when immersed in water over an 8-hour period.

Results: PXRD of the freeze-dried monolith confirmed the amorphous state of the formulation. This was further confirmed via SEM-EDX imaging, shown in figure 2, showing a uniform dispersion with no visible variation in drug concentration through the structure. Post VCM the samples were analysed by pXRD and crystallinity was observed for samples processed above 70 °C, with the diffraction pattern matching that of crystalline TAF. SEM-EDX analysis did not show any differences in structure between samples processed at 70, 86, and 110 °C. Hydration of both the freeze-dried monolith and VCM processed samples appeared to show crystallisation of TAF, likely due to its water solubility. PVA containing samples were analysed using micro-computed tomography (µCT) to assess the volume change on hydration. 3-d scans were obtained for a dry sample and an analogous sample suspended in 0.5 wt% carrageenan gel for 24 hrs. A 36% increase in volume was observed after hydration. Coatings made from PCL and PEG were sprayed onto the surface of the SIDs and a reduction in the rate of TAF release was observed in vitro. The structure of the films was assessed using scanning electron microscopy (SEM). Films containing ratios up to and between 0-100 wt% PCL and PEG were sprayed onto glass slides. The dry film was imaged before and after immersion in water overnight. Variation in structure was observed dependent on the wt% of PEG. Film porosity increased with PEG wt% until 70 wt% when the films lost structural integrity after immersion in water.

Conclusion: The structure and properties of TAF SIDs were investigated. It has been shown that crystallisation of TAF occurs with both heating and hydration of the SDNs. The application of polymer film coatings to SIDs has been shown to be an effective strategy for modulating the release of TAF in vitro. This is a step towards developing a long-acting form of TAF for HIV treatment and PrEP.

Figure 1: Left: exploded cross section view of VCM equipment. Right: assembled cross section of VCM equipment. Grey: body or equipment. Orange: rubber o-ring seals. Light blue: silicon tube. Yellow: sample.

Figure 2: SEM-EDX scan of TAF 70wt%, PVA 30wt% freeze dried monolith.