A. Krovi, D. Cruz, L. Li, G. Jimenez, C. Areson, P. Johnson, E. Luecke, C. Norton, L. Johnson
Keywords: implant, biodegradable, subcutaneous, HIV PrEP, controlled release
Summary:Long-acting and systemic delivery of antiretrovirals (ARVs) for HIV pre-exposure prophylaxis (PrEP) can mitigate challenges associated with adherence to daily or on-demand regimens. RTI International is developing an implantable platform technology that can improve HIV PrEP regimens by offering user independence for improved adherence, biodegradation, long-term protection, and the option for retrievability for the duration of drug delivery. This reservoir-style implant comprises poly(ε-caprolactone) (PCL), a biodegradable and clinically-marketed polymer that can advantageously eliminate the requirement of a medical procedure for implant removal after drug depletion. Here, we demonstrate the advancement of product specifications for the implant with a focus on new PCL formulations to optimize drug release rates, mechanical properties, and biodegradation profiles. These PCL implants were designed to deliver ARVs including bictegravir (BIC) and 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), wherein product specifications (surface area, wall thickness, number average molecular weight (Mn) of PCL) were tailored to achieve targeted doses at zero-order release kinetics. Raw PCL pellets with different molecular weights were extruded into tubes via hot-melt extrusion with dimensions compatible with current market-available trocars (outer diameter 2.5 mm, length ≤ 40 mm): PCL-1 Mn 37 kDa, PCL-2 Mn 47 kDa, PCL-3 Mn 56 kDa, PCL-4 Mn 80 kDa, and PCL-5 Mn 77 kDa. ARV-excipient formulations were loaded into extruded tubes, enclosed via heat sealing, and sterilized with gamma irradiation (18-24 kGy) prior to in vitro release (IVR) studies. IVR assays were used to determine the release kinetics of ARVs from implants submerged in phosphate buffered saline (PBS, pH 7.4) with gentle agitation at 37 °C to mimic physiological conditions. Drug concentrations were analyzed by UV-Vis spectroscopy or high-performance liquid chromatography. The crystallinity and Mn of PCL were characterized using differential scanning calorimetry and gel permeation chromatography, respectively. Results show the ability to tune the zero-order release profiles of ARVs from the PCL implant through the Mn of the PCL homopolymer, PCL-3>PCL-4>PCL-5>PCL-2>PCL-1, as observed by the 90-day cumulative release profiles of BIC and EFdA. A pronounced change in the percent crystallinity of PCL exists between PCL-2 and PCL-3, whereupon the values plateau. Overall, PCL-3 exhibited optimal performance in this implant system, with sustained drug release profiles for BIC at ~35-60 µg/cm/day and EFdA ~2-5 µg/cm/day and estimated duration drug delivery >2 years for both ARVs. Release rates were further tuned by varying the wall thickness of the implants from 70 µm to 300 µm resulting in release rates at ~75-630 µg/cm/day for BIC and ~2-20 µg/cm/day for EFdA. This implantable platform technology is a versatile long-acting, biodegradable drug delivery system capable of delivering a portfolio of formulated drugs and it offers an effective approach for tuning drug release in a controlled and sustained fashion by leveraging implant attributes, including polymer compositions, drug formulations, and implant dimensions. Future studies probing the biodegradation profiles of the different Mn of PCL will inform new implant designs to accommodate requisite degradation timeframes.