Engineering a degradable polyurethane intravaginal ring for sustained delivery of dapivirine

Abstract

We describe the engineering of a degradable intravaginal ring (IVR) for the delivery of the potent HIV-1 reverse transcriptase inhibitor dapivirine. The degradable polymer used in fabricating the device incorporated poly(caprolactone) ester blocks in a poly(tetramethylene ether) glycol ABA type polyurethane backbone. The polymer was designed to maintain its structure for 1 month during usage and then degrade in the environment post-disposal. In vitro release of dapivirine showed zero-order kinetics for up to 1 month and significant levels of drug release into engineered vaginal tissue. The mechanical properties of the degradable IVR were comparable to those of a widely used contraceptive intravaginal ring upon exposure to simulated vaginal conditions. Incubation under simulated vaginal conditions for a month caused minimal degradation with minimal effect on the mechanical properties of the ring and polymer. The cytotoxicity evaluation of the drug-loaded IVRs against Vk2/E6E7 human vaginal epithelial cells, Lactobacillus jensenii, and engineered vaginal tissue constructs showed the degradable polyurethane to be non-toxic. In vitro evaluation of inflammatory potential monitored through the levels of inflammatory cytokines IL-8, IL-1α, IL-6, IL-1β, and MIP-3α when engineered EpiVaginal™ tissue was incubated with the polyurethanes suggested that the degradable polyurethane was comparable to commercial medical grade polyurethane. These results are encouraging for further development of this degradable IVR for topical vaginal delivery of microbicides.

An Intravaginal Ring for the Simultaneous Delivery of an HIV-1 Maturation Inhibitor and Reverse-Transcriptase Inhibitor for Prophylaxis of HIV Transmission

“…The IVRs were fabricated by hot‐melt extrusion of cryoground PEU mixed with the ARVs using a benchtop twin‐screw extruder (ThermoHaake, Waltham, Massachusetts) at 147°C, screw speed of 50 rpm, and 4.3 mm wide die . The target ARV loadings were 1 and 10 wt % SAMT‐10 for the single‐agent SAMT‐10 IVR, 10 wt % for IQP‐0528 PEU IVR, and 10 wt % each of SAMT‐10 and IQP‐0528 for the combination of SAMT‐10/IQP‐0528 PEU IVR.…”

Sustained Release Drug Delivery Applications of Polyurethanes

“…Biodegradable poly(ester urethanes) have been prepared from lysine diisocyanate with d , l -lactide, ε-caprolactone and other monomers [ 41 ]. Kaur et al developed a biodegradable intravaginal ring composed of a poly(ester urethane) prepared from bis(4-isocynaatocyclohexyl)methane with poly(tetramethylene ether)glycol and ε-caprolactone, which released the antiretroviral dapivirine at target levels for one month [ 42 ]. Yu et al developed biodegradable polyurethanes based on L-phenylalanine that possess tunable mechanical properties and degradation rates over a wider range than was achievable with poly(lactic acid) [ 43 ].…”

Past, Present, and Future Drug Delivery Systems for Antiretrovirals

“…Dapivirine was released at a near-zero order rate and the rate of drug release depended on the initial drug loading. Kaur et al 93 developed a poly(ester-co-ether) incorporated into the polyurethane backbone to provide it with biodegradable properties. The mechanical properties of rings made with this polymer were similar to those of the commercially used EVA ring.…”