The Need for Multi-product Technologies for Women Participating in Vaginal Microbicide Trials

Abstract

Background: Combination drug products can display thermal behaviour that is more complex than for the corresponding single drug products. For example, the contraceptive vaginal ring (VR) Nuvaring contains a eutectic (lowest melting) composition of etonogestrel (ETN) and ethinyl estradiol. Here we report the predisposition of dapivirine (DPV) to form reduced melting/eutectic mixtures when combined with other contraceptive hormones and antiretrovirals, and discuss the implications for development of combination microbicide and multipurpose prevention technology (MPT) products. Methods: Binary mixtures of DPV with darunavir (DRV), levonorgestrel (LNG), ETN or maraviroc (MVC) were prepared either by physical mixing or by solvent evaporation. Selected binary mixtures were also incorporated into silicone elastomer (SE) VR devices. Thermal behavior of the mixtures was analyzed using differential scanning calorimetry (DSC) operating in standard heating ramp mode (10°C/min). DSC data were used to construct two component phase diagrams for each binary system. Results: Drug mixtures typically showed reduced melting transitions for both drug components, with clear evidence for a eutectic mixture at a well-defined intermediate composition. Eutectic temperatures and compositions for the various mixtures were: 40% DPV / 60% ETN -170°C; 25% DPV / 75% MVC -172°C; 65% DPV / 35% LNG -192°C. In each case, the eutectic composition was also detected when the drug mixtures were incorporated into SE VRs. For the DPV/DRV system, the thermal behaviour is complicated by desolvation from the darunavir ethanolate polymorph. Conclusions: When DPV is combined with small molecular weight hydrophobic drugs, the melting temperature for both drugs is typically reduced to a degree dependent on the composition of the mixture. At specified compositions, a low melting eutectic system results. The formation of eutectic behavior in binary drug systems needs to be carefully characterised in order to define product performance and drug release.Background: A vaginal ring (VR) that can prevent both unintended pregnancy and the spread of sexually transmitted infec-tions has the potential to significantly improve women's sexual and reproductive health. Here, we report in vitro evaluation of four hormonal contraceptive compounds -levonorgestrel (LNG), ethinylestradiol (EE), etonogestrel (ET) and nestorone (NES) -for co-formulation with dapivirine (DPV) in a silicone elastomer (SE) vaginal ring device. Methods: The influence of each steroid hormone on the SE cure characteristics was assessed using flow rheology. The thermal stability of each API and the potential for drug-polymer and drugdrug interactions were assessed using thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Matrixtype and reservoir-type VRs containing various loadings of each steroid were manufactured using both a condensation-cure and an addition-cure SE systems and in vitro release rates assessed. Results: TGA confirmed all steroids were stable in the temperature...