Development of Reservoir Vaginal Rings Containing Dapivirine or Hormonal Contraceptive Steroids

Abstract

ARV: TDF, tenofovir, maraviroc, and IQP-0528 and several macromolecules. We evaluated IQP-0528 IVR-pumps in sheep for drug release rate, and drug concentration and distribution in the vaginal canal. Results: Altering the type of swelling polymer, drug loading, orifice design and the mass of pellets can control the drug release rate and duration. Formulations for high molecular weight species like IgG and linear polymers could be obtained that were nearly zero order for a month. Less controlled release profiles were achieved with more water-soluble drugs including maraviroc, tenofovir and TDF since the drugs possess much higher diffusivity in the hydrated polymer matrix. We observed mg per day release rates in sheep with an average IQP-0528 concentration in vaginal fluid of 270 lg/mL (*10 5 x the IC 90 ). Conclusions: This device provides an adaptable platform for vaginal drug delivery. We have been able to deliver impressive quantities of hydrophobic drugs as microparticles and high molecular weight agents for a month in animal models.Background: By extending the use duration of vaginal rings (VRs), the overall production cost per patient per month can be greatly reduced. Matrix-type ring designs produce an initial burst of drug release, and concentrations during the burst must be maintained within safe limits. This constrains both the maximum drug load and, in turn, the use duration of a matrix ring. By contrast, reservoir-type VRs comprise a drug-loaded reservoir surrounded by a rate-controlling non-medicated sheath, such that initial burst release is minimised and constant daily release rates are achieved. In this way, greater drug loadings and longer use periods are possible. Here, we report the development of reservoir VRs formulations containing dapivirine (DPV) and various contraceptive steroids. Methods: Reservoir VRs were manufactured with injection molded cores containing ethinyl estradiol (EE), etonogestrel (ETO), levonorgestrel (LNG) or DPV. Addition-and condensation-cured silicone cores were tested. All cores were overmolded with a blank 1.5 mm addition-cured silicone sheath. Invitro release was assessed for up to 60 days. Results: VRs comprising addition cured silicone cores and blank addition cured silicone sheath layers provided zero order release of DPV (95 lg/day) and LNG (30 lg/day), but not EE (detectable release on days 2 to 10 only) or ETO (no detectable release at any time). Rings comprising a condensation-cured silicone core provided zero order release of DPV (119 lg/day), EE (328 lg/day, days 4 to 18), ETO (422 lg/day, days 4 to 18) and LNG (69 lg/day). Conclusions: Reservoir-type VRs offering zero order release kinetics have potential as a multipurpose prevention technology (MPT) product for contraception and HIV-prevention with use duration of several months. However, the contraceptive hormones require careful selection of the silicone polymer system to ensure adequate release, while DPV is readily released from both types tested.Background: Multipurpose drug delivery systems (MDDS) hav...