A novel intravaginal ring to prevent HIV-1, HSV-2, HPV, and unintended pregnancy

Abstract

Women urgently need a self-initiated, multipurpose prevention technology (MPT) that simultaneously reduces their risk of acquiring HIV-1, HSV-2, and HPV (latter two associated with increased risk of HIV-1 acquisition) and prevents unintended pregnancy. Here, we describe a novel core-matrix intravaginal ring (IVR), the MZCL IVR, which effectively delivered the MZC combination microbicide and a contraceptive. The MZCL IVR contains four active pharmaceutical ingredients (APIs): MIV-150 (targets HIV), zinc acetate (ZA; targets HIV and HSV-2), carrageenan (CG; targets HPV and HSV-2), and levonorgestrel (LNG; targets unintended pregnancy). The elastomeric IVR body (matrix) was produced by hot melt extrusion of the non-water swellable elastomer, ethylene vinyl acetate (EVA-28), containing the hydrophobic small molecules, MIV-150 and LNG. The solid hydrophilic core, embedded within the IVR by compression, contained the small molecule ZA and the macromolecule CG. Hydrated ZA/CG from the core was released by diffusion via a pore on the IVR while the MIV-150/LNG diffused from the matrix continuously for 94 days (d) in vitro and up to 28d (study period) in macaques. The APIs released in vitro and in vivo were active against HIV-1ADA-M, HSV-2, and HPV16 PsV in cell-based assays. Serum LNG was at levels associated with local contraceptive effects. The results demonstrate proof-of-concept of a novel core-matrix IVR for sustained and simultaneous delivery of diverse molecules for the prevention of HIV, HSV-2 and HPV acquisition, as well as unintended pregnancy.

Microbicide vaginal rings: Technological challenges and clinical development

“…A combination EVA matrix-type ring providing simultaneous release of the microbicide candidate UC781 and the contraceptive progestin levonorgestrel (LNG) has also been reported [40]. The Population Council are developing an EVA core-matrix ring for simultaneous delivery of Medivir-150 (MIV-150), carrageenan (CG), zinc acetate (ZA) and levonorgestrel (LNG) [60].…”

First-in-Human Trial of MIV-150 and Zinc Acetate Coformulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence, and Pharmacodynamics

“…Zn 2+ concentrations (CVL) were determined by atomic emission spectroscopy (Alliance Analytical Lab; Coopersville, MI). Antiviral activity in CVL was assessed using a TZM-bl assay with an HIV-1 ADA-M laboratory strain, 28 a colorimetric assay using an HSV-2 G strain, 41 and a luciferase assay using HPV16 pseudovirus. 28 Assays were performed on serial dilutions to establish a dose–response curve.…”

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

“…Maraviroc is an established antiretroviral used in HIV treatment that inhibits entry of HIV into host cells by targeting the CCR5 receptor (Chen et al, 2015;; darunavir is a protease inhibitor already used in combination with other antiretrovirals in the treatment of HIV infection (Mallolas, n.d.). Other combination microbicide vaginal rings have also been reported, including dapivirine and tenofovir (Johnson et al, 2010), tenofovir disoproxil fumarate and maraviroc (Moss et al, 2016), MIV-150 and zinc acetate (plus other drugs) (Ugaonkar et al, 2015), and tenofovir, nevirapine, and saquinavir (plus other drugs) (Moss et al, 2013).…”