title: 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-1), zinc acetate (ZA; targets HIV-1 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 28 d (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.
authors.affiliation: The Population Council, NY 10065, USA. Electronic address: sugaonkar@popcouncil.org.
authors.forename: Shweta R
authors.initials: SR
authors.lastname: Ugaonkar
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Asa
authors.initials: A
authors.lastname: Wesenberg
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wilk
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Seidor
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Mizenina
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Larisa
authors.initials: L
authors.lastname: Kizima
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Aixa
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Levendosky
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kenney
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Meropi
authors.initials: M
authors.lastname: Aravantinou
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Derby
authors.affiliation: Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA.
authors.forename: Brooke
authors.initials: B
authors.lastname: Grasperge
authors.affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, NY 10065, USA.
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.affiliation: Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA.
authors.forename: James
authors.initials: J
authors.lastname: Blanchard
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Narender
authors.initials: N
authors.lastname: Kumar
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Roberts
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Robbiani
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández-Romero
authors.affiliation: The Population Council, NY 10065, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Zydowsky
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002351:Carrageenan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003271:Contraceptive Agents, Female / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D003274:Contraceptive Devices, Female / Q000821:virology*; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004867:Equipment Design; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006558:Herpes Genitalis / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000187:drug effects; D052162:Human papillomavirus 16 / Q000187:drug effects; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D030361:Papillomavirus Infections / Q000517:prevention & control*; D011247:Pregnancy; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D019345:Zinc Acetate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D003271:Contraceptive Agents, Female; C510296:MIV 150; D011725:Pyridines; D016912:Levonorgestrel; D014508:Urea; D002351:Carrageenan; D054303:HIV Reverse Transcriptase; D019345:Zinc Acetate
keywords: Contraception; Core–matrix design; Efficacy; Intravaginal ring; Microbicides; Multipurpose prevention technology