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

Shweta R. Ugaonkar, Justin T. Clark, Lexie B. English, Todd J. Johnson, Karen W. Buckheit, Robert J. Bahde, Daniel H. Appella, Robert W. Buckheit, Patrick F. Kiser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Nucleocapsid 7 (NCp7) inhibitors have been investigated extensively for their role in impeding the function of HIV-1 replication machinery and their ability to directly inactivate the virus. A class of NCp7 zinc finger inhibitors, S-acyl-2-mercaptobenzamide thioesters (SAMTs), was investigated for topical drug delivery. SAMTs are inherently unstable because of their hydrolytically labile thioester bond, thus requiring formulation approaches that can lend stability. We describe the delivery of N-[2-(3,4,5-trimethoxybenzoylthio)benzoyl]-β-alaninamide (SAMT-10), as a single agent antiretroviral (ARV) therapeutic and in combination with the HIV-1 reverse-transcriptase inhibitor pyrimidinedione IQP-0528, from a hydrophobic polyether urethane (PEU) intravaginal ring (IVR) for a month. The physicochemical stability of the ARV-loaded IVRs was confirmed after 3 months at 40C/75% relative humidity. In vitro, 25 ± 3 mg/IVR of SAMT-10 and 86 ± 13 mg/IVR of IQP-0528 were released. No degradation of the hydrolytically labile SAMT-10 was observed within the matrix. The combination of ARVs had synergistic antiviral activity when tested in in vitro cell-based assays. Toxicological evaluations performed on an organotypic EpiVaginal tissue model demonstrated a lack of formulation toxicity. Overall, SAMT-10 and IQP-0528 were formulated in a stable PEU IVR for sustained release. Our findings support the need for further preclinical evaluation.

Original languageEnglish (US)
Pages (from-to)3426-3439
Number of pages14
JournalJournal of Pharmaceutical Sciences
Volume104
Issue number10
DOIs
StatePublished - Oct 1 2015

Keywords

  • HIV/AIDS
  • biocompatibility
  • controlled release
  • epithelial delivery/permeability
  • extrusion
  • mucosal drug delivery
  • physicochemical properties
  • polymeric drug delivery system
  • preformulation
  • stability

ASJC Scopus subject areas

  • Pharmaceutical Science

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