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
Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112
Search for more papers by this authorJustin T. Clark
Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208
Search for more papers by this authorLexie B. English
Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112
Search for more papers by this authorTodd J. Johnson
Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112
Search for more papers by this authorKaren W. Buckheit
ImQuest BioSciences, Frederick, Maryland, 21704
Search for more papers by this authorRobert J. Bahde
Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland, 20892
Search for more papers by this authorDaniel H. Appella
Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland, 20892
Search for more papers by this authorRobert W. Buckheit Jr
ImQuest BioSciences, Frederick, Maryland, 21704
Search for more papers by this authorCorresponding Author
Patrick F. Kiser
Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112
Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208
Telephone: +847-467-5468; Fax: +801-583-4531; E-mail: [email protected]Search for more papers by this authorShweta R. Ugaonkar
Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112
Search for more papers by this authorJustin T. Clark
Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208
Search for more papers by this authorLexie B. English
Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112
Search for more papers by this authorTodd J. Johnson
Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112
Search for more papers by this authorKaren W. Buckheit
ImQuest BioSciences, Frederick, Maryland, 21704
Search for more papers by this authorRobert J. Bahde
Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland, 20892
Search for more papers by this authorDaniel H. Appella
Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland, 20892
Search for more papers by this authorRobert W. Buckheit Jr
ImQuest BioSciences, Frederick, Maryland, 21704
Search for more papers by this authorCorresponding Author
Patrick F. Kiser
Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112
Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208
Telephone: +847-467-5468; Fax: +801-583-4531; E-mail: [email protected]Search for more papers by this authorAbstract
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 40°C/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. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3426–3439, 2015
Supporting Information
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