title: An Intravaginal Ring for the Simultaneous Delivery of an HIV-1 Maturation Inhibitor and Reverse-Transcriptase Inhibitor for Prophylaxis of HIV Transmission.
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 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.
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112.
authors.forename: Shweta R
authors.initials: SR
authors.lastname: Ugaonkar
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Clark
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112.
authors.forename: Lexie B
authors.initials: LB
authors.lastname: English
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Johnson
authors.affiliation: ImQuest BioSciences, Frederick, Maryland, 21704.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Buckheit
authors.affiliation: Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland, 20892.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bahde
authors.affiliation: Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland, 20892.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Appella
authors.affiliation: ImQuest BioSciences, Frederick, Maryland, 21704.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112.|Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Kiser
mesh_terms: D000282:Administration, Intravaginal; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004055:Differential Thermal Analysis; D016503:Drug Delivery Systems; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009924:Organ Culture Techniques; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use*; D012995:Solubility
chemical_list: D019380:Anti-HIV Agents; D001549:Benzamides; D003692:Delayed-Action Preparations; C573126:IQP-0528; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; C554254:S-acyl-2-mercaptobenzamide thioester
keywords: HIV/AIDS; biocompatibility; controlled release; epithelial delivery/permeability; extrusion; mucosal drug delivery; physicochemical properties; polymeric drug delivery system; preformulation; stability