title: Development and in vitro evaluation of a vaginal microbicide gel formulation for UAMC01398, a novel diaryltriazine NNRTI against HIV-1.
abstract: Diaryltriazines (DATAs) constitute a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are being investigated for use as anti-HIV microbicides. The aim of the present study was (1) to assess the biopharmaceutical properties of the DATA series, (2) to select the lead candidate as vaginal microbicide and (3) to develop and evaluate gel formulations of the lead candidate. First, the vaginal tissue permeation potential of the different DATAs was screened by performing permeability and solubility measurements. To obtain a suitable formulation of the lead microbicide candidate, several hydroxyethylcellulose-based gels were assessed for their cellular toxicity, stability and ability to enable UAMC01398 epithelial permeation. Also, attention was given to appropriate preservative selection. Because of its favourable in vitro activity, safety and biopharmaceutical profile, UAMC01398 was chosen as the lead microbicide candidate among the DATA series. Formulating UAMC01398 as a vaginal gel did not affect its anti-HIV activity. Safe and chemically stable gel formulations of UAMC01398 (0.02%) included a non-solubilizing gel and a gel containing sulfobutyl ether-β-cyclodextrin (SBE-βCD, 5%) as solubilizing excipient. Inclusion of SBE-βCD in the gel formulation resulted in enhanced microbicide flux across HEC-1A epithelial cell layers, to an extent that could not be achieved by simply increasing the dose of UAMC01398. The applied rational (pre)formulation approach resulted in the development of aqueous-based gel formulations that are appropriate for further in vivo investigation of the anti-HIV microbicide potential of the novel NNRTI UAMC01398.
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
authors.forename: Carolien
authors.initials: C
authors.lastname: Grammen
authors.affiliation: Laboratory of Virology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Ariën
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Venkatraj
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Heeres
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lewi
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Haenen
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.affiliation: Laboratory of Virology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Department of Biomedical Sciences, Faculty of Pharmacology, Veterinary and Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Guido
authors.initials: G
authors.lastname: Vanham
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium. Electronic address: joachim.brouwers@pharm.kuleuven.be.
authors.forename: Joachim
authors.initials: J
authors.lastname: Brouwers
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D010539:Permeability; D012995:Solubility; D014622:Vaginal Creams, Foams, and Jellies / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D000890:Anti-Infective Agents; D014622:Vaginal Creams, Foams, and Jellies
keywords: Anti-HIV microbicide; Biopharmaceutical profiling; In vitro toxicity; Vaginal flux; Vaginal gel formulation