title: Formulation of the microbicide INP0341 for in vivo protection against a vaginal challenge by Chlamydia trachomatis.
abstract: The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.
authors.affiliation: Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Pedersen
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, United States of America.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Slepenkin
authors.affiliation: Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden.
authors.forename: Sara B E
authors.initials: SB
authors.lastname: Andersson
authors.affiliation: Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden.
authors.forename: Jonas H
authors.initials: JH
authors.lastname: Fagerberg
authors.affiliation: Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden.
authors.forename: Christel A S
authors.initials: CA
authors.lastname: Bergström
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, United States of America.
authors.forename: Ellena M
authors.initials: EM
authors.lastname: Peterson
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D002692:Chlamydia trachomatis; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D008219:Lymphogranuloma Venereum / Q000188:drug therapy*; D051379:Mice; D014621:Vagina / Q000382:microbiology; D014622:Vaginal Creams, Foams, and Jellies / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D003692:Delayed-Action Preparations; D006834:Hydrazines; C541377:INP 0341; D014622:Vaginal Creams, Foams, and Jellies