title: Early identification of availability issues for poorly water-soluble microbicide candidates in biorelevant media: a case study with saquinavir.
abstract: In the search for a successful HIV microbicide, many poorly water-soluble antiviral agents are currently being investigated. Unfortunately, solubility and precipitation issues may limit intravaginal concentrations and thus availability of these agents upon application of an aqueous gel formulation. In the present study, we evaluated the in vitro precipitation behavior of the HIV protease inhibitor saquinavir in vaginal and seminal fluid simulants (VFS and SFS). Despite its limited solubility, the mesylate salt of saquinavir enables formulation of sufficiently high concentrations (2.5 mM, i.e. ca. 10(5)-fold in vitro IC(50) values) in a standard aqueous vehicle. While saquinavir stays in solution upon dilution with VFS, SFS induces precipitation of saquinavir, resulting in a 5-fold reduced availability and antiviral potency. Inclusion of the solubilizing excipients polyethylene glycol 1000 (12%) and hydroxypropyl-β-cyclodextrin (2.5%) was required to avoid saquinavir precipitation in SFS and to restore the antiviral potency of the formulation. This study illustrates the importance of identifying solubility and precipitation issues of microbicide candidates in biorelevant media and provides a simple in vitro procedure to implement this evaluation in early microbicide development.
authors.affiliation: Laboratory for Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, Leuven, Belgium. joachim.brouwers@pharm.kuleuven.be
authors.forename: Joachim
authors.initials: J
authors.lastname: Brouwers
authors.forename: Kurt
authors.initials: K
authors.lastname: Vermeire
authors.forename: Carolien
authors.initials: C
authors.lastname: Grammen
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002460:Cell Line; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical; D005079:Excipients / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D011092:Polyethylene Glycols / Q000737:chemistry; D019258:Saquinavir / Q000008:administration & dosage / Q000737:chemistry*; D012995:Solubility; D014622:Vaginal Creams, Foams, and Jellies / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D005079:Excipients; D017320:HIV Protease Inhibitors; D014622:Vaginal Creams, Foams, and Jellies; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011092:Polyethylene Glycols; D019258:Saquinavir