title: The use of supersaturation for the vaginal application of microbicides: a case study with dapivirine.
abstract: In this study, we investigated the potential of supersaturation for the formulation of the poorly water-soluble microbicide dapivirine (DPV) in an aqueous vaginal gel in order to enhance its vaginal tissue uptake. Different excipients such as hydroxypropylmethylcellulose, polyethylene glycol 1000, and cyclodextrins were evaluated for their ability to inhibit precipitation of supersaturated DPV in the formulation vehicle as such as well as in biorelevant media. In vitro permeation assessment across HEC-1A cell layers demonstrated an enhanced DPV flux from supersaturated gels compared with suspension gels. The best performing supersaturated gel containing 500 μM DPV (supersaturation degree of 4) in the presence of sulfobutyl ether-beta-cyclodextrin (2.5%) appeared to be stable for at least 3 months. In addition, the gel generated a significant increase in vaginal drug uptake in rabbits as compared with suspension gels. We conclude that supersaturation is a possible strategy to enhance the vaginal concentration of hydrophobic microbicides, thereby increasing permeation into the vaginal submucosa.
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
authors.forename: Carolien
authors.initials: C
authors.lastname: Grammen
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
authors.forename: Jakob
authors.initials: J
authors.lastname: Plum
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Van Den Brande
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Darville
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
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: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D002460:Cell Line; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D005240:Feasibility Studies; D005260:Female; D005782:Gels; D057927:Hydrophobic and Hydrophilic Interactions; D009092:Mucous Membrane / Q000378:metabolism; D010539:Permeability; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D011817:Rabbits; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D014621:Vagina / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D005079:Excipients; D005782:Gels; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; C481671:Dapivirine
keywords: excipients; hydrogels; in vitro models; in vivo rabbit; precipitation; supersaturation; vaginal drug delivery