TY - JOUR

T1 - The use of supersaturation for the vaginal application of microbicides

T2 - a case study with dapivirine

AU - Grammen, Carolien

AU - Plum, Jakob

AU - Van Den Brande, Jeroen

AU - Darville, Nicolas

AU - Augustyns, Koen

AU - Augustijns, Patrick

AU - Brouwers, Joachim

N1 - © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

PY - 2014/11

Y1 - 2014/11

N2 - 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.

AB - 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.

KW - Animals

KW - Anti-HIV Agents

KW - Cell Line

KW - Chemical Precipitation

KW - Chemistry, Pharmaceutical

KW - Drug Stability

KW - Excipients

KW - Feasibility Studies

KW - Female

KW - Gels

KW - Hydrophobic and Hydrophilic Interactions

KW - Mucous Membrane

KW - Permeability

KW - Pyrimidines

KW - Rabbits

KW - Reverse Transcriptase Inhibitors

KW - Solubility

KW - Technology, Pharmaceutical

KW - Vagina

KW - beta-Cyclodextrins

U2 - 10.1002/jps.24176

DO - 10.1002/jps.24176

M3 - Journal article

C2 - 25231545

VL - 103

SP - 3696

EP - 3703

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 11

ER -