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Transport phenomena and pharmacokinetics of anti-HIV microbicide drug delivery

  • Author(s): Tasoglu, Savas
  • Advisor(s): Szeri, Andrew J
  • et al.
Abstract

Microbicides are agents that can be applied to vaginal mucosal surfaces with the goal of blocking the transmission of sexually transmitted pathogens including HIV. They can be formulated in various delivery vehicles, including gels, creams, lotions, tablets or films. A recent study in South Africa has confirmed, for the first time, that a vaginal gel formulation of the antiretroviral drug Tenofovir, when topically applied, significantly inhibits sexual HIV transmission to women. However the gel for this drug, and anti-HIV microbicide vehicles in general, have not been designed using an understanding of how their spreading and retention in the vagina govern successful drug delivery.

Elastohydrodynamic lubrication theory can be applied to model spreading of microbicide gels and films. This should incorporate the full rheological behavior, including how rheological properties change due to contact with, and dilution by, ambient vaginal fluids. A Carreau-like non-Newtonian model is adopted as a rheological model. The effects of three important factors, i.e., dilution by vaginal fluid, a yield stress of the gel and swelling, are investigated. Dilution accelerates the coating flow by creating a slippery region near the vaginal wall akin to a dilution boundary layer. The concept of a yield stress fluid is attractive because such a material may tend to stay in place after coating vulnerable surfaces. We show that the lubrication approximation, which eases the efforts of design, may be applied to the elastic wall-squeezing problem for a prototype gel with yield stress. For the important presence of significant swelling of the gel by absorption of vaginal fluid, the model indicates more rapid coating. Then we study films that can be preferable over gels due to several reasons in many parts of the world. A model is developed for transient swelling and spreading of a film, and subsequent distribution of an active drug throughout the vaginal lumen. We investigate the effects of combination of many factors.

The theory developed here improves our understanding of the biophysics of microbicide gel and film flows in vivo. Ultimately, this dissertation contributes to a methodology that provides objective evaluations of microbicide gel and film performance and in the design of new, improved vehicles.

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