There is a widespread agreement that more effective drug delivery vehicles with more alternatives, as well as better active pharmaceutical ingredients (APIs), must be developed to improve the efficacy of microbicide products. For instance, in tropical regions, films are more appropriate than gels due to better stability of drugs at extremes of moisture and temperature. Here, we apply fundamental fluid mechanical and physicochemical transport theory to help better understand how successful microbicide API delivery depends upon properties of a film and the human reproductive tract environment. Several critical components of successful drug delivery are addressed. Among these are: elastohydrodynamic flow of a dissolved non-Newtonian film; mass transfer due to inhomogeneous dilution of the film by vaginal fluid contacting it along a moving boundary (the locally deforming vaginal epithelial surface); and drug absorption by the epithelium. Local rheological properties of the film are dependent on local volume fraction of the vaginal fluid. We evaluated this experimentally, delineating the way that constitutive parameters of a shear-thinning dissolved film are modified by dilution. To develop the mathematical model, we integrate the Reynolds lubrication equation with a mass conservation equation to model diluting fluid movement across the moving vaginal epithelial surface and into the film. This is a complex physicochemical phenomenon that is not well understood. We explore time- and space-varying boundary flux model based upon osmotic gradients. Results show that the model produces fluxes that are comparable to experimental data. Further experimental characterization of the vaginal wall is required for a more precise set of parameters and a more sophisticated theoretical treatment of epithelium.
Received 01 September 2012Accepted 05 February 2013Published online 04 March 2013
D.F.K. acknowledges support from NIH grants (Grant Nos. U19 AI077289 and RO1 HD 072702). S.T. acknowledges support from The Scientific and Technological Research Council of Turkey (Tubitak).
Article outline: I. INTRODUCTION II. PROBLEM FORMULATION A. Flowmodel B. Drug distribution model III. RESULTS A. Experimental results B. Homogeneous spreading C. Transient swelling and spreading 1. Boundary flux dependent on the osmotic gradient 2. Drug absorption IV. CONCLUSIONS
4.A. J. Szeri, S. C. Park, S. Verguet, A. Weiss, and D. F. Katz, “A model of transluminal flow of an anti-HIV microbicide vehicle: Combined elasticsqueezing and gravitational sliding,” Phys. Fluids20, 083101 (2008).
5.S. Tasoglu, S. C. Park, J. J. Peters, D. F. Katz, and A. J. Szeri, “The consequences of yield stress on deployment of a non-Newtonian anti-HIV microbicide gel,” J. Non-Newtonian Fluid Mech.166(19–20) 1116–22 (2011).
6.S. Tasoglu, J. J. Peters, S. C. Park, S. Verguet, D. F. Katz, and A. J. Szeri, “The effects of inhomogeneous boundary dilution on the coating flow of an anti-HIV microbicide vehicle,” Phys. Fluids.23, 093101 (2011).
8.C. Coggins, C. J. Elias, R. Atisook, M. T. Bassett, V. Ettiegnene-Traore, P. D. Ghys, L. Jenkins-Woelk, E. Thongkrajai, and N. L. VanDevanter, “Women's preferences regarding the formulation of over-the-counter vaginal spermicides,” AIDS12, 1389–91 (1998).
9.S. Garg, K. Vermani, A. Garg, R. A. Anderson, W. B. Rencher, and L. J. D. Zaneveld, “Development and characterization of bioadhesive vaginal films of sodium polystyrene sulfonate (PSS), a novel contraceptive antimicrobial agent,” Pharm. Res.22, 584–595 (2005).
18.A. R. Geonnotti, M. J. Furlow, T. Wu, M. G. DeSoto, M. H. Henderson, P. F. Kiser, and D. F. Katz, “Measuring macrodiffusion coefficients in microbicide hydrogels via postphotoactivation scanning,” Biomacromolecules9, 748–51 (2008).
19.K. Podual, F. DoyleIII, and N. A. Peppas, “Modeling of water transport in and release from glucose-sensitive swelling-controlled release systems based on poly (diethylaminoethyl methacrylate-g-ethylene glycol),” Ind. Eng. Chem. Res.43, 7500 (2004).
20.B. E. Lai, Y. Q. Xie, M. Lavine, A. J. Szeri, D. H. Owen, and D. F. Katz, “Dilution of microbicide gels with vaginal fluid and semen simulants: Effects on rheology and coating flow,” J. Pharm. Sci.97, 1030 (2008).
22.L. Langbein, C. Grund, C. Kuhn, S. Praetzel, J. Kartenbeck, J. M. Brandner, I. Moll, and W. W. Franke, “Tight junctions and compositionally related junctional structures in mammalian stratified epithelia and cell cultures derived therefrom,” European J. Cell Biol.81(8), 419–35 (2002).
24.M. Rowland and T. N. Tozer, Clinical Pharmacokinetics: Concepts and Applications, 3rd ed. (Williams and Wilkins, Media, PA, 1995).
25.H. H. Usansky and P. J. Sinko, “Estimating human drug oral absorption kinetics from caco-2 permeability using an absorption-disposition model: Model development and evaluation and derivation of analytical solutions for ka and Fa,” J. Pharmacol. Exp. Ther.314, 391–399 (2005).
27.A. Rubashkin, P. Iserovich, J. A. Hernandez, and J. Fischbarg, “Epithelial fluid transport: Protruding macromolecules and space charges can bring about electro-osmotic coupling at the tight junctions,” J. Membr. Biol.208, 251–263 (2005).
31.A. J. Szeri, S. C. Park, S. Tasoglu, S. Verguet, A. Gorham, Y. Gao, and D. F. Katz, “Epithelial coating mechanisms by semi-solid materials: Application to microbicide gels,” Biophys. J.98(3), 604a–604a (2010).