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TECHNICAL PAPERS: Fluids/Heat/Transport

Squeezing Flows of Vaginal Gel Formulations Relevant to Microbicide Drug Delivery

[+] Author and Article Information
Sarah L. Kieweg1

Department of Biomedical Engineering, Duke University, Durham, NC 27704kieweg@ku.edu

David F. Katz

Department of Biomedical Engineering, Department of Obstetrics & Gynecology, Duke University, Durham, NC 27704

1

Corresponding author. Present address: Department of Mechanical Engineering, University of Kansas, Lawrence, KS 66045.

J Biomech Eng 128(4), 540-553 (Feb 01, 2006) (14 pages) doi:10.1115/1.2206198 History: Received June 07, 2005; Revised February 01, 2006

Efficacy of topical microbicidal drug delivery formulations against HIV depends in part on their ability to coat, distribute, and be retained on epithelium. Once applied to the vagina, a formulation is distributed by physical forces including: gravity, surface tension, shearing, and normal forces from surrounding tissues, i.e., squeezing forces. The present study focused on vaginal microbicide distribution due to squeezing forces. Mathematical simulations of squeezing flows were compared with squeezing experiments, using model vaginal gel formulations. Our objectives were: (1) to determine if mathematical simulations can accurately describe squeezing flows of vaginal gel formulations; (2) to find the best model and optimized parameter sets to describe these gels; and (3) to examine vaginal coating due to squeezing using the best models and summary parameters for each gel. Squeezing flow experiments revealed large differences in spreadability between formulations, suggesting different coating distributions in vivo. We determined the best squeezing flow models and summary parameters for six test gels of two compositions, cellulose and polyacrylic acid (PAA). We found that for some gels it was preferable to deduce model input parameters directly from squeezing flow experiments. For the cellulose gels, slip conditions in squeezing flow experiments needed to be evaluated. For PAA gels, we found that in the absence of squeezing experiments, rotational viscometry measurements (to determine Herschel-Bulkley parameters) led to reasonably accurate predictions of squeezing flows. Results indicated that yield stresses may be a strong determinant of squeezing flow mechanics. This study serves as a template for further investigations of other gels and determination of which sources of rheological data best characterize potential microbicidal formulations. These mathematical simulations can serve as useful tools for exploring drug delivery parameters, and optimizing formulations, prior to costly clinical trials.

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Copyright © 2006 by American Society of Mechanical Engineers
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Figures

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Figure 1

Diagram of constant-radius squeezing flow notation. The sample radius is equal to the plate radius. For constant-volume squeezing flow, the initial sample radius was less than the plate radius, and the volume between the plates remained constant.

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Figure 2

Squeeze flow curves with applied force ramp at initial gap separation of 1mm. Gynol II data (not shown here) overlaps Conceptrol data. Heavier lines (KY Plus, Replens, Advantage-S): 0.25N∕min. Lighter lines (Conceptrol, KY Jelly): 0.025N∕min.

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Figure 3

Squeeze flow curves with applied force ramp (0.25N∕min) for PAA gels at two different initial gap separations (initial gap indicated by each curve). Not all the curves continue to the same point due to gel overflow from the apparatus.

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Figure 4

Comparison of squeezing experiments for cellulose gels. Squeezing condition label indicated above each bar; refer to Table 2 for descriptions of “Low” (L), “Medium” (M), and “High” (H) squeezing conditions. Projected value is from early time point (8min) in order to prevent overflow in experiment. Error bars indicate median±max∕min.

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Figure 5

Comparison of squeezing experiments for PAA gels. Squeezing condition label indicated above each bar. Note that squeezing conditions differ for each gel; refer to Table 2 for descriptions of “Low” (L), “Medium” (M), “High” (H), and “High #2” (H2) squeezing conditions. Error bars indicate median±max∕min.

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Figure 6

Squeezing experiment data for three PAA gels with CAM theory using summary fit values as input (italics in Table 4). Experimental values (open circles) are median values, not all points shown for clarity.

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Figure 7

Squeezing experiment data and theory for cellulose gels. Experimental values (open circles) are median values, not all points shown for clarity. Solid lines are model results using summary fit values (italics in Table 5) as input to the partial-slip power-law model.

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Figure 8

Predicted coating thickness over 10min of constant-volume squeezing, using best mathematical models with summary fit values as input (italics in Tables  45). F=4.448N(1lbf) and V=3mL.

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Figure 9

Predicted maximum surface area coated (cm2) for PAA gels over range of forces and applied volumes. Constant-volume CAM model is applied, with summary values as input (italics in Table 4). 2h0=0.2cm. Biologically relevant forces range from approximately 4.448–44.48N(1to10lbf).

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Figure 10

Predicted surface area coated (cm2) after 10min for cellulose gels over range of forces and applied volumes. Constant-volume partial-slip model is applied, with summary values as input (italics in Table 5). 2h0=0.2cm. Biologically relevant forces range from approximately 4.448–44.48N(1to10lbf).

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Figure 11

Predicted vaginal surface area covered after 5min of constant-volume squeezing, using best mathematical models with two types of input: (1) summary fit values (italics in Tables  45) or (2) viscometry values (Table 3). Five minutes was chosen because under these conditions, the six gels have established their respective rankings by that time. F=4.448N(1lbf), V=3mL and 2h0=0.2cm.

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