Jennifer J. Peters

Rheological properties of contraceptive gels

The rheological properties of 4 commercially available contraceptive drug delivery gels and their dilutions with a vaginal fluid simulant were measured. These properties govern the critical functions of spreading and retention of these gels over the vaginal surfaces. Measurements made on Conceptrol, KY Plus, Gynol II, and Advantage-S included stress growth, stress relaxation and residual stress, and the shear rate dependence of viscosity. All gels exhibited non-Newtonian behavior including shear thinning and viscoelasticity. Conceptrol and Gynol II had no residual stress, while both KY Plus and Advantage-S did. The gels differed in their response to dilution with vaginal fluid simulant.

Zinc Acetate/Carrageenan Gels Exhibit Potent Activity In Vivo against High-Dose Herpes Simplex Virus 2 Vaginal and Rectal Challenge

ABSTRACT Topical microbicides that block the sexual transmission of HIV and herpes simplex virus 2 (HSV-2) are desperately needed to reduce the incidence of HIV infections worldwide. Previously we completed phase 3 testing of the carrageenan-based gel Carraguard. Although the trial did not show that Carraguard is effective in preventing HIV transmission during vaginal sex, it did show that Carraguard is safe when used weekly for up to 2 years. Moreover, Carraguard has in vitro activity against human papillomavirus (HPV) and HSV-2 and favorable physical and rheological properties, which makes it a useful vehicle to deliver antiviral agents such as zinc acetate. To that end, we previously reported that a prototype zinc acetate carrageenan gel protects macaques against vaginal challenge with combined simian-human immunodeficiency virus reverse transcriptase (SHIV-RT). Herein, we report the safety and efficacy of a series of zinc acetate and/or carrageenan gels. The gels protected mice (75 to 85% survival; P < 0.001) against high-dose (106-PFU) HSV-2 vaginal or rectal challenge. In contrast, zinc acetate formulated in HEC (hydroxyethylcellulose; or the Universal Placebo) failed to protect mice against the high-dose vaginal HSV-2 challenge (similar to aqueous zinc acetate solution and the placebo controls). The gels were found to be effective spreading gels, exhibited limited toxicity in vitro, caused minimal damage to the architecture of the cervicovaginal and rectal mucosae in vivo, and induced no increased susceptibility to HSV-2 infection in a mouse model. Our results provide a strong rationale to further optimize and evaluate the zinc acetate/carrageenan gels for their ability to block the sexual transmission of HIV and HSV-2.

Effect of temperature and pH on contraceptive gel viscosity

The rheological properties of four commercially available spermicidal gels (two polyacrylic acid derivatives and two carboxymethylcellulose based) and their dilutions with a vaginal fluid simulant (pH 4.2) and a semen simulant (pH 7.7) were measured at 25 degrees C and 37 degrees C over a biologically relevant range of shear rates. All four gels were shear thinning with temperature-dependent rheological properties. The two types of gels responded differently to dilution. The rheological properties of the polyacrylic acid derivative gels were strongly dependent on the type of diluent used. Their viscosities after dilution with the semen simulant were 100 times greater than after comparable dilutions with the vaginal fluid simulant, this effect being due primarily to the higher pH. The cellulose gels did not exhibit such an effect. These results suggest that the polyacrylic acid and cellulose gels interact differently with the vaginal environment in vivo. Such differences could lead to differences in the extent and durability of epithelial coating.

Design of tenofovir–UC781 combination microbicide vaginal gels

Tenofovir (TFV) is a proven microbicide when administered topically as a vaginal gel. To improve its efficacy, TFV was combined with the nonnucleoside reverse-transcriptase inhibitor UC781 in a vaginal gel. Mixture design of experiments theory was used to define a range of gel compositions with varying rheological properties and to assess in vitro drug release and tissue retention. Experiments and computations led to the specification of three different gels referred to as a spreading gel (SG), an intermediate spreading gel (ISG), and a bolus gel (BG). These three gels, all containing 1.0% TFV and 0.1% micronized UC781, were evaluated for in vitro release, in vitro tissue retention and safety, and in vivo pharmacokinetics in the rabbit. There were some differences in in vitro release rates of UC781 (the higher the gel viscosity, the slower the release rate) across gels, while release of TFV was independent of gel type. In an organotypic human vaginal-ectocervical (VEC) tissue model, the amounts of tissue-associated TFV and UC781 were several orders of magnitude higher than their in vitro half-maximal inhibitory concentration. There were no differences in VEC tissue concentrations of TFV or UC781 between the SG, ISG, and BG. All three gels were well tolerated in the VEC model as assessed by tissue viability, electrical resistance, histology, and cytokine (interleukin-8 and interleukin-1 beta) release. The local vaginal tissue concentrations in rabbits following a single dose or seven once-daily doses were variable and generally lower than those found in the VEC tissue model. The approach described herein provides a rational schema to design and evaluate vaginal gels for use as microbicides.

Comparison of the rheological properties of Advantage-S and Replens.

The rheological properties of Advantage-S and Replens were measured at body (37 degrees C) and room temperature (25 degrees C) over a range of physiologically relevant shear rates. The viscosity of Replens was found to differ from that of Advantage-S, particularly at room temperature. In addition, the two materials differed in their miscibility with a vaginal fluid simulant.

Optical instrument for measurement of vaginal coating thickness by drug delivery formulations

An optical device has been developed for imaging the human vaginal epithelial surfaces, and quantitatively measuring distributions of coating thickness of drug delivery formulations—such as gels—applied for prophylaxis, contraception or therapy. The device consists of a rigid endoscope contained within a 27-mm-diam hollow, polished-transparent polycarbonate tube (150mm long) with a hemispherical cap. Illumination is from a xenon arc. The device is inserted into, and remains stationary within the vagina. A custom gearing mechanism moves the endoscope relative to the tube, so that it views epithelial surfaces immediately apposing its outer surface (i.e., 150mm long by 360° azimuthal angle). Thus, with the tube fixed relative to the vagina, the endoscope sites local regions at distinct and measurable locations that span the vaginal epithelium. The returning light path is split between a video camera and photomultiplier. Excitation and emission filters in the light path enable measurement of fluorescence of t...

The effects of inhomogeneous boundary dilution on the coating flow of an anti-HIV microbicide vehicle

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 [Karim et al., Science 329, 1168 (2010)]. However, the gel for this drug and anti-HIV microbicide gels in general have not been designed using an understanding of how gel spreading and retention in the vagina govern successful drug delivery. Elastohydrodynamic lubrication theory can be applied to model spreading of microbicide gels [Szeri et al., Phys. Fluids 20, 083101 (2008)]. This should incorporate the full rheological behavior of a gel, including how rheological properties change due to contact with, and dilution by, ambient vaginal fluids. Here, we extend our initial analysis, incorporating the effects of gel dilution due to contact with vaginal fluid produced at the gel-tissue interface. Our original model is supplemented with a convective-diffusive transport equation to characterize water transport into the gel and, thus, local gel dilution. The problem is solved using a multi-step scheme in a moving domain. The association between local dilution of gel and rheological properties is obtained experimentally, delineating the way constitutive parameters of a shear-thinning gel are modified by dilution. Results show that dilution accelerates the coating flow by creating a slippery region near the vaginal wall akin to a dilution boundary layer, especially if the boundary flux exceeds a certain value. On the other hand, if the diffusion coefficient of boundary fluid is increased, the slippery region diminishes in extent and the overall rate of gel spreading decreases.

Transport Theory for HIV Diffusion through In Vivo Distributions of Topical Microbicide Gels

Topical microbicide products are being developed for the prevention of sexually transmitted infections. These include vaginally-applied gels that deliver anti-HIV molecules. Gels may also provide partial barriers that slow virion diffusion from semen to vulnerable epithelium, increasing the time during which anti-HIV molecules can act. To explore the barrier function of microbicide gels, we developed a deterministic mathematical model for HIV diffusion through realistic gel distributions. We applied the model to experimental data for in vivo coating distributions of two vaginal gels in women. Time required for a threshold number of virions to reach the tissue surface was used as a metric for comparing different scenarios. Results delineated how time to threshold increased with increasing gel layer thickness and with decreasing diffusion coefficient. We note that for gel layers with average thickness > approximately 100 microm, the fractional area coated, rather than the gel layer thickness, was the primary determinant of time to threshold. For gel layers < approximately 100 microm, time to threshold was brief, regardless of fractional area coated. Application of the model to vaginal coating data showed little difference in time to threshold between the two gels tested. However, the protocol after gel application (i.e., with or without simulated coitus) had a much more significant effect. This study suggests that gel distribution in layers of thickness >100 microm and fractional area coated >0.8 is critical in determining the ability of the gel to serve as a barrier to HIV diffusion.

The rational design and development of a dual chamber vaginal/rectal microbicide gel formulation for HIV prevention

The DuoGel™ was developed for safe and effective dual chamber administration of antiretroviral drugs to reduce the high incidence of HIV transmission during receptive vaginal and anal intercourse. The DuoGel™s containing IQP-0528, a non-nucleoside reverse transcriptase inhibitor (NNRTI), were formulated from GRAS excipients approved for vaginal and rectal administration. The DuoGel™s were evaluated based upon quantitative physicochemical and biological evaluations defined by a Target Product Profile (TPP) acceptable for vaginal and rectal application. From the two primary TPP characteristics defined to accommodate safe rectal administration three DuoGel™ formulations (IQB3000, IQB3001, and IQB3002) were developed at pH 6.00 and osmolality ⩽400mmol/kg. The DuoGel™s displayed no in vitro cellular or bacterial toxicity and no loss in viability in ectocervical and colorectal tissue. IQB3000 was removed from consideration due to reduced NNRTI delivery (∼65% reduction) and IQB3001 was removed due to increase spread resulting in leakage. IQB3002 containing IQP-0528 was defined as our lead DuoGel™ formulation, possessing potent activity against HIV-1 (EC50=10nM). Over 12month stability evaluations, IQB3002 maintained formulation stability. This study has identified a lead DuoGel™ formulation that will safely deliver IQP-0528 to prevent sexual HIV-1 transmission in the vagina and rectum.

Design and validation of a multiplexed low coherence interferometry instrument for in vivo clinical measurement of microbicide gel thickness distribution

We present a multiplexed, Fourier-domain low coherence interferometry (mLCI) instrument for in vivo measurement of intravaginal microbicide gel coating thickness distribution over the surface of the vaginal epithelium. The mLCI instrument uses multiple delivery fibers to acquire depth resolved reflection profiles across large scanned tissue areas. Here mLCI has been adapted into an endoscopic system with a custom imaging module for simultaneous, co-registered measurements with fluorimetric scans of the same surface. The resolution, optical signal-to-noise, and cross-talk of the mLCI instrument are characterized to evaluate performance. Validation measurements of gel thickness are made using a calibration socket. Initial results from a clinical study are presented to show the in vivo capability of the dual-modality system for assessing the distribution of microbicide gel vehicles in the lower human female reproductive tract.