Vaginal deployment and tenofovir delivery by microbicide gels

Abstract

Gels are one of the soft material platforms being evaluated to deliver topically acting anti-HIV drugs (microbicides) to the vaginal environment. For each drug, its loaded concentration, gel properties and applied volume, and frequency of dosing can be designed to optimize PK and, thence, PD. These factors also impact user sensory perceptions and acceptability. Deterministic compartmental modeling of vaginal deployment and drug delivery achieved by test gels can help delineate how multiple parameters characterizing drug, vehicle, vaginal environment, and dosing govern details of PK and PD and also gel leakage from the canal. Such microbicide delivery is a transport process combining convection, e.g., from gel spreading along the vaginal canal, with drug diffusion in multiple compartments, including gel, mucosal epithelium, and stroma. The present work builds upon prior models of gel coating flows and drug diffusion (without convection) in the vaginal environment. It combines and extends these initial approaches in several key ways, including: (1) linking convective drug transport due to gel spreading with drug diffusion and (2) accounting for natural variations in dimensions of the canal and the site of gel placement therein. Results are obtained for a leading microbicide drug, tenofovir, delivered by three prototype microbicide gels, with a range of rheological properties. The model includes phosphorylation of tenofovir to tenofovir diphosphate (which manifests reverse transcriptase activity in host cells), the stromal concentration distributions of which are related to reference prophylactic values against HIV. This yields a computed summary measure related to gel protection (“percent protected”). Analyses illustrate tradeoffs amongst gel properties, drug loading, volume and site of placement, and vaginal dimensions, in the time and space history of gel distribution and tenofovir transport to sites of its anti-HIV action and concentrations and potential prophylactic actions of tenofovir diphosphate therein.Electronic supplementary materialThe online version of this article (doi:10.1007/s13346-015-0227-1) contains supplementary material, which is available to authorized users.

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

“…The DuoGel™ formulations developed were composed of excipients either listed in the FDA Inactive Ingredients Database (http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm) as accepted excipients in vaginal products, rectal products, or already used in over the counter products. The TPP viscosity of the DuoGel™ was initially defined at 120 Pa·s at 1 sec −1 shear stress in order to provide sufficient gel coverage in the vagina and rectum without causing leakage (Gao et al ., 2015). The DuoGel™ TPP pH of 6.1 was based on achieving a compromise value that does not harmfully perturb ambient conditions in the vagina or rectum.…”

“…From the onset of formulation development of the DuoGel™, a range of gel viscosities was chosen, from relatively “low” (IQB3001) to “high” (IQB3000), to vary the rate and extent of gel spreading (Gao et al ., 2015; Kieweg and Katz, 2006). As per the TPP, the gels were manufactured to have a point viscosity (@ 1 s −1 ) of less than 120 Pa·s (Ham et al ., 2012; Mahalingam et al ., 2011; Rohan et al ., 2010).…”

“…Raw rheometric data were fit to the Carreau-like constitutive equation, which relates viscosity to shear rate: $$Ffalse(tfalse)=\frac{1}{m_0}+\frac{1}{m}{true(\frac{\tau }{m}true)}^{\frac{1-n}{n}}$$ $$\text{italicwhere}\stackrel{.}{\gamma }=\tau Ffalse(\tau false)$$ Here, τ is shear stress and γ̇ is shear strain rate; m o , m and n are parameters that characterize the rheological behavior of the material. Rheological parameters computed from these analyses were input to a computational model of gel spreading along the vaginal canal (Gao et al ., 2015). …”

Combination Pod-Intravaginal Ring Delivers Antiretroviral Agents for HIV Prophylaxis: Pharmacokinetic Evaluation in an Ovine Model

“…By analogy to highly active antiretroviral therapy (HAART), a combination of ARV agents likely is essential for optimally effective HIV PrEP (1,2). Multiple HIV PrEP clinical trials have demonstrated that vaginal and oral ARV regimens based on the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir (TFV) can be effective in susceptible men, women, and partners of HIV-infected individuals (3)(4)(5)(6)(7)(8)(9), but other studies based on analogous drug regimens were unsuccessful at reducing the rates of HIV acquisition (10)(11)(12). A critical factor driving success in these trials appears to involve sustaining high adherence to frequent dosing (13).…”

On-demand microbicide products: design matters

“…The product retention in the vagina and rectum will depend on the physical state. For liquid and semisolid preparations, product viscosity and the administered volume are important attributes that dictate leakage from and spreading within the vaginal and rectal compartments [30, 31]. For solid dosage forms such as vaginal tablets, inserts, suppositories, and films, disintegration will impact drug delivered to the mucosal site.…”