A 90-day tenofovir reservoir intravaginal ring for mucosal HIV prophylaxis.

A vaginal gel containing the antiretroviral tenofovir (TFV) recently demonstrated 39% protection against HIV infection in women. We designed and evaluated a novel reservoir TFV intravaginal ring (IVR) to potentially improve product effectiveness by providing a more controlled and sustained vaginal dose to maintain cervicovaginal concentrations. Polyurethane tubing of various hydrophilicities was filled with a high-density TFV/glycerol/water semisolid paste and then end-sealed to create IVRs. In vitro, TFV release increased with polyurethane hydrophilicity, with 35 weight percent water-swelling polyurethane IVRs achieving an approximately 10-mg/day release for 90 days with mechanical stiffness similar to that of the commercially available NuvaRing. This design was evaluated in two 90-day in vivo sheep studies for TFV pharmacokinetics and safety. Overall, TFV vaginal tissue, vaginal fluid, and plasma levels were relatively time independent over the 90-day duration at approximately 10(4) ng/g, 10(6) ng/g, and 10(1) ng/ml, respectively, near or exceeding the highest observed concentrations in a TFV 1% gel control group. TFV vaginal fluid concentrations were approximately 1,000-fold greater than levels shown to provide significant protection in women using the TFV 1% gel. There were no toxicological findings following placebo and TFV IVR treatment for 28 or 90 days, although slight to moderate increases in inflammatory infiltrates in the vaginal epithelia were observed in these animals compared to naïve animals. In summary, the controlled release of TFV from this reservoir IVR provided elevated sheep vaginal concentrations for 90 days to merit its further evaluation as an HIV prophylactic.

Design of a semisolid vaginal microbicide gel by relating composition to properties and performance.

PURPOSE: Develop a preclinical in vitro algorithm enabling de novo design of semisolid vaginal drug delivery gels, by using biomechanical modeling of gel spreading in the vaginal canal and empirically relating gel composition to mechanical properties and predicted performance. METHODS: Gel performance was defined through a multivariate objective function constructed from gels' mechanical properties and selected performance criteria for gel spreading within the vaginal canal. Mixture design of experiment was used to establish a semi-empirical relationship linking composition-property and property-performance relationships for gels with varying concentrations of hydroxyethylcellulose and Carbopol 974P. This permits definition of a local optimum for gel composition and volume of administration, within a defined gel composition space. RESULTS: Rheological behavior and, consequently, the value of the objective function varied broadly with composition. The algorithm indicated a 3.0 wt% HEC gel as the near optimal composition for a 3.5 mL applied volume for gels designed to spread throughout the vagina. CONCLUSIONS: The algorithm introduced herein is a novel tool that facilitates an understanding of the composition-property-performance relationship for vaginal semisolid drug delivery gels. This approach has promise as a scientific methodology for evaluation and optimization of vaginal gels prior to in vivo investigations.

Engineering a segmented dual-reservoir polyurethane intravaginal ring for simultaneous prevention of HIV transmission and unwanted pregnancy.

The HIV/AIDS pandemic and its impact on women prompt the investigation of prevention strategies to interrupt sexual transmission of HIV. Long-acting drug delivery systems that simultaneously protect womenfrom sexual transmission of HIV and unwanted pregnancy could be important tools in combating the pandemic. We describe the design, in silico, in vitro and in vivo evaluation of a dual-reservoir intravaginal ring that delivers the HIV-1 reverse transcriptase inhibitor tenofovir and the contraceptive levonorgestrel for 90 days. Two polyether urethanes with two different hard segment volume fractions were used to make coaxial extruded reservoir segments with a 100 µm thick rate controlling membrane and a diameter of 5.5 mm that contain 1.3 wt% levonorgestrel. A new mechanistic diffusion model accurately described the levonorgestrel burst release in early time points and pseudo-steady state behavior at later time points. As previously described, tenofovir was formulated as a glycerol paste and filled into a hydrophilic polyurethane, hollow tube reservoir that was melt-sealed by induction welding. These tenofovir-eluting segments and 2 cm long coaxially extruded levonorgestrel eluting segments were joined by induction welding to form rings that released an average of 7.5 mg tenofovir and 21 µg levonorgestrel per day in vitro for 90 days. Levonorgestrel segments placed intravaginally in rabbits resulted in sustained, dose-dependent levels of levonorgestrel in plasma and cervical tissue for 90 days. Polyurethane caps placed between segments successfully prevented diffusion of levonorgestrel into the tenofovir-releasing segment during storage.Hydrated rings endured between 152 N and 354 N tensile load before failure during uniaxial extension testing. In summary, this system represents a significant advance in vaginal drug delivery technology, and is the first in a new class of long-acting multipurpose prevention drug delivery systems.

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.

Quantitative evaluation of a hydrophilic matrix intravaginal ring for the sustained delivery of tenofovir.

In vitro testing and quantitative analysis of a matrix, hydrophilic polyether urethane (HPEU) intravaginal ring (IVR) for sustained delivery of the anti-HIV agent tenofovir (TFV) are described. To aid in device design, we employed a pseudo-steady-state diffusion model to describe drug release, as well as an elastic mechanical model for ring compression to predict mechanical properties. TFV-HPEU IVRs of varying sizes and drug loadings were fabricated by hot-melt extrusion and injection molding. In vitro release rates of TFV were measured at 37 °C and pH 4.2 for 30 or 90 days, during which times IVR mechanical properties and swelling kinetics were monitored. Experimental data for drug release and mechanical properties were compared to model predictions. IVRs loaded with 21% TFV (w/w) released greater than 2mg TFV per day for 90 days. The diffusion model predicted 90 day release data by extrapolating forward from the first 7 days of data. Mechanical properties of IVRs were similar to NuvaRing, although the matrix elastic modulus decreased up to three-fold following hydration. This is the first vaginal dosage form to provide sustained delivery of milligram quantities of TFV for 90 days. Drug release and mechanical properties were approximated by analytical models, which may prove useful for the continuing development of IVRs for HIV prevention or other women's health indications.

Approaches to improve the stability of the antiviral agent UC781 in aqueous solutions.

In this work, we evaluated the chemical stability profiles of UC781 based solutions to identify excipients that stabilize the microbicidal agent UC781. When different antioxidants were added to UC781 in sulfobutylether-beta-cyclodextrin (SBE-beta-CD) solutions and subjected to a 50 degrees C stability study, it was observed that EDTA was a better stabilizing agent than sodium metabisulfite, glutathione or ascorbic acid. Some antioxidants accelerated the degradation of UC781, suggesting metal-catalyzed degradation of UC781. Furthermore, we observed substantial degradation of UC781 when stored in 1% Tween 80 and 1% DMSO solutions alone or in those with 10mM EDTA. On the other hand, improved stability of UC781 in the presence of 100 and 200mM of EDTA was observed in these solutions. The addition of both EDTA and citric acid in the stock solutions resulted in recovery of more than 60% of UC781 after 12 weeks. Generally, 10% SBE-beta-CD in the presence of EDTA and citric acid stabilized UC781 solutions: the amount of UC781 recovered approaching 95% after 12 weeks of storage at 40 degrees C. We also showed that the desulfuration reaction of the UC781 thioamide involves oxygen by running solution stability studies in deoxygenated media. Improved stability of UC781 in the present study indicates that the incorporation of EDTA, citric acid and SBE-beta-CD and the removal of oxygen in formulations of this drug will aid in increasing the stability of UC781 where solutions of the drug are required.

Segmented polyurethane intravaginal rings for the sustained combined delivery of antiretroviral agents dapivirine and tenofovir.

Dual segment polyurethane intravaginal rings (IVRs) were fabricated to enable sustained release of antiretroviral agents dapivirine and tenofovir to prevent the male to female sexual transmission of the human immunodeficiency virus. Due to the contrasting hydrophilicity of the two drugs, dapivirine and tenofovir were separately formulated into polymers with matching hydrophilicity via solvent casting and hot melt extrusion. The resultant drug loaded rods were then joined together to form dual segment IVRs. Compression testing of the IVRs revealed that they are mechanically comparable to the widely accepted NuvaRing IVR. Physical characterization of the individual IVR segments using wide angle X-ray scattering and differential scanning calorimetry determined that dapivirine and tenofovir are amorphous and crystalline within their polymeric segments, respectively. In vitro release of tenofovir from the dual segment IVR was sustained over 30 days while dapivirine exhibited linear release over the time period. A 90 day accelerated stability study confirmed that dapivirine and tenofovir are stable in the IVR formulation. Altogether, these results suggest that multisegment polyurethane IVRs are an attractive formulation for the sustained vaginal delivery of drugs with contrasting hydrophilicity such as dapivirine and tenofovir.