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AAPS Showcases Vaginal Ring with Tenofovir + Contraceptive, Gel Suitable for Vaginal and Rectal Use

A new intravaginal ring delivers both tenofovir for HIV prevention and levonorgestrel for contraception for 3 months, researchers reported at the American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition taking place this week in San Antonio. Other studies looked at a novel gel for both vaginal and rectal use containing the antiretroviral IQP-0528, and a bio-adhesive vaginal gel combining tenofovir and the anti-herpes drug acyclovir.

The field of biomedical HIV prevention has seen major advances in recent years. Pre-exposure prophylaxis (PrEP) using oral tenofovir or Truvada (tenofovir/emtricitabine) has been shown to dramatically reduce the risk of HIV infection in various populations, but it only works with good adherence. Researchers are therefore exploring other delivery methods that might be more convenient and encourage better adherence than daily pills.

The CAPRISA 004 trial showed that a 1% tenofovir microbicide gel applied before and after sex decreased HIV acquisition by about 40% overall. A similar gel is also being tested for rectal use during anal sex. Tenofovir gel also offers protection against herpes simplex virus type 2 (HSV-2), which causes genital herpes.

Tenofovir/Levonorgestrel Ring

Another method uses a hollow intravaginal ring that releases tenofovir or other compounds over time, allowing them to be left in place and not requiring insertion right before having sex. This type of ring has been shown to protect macaque monkeys from vaginal exposure to an HIV-like virus.

Multipurpose prevention technologies (MPTs) -- for example, combining protection against HIV and other sexually transmitted infections, or HIV protection and contraception -- could further improve convenience and encourage consistent use.

Patrick Kiser from Northwestern University, Meredith Clark from the reproductive health research organization CONRAD, and colleagues evaluated an intravaginal ring designed for sustained co-delivery of tenofovir and the hormonal contraceptive levonorgestrel (a synthetic progesterone) for 90 days.

Because these agents have different biochemical properties and release rates, they can be difficult to administer together. In particular, tenofovir is hydrophilic and attracts water, while levonorgestrel is hydrophobic and repels water (this article from MIT explains the difference).

The researchers developed a segmented polyurethane ring with separate reservoirs that can deliver both drugs simultaneously. They used tubes of different lengths to change the amount of drugs released. After optimizing segments for each drug, they tested the combination rings in rabbits and sheep.

By altering release rates, they were able to achieve target levels of 10 mg/d for tenofovir and 10 or 20 mcg/d for levonorgestrel. In sheep, pharmacokinetic studies showed tenofovir levels in vaginal tissue and fluid similar to those obtained with 1% tenofovir gel in human clinical trials.

"We saw the urgent need to make this dual-protection intravaginal ring because a majority of the world's unintended pregnancies occur within resource-poor regions where the HIV/AIDS pandemic is most prevalent, such as sub-Saharan Africa," Clark explained in an AAPS press release. "MPTs are a relatively new reproductive health technology that we expect will have a good deal of support from potential users, donors, and public health organizations, particularly in the developing world."

"Products only work when they are used," added CONRAD product development director David Friend in another press release. "By having a ring that can remain in the body for up to 90 days, our hope is that this ring will offer a solution to increase adherence, and therefore provide greater protection against HIV while also preventing pregnancy."

CONRAD and collaborators anticipate starting Phase 1 clinical trials in women in early 2014, comparing the combination tenofovir/levonorgestrel ring versus the tenofovir-only version.

As described in another presentation, Kiser and colleagues are also working on "osmotic pump" technology for releasing compounds into the vagina regardless of their chemical properties. They have tested this technology in a segmented intravaginal ring that releases the experimental HIV drug IQP-0528 (see below).

IQP-0528 DuoGel

Anthony Ham from ImQuest BioSciences and colleagues described the development of DuoGel, a microbicide gel for HIV prevention designed for both vaginal and rectal use.

The original 1% tenofovir gel used in CAPRISA 004 proved too irritating for rectal use, though a reformulated version containing less glycerin was more acceptable. The ImQuest team was motivated to develop a dual use product because many people have both vaginal and anal intercourse during the same sexual episode.

IQP-0528 is a pyrimidinedione compound that acts as both a non-nucleoside reverse transcriptase inhibitor (NNRTI) and HIV entry inhibitor. It has been tested invaginal gels and vaginal films, both alone and in combination with tenofovir.

The researchers developed IQP-0528 DuoGels using "generally regarded as safe" excipients (inactive carrier compounds) approved for both vaginal and rectal administration, including hydroxyethyl cellulose, glycerin, methyl/propyl paraben, and carbomer. Starting with a vaginal formulation, they altered the pH and osmolality to be more suitable for rectal use.

They tested the gels' biochemical properties, drug release, toxicity, and anti-HIV activity in laboratory cell cultures. Toxicity, permeability, and efficacy were also evaluated in cervical and rectal tissue explants.

The best DuoGel formulation "displayed no in vitro cellular or bacterial toxicity" at the highest concentration tested (1000 mcg/mL) and "displayed no loss in viability in both explant ectocervical and colorectal tissue," the researchers concluded.

"It is recognized that both vaginal and rectal intercourse occur during the same sexual act, so a single product that is safe for both compartments makes sense in terms of convenience, which is likely to result in higher compliance," Ham explained in an AASP press release. "In addition, these DuoGels will be much safer products for HIV prevention in males practicing receptive anal intercourse."

Acceptability and adherence are now being evaluated using a placebo DuoGel without the active ingredient, according to the release. The researchers are preparing the current gel for animal studies and hope to begin Phase 1 human clinical trials in early 2015. In the next stage they plan to create a multidrug DuoGel that contains IQP-0528 plus tenofovir.

Tenofovir/Acyclovir Gel

Finally, researchers from SRI International reported on the development of a vaginal gel combining tenofovir and acyclovir, which is used to treat and prevent outbreaks of genital herpes.

The research team developed gels made with different combinations of 2 polymers, Pluronic F-127 and Noveon AA1, and evaluated their biochemical properties under conditions simulating vaginal sex.

Among the tested gels, only one dubbed SR-2P retained its structure when diluted with simulated vaginal fluid and semen and subject to "mild simulated coital stress." This formulation showed good adhesion to pig vaginal tissue and caused little or no irritation in a mouse model.

Because tenofovir is compatible with Noveon AA1 while acyclovir is compatible with Pluronic F-127, the researchers are working on a dual-syringe strategy that administers the 2 drug/polymer mixes from separate compartments.

"The results of this study demonstrated the potential application of SR-2P as a vaginal microbicide vehicle for delivery of acyclovir and tenofovir," they concluded.

11/15/13

References

P Kiser, M Clark, J Clark, et al. Development and Pharmacokinetics of a 90-Day Intravaginal Ring for the Sustained Co-Delivery of the Microbicide Tenofovir and Contraceptive Levonorgestrel. American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition. San Antonio. November 10-14, 2013. Abstract T2063.

R Teller, R Rastogi, P Mesquita, et al. Intravaginal Osmotic Pump for Sustained Release of an HIV Prevention Agent. Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition. San Antonio. November 10-14, 2013. Abstract T2077.

A Ham, W. Lustig, S Nugent, et al. Formulation Development of the DuoGel: A Dual Chamber Vaginal/Rectal Anti-HIV Microbicide Gel. American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition. San Antonio. November 10-14, 2013. Abstract R6132.

S Podaralla, M Liu, B Francavilla, et al. Formulation Development of Acyclovir/Tenofovir Loaded Two-Polymer (SR-2P) Bioadhesive Vaginal Gel. American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition. San Antonio. November 10-14, 2013. Abstract T2073.

Other Sources

American Association of Pharmaceutical Scientists. First Dual-Protection Intravaginal Ring Design Shows Promise in Long-term HIV & Pregnancy Prevention. Press release. November 12, 2013.

CONRAD. CONRAD Presents New Technology Combining Contraception, HIV and Herpes Simplex Virus-2 (HSV-2) Prevention. Press release. November 12, 2013.

American Association of Pharmaceutical Scientists. Novel Microbicide Gel for Vagina and Rectum Shows Potential for HIV Prevention. Press release. November 14, 2013.