STD Quarterly: Research eyes ring for microbicide delivery
STD Quarterly
Research eyes ring for microbicide delivery
Women in the United States now account for more than one-quarter of all new HIV/AIDS diagnoses.1 To combat the epidemic, the National Institutes of Health has awarded Albert Einstein College of Medicine of Yeshiva University in Bronx, NY, a four-year, $7.2 million grant to develop a microbicide-releasing intravaginal ring to prevent HIV transmission.
"While condoms are excellent at preventing the transmission of HIV, it's often difficult for women to negotiate their use," says Betsy Herold, MD, professor of pediatrics, microbiology & immunology, and obstetrics & gynecology and women's health at Einstein, who will serve as principal investigator for the research. "It's imperative that women have alternative strategies available to protect their own health."
Much research effort is being aimed at developing coitally-independent, sustained release formulations for long-term administration of HIV microbicides. Vaginal ring devices are at the forefront of this formulation strategy.2
Intravaginal rings offer a variety of benefits for microbicide delivery, observes Patrick Kiser, PhD, associate professor of bioengineering at the University of Utah's College of Engineering, another principal investigator in the proposed research. They are particularly easy to use and can last for a long time, which makes patient compliance with the therapy much higher than with other dosage forms, Kiser notes.
Because rings can be placed in the vagina before sex, they offer protection to women who might not be able to negotiate condom use with their partners. Many men, particularly with the kind of rings being developed at the University of Utah, cannot detect the presence of the ring in the woman's vagina, says Kiser.
Kiser's research group is examining the use of thermoplastic elastomers to construct intravaginal rings. Such rings have been shown in vitro to be capable of sustained delivery of antiviral compounds over 30 days.3 The Utah scientists are evaluating several intravaginal ring designs that are capable of delivering hydrophilic and hydrophobic drugs simultaneously in the vaginal lumen.
Focus on anti-HIV microbicides
Herold and colleagues will look at several anti-HIV microbicides, focusing on a two-drug combination for ring delivery. By targeting HIV infection at different steps very early in its life cycle, scientists hope to prevent the establishment of infection, she notes. Potential drug candidates include tenofovir, which is used as an oral systemic therapy against HIV, but which also has shown promise as a topical microbicide.4 The team also will examine fusion inhibitors, such as maraviroc and PIE12-trimer, which block the virus from entering target immune cells by different mechanisms.
"We've deliberately chosen to focus on drugs that have already been approved for systemic use or are far along in the regulatory process," says Herold. "This should shorten the time it takes to begin clinical trials."
Safety is an important issue in development and use of rings for microbicide delivery, says Herold. The configuration of cells in the vaginal epithelium form an impermeable barrier to HIV; if a microbicide disrupts the barrier, HIV may be able to slip through the gaps and infect circulating T cells, as evidenced by earlier work by Herold's research team.5
These findings are leading Herold's team to search for the right combinations to preserve the protective barrier in the vaginal epithelium, while adding drugs that will be at the right place, at the right time, when the virus presents. The ring, which can provide sustained delivery of a microbicide over three to four weeks, offers promise as a delivery candidate, Herold contends.
"There are hurdles to go, I think it's a really exciting area, and I think we will get there," she says. "I'm optimistic, but I think it is going to take some very careful, rigorous science to make sure that we address all the right questions before we start doing large-scale clinical trials."
References
- Centers for Disease Control and Prevention. HIV/AIDS Among Women. Fact sheet. Accessed at www.cdc.gov/hiv/topics/women/resources/factsheets/women.htm.
- Promadej-Lanier N, Smith JM, Srinivasan P, et al. Development and evaluation of a vaginal ring device for sustained delivery of HIV microbicides to non-human primates. J Med Primatol 2009; 38:263-271.
- Gupta KM, Pearce SM, Poursaid AE, et al. Polyurethane intravaginal ring for controlled delivery of dapivirine, a nonnucleoside reverse transcriptase inhibitor of HIV-1. J Pharm Sci 2008; 97:4,228-4,239.
- Hillier SL. Safety and acceptability of daily and coitally dependent use of 1% tenofovir over six months of use. Presented at the Microbicides 2008 Conference. New Delhi; February 2008.
- Mesquita PM, Cheshenko N, Wilson SS, et al. Disruption of tight junctions by cellulose sulfate facilitates HIV infection: Model of microbicide safety. J Infect Dis 2009; 200:599-608.
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