The researchers loaded suppositories with the antiretroviral drug tenofovir (TFV, made by Gilead under the name Viread) in a proof-of-concept study which showed 45% of the drug diffused out in two hours (even with the presence of artificial vaginal and seminal fluid.
Drugs applied inside the vagina or rectum to protect against sexually transmitted infections, including HIV, are called microbicides.
There are no effective microbicides on the market, and the World Health Organisation (WHO) encourages their development, saying they rank alongside condoms in feasible HIV prevention, and empower women in resource-poor regions, who can use them even without their male partner’s cooperation.
Scientists from Pennsylvania State University’s Food Science department worked with carrageenan, an extract from edible seaweed to design a suppository which is more effective at drug delivery and more acceptable to women than previous efforts.
Carraguard, a carrageenan-based gel, has been previously investigated in HIV prevention (without tenofovir), and found to be well-tolerated in patients but inefficient in HIV transmission.
In studies of other microbicides, problems like liquid gels leaking and hard tablets being hypertonic (drawing in liquid through osmosis) lowered absorption of the drug.
The Pennsylvania team chose a semi-soft gel technology to find a happy medium between the two formulations. Gelatine is the standard soft-gel excipient, but the researchers chose carrageenan, saying it removed the possibility of animal (zoonotic) infections, is acceptable to vegetarians, and is heat-stable in hot countries.
Previous research has shown that improving patient adherence rates is vital to microbicide success and HIV prevention.
One study tested tenofivor – currently marketed only for oral use – as a 1% vaginal gel. It found a large difference in HIV transmission rates between women according to their adherence rates: participants reporting over 80% compliance showed a 54% decrease in HIV incidence, compared to only a 28% decrease in low-adherence users.
Acceptability studies have found women prefer a fast-acting product for a short waiting period between inserting the medicine and having sex.
Fluids present in the vagina during sex control drug release rates, as well as diluting the product and forming a barrier for drug absorption into the vaginal walls.
To test these absorption rates of their prototype, the Pennsylvania team simulated conditions in the vagina in vitro, surrounding the suppositories with water, artificial vaginal fluid, and artificial semen.
Researchers were particularly concerned with the ions present in these fluids, since cations such as K+ and Ca2+ affect carrageenan gelling.
They found the volume of fluids surrounding the suppository determined the rate of tenofovir diffusion, but it always remained between 45-50% after two hours. The model showed a rapid initial release followed by a slow release curve over the next 24 hours, suiting the preferences expressed by women.
The authors noted a drawback to the carrageenan suppositories: unlike some other microbicides they do not break down in the presence of sexual fluids and therefore cannot be used secretly by women. Work to formulate eroding suppositories is already underway, they said.
Source: Release of Tenofovir from Carrageenan-Based Vaginal Suppositories, Pharmaceutics 2014, 6(3), 366-377.