Microbicides: the quest for user-friendly formulations

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A large number of presentations at the Microbicides 2010 Conference in Pittsburgh documented the development of microbicides very different from gels or creams. Vaginal rings, quick-dissolve pills and thin films smaller than sticks of gum are all being tested.

Poor adherence was probably one of the reasons the last few efficacy trials of microbicides failed, and there is clearly an urgent need to develop formulations that do not require daily adherence or to be applied every time before sex, and which are also convenient and portable.

Vaginal ring drug delivery

The International Partnership for Microbicides (IPM), the largest and best-funded microbicide research programme, clearly believe that lower-frequency products are the way ahead, because they are now devoting the biggest slice of their budget to developing vaginal rings that sit on the cervix and slowly deliver antiretroviral drugs over a period of a month.

Vaginal rings have been used before to deliver contraceptives. Researchers so far have measured absorption and delivery rates of rings made of different plastics and have completed an acceptability trial of an inert, non-drug-containing ring in HIV-negative women.

Glossary

microbicide

A product (such as a gel or cream) that is being tested in HIV prevention research. It could be applied topically to genital surfaces to prevent or reduce the transmission of HIV during sexual intercourse. Microbicides might also take other forms, including films, suppositories, and slow-releasing sponges or vaginal rings.

vaginal ring

A device that is worn inside the vagina for a month at a time, which women can insert and remove themselves. A vaginal ring for HIV prevention that slowly releases the antiretroviral drug dapivirine is being developed.

rectum

The last part of the large intestine just above the anus.

cervix

The cervix is the neck of the womb, a tight ‘collar’ of tissue that closes off the womb except during childbirth. Cancerous changes are most likely in the transformation zone where the vaginal epithelium (lining) and the lining of the womb meet.

entry inhibitors

A group of antiretroviral medications that block HIV from entering a host CD4 cell. Includes both CCR5 inhibitors and fusion inhibitors.

An intravaginal ring made from the plastic ethyl-vinyl acetate copolymer (EVA) and loaded with the two drugs dapivirine and maraviroc – already found to enhance each other’s potency - can deliver therapeutic levels of both drugs for as long as a month, according to test-tube studies. Fifteen days after being placed in a water/alcohol mixture, the ring was delivering half a gram of dapivirine and a gram of maraviroc per day.

Mark Mitchnick of manufacturers Particle Sciences, Inc, who tested the EVA ring, acknowledged that in vivo drug release may be very different from test-tube studies. “We’re probably about a year away from clinical studies,” he said.

Joe Romano of IPM said that they had completed four EVA vaginal ring studies and two more were ongoing in the EU, plus an expanded safety study in Africa.

Vaginal ring acceptability

Separately, IPM has also conducted a safety and acceptability study of a silicone ring (without any drugs) in Africa. In this study women were randomised to wear the ring for 30 days with another 30 days’ observation or to be observed for 30 days first and then wear the ring for 30 days (a crossover design).

One hundred and seventy women were randomised and 144 completed the study. Adverse events like bleeding during sex were equally distributed between women using the ring and those not using it. Four adverse events were classed as related to the ring and 22 possibly related. Ninety-six per cent of the women said they liked the ring and they did not feel it when it was inserted, and they found insertion and removal easy.

The main issue that arose was that 16 reported the ring spontaneously falling out while 17 removed it for cleaning, despite being told not to. Both these incidents tended to happen while women were having their periods and there is a clear need for better guidance around this issue (rings containing contraceptives are designed not to be used during periods).

Women displayed contradictory attitudes about telling their partners about using a microbicide ring. While 84% said it was important their partner agreed to their using the ring, 63% said that at the same time it would be important to them to be able to use it without a partner’s knowledge and 66% said that it should not be noticeable during sex. Concerns included worry that it might disappear into the body or that it couldn’t be removed.

Researchers now consider the ring ready for full safety tests. A full efficacy trial is unlikely before 2012, however.

Vaginal/rectal tablets

Another alternative to gel is a vaginal tablet that dissolves quickly, turns into a “thick gel-like mass” and delivers sustained levels of antiretrovirals. The tablet is ‘bioadhesive’ – this means the voluminous gel gets the drug delivered to all the mucous surfaces needed and then dissolves away. It also binds the drug to the mucous membranes, concentrating it at the surfaces needed and guaranteeing a consistent level of drug over 8-12 hours.

A convenient tablet about the size of an almond has been developed containing dapivirine plus a gp120 (attachment) inhibitor called DS003 (originally developed by Bristol-Myers Squibb as BMS 599793 before being licensed to IPM).

Sanjay Garg of the University of Auckland said that 38% of the dapivirine in the tablet and 28% of the DS003 had been released into tissue after eight hours and that delivery of therapeutic levels could be achieved for at least twelve hours after insertion. A formulation containing tenofovir and the NNRTI UC781 is also being developed.

IPM’s Joe Romero commented that there would be “no problem adapting this for rectal use.”

Quick-dissolve film

Finally, a team have developed a vaginal microbicide as a film smaller than a stick of gum and as thin as a sheet of paper. The film is made of a thin polyvinyl alcohol polymer, a water-soluble synthetic plastic used in multiple consumer and biomedical products, including contraceptive films, contact lens solutions and mouthwash strips.

It proved fairly easy to impregnate with an antiretroviral drug. The drug in question is another new compound called IQP-0528 which has two modes of action, as both as an NNRTI drug and as an entry inhibitor.

Anthony Ham of ImQuest BioSciences, the film’s manufacturers, said it was not toxic to cells and had no negative effect on normal vaginal flora. Films had low production costs, he said. Acceptance studies of different formulations would be the next step, and there was some initial work being done to see if it could be used rectally.

References

Loxley A et al. Combination ethylene vinyl acetate intravaginal vaginal rings containing dapivirine and maraviroc. Microbicides 2010 Conference, Pittsburgh. Abstract 185. 2010.

Woodsong C et al. Safety and acceptability of vaginal ring as microbicide delivery method in African women. Microbicides 2010 Conference, Pittsburgh. Abstract LB4. 2010.

Garg S et al. Design of novel solid vaginal dosage form of dapivirine NNRTI and BMS-599793 (DS003) entry inhibitor in combination. Microbicides 2010 Conference, Pittsburgh. Abstract 181. 2010.

Ham AS et al. Vaginal film drug delivery of the pyrimidinedione IQP-0528 for the prevention of HIV infection. Microbicides 2010 Conference, Pittsburgh. Abstract 189. 2010.