Formulation and delivery of a microbicide is an entirely different kind of challenge to formulating drugs or vaccines to be taken by mouth or injected. Measuring blood levels is not relevant – except, perhaps, to show that a microbicide is not absorbed! What does matter is how a substance behaves in the special environment in which it is placed.
Dr Guy Van Den Mooter reviewed formulation issues in a plenary session of the Microbicides 2002 meeting in Antwerp, beginning with a description of vaginal fluids.
Vaginal fluids are low in volume, which means that substances cannot easily dissolve into them. They are normally acid (pH 4 to 5) although this varies with the menstrual cycle and a woman’s age, and decreases during pregnancy. This means that a microbicide whose active ingredient won’t work in an acid environment should be avoided, since there is evidence that this acidity helps protect women from infections and should therefore be maintained. A variety of enzymes are released by the body into the vaginal fluids, although fewer than in the gut (and rectum). Again, a microbicide must be stable in the presence of these.
Absorption of a microbicide from the vagina – indeed, absorption of many drugs – varies during menstrual cycles, with changes in the thickness of the lining. It also depends on the physicochemical properties of the drug or other substance.
The physical properties of a microbicide will determine whether and how it reaches the surface it needs to cover, if it is to provide protection. The surface area of the vaginal cavity is 60 cm2, and whether a substance coats this rapidly and evenly depends on how it reacts with water, its spreadability and viscosity.
How long a substance stays in the vagina might depend on its bio-adhesive quality, which is not easy to predict and seems to depend on a range of chemical characteristics. One way to keep a substance in the vagina, despite its natural self-cleaning tendency, is to use materials that change their properties as they warm up or become more acid.
Another approach to ensuring microbicides are present when needed would be through slow-release formulations, which might however be expensive to produce. Indeed, one comment from the audience was that gels and creams are so expensive to package and deliver that tablets would be greatly preferable in practice (although there were obviously questions about how well and how fast tablets would dissolve and/or spread to where they were needed).
Ultimately, what matters most is meeting the needs of the product users for something that is very easy to apply, and is either completely unobtrusive during sex and other activities of daily life, or which actually enhances the experience of sex.
Measuring some of these properties of substances placed in the vagina is another challenge, explored in a number of presentations.
One of the most remarkable images of sex in progress that I have ever seen at a scientific meeting was provided by Dr Kurt Barnhart of the University of Pennsylvania.
With help from some very public spirited volunteers, he had used magnetic resonance imaging to look at what happened when a gel, labelled with non-toxic and non-radioactive gadolinium, was placed in a woman’s vagina. Because this method is non-invasive, and individual scans take around 30 seconds, it is possible to see how the gel is distributed inside the body before, during and after sexual intercourse. Some of the images were taken during actual intercourse, others during and after simulated intercourse using an artificial phallus.
The results of these efforts were to show that while the gel was at first lodged in the upper vagina, near the cervix, it became much more evenly distributed throughout the vagina during intercourse, following a similar pattern with actual and simulated sex. If a woman stands up and walks around, this too has a big effect on the distribution of the gel. It is also clear from his work, as from other people’s, that gel is taken into the cervix where it reaches the uterus. Again, this increases greatly after actual or simulated intercourse.
An alternative and complementary approach, taken by Dr David Katz of Duke University, to looking at what happens to gels inside the vagina (or the rectum) is to use fluorescent markers, and to place a transparent phallus-shaped tube inside the vagina (or rectum) and use a scanning system to check the thickness of the gel film along and around the tube. This method shows that different gels do have different properties, and a greater or lesser likelihood of leaving patches of the vaginal wall unprotected.
A major implication of research showing the microbicides – and of course semen – are taken up into the uterus is a renewed interest in preventing this using internal barrier methods, such as reusable silicone caps, which can also be turned into a means of delivering (and removing) microbicides from a woman’s vagina.
Surprisingly, there has still been no randomised controlled trial to look at the effectiveness of internal barriers in preventing either HIV or other STIs, although on Tuesday, Dr Craig Cohen of the University of Washington, working with the University of Nairobi in Kenya, reported that he and his colleagues have begun recruiting women from clinics treating STIs into a clinical trial which will look at the recurrence rates of gonorrhoea and chlamydia when diaphragms are or are not used. 60 women had already been recruited, and the goal was to recruit 400, each to be followed up for 8 weeks at two week intervals.
The challenges of rectal microbicides were discussed in numerous sessions through the meeting, with a substantial presentation by Dr Kenneth Mayer of Brown University, Rhode Island, based on a meeting in June 2001 sponsored by the US National Institutes of Health, of which a report is now available.
Among many issues are the possible need for much greater volumes of products – perhaps as much as 40 or 50 millilitres to be used anally, compared to 3 to 5 for vaginal use, and the very different chemical and biological environment in the rectum compared to the vagina.