Formulations and devices

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.

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 (van den Mooter).

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 (and see: Burruano).

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 the vagina's 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. One approach is to use magnetic resonance imaging to visualise what happens when a gel, labelled with non-toxic and non-radioactive gadolinium, is 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. This has produced some of the most remarkable images of sex in progress ever presented at a scientific meeting! (Barnhart).

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 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 (Katz).