Advances in drug formulation and delivery
technology have dramatically expanded the formats in which effective,
acceptable microbicides might be developed. The first-generation microbicides
all took gel form because this is the easiest formulation to make and women
generally like its lubricating qualities. The disadvantages of gels, however,
include the fact that they are sometimes perceived as messy, they are expensive
to ship (because they are heavier and bulkier than tablets, rings or films) and
they are coitally-dependent.
Some
people prefer coitally-dependent products (that can be set aside during times
when they are not sexually active) and others prefer coitally-independent
products (that do not require application before each sex act). Ultimately,
both options must be available. But, given that poor adherence likely
compromised the results of many (if not all) of the first-generation trials, it
is immediately evident that more acceptable, convenient, portable formulations
are clearly needed.
Among
the new alternatives now in development are slow-releasing vaginal rings, thin
films and tablets. The films and tablets can to be applied without an applicator
and dissolve inside the body.
The
International Partnership for Microbicides (IPM) clearly believes time-released,
coitally-independent products are the way ahead, because they are now devoting
substantial resources to developing vaginal
rings that sit on or near the cervix and slowly deliver antiretroviral
drugs over a period of a month (for example, trials of a dapivirine ring). As
noted above, such rings are already marketed as the bearers of contraceptives and
hormone therapies.
Another
alternative to gel is a vaginal tablet
that dissolves quickly, turns into a thick gel-like mass and delivers sustained
levels of ARV. IPM’s tablet is ‘bioadhesive’ – meaning that the gel adheres to
the mucous membrane, concentrating the drug at the surfaces where it is needed
and providing a consistent level of drug delivery over an eight- to twelve-hour
period.
Being
ARV-based, this method does not require the resulting gel to form a physical
barrier, as did some of the first-generation products. Given the drug’s
potency, a smaller volume of gel is needed, reducing the risk of messiness
sometimes reported with first-generation products.
In
terms of rectal microbicide development, researcher Robin Shattock has
speculated that thicker tablet/gel formulations could be developed that would
enable the drug to adhere to the colorectal mucosa for long periods, though
there would have to be careful studies to assess the safety of this concept.30
One
of IPM’s dissolving tablets, about the size of an almond, has been developed
containing dapivirine. Designed for vaginal use, it dissolves in less than
three minutes and delivers
therapeutic
levels of the drug for at least twelve hours after insertion. IPM report that they
are also developing a version containing a tenofovir/ UC781 combination. They
anticipate that this formulation could be adapted for rectal use without
difficulty.31
Other
US
researchers have developed a film
delivery format that is smaller than a stick of gum and as thin as a sheet of
paper. The film, itself, is made of a polyvinyl alcohol polymer, a
water-soluble synthetic plastic used in multiple consumer and biomedical
products, including contraceptive films, contact-lens solutions and mouthwash
strips.
ImQuest
BioSciences, the film’s manufacturer, have impregnated the film with a
microbicide candidate called IQP-0528 which acts both as an NNRTI and as an
entry inhibitor. They report that the resulting product is not cytotoxic, has
no negative effect on normal vaginal flora, and is inexpensive to produce.
Acceptability studies are the next step for this product.32
IPM is also supporting development of two
quick-dissolving films, one loaded with a maraviroc/tenofovir combination and
the other with a maraviroc/dapivirine combination.33
Finally, the possibility of using microbicides as a condom
coating has generated renewed interest. Condom manufacturers began to add a
nonoxynol-9 coating to condoms in the 1980s, as a feature that might enhance
their HIV-prevention capabilities. After evidence was released indicating that
N-9 was actually even more damaging to rectal than to vaginal mucosa, the
Global Campaign for Microbicides initiated a public call for the removal of N-9
from all lubricants and condoms, on the grounds that rectal use of such
products during anal sex could exacerbate HIV risk if the condom broke or
slipped.34 While SSL Laboratories
(makers of Durex) and some other
condom manufacturers complied with this request, two major companies did not.
N-9-coated condoms remain on the market, despite the fact that the N-9 coating
provides no demonstrable benefit, either for contraception or HIV prevention,
and may increase HIV risk, especially among those who use them rectally. The
idea of adding a safe microbicidal layer of protection to the physical layer
provided by a condom, however, remains a viable delivery option. In 2007,
StarPharma announced that they had signed an agreement with SSL Laboratories to
develop VivaGel-coated condoms
(presumably to be manufactured after VivaGel
is proven both safe and effective).35
PATH (Program for Appropriate Technology in Health)
and CONRAD are collaborating on development of a novel female condom with
UC781. To facilitate easy insertion, the body of the PATH women’s condom is
gathered into a dissolving capsule that is roughly the size and shape of a
tampon. Once inserted, the capsule film dissolves and helps the condom adhere
to the vaginal lining. The developers
have added UC-781 to the capsule film for additional protection and are now
optimizing the modification to ensure uniformity of drug distribution and
long-term stability.36