Pharmaceutical Manufacturing Handbook: Production and

CLINICAL USAGE AND POTENTIAL OF VAGINAL DRUG DELIVERY 845
scientifi c community is the synergistic association of microbicides with different
action mechanisms in order to improve protection [242] .
Early expectations created around the possibility of using nonoxynol - 9 (widely
used as a vaginal contraceptive) as an effective microbicide, based on its in vitro
effi cacy against HIV, were frustrated in clinical trials [243] . Several hypotheses for
this failure were brought up, an inadequate choice of drug delivery system being
one of them. These results confi rm that preformulation and formulation studies
play an important role in microbicide rational design and development, being a
big challenge to overcome. Although clinical development recommendations have
been extensively reviewed [244, 245] , pharmaceutical development algorithms for
microbicides are yet to be defi ned. Nonetheless, it is known that preformulation
parameters such as organoleptic characteristics, stability, permeability, inherent
bioadhesion and retention features, and compatibility with excipients and condoms
of candidate drugs, among others, play a crucial role when developing drug delivery
systems containing microbicides [246] . After collection of this information,
formulation studies are necessary in order to obtain a fi nal product that fulfi lls
microbicide objectives and requirements, namely safety, effi cacy, acceptability,
affordability, and regulatory duties [247] . As well as providing effective protection,
microbicide formulations must also be safe on multiple exposures over time, chemically
and physically stable, compatible with latex and other materials used in
barrier devices, and affordable and acceptable to the end user. Ideally, they should
be colorless, odorless, tasteless, and nonmessy [234, 248] . Tested microbicides have
been formulated mostly as gels, although creams, vaginal rings, foams, sponges,
vaginal suppositories, and fi lms may also be considered. Nonetheless, alternative
innovative options for the delivery of microbicides have been developed in recent
years. For instance, the formulation of a safe and inexpensive “ universal ” drug
carrier for microbicidal substances is an interesting strategy that may potentially
ensure the effi cacy of most currently researched molecules [249] . Another interesting
approach for the delivery of microbicides was proposed by Chang et al. These
researchers studied the possibility of using genetically modifi ed comensal vaginal
bacteria ( Lactobacillus jensenii ) to produce anti - HIV proteins [250] . In vitro experiments
showed that this strategy can be a new step toward an effective microbicide
formulation.
5.12.6.2 Antimicrobials
Vaginitis is a common condition in women which can be caused by bacteria, yeasts,
or protozoa. Treatment of vaginitis has been achieved by oral or vaginal administration
of antimicrobials, often with similar effi cacy rates [251] . Several drugs are
currently available for intravaginal treatment of bacterial (e.g., metronidazole,
clindamycin), fungal (e.g., azoles, boric acid, nystatin), and protozoal (e.g., metronidazole)
vaginitis [252] . Also, alternative vaginal therapies have been investigated
in order to treat vaginitis. For instance, herbal formulations, particularly those containing
essential oils, have been referred as potential antimicrobials for the treatment
of both fungal and bacterial infections [253, 254] . Several vaginal drug delivery
systems have been used in order to administer antimicrobial substances, particularly
gels, creams, tablets, and vaginal suppositories. Current research in antimicrobial
vaginal drug delivery systems is focused on more convenient single - dose