Pharmaceutical Manufacturing Handbook: Production and

838 VAGINAL DRUG DELIVERY
results. Nonetheless, these features do not refl ect the normal histological architecture
of fertile women, being able to signifi cantly alter the permeability profi les for
many drugs. Along with vaginal mucosal tissue, other model membranes, such as
vaginal and cervical cell monolayer membranes, have been suggested in recent years
in order to predict in vivo absorption [172] .
It is also noteworthy that many of the in vitro results of vaginal permeability
studies cited in the literature have limitations related to the experimental conditions
that were used, particularly pH values at which they have been performed. Differences
in permeability values are particularly expected when ionization characteristics
change between experimental pH and vaginal pH [183] . However, in vitro
results should only be considered as evidence that the vaginal mucosa is able to be
permeated.
In vivo studies performed in animals are an important step before considering
human experimentation. Animal species commonly used in vaginal permeability
studies include rabbits, rats, and mice [53, 158, 184] . Although potentially more
accurate in predicting human vaginal absorption of drugs, animal experimentation
have some limitations. A major problem is the variability of the vaginal epithelium
properties throughout the estrous cycle, thus infl uencing drug absorption [184, 185] .
In order to minimize this variability and standardize the thickness of the epithelium,
animals are usually ovariectomized. Also, vaginal enzymatic activity is an important
parameter in choosing animal models. It is recommended that the enzymatic profi le
of such animal should be comparable to that of the woman. Taking this into consideration,
rats and rabbits seem to be good models for vaginal permeability studies,
particularly when protein and peptide drugs are considered [27] .
5.12.5.3
p H and Acid - Buffering Capacity
As already referred, pH is an important parameter concerning the health and
normal physiology of the vagina, being important that vaginal formulations do not
interfere with its normal value. Also, the pH of the vagina can be elevated due to
changes in its normal physiology (e.g., bacterial vaginitis) or the presence of semen.
Vaginal formulations presenting good acid - buffering capacity have the potential to
reestablish normal pH or to prevent it from rising.
The acid - buffering capacity of a vaginal formulation can be measured by simple
titration with an inorganic alkali, such as sodium hydroxide. The physiologically
relevant acid - buffering capacity can be defi ned as the amount of alkali required to
elevate the pH from its initial value to the maximum desirable value when considering
the healthy vagina [186] . Also, mixtures of vaginal formulations with semen may
be useful in determining their buffering capacity, this proceeding being particularly
helpful when testing products used during sexual intercourse.
Variations in vaginal pH of the vagina can infl uence drug stability, particularly
when extreme values are observed. Thus, the adjustment of the formulation pH can
also be important in order to assure maximum stability or pharmacological activity
of the active substance(s). As an example, the administration of antibodies in the
vaginal milieu can compromise their activity because of the acidic pH. Generally
monoclonal human antibodies are more stable at pH 4 – 7, losing binding and neutralizing
activity below pH 4 [187] . These fi ndings underline the importance of pH
buffering when delivering pH - sensible molecules such as antibodies.