Pharmaceutical Manufacturing Handbook: Production and

THE HUMAN VAGINA 815
the upper reproductive tract such as cervical mucus and endometrial and tube fl uids.
Vaginal fl uid consists of 90 – 95% water, inorganic and organic salts, urea, carbohydrates,
glycerol, mucins, fatty acids, albumins, immunoglobulins, enzymes, leukocytes,
and epithelial debris. Although quite variable, normal daily production of vaginal
fl uid is estimated at around 6 mL, increasing at midcycle and decreasing around the
menstruation period [21] . In fact, the menstrual cycle plays an important role in
vaginal fl uid characteristics, particularly on pH values, rheological properties, color
(from milky white to transparent), and antimicrobial activity. Estrogens induce the
production of vaginal fl uid, leading to the lubrication of the mucosa. Decline of
serum estrogen levels, as during prepubertal or postmenopausal periods, results in
a reduction of vaginal moisture [22, 23] . This variability may infl uence drug release,
dissolution, absorption, and removal and thus its activity. Also, vaginal fl uid is selectively
antimicrobial, lactic acid and to a lesser extent antimicrobial peptides and
proteins (calprotectin, lysozyme, histones, and others) being partially responsible by
the resistance of the normal vagina to colonization by exogenous microorganisms
[24] .
Cervical mucus is an important component of the vaginal fl uid, although it presents
substantial differences when compared with whole vaginal fl uid, mainly in pH
value (approximately 7.0). It is produced in the cervix, leaking down into the vagina,
particularly during the three - to fi ve - day interval that precedes ovulation. Its properties
are also infl uenced by the menstrual cycle, particularly pH (range of 5.4 – 8.0)
and antimicrobial activity [25] . Also, estrogens stimulate the secretion of abundant
and fl uid cervical mucus, while progesterone induces the formation of thick cervical
mucus. These changes in viscosity infl uence the capacity of sperm and other substances,
such as drugs, to pass the cervix and migrate to the uterus [22, 23] .
Interaction between vaginal fl uids and drug delivery systems is an important
aspect that has to be managed during drug design, as it may infl uence the fl ow,
retention, drug delivery kinetics, and bioactivity of vaginal formulations [21] . Since
fl uids present in the vaginal environment are diffi cult to obtain, simulated fl uids
have been developed in order to emulate their physical and chemical properties.
Recently, a vaginal fl uid simulant was proposed by Owen and Katz [21] , whether
Burruano et al. [26] developed a synthetic cervical mucus formulation. These fl uids
have been successfully used to evaluate vaginal formulations in vitro, being able to
mimic with considerable accuracy the physiological fl uids. Also, the standardization
of a single composition provides the possibility of comparing results obtained by
different investigators. Table 1 presents the main features of these two simulants.
Enzymes present in the vagina may infl uence drug delivery, as they can degrade
and infl uence the permeability of the administered drugs. Although the enzymatic
activity in the vagina is not as high as in other drug delivery sites, several enzymes
can be found in the vaginal fl uid and in different vaginal epithelium cells, namely
succinic and lactic dehydrogenase, acid and alkaline phosphatases, β - glucuronidase,
phosphoamidase, lactate dehydrogenase, aminopeptidase, and esterases [27, 28] .
This enzymatic activity can limit drug bioavailability and decrease the stability of
prolonged delivery formulations.
Understanding the immune mechanisms responsible for the defense of the female
genital tract is of extreme importance concerning the development of vaccines that
are effective against pathogens. The female genital tract has several mechanisms of
defense against infectious agents, which appear complementary, additive, and even