Int Urogynecol J (2013) 24:537–543
DOI 10.1007/s00192-012-2009-3
REVIEW ARTICLE
The vagina as a route for drug delivery: a review
Sushma Srikrishna & Linda Cardozo
Received: 12 November 2012 / Accepted: 22 November 2012 / Published online: 11 December 2012
# The International Urogynecological Association 2012
Abstract Overactive bladder (OAB) syndrome has a signif-
icant deleterious impact on quality of life. After conservative
therapy and bladder retaining, antimuscarinic drugs remain
the mainstay of OAB management. Oral therapy is associated
with frequent side effects, leading to the development of
alternative agents and formulations or the use of novel routes
of drug administration, such as the vaginal route. The vagina
is often ideal for drug delivery because it allows the use of
lower doses, maintains steady drug administration levels, and
requires less frequent administration than the oral route. With
vaginal drug administration, absorption is unaffected by gas-
trointestinal disturbances, there is no first-pass effect, and use
is discreet. The aim of this review is to provide a background
overview of vaginal development, anatomy, and physiology
and the effect this has on the use of this route for both local and
systemic drug delivery, with special reference to OAB man-
agement. Vaginal therapy continues to be an underused route
of drug delivery. Vaginal administration allows nondaily, low,
continuous dosing, which results in stable drug levels and
may, in turn, achieve a lower incidence of side effects and
improve patient compliance. These benefits must be balanced
against inherent patient or physician bias against using this
route and the need to overcome cultural, personal, and
hygiene-related barriers to this form of therapy. More sophis-
ticated and programmable vaginal rings are being developed
for systemic delivery of therapeutically important macromo-
lecules, such as antimuscarinic therapy in OAB management.
Keywords Overactive bladder . Antimuscarinics .
Oxybutynin . Anatomy . Embryology of vagina . Drug
delivery
S. Srikrishna (*) : L. Cardozo
Department of Urogynaecology, King’s College Hospital,
Denmark Hill,
London SE5 9RS, UK
e-mail: sushmasrikrishna@nhs.net
Introduction
In recent years, there have been a number of technological
advancements in drug delivery. In part, this is due to ongoing
issues with patient tolerance of side effects as well as adher-
ence, persistence, and compliance with traditional methods of
drug administration. The vaginal route of drug delivery
remains largely underexplored despite its potential as a non-
invasive route. The presence of a dense network of blood
vessels in the vagina makes it an excellent route for delivery
of both systemic and local therapy. Despite several advantages
of vaginal drug delivery, such as the ability to avoid first-pass
metabolism, the ease of administration, and high permeability
for low molecular weight drugs, other factors, including gen-
der specificity, individual sensitivities and beliefs regarding
personal hygiene, local irritation, influence of sexual inter-
course, and variability in drug absorption based on epithelial
thickness, have proven to be limitations in using this route to
its maximal potential. The aim of this review is to provide a
background overview of vaginal development, anatomy, and
physiology and the effect this has on the use of this route for
delivery of both local and systemic drugs, with special em-
phasis on managing overactive bladder (OAB) syndrome.
Embryological development of the vagina
The development of the human genital tract is undifferentiated
up to the 9th week of gestation. Prior to gonadal differentia-
tion, both the male and female embryos have two sets of
paired ducts: the paramesonephric (Müllerian) and the meso-
nephric (Wolffian) ducts. Both duct systems are related to the
endodermal urogenital sinus and external genitalia and origi-
nate from the intermediate mesoderm [1]. In the female em-
bryo, in the presence of two X chromosomes and the absence
of testosterone, the mesonephric duct regresses completely
and the paramesonephric duct (Müllerian duct), develops into
538
the fallopian tubes, uterus, and proximal vagina [2]. The exter-
nal genitalia develop from the genital tubercle, folds, and
swellings. The distal ends of the two paramesonephric ducts
from the opposite sides meet in the midline in a Y shape,
forming the uterovaginal duct, which subsequently develops
into the uterus [2]. The distal end of the combined parameso-
nephric ducts or uterovaginal canal then comes into contact
with the posterior wall of the urogenital sinus, forming a pair of
endodermal swellings called the sinovaginal bulbs. These sino-
vaginal bulbs form the lower two thirds of the vagina. They are
originally solid, and vaginal lumen develops later. The vaginal
lumen remains separated from the remaining urogenital sinus
by a thin membrane, the hymen, whereas the urogenital sinus
caudal to the vaginal opening becomes the vestibule. The
vagina, therefore, is made in part from the paramesonephric
duct and the sinovaginal bulb of the urogenital sinus [3]. The
genital tubercle develops into the clitoris, and canalization of
the vaginal plate results in the lower part of vagina [2].
Anatomy and physiology of the vagina
The vagina is a slightly S-shaped fibromuscular structure be-
tween 6 and 12 cm long, with two distinct and differently
orientated portions with a 130° angle between them. The lower
part is convex, and the wider upper portion is almost horizontal
in the upright posture [4]. Histologically, the vaginal wall
consists of three layers: the superficial nonsecretory stratified
squamous epithelial layer, the middle muscularis with smooth
muscle fibers running in both circular and longitudinal direc-
tions, and the tunica adventitia, which consists of areolar
connective tissue [5]. The surface area of the vagina is greatly
increased by the presence of several rugae, and its elasticity is
augmented by the smooth elastic fibers in the muscularis and
the loose connective tissue of the tunica adventitia. There are
no fat cells, glands, or hair follicles within the vagina, and all
vaginal secretions are transudate in nature [6].
Venous drainage is complex and bypasses the hepatoportal
system. The vaginal veins form venous plexuses along the
sides of the vagina and within its mucosa and communicate
with the vesical, uterine, and rectal venous plexuses and
ultimately drain into the internal iliacs. In addition, vaginal,
uterine, vesical, and rectosigmoid veins from the middle and
upper vagina drain directly in to the inferior vena cava [7]. A
“first uterine pass effect” has been postulated when hormones
are administered vaginally owing to the of extensive vascular
connections between the vagina and uterus [8].
The lymphatic drainage of the vagina is interesting in
regard to its embryologically different compartments. The
lower third of the vagina drains to the inguinal lymph nodes
and the upper two thirds to the pelvic and para-aortic lymph
nodes. The vagina has both somatic and visceral innerva-
tion. Somatic innervation is mainly to the lower portion via
Int Urogynecol J (2013) 24:537–543
the pudendal nerve, whereas visceral innervation via inferior
hypogastric and uterovaginal plexuses [9] is much more
significant for the upper vagina.
Advantages and disadvantages of vaginal drug therapy
The main advantages of the vaginal route of drug administra-
tion are that it facilitates the use of prolonged dosing regimens,
lower daily doses, and continuous medication release. Longer
intervals between doses are generally perceived as more con-
venient than daily oral intake and consequently may improve
and/or enhance patient compliance. This is of particular sig-
nificance in association with contraception, where missing an
oral pill can be a recurrent problem for some patients, with
disastrous effects on efficacy. Alternatives such as the vaginal
contraceptive ring have the advantage of being nondaily while
maintaining constant serum levels [10]. Vaginal administra-
tion of drugs also helps avoid gastrointestinal (GI) absorption
and the hepatic first-pass effect. Some drugs, such as propran-
olol, show greater bioavailability after vaginal administration
compared with oral delivery [11]. Nonoral administration may
also decrease the incidence of side effects seen with oral
administration, as observed during the vaginal delivery of
bromocriptine [12]. Absorption is not compromised by vomit-
ing, interdrug interference, or decreased intestinal absorption
capacity. This is particularly advantageous for compounds that
undergo a high degree of hepatic metabolism [13]. Vaginal
drug therapy can also allow for selective local administration,
leading to little or no systemic changes. A prime example of
this is the use of vaginal estrogen therapy in urogenital atro-
phy. Some drugs, such as misoprostol used to induce labor, are
also known to be more efficacious when administered vagi-
nally compared with via other routes [14]. Vaginal therapy
also avoids the inconvenience that may be caused by pain,
tissue damage, and potential for infection by other parenteral
routes. Finally, this form of therapy is amenable to self-
insertion and removal of the drug, which reduces the burden
of repeated hospital/physician appointments [15].
The main disadvantages of vaginal drug therapy include
cultural beliefs patients may associate with this route, issues
around perceived interference with personal hygiene, and
adverse influence on coitus in sexually active women. In
addition, it may cause local irritation in some cases. There
may also be considerable variability in the rate and extent of
drug absorption. Finally, an insurmountable barrier is that,
by definition, this route is for women only
Factors affecting vaginal absorption of drugs
Absorption of drugs from vaginal delivery systems occurs in
two main steps: drug dissolution in the vaginal lumen and
Int Urogynecol J (2013) 24:537–543
membrane penetration. Therefore, any factor that affects
this could potentially affect vaginal drug absorption pro-
file. Cyclical changes in the thickness of the vaginal
epithelium are known to alter drug absorption. There
are confounding reports in the literature regarding the
change in drug absorption with the increase in vaginal
epithelium. Steroids and local estrogen appear to be
better absorbed from thinner postmenopausal epithelium,
whereas progesterone appears to be better absorbed from
thicker, more vascularized epithelium [16–18]. The mi-
crobial balance between lactobacilli as the dominating
flora and other, mainly Gram-negative anaerobes, can
also influence drug absorption. Similarly, changes in vag-
inal fluid volume and composition, pH, and sexual arous-
al could potentially affect drug release, as can the
presence of cervical mucus [19, 20]. Finally, the actual
properties of the drug itself, such as its molecular weight,
lipophilicity, ionization, and surface charge, can influence
vaginal absorption. Longer chain length straight-chain
aliphatic alcohols are better absorbed from the vagina,
as are lipophilic steroids (estrone/progesterone) compared
with hydrophilic ones (hydrocortisone) [21, 22]. On the
other hand, low molecular weight lipophilic drugs are
better absorbed than large molecular weight lipophilic
or hydrophilic drugs, although the molecular weight
limit above which compounds are not absorbed may
be higher for the vagina than other mucosal surfaces
[23].
Applications for drug delivery
Originally, the vaginal route was mainly used to deliver
locally acting drugs. These included antimicrobials and anti-
virals, spermicidal agents, prostaglandins, and steroids [15].
Advances in local vaginal therapy led to the development of
microbicides, which are formulations that can provide an
improved level of protection and prevent transmission of
sexually transmitted infections than can standard barrier
methods of contraception. They also have the benefit of
providing bidirectional protection to both partners [24, 25].
The vagina also has great potential for systemic delivery
because of its large surface area, rich blood supply, and
permeability to a wide range of compounds, including
peptides and proteins. Some drug formulations that are
well absorbed through the vagina compared with other
parenteral routes include bromocriptine, propranolol,
oxytocin, calcitonin, luteinizing hormone-releasing hor-
mone (LHRH) agonists, human growth hormone, insu-
lin, and steroids used in hormone replacement therapy
or for contraception [11, 12, 26]. The vaginal route also
has potential for uterine targeting of active agents such
as progesterone and danazol [8, 26].
539
Dosage forms
Traditionally, vaginal formulations comprised creams, gels,
tablets, pessaries, foams, ointments, and douches. More
recently, the vaginal ring was introduced for hormone re-
placement and contraceptive therapy (Appendix 1) [27–29].
Drug distribution and coverage of vaginal tissue varies
considerably with the nature of the delivery system. Solu-
tions, suspensions, and foam show greater absorption than
the tablet form [30]. The choice of vaginal drug administra-
tion depends on the intended effect of therapy; i.e., local,
topical, or systemic. Drugs intended for local effect should
distribute uniformly throughout the vaginal cavity, and a
semisolid or fast-dissolving solid system is thus preferable.
For a topical effect, a bioadhesive dosage form or intra-
vaginal ring system is more suitable.
Creams and gels
Some contraceptives and antibacterial agents are available
in this form. However, these forms are limited by the fact
that they can be messy to apply, are uncomfortable, and may
leak on to clothes. However, they can be as effective as
orally administered medication in the treatment of bacterial
vaginosis [31]. Other medications available as a vaginal gel
include intravaginal vaccine delivery [32], drugs for cervical
ripening and labor induction [33, 34], as well as abortifa-
cients. Recent work shows that vaginal vaccination may be
effective against chlamydia and HIV [35, 36].
Suppositories and vaginal tablets
These forms are most commonly used to administer drugs
for cervical ripening prior to childbirth and for local delivery
of drugs. Some examples of vaginal suppositories are dehy-
droepiandrosterone sulphate [37] for cervical ripening,
miconazole for vaginal candidiasis [38], and progesterone
for hormonal replacement therapy. Drugs administered as
vaginal tablets include itraconazole, clotrimazole, prosta-
glandins, and estrogens for urogenital atrophy.
Vaginal rings
Vaginal rings are circular drug delivery devices designed to
release the drug in a controlled fashion after the ring’s
insertion into the vagina. These are an alternative route of
drug delivery for systemic application. Vaginal rings were
developed in 1966, initially as contraceptive devices, after
the demonstration that hormones could diffuse through si-
lastic tubes or solid discs at a constant rate [39]. Since then,
vaginal rings have been made from flexible polysiloxane
and then ethylene vinyl acetate copolymer. Contraceptive
rings have been used for years, both to deliver progestogens
540
alone or in combination with estrogen [40, 41]. Contraceptive
rings do not act as a physical barrier to sperm but prevent
pregnancy by hormonal mechanisms, either by suppressing
ovulation or changing cervical mucus. These rings, unlike the
cervical cap or diaphragm, do not need to be fitted or placed
over the cervix. The ring is simply inserted into the vagina, in
contact with the vaginal epithelium. Contraceptive hormones
are absorbed through the vaginal epithelium into the systemic
circulation. The best studied ring is the levonorgestrel ring
developed by the World Health Organization [42]. However,
as with other progestogen-only methods, progestogen-only
vaginal rings do not completely suppress ovulation and have
been associated with variable bleeding patterns, which led to
the development of combined rings because the estrogen
component maintains the endometrium and prevents break-
through bleeding. Rings for other than contraceptive use have
been evaluated for delivery of oestrogen for postmenopausal
hormone therapy [43]. Vaginal administration of estradiol is
more effective in increasing serum and endometrial levels
than is the oral route [44]. Estring, made of silicone polymers,
contains 2 mg of estradiol and delivers 7.5 mcg per day; each
ring is used for up to 3 months. It is indicated for treating
symptoms of postmenopausal urogenital atrophy. It has also
been shown to lower vaginal pH in women with recurrent
urinary tract infections, thereby reducing the risk of further
recurrence [45]. Vaginal rings are also being evaluated as a
treatment option for endometriosis using danazol [46].
Bioadhesive delivery systems
Bioadhesive drug delivery systems were created to circum-
vent the disadvantages of conventional vaginal formula-
tions, such as low retention to the vaginal epithelium,
leakage, and messiness. ReplensR is one such preparation
used to retain moisture and lubricate the vagina. The formu-
lation remains in the vagina for 2–3 days and maintains a
healthy, acidic pH. Other drugs that have been modified to
incorporate bioadhesive delivery include nonoxynol-9 [47],
used as a spermicide, and clotrimazole [48], used to treat
yeast infections.
Properties of the “ideal” vaginal drug
Information from various consumer surveys suggest that an
ideal vaginal formulation should possess the following char-
acteristics [49–51].
& Have no adverse effect on coitus
& Be odorless and colorless
& Be suitable for application several hours before intercourse
& Not associated with leakage, messiness, or feeling of
vaginal fullness
Int Urogynecol J (2013) 24:537–543
& Cause no local irritation
& Be amenable to use with or without an applicator
The use of such products is a very personal choice, and
choice appears to vary according to the individual, her
partner(s), cultural norms, age, and economic, social, and
climatic conditions of the specific geographical region in
which the user lives. Choosing the type of vaginal therapy
also differs among women from different backgrounds and
countries. For example, gel is the preferred formulation in
USA, whereas film formulations are preferred in countries
such as Zimbabwe and Thailand [50].
Application of vaginal therapy in overactive bladder
syndrome
Oxybutynin remains the most widely prescribed compound
for OAB in the world. It is also widely used in patients with
neurogenic OAB. Oxybutynin is a tertiary amine ester that
when administered orally is frequently discontinued by the
patient because of bothersome anticholinergic side effects,
especially dry mouth and constipation. Oxybutynin competi-
tively binds muscarinic receptors in the detrusor muscle,
inhibiting detrusor contractions. It is well absorbed and under-
goes extensive upper gastrointestinal and first-pass hepatic
metabolism via the cytochrome P450 system. Its primary
metabolite, N-desethyloxybutynin (N-DEO), has similar phar-
macological properties but occurs in much higher concentra-
tions after oral administration and is largely believed to be the
cause for the most bothersome side effect of dry mouth [52].
Vaginal oxybutynin therapy offers several advantages over the
oral route, including avoidance of first-pass hepatic metabo-
lism, ability to deliver extended-release therapy, and enhanced
patient compliance, particularly for elderly patients taking
multiple medications. Finally, intravaginal rings may be self-
inserted and removed [53].
One of the first studies investigating vaginally administered
oxybutynin was in gel form in a rabbit model in 2003 [54].
High doses of vaginal oxybutynin gel increased bladder com-
pliance and functional bladder capacity, decrease bladder
pressure, and inhibited bladder contractions on urodynamic
testing. This was further corroborated by other animal studies
[55], although this formulation has not been evaluated in
human trials to date. The vaginal oxybutynin ring delivery
system consists of a flexible, molded silicone ring with one
cylindrically shaped cavity that allows for loading with rods of
oxybutynin to deliver 2, 4, or 6 mg daily [52]. Gittleman et al.
reported the use of a vaginal ring to deliver oxybutynin trans-
vaginally into the circulation to treat OAB. In a phase II
randomized controlled trial, they compared dosages of 4 and
6 mg/day to placebo administered monthly through a slow-
release vaginal ring [56]. However, clinical results from this
trial are still to be reported.
Int Urogynecol J (2013) 24:537–543
Conclusion
Vaginal therapy continues to be an underutilized route of
drug delivery. The efficacy of vaginal administration is well
established. Drugs are easily and rapidly absorbed through
the vaginal epithelium into the systemic circulation, and
there is no adipose tissue or other cell layers with metabolic
enzymes to traverse, as there is with the transdermal or oral
routes. The gastrointestinal tract and hepatic first-pass
effects are avoided. Vaginal administration allows nondaily,
low, continuous dosing, which results in stable drug levels
and may, in turn, achieve a lower incidence of side effects
and improve patient compliance. These benefits must be
balanced with inherent patient or physician bias against
using this route, and it is necessary to overcome cultural,
personal, and hygiene-related barriers to this form of thera-
py. Vaginal ring technology makes drug administration easy
and discreet for patients, giving them complete control over
the method and its reversibility. Intravaginal rings have
shown significant promise and are well accepted by the
majority of women. More sophisticated and programmable
vaginal rings are being developed for systemic delivery of
therapeutically important macromolecules, such as antimus-
carinic therapy in OAB management.
Conflicts of interest Sushma Srikrishna:speaker honorarium, Record-
ati; consultant, Astellas; travel grant to attend ICS from Boston Scientific,
Recordati. Dudley Robinson: consultant for Astellas, Pfizer, Gynaecare,
Ferring; speaker honorarium Astellas, Pfizer, and Gynaecare; meeting
expenses from Astellas and Pfizer. Linda Cardozo: consultant, Astellas,
Pfizer, Teva, Ethicon, Merck, Lilly; speaker honorarium, Astellas, Pfizer;
trial participation Astellas, Pfizer; research grant, Pfizer
Appendix
Medications currently available in the U.K. as vaginal
therapy
1. Combined contraceptive vaginal ring:
& NuvaRing® (vaginal ring, releasing ethinylestradiol
approximately. 15 μg/24 h and etonogestrel approx-
imately 120 μg/24 h; net price three-ring pack 0
£27.00. Counselling, administration dose 1 ring to
be inserted into the vagina, removed on day 22;
subsequent courses repeated after 7-day ring-free
interval (during which withdrawal bleeding occurs)
2. Spermicidal contraceptives:
& Gygel® gel, nonoxynol ‘9’ 2 %, net price 30 g 0
£4.25
3. Contraceptive pessaries:
& Type A/B/C
541
4. Topical estrogens:
& Gynest® intravaginal cream, estriol 0.01 %, net
price 80 g with applicator 0 £4.67
& Ovestin® intravaginal cream, estriol 0.1 %, net price
15 g with applicator 0 £4.45
& Ortho-Gynest®, estriol 500 μg, net price 15
pessaries 0 £4.73
& Vagifem® vaginal tablets, f /c, estradiol 10 μg in
disposable applicators, net price 24-applicator pack 0
£16.72; estradiol 25 μg in disposable applicators, 15-
applicator pack 0 £10.56
& Estring® vaginal ring, releasing estradiol approxi-
mately 7.5 μg/24 h, net price 1-ring pack 0 £31.42.
Label: 10, patient information leaflet; for postmen-
opausal urogenital conditions (not suitable for vaso-
motor symptoms or osteoporosis prophylaxis), to be
inserted into upper third of vagina and worn contin-
uously; replace after 3 months; maximum duration
of continuous treatment 2 years
5. Nonhormonal preparations for vaginal atrophy:
& Replens MD® and Sylk®; acidic, nonhormonal vag-
inal moisturizers; Replens MD® provides a high
moisture content for up to 3 days
6. Preparations for vaginal and vulval candidiasis:
& Imidazole drugs (clotrimazole, econazole, fentico-
nazole, miconazole) available as vaginal cream,
pessaries, capsules, and tablets
& Clotrimazole
& Canesten®
& Gyno-Daktarin®
& Gyno-Pevaryl®
& Gynoxin®
& Nizoral®
7. Preparations for other types of vaginal infections:
& Clindamycin cream and metronidazole gel; indicat-
ed for bacterial vaginosis
& Dalacin®; clindamycin cream
& Zidoval®; metronidazole gel
& Relactagel® and Balance Activ Rx®; vaginal prep-
arations intended to restore normal acidity may pre-
vent recurrence of vaginal infections and permit the
re-establishment of normal vaginal flora
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