Vaginal Administration of Contraceptives

Abstract

While contraceptive drugs have enabled many people to decide when they want to have a baby, more than 100 million unintended pregnancies each year in the world may indicate the contraceptive requirement of many people has not been well addressed yet. The vagina is a well-established and practical route for the delivery of various pharmacological molecules, including contraceptives. This review aims to present an overview of different contraceptive methods focusing on the vaginal route of delivery for contraceptives, including current developments, discussing the potentials and limitations of the modern methods, designs, and how well each method performs for delivering the contraceptives and preventing pregnancy.

Full text

Scientia
Pharmaceutica
Review
Vaginal Administration of Contraceptives
Esmat Jalalvandi 1, *, Hafez Jafari 2, Christiani A. Amorim 3, Denise Freitas Siqueira Petri 4, Lei Nie 5, *
and Amin Shavandi 2, *


Citation: Jalalvandi, E.; Jafari, H.;
Amorim, C.A.; Petri, D.F.S.; Nie, L.;
Shavandi, A. Vaginal Administration
of Contraceptives. Sci. Pharm. 2021,
89, 3. https://dx.doi.org/10.3390/
scipharm89010003
Received: 18 October 2020
Accepted: 15 December 2020
Published: 25 December 2020
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1School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK
2BioMatter Unit, École Polytechnique de Bruxelles, UniversitéLibre de Bruxelles, Avenue F.D. Roosevelt,
50-CP 165/61, 1050 Brussels, Belgium; Seyed.Hafez.Jafari@ulb.ac.be
3Pôle de Recherche en Gynécologie, Institut de Recherche Expérimentale et Clinique,
UniversitéCatholique de Louvain, 1200 Brussels, Belgium; christiani.amorim@uclouvain.be
4Fundamental Chemistry Department, Institute of Chemistry, University of São Paulo,
Av. Prof. Lineu Prestes 748, São Paulo 05508-000, Brazil; dfsp@iq.usp.br
5College of Life Sciences, Xinyang Normal University, Xinyang 464000, China
*Correspondence: ejalalvandi@yahoo.com (E.J.); nieleifu@yahoo.com (L.N.); amin.shavandi@ulb.be (A.S.);
Tel.: +32-2-650-3681 (A.S.)
Abstract:
While contraceptive drugs have enabled many people to decide when they want to have
a baby, more than 100 million unintended pregnancies each year in the world may indicate the
contraceptive requirement of many people has not been well addressed yet. The vagina is a well-
established and practical route for the delivery of various pharmacological molecules, including
contraceptives. This review aims to present an overview of different contraceptive methods focusing
on the vaginal route of delivery for contraceptives, including current developments, discussing the
potentials and limitations of the modern methods, designs, and how well each method performs for
delivering the contraceptives and preventing pregnancy.
Keywords: vaginal drug delivery; contraceptives; vaginal rings; vaginal spermicides
1. Introduction
Every year, approximately 213 million pregnancies occur, and as many as 99 million
of these pregnancies are not intended [
1
]. Several contraceptives methods and strategies
have been conducted to address unplanned pregnancies, as well as to minimize the side
effects and to solve the possible important health problem. However, there are still some
limitations, such as high cost and the need for professional skill for the placement of
long-acting reversible contraceptives (LARC) [
2
]. In the case of oral administration, there is
also the risk of side effects from high dosage estrogen and progestogen [3].
A great deal of research also has been done on identifying new contraceptive delivery
systems to increase effectiveness by improving user compliance [
4
]. However, poor user
adherence to pill regimens is responsible for the considerable difference between thenum-
ber of women experiencing an unplanned pregnancy within the first year of use of oral
contraceptives with perfect use (0.3%) and typical use (8%) [5].
Unlike the oral route, the vaginal counterpart avoids the gastrointestinal and hepatic
first-pass effect. It lacks cell layers with metabolic enzymes, so drugs can directly reach the
systemic circulation, and therefore lower doses are necessary, which in turn decreases the
incidence of side effects. Moreover, due to continuous and stable drug release, this route
improves patient compliance. Due to the presence of a dense network of blood vessels, the
ability to bypass first-pass metabolism and a high permeability for drugs (especially low
molecular weight drugs), the vaginal route is a convenient route for drug delivery [6,7].
Vaginal contraceptives, such as gels and rings, are also discreet and reversible. It can
be part of a multipurpose prevention technology approach when combined with drugs
for sexually transmitted disease (STD) prophylaxis [
8
]. Indeed, multipurpose prevention
Sci. Pharm. 2021,89, 3. https://dx.doi.org/10.3390/scipharm89010003 https://www.mdpi.com/journal/scipharm

Sci. Pharm. 2021,89, 3 2 of 17
technology through the vaginal route has been thought to be a promising strategy to
address reproductive and sexual health needs and can, therefore, be particularly beneficial
for users and the health system [9].
This review aims to discuss available contraceptives as well as the ongoing research
on the design of novel vaginal contraceptive systems.
2. Contraceptives
The contraceptive method is a product or medical procedure that inhibits reproduction
from acts of sexual intercourse [
10
]. Access to safe and effective contraception is essential for
supporting individual and public health and promotes the autonomy of women worldwide.
Women can choose from a vast plethora of contraceptives based on convenience, cost,
esthetic considerations, intercourse periodicity, method efficiency rate, ease of use, etc.
Cultural and religious considerations can also influence a woman’s choice. When choosing
a contraceptive method, women and their health care providers must consider the risks
and benefits of the available options [
11
]. Currently, various non-vaginal contraceptive
options are available, which will be discussed briefly in the following sections. Herein, the
focus is on the local delivery of contraceptives to the vagina.
Non-Vaginal Contraceptives
Non-vaginal contraceptives include a wide range of methods, such as barrier and oral
contraceptives, contraceptive patches and injections, implants, and intrauterine devices.
Barrier contraceptives, including the diaphragm, cervical cap, sponge, female, and male
condoms, are the earliest contraceptives aim to inhibit fertilization by blocking sperm and
egg interaction (physically or chemically) [12].
Barrier contraceptives are well known, easy to use, and have about 80% success rate in
preventing pregnancy when used correctly [
13
], and if used with a spermicide, they could
be up to 96% effective [
14
]. In addition to their contraceptive efficacy, these methods have
been investigated for their effectiveness in disease prevention (e.g., STDs) [
15
]. However, it
is important to stress that an initial clinical examination is required for a diaphragm fitting
and, one needs to master the correct insertion and removal technique for the best results.
While rare, the use of a sponge and diaphragm has been reported to increase the risk of
toxic shock syndrome, risk of urinary tract infections (UTIs), and latex allergy [16].
Oral administration is the most common form of contraceptives used by more than
140 million women worldwide [
14
,
15
]. Combined oral contraceptives comprise estrogen
and progestin, which inhibit ovulation and change the cervical mucus that prevents sperm
penetration.
All combined oral contraceptives are taken daily, and this may cause hormonal fluctu-
ations and, consequently, poor compliance. Various side effects have been reported because
of using oral contraceptives, including headache, nausea, breast tenderness, vaginal dry-
ness, loss of libido, weight gain, irritability, and depression [
17
,
18
]. Some studies reported
that the use of combined oral contraceptives is associated with an increased risk of breast
cancer due to the carcinogenic nature of estrogen-progesterone contraceptives [
19
], cervical
cancer [
20
], venous thromboembolism [
21
], and HIV [
22
,
23
]. Hence, due to the adverse
effect of combined oral contraceptives, there is an immense need to focus on herbal analogs
of these contraceptives, which can provide safe and effective contraception.
The combined hormonal transdermal contraceptive patch development goes back to
the early 1990s. In 2002, Ortho EvraTM was approved by the FDA as the first contraceptive
patch [
24
]. The patch releases norelgestromin (6 mg) and ethinyl estradiol (0.75 mg) to the
systemic circulation in a week [
25
]. Contraceptive patches are more effective compared to
non-hormonal barriers; their advantages are the ease of use and their low-cost. However,
some serious side effects such as venous thromboembolism (VTE) due to the high levels of
estrogen (>30
µ
g), lack of protection against sexually transmitted infections (STIs), and in
some cases, skin irritation can limit contraceptive patch applications [21].

Sci. Pharm. 2021,89, 3 3 of 17
Furthermore, unlike the contraceptive patches, contraceptive injections and implants
provide the possibility of birth control based on progestin only. A long-acting contraceptive
is an injectable method, preventing pregnancy for 8–13 weeks by releasing progestin
into the bloodstream. Depo-Provera
®
, Syana
®
Press (medroxyprogesterone acetate), and
Noristerat
®
(norethisterone enanthate) are the most common contraceptive injections given
in the UK. Common side effects of using injections include headache, cycle disturbance,
amenorrhea, irregular bleeding, weight gain, and abdominal pain, as well as the disability
to protect women against STDs [
26
,
27
]. Moreover, the long-term contraception effect (up
to one year) is not suitable for women planning for pregnancy soon. Hence, there is an
immense need to address the side effects and limitations of conventional contraception
methods.
3. The Vaginal Route Delivery
Until the 1920s, the vagina was considered a site for the delivery of locally acting drugs
only. However, this organ proved to be of great importance for systemic drug delivery,
uterine targeting, or even vaccination [
28
,
29
] due to its large surface area, a dense network
of blood vessels, and permeability to a wide range of compounds [
30
]. Topical delivery
to the vaginal mucosa has many significant applications for preventing human immun-
odeficiency virus (HIV) and other STDs, mucosal vaccines, treatment of various sexually
transmitted infections (STIs), and maintenance of reproductive health. Several drug classes
have been administered through the vaginal mucosa, such as antimicrobials, labor induc-
ers, spermicides, and sexual hormones [
31
,
32
]. Compared to the intestinal counterpart,
vaginal mucosa permeability is higher with some substances such as water, 17-
β
-estradiol,
arecoline, and arecaidine [
33
]. The permeation mechanism to most substances is simple
diffusion, where the intracellular route preferentially absorbs hydrophobic substances. In
contrast, hydrophilic drugs are preferentially absorbed by pores present in the vaginal
mucosa by paracellular diffusion mechanism, with higher absorbability for low molecular
weight lipophilic drugs compared to larger molecules or even hydrophilic drugs [34,35].
Nowadays, vaginal administration of different pharmacologically active molecules is a
common practice, with a specific interest in managing local genital conditions, like infection,
neoplastic lesions, or vaginal atrophy, or with contraceptive and labor-inducing/prevention
purposes [36].
The vaginal route of administration has several advantages over conventional drug
delivery methods, such as the ability to bypass hepatic first-passage, avoidance of gas-
trointestinal side effects, and reduction in hepatic side effects of steroids used in hormone
replacement therapy or contraception [
37
,
38
]. Moreover, the vaginal route overcomes the
inconvenience caused by pain, damage to the tissue, and possible infection by other par-
enteral routes. In addition, self-insertion and removal of the dosage form are possible [
39
].
Moreover, the vagina has a relatively high permeability to a wide range of molecular
weight drugs that contributes to its pharmacokinetic advantages [
40
]. Nevertheless, the
complexity of the vagina may limit the design and use of vaginal delivery formulations. It
is also important to consider cyclic variations, cultural sensitivity, local irritation, and the
influence of sexual intercourse [39].
From a drug delivery viewpoint, the vagina is a continually changing environment.
It is a complex organ with multiple functions and physicochemical, physiological, histo-
logical, and anatomical parameters that change with age, menstrual cycle, pregnancy, and
sexual arousal, all of which play a role in the efficiency and potential duration of vaginal
contraceptive delivery [
39
]. In addition, the self-cleansing action of the vaginal tract will
affect therapeutic outcome [
41
]. For example, several vaginal formulations (tablets, creams,
gels, pessaries, and foams) have limited efficacy due to their lesser residence time on
vaginal epithelium due to the self-cleansing action of the vagina. Mucoadhesive polymers
such as polystyrene sulfonate, polycarbophil, hydroxypropyl cellulose, poly (acrylic acid),
poly(ethylene glycol)-based block copolymers, and chitosan extend the contact with vaginal
mucosa [42–46].

Sci. Pharm. 2021,89, 3 4 of 17
Furthermore, the vagina has natural biomechanical forces and fluid dynamics, which
lead to a physiological removal mechanism that results in the limited absorption of drugs.
The utilization of mucoadhesive formulations can prolong the permanence of the drug in
the vaginal mucosa [
38
]. Therefore, the design of any vaginal drug delivery system must
consider the anatomy and physiology of the vagina.
Vaginal Anatomy and Physiology
The human vagina is an S-shaped fibromuscular collapsed canal that extends from
the lower part of the uterine cervix to the outer part of the vulva known as the labia minor.
In adult women, it presents approximately 7–10 cm in length, more than 4 cm in width,
and 150–200
µ
m in thickness [
35
]. The vagina lies at a 90
◦
angle to the uterus and is held in
place by endopelvic fascia and ligaments. The vaginal tube is composed of four different
areas, which are related to the cervix: an anterior and two laterals shallow fornices and an
ample posterior fornix. The anterior and posterior walls of the vagina join together to form
two ridges of folds creating an H-shape appearance in cross-section [47].
Histologically, the vaginal wall is composed of three layers: tunica adventitia, mus-
cular, and mucosa. The adventitia layer covers the muscular coat; its composition rich in
collagen and elastic fibers contributes to the elasticity of the vagina. The muscular layer
comprises smooth and elastic fibers in a spiral arrangement, which gives an incredible elas-
ticity to this organ. The mucosa layer is divided into three sublayers (epithelium, lamina
propria, and submucosa) and, due to changes in hormone level, its thickness changes at
different stages of the menstrual cycle by about 200–300
µ
m. Hence, the menstrual cycle
may influence drug absorption through the vaginal mucosa. It forms a series of transverse
folds at the surface area of the vagina called “rugae”. This provides the vagina with a
relatively large surface area [
47
]. While the vaginal epithelium is usually considered a
mucosal surface, there are no glands in the vaginal mucosa, and it lacks the direct release of
mucin. The vagina’s secretion is a mixture of cervical mucus, transudate from the vaginal
mucosa, desquamated cellular debris, and leukocytes [
48
]. This mucus coating has several
important physiological functions, playing an essential role in drug absorption or action.
Throughout the menstrual cycle, viscoelastic properties, and the rate of production of
vaginal mucus will change. During ovulation, cervical mucus is less viscoelastic, resulting
in higher permeability of molecules [39].
The vagina’s pH with healthy, lactobacilli-dominated microbiota is acidic between
about 3.5–4.0 [
49
]. This pH value is sustained by lactobacilli that convert glycogen from
exfoliated epithelial cells into lactic acid. The vaginal tube has a pH gradient where
the pH is lowest nearest the cervix. The pH changes with age, stages of the menstrual
cycle, infections, and sexual arousal. For example, menstrual blood, cervical, and uterine
secretions, yeast infection, and semen introduction to the vagina will act as alkaline agents
and increase the vaginal pH [
48
,
50
] verm. The change in pH will affect the ionization and
absorption of certain drugs, as well as the release profile of pH-sensitive drugs. Indeed,
at normal vaginal pH, most weak bases drugs can be found in their ionized form due
to their pKa value (8.5–10.5), while weak acids are mostly in un-ionized form because
of their low pKa < 5.5. However, altering the pH of the vagina due to certain illnesses
such as bacterial vaginosis and yeast infections, and even stress [
51
] can change the drug
absorption profile [
52
]. Therefore, the basic physiology of the vagina must be considered
when designing vaginal dosage formulations [53].
Uterine and pudendal arteries supply blood to the vagina. These arteries arise from
the internal iliac arteries and generate the cervicovaginal artery, which branches to source
the cervix and the anterior and posterior vagina surfaces [54], as shown in Figure 1A,B.

Sci. Pharm. 2021,89, 3 5 of 17
Figure 1.
(
A
) Arteriography of the uterus, ovaries, fallopian tubes, and upper vaginal segment. With permission from Ref
(Belou P. Atlas estereosco’pico de anatomı’a de las arterias del hombre. Tomo III 2da parte. En: Revisión anatómica del
sistema arterial (Stereoscopic Atlas of Human Arterial Anatomy. Volume 3; 2nd Part in: Anatomic Revision of Arterial
System). Buenos Aires: El Ateneo, 1934:98–119). LIIA, left internal iliac artery; LLVA, lower left vaginal artery; LUA, left
uterine artery; MLVA, middle left vaginal artery; MRVA, middle right vaginal artery; RLA, round ligament artery; ROA,
right ovarian artery; RUA, right uterine artery; UB, the uterine body; VA, vagina. (
B
) Cadaveric specimen. Upper and
left view of the genital- urinary organs. In the middle sector of the illustration, a thick intrauterine anastomosis can be
identified. Below, thick vaginal branches anastomosing with the uterine artery can be observed. LAM, levator ani muscle;
LIIA, left internal iliac artery; LIPA, left internal pudendal artery; LLVA, lower left vaginal artery; LTOA, left tubo-ovarian
artery; LUA, left uterine artery; OV, ovary; TIA, transmedial inter uterine anastomosis; UVA, uterovaginal anastomosis [
54
].
Figure license number: 4810031431586.
4. Vaginal Contraceptives
The vaginal route can be an optimal alternative for delivering hormonal contraceptives.
It has lower drug interactions compared to the gastrointestinal tract, and so a lower dose of
contraceptives is required to increase the bioavailability [
55
,
56
]. Additionally, compared
to oral contraceptives, controlled-release products, such as vaginal rings, would increase
effectiveness by improving user compliance.
4.1. Vaginal Rings
The contraceptive vaginal ring is an effective contraception with a low dose of hor-
mones, self-administration, and high stability of drug diffusion. It does not require skilled
providers and frequent high dosing than other common contraceptive methods [17,57].
Initial development of vaginal rings dates back to more than 50 years ago based on
two known facts: the capacity of vaginal epithelium to absorb steroids and the capacity
of elastomers to provide a sustained release of these hormones [
58
]. Distinct from oral
contraceptives that require daily dosage, vaginal rings release a continuous dose of estrogen
and progesterone into the bloodstream to inhibit ovulation. They are, therefore, more
efficient and convenient. For this reason, several studies showed a high acceptance of the
vaginal ring, and participants also highlighted how easy it is to use this contraceptive
option [59–61]. The typical commercially available vaginal rings are shown in Table 1.
Various ring prototypes have been evaluated: progestin-only rings and combined
progestin-estrogen rings, as well as different combinations of progestins and estrogens [
62
].
The most common vaginal ring, Nuvaring
®
(MSD, Oss, The Netherlands), is made of
ethylene-vinyl acetate copolymer and magnesium stearate and releases both ethinyl estra-
diol and etonogestrel. Another common vaginal ring is Progering (Silesia; Santiago, Chile).
Nuvaring releases both ethinyl estradiol and etonogestrel for one month, while Progering

Sci. Pharm. 2021,89, 3 6 of 17
releases progesterone for three months and the ring should be removed and replaced after
this period. Nuvaring and Progering are considered expensive products with low availabil-
ity in low-income and middle-income countries. Indeed, high cost, short-term effectiveness,
as well as storage condition (+4 ◦C) hindered their worldwide acceptability [63].
Table 1. Characteristics of commercially available vaginal formulations.
Contraceptive Product Name Chemical Composition Protect
against STD Hormones/Drug Effectiveness
Duration Ref
Vaginal
rings
Nuvaring®(MSD,
Oss, the Netherlands)
Ethylene-vinyl acetate
copolymer and
magnesium stearate No Ethinyl estradiol
and etonogestrel One month [64]
Progering (Silesia;
Santiago, Chile) Silicone No Progesterone Three months [65]
AnnoveraTM Silicone elastomer No Nestorone®and
ethinyl estradiol One year [66]
Ornibel®(Exeltis
Healthcare, Spain)
polyurethane core, and
ethylene-vinyl acetate
membrane No Etonogestrel and
ethinyl estradiol Three weeks [67]
Femring®Silicone No 17β-estradiol-3-acetate Three months [68]
Implants
Norplant®Six flexible closed capsules
made of silicone rubber tubing
No Progestin levonorgestrel Five years [69]
Implanon®Ethylene-vinyl acetate
copolymer No Etonogestrel Five years [70]
Uniplant Silicone rubber Nomegestrol acetate One year [71]
Patch Ortho EvraTM Polyethylene, polyester No Norelgestromin /
ethinyl estradiol Three weeks [25]
Twirla Polyacrylate, polyisobutylene
adhesive layer No Levonorgestrel/
ethinyl estradiol Every seven
days [72]
A recent FDA approved vaginal ring offers more prolonged protection against preg-
nancy [
66
]. AnnoveraTM is a reusable vaginal ring based on segesterone acetate/ethinyl
estradiol combined hormonal contraceptives and can be used for one year of birth con-
trol [
66
]. Annovera is an opaque white ring made of silicone elastomer with a dimension of
56 mm in outside diameter and 8.4 mm in cross-sectional diameter containing two steroid-
releasing channels. High effectiveness (97.5%) and patient acceptability (89% patient
satisfaction) have been reported for the AnnoveraTM by Kaplan–Meier analysis [
73
]. A
phase 3 clinical trial, including 2265 participants, showed that only 1.8% of the participants
experienced unacceptable bleeding over the course of a year, which led to discontinuation
of the Annovera ring [74].
Ornibel
®
(Exeltis, Madrid, Spain) is another recent contraceptive ring with the same
size and external appearance as Nuvaring
®
(54 mm in outside diameter and 4 mm in
cross-sectional diameter).
Ornibel
®
is made of a different polymeric composition, polyurethane core, and
ethylene-vinyl acetate membrane containing 28% vinyl acetate, which allows the ring to
show a gradual release of the hormone on the first day of use, particularly for ethinylestra-
diol. Moreover, there is no special storage condition needed for this ring [67].
Recently, a newly developed vaginal ring containing segesterone acetate and ethinyl
estradiol with the sustainable daily release of 150
µ
g segesterone acetate and 15
µ
g ethinyl
estradiol (for a year) has received FDA approval. The authors investigated the factors
associated with non-adherence to instructions for using the contraceptive ring. The clinical
trial (phase 3) demonstrated that two critical factors related to the non-adherence to
instructions for using the ring are removing the ring for washing and for intercourse, which
should be considered for the design of a contraceptive ring [75].
The development of vaginal rings releasing ulipristal acetate (UPA), which is a selec-
tive progesterone receptor modulator, has attracted a great deal of interest. The contra-
ceptive effect of UPA is due to its ability to selectively bind to human PRs [
76
]. Currently,
UPA is approved for use as an emergency contraception uterine leiomyoma treatment.
Although a clinical trial with 39 women exhibited a high efficacy (two-thirds of the cycles)

Sci. Pharm. 2021,89, 3 7 of 17
of UPA in ovulation inhabitation, the design of a vaginal ring with different dosages of
UPA should be investigated to enhance its effectiveness as a promising contraceptive [
77
].
Recently, the development of vaginal rings as a multipurpose technology is growing
fast due to the opportunity of addressing multiple sexual and reproductive health problems.
Moreover, in addition to the contraception effect, vaginal rings can have anti-HIV activity
by releasing microbicides [
78
]. It has been reported that a monthly vaginal ring releasing
dapivirine could decrease the risk of HIV-1 infection higher adherence [79].
However, similar to oral contraceptives, the vaginal ring containing 20
µ
g ethinyl
estradiol and 1 mg norethindrone acetate may cause transient nausea [
80
]. While vaginal
rings can better control a woman’s cycles, some adverse effects may lead to higher dis-
continuation rates than combined oral contraceptives [
81
]. Indeed, studies reported some
common side effects, such as headache, vaginitis, weight increase, vaginal discomfort, and
acne [5], as well as rare reactions like vein thrombosis and strabismus [82,83].
4.2. Vaginal Spermicides as Non-Hormonal Contraceptives
Hormonal contraceptives and copper-based IUDs come with a series of side effects,
and they do not offer any protection against STDs. Therefore, safe, effective, and convenient
topical formulations with both microbicide and spermicidal activity are a global need to
control the human population and spread STDs [84,85].
Spermicides are chemical agents that can be found in the format of gels, foam, film,
or suppositories that immobilize the spermatozoa and can exert the contraceptive effect
in the female genital tract by disrupting normal sperm activity by causing irreversible
cell damage or death. An effective spermicidal agent must act rapidly to prevent the
penetration of spermatozoa into the endocervical canal of the uterus and show a good
cervical mucus bio diffusion [
86
]. It must be non-irritating and non-hostile to vaginal flora
and penile mucosa, which must not have any adverse effect on the developing embryo or
fetus and should also be less-toxic [
87
]. An ideal spermicide should preferably be free of
detergent and surfactant molecules. Although many detergents have shown substantial
microbicidal properties [
88
], some studies have suggested that detergent spermicides do
not protect against STDs, including HIV [
89
,
90
]. Indeed, spermicides nonoxynol-9 (N-9) do
not have a protective effect against HIV infection; besides, they can increase the risk of HIV
transmission if used frequently. This may be due to the surfactant nature of these chemicals
that irritate the epithelium membrane of the vagina and causes damage by repeated use,
making the vagina more susceptible to STD infections. Stability and activity duration
of spermicides, as well as their tissue reactivity, should be considered for the design of
epidermal devices [
91
]. Based on their mode of action, spermicides are categorized as
described below.
4.2.1. Bactericides/Surfactant
Membrane integrity and its composition are the fundamental characteristics of the
sperm membrane. Changes in the fatty acid composition of membranes and the num-
ber of integral proteins account for the shift in fluidity that affects sperm’s function [
92
].
Bactericides often interact with components in the sperm membrane and immobilize the
cell. For example, benzalkonium chloride (a cationic surfactant) and sodium docusate
(an anionic detergent) is used as a vaginal spermicide [
93
]. Piperazine dicarboxamidine
derivatives, quaternary ammonium chlorides, and octyl-phenoxy poly ethoxy ethanol
are good bactericides with germicidal and spermicidal effects [
87
,
94
,
95
]. Many surfactant
agents, such as nonoxynol-9 (N-9), can interact with the lipotropic membrane of sperma-
tozoa. N-9 is a non-ionic spermicide approved by FDA and is the most commonly used
spermicidal contraceptive in the UK and USA [
14
,
96
]. N-9 is the active ingredient of many
contraceptive formulations, including foams, gels, creams, suppositories, and sponges [
97
].
In a study by Lee et al. [
98
], a mucoadhesive drug delivery system, gel, was developed
using carbopol 934P for controlled delivery of N-9, while in another study, incorporation

Sci. Pharm. 2021,89, 3 8 of 17
of N-9 into a silicon-based vaginal ring was proposed to investigate the potential use of
this intravaginal ring to prevent STDs [99].
Although the primary function of N-9 is to prevent pregnancy, it is an effective barrier
against STDs, including gonorrhea, chlamydia1 infection candidiasis, syphilis, genital her-
pes, trichomoniasis, and the acquired immunodeficiency syndrome [
100
–
102
]
.
However,
because of the strong surfactant action of N-9, it often disrupts the vaginal mucosa [
103
]
and targets other cells in the vagina, such as the cervicovaginal epithelia that are essential
for maintaining a natural barrier to pathogen invasion, especially
HIV [104,105]
. Thus,
N-9 causes an acute tissue inflammatory response, increasing the risk of STDs such as
HIV [106,107].
Amphora, which was previously known as Acidform, is another spermicide with
FDA approval as a vaginal lubricant that immobilizes and kills sperms by maintaining the
acidity of the vagina (pH < 5, for hours) without any disadvantages. Moreover, the high
adhesiveness of amphora to vaginal walls and the cervix paves the way for decreasing
leakage, which results in preserving its activity for hours. It has been reported that amphora
could be a promising alternative to N-9 as a contraceptive [108].
Another recent bactericide that has been investigated as a potential contraceptive is
B07, a small molecule CCR5 antagonist-based HIV-1 entry inhibitor, which is used as an
anti-HIV microbicide. A recent study demonstrated that B07 could exhibit a concentration-
and time-dependent inhibitory effect against sperm motility and movement patterns tested
on female rabbits. Although a slight irritation was reported for the B07, sound spermicidal
effects against human sperm, and its anti-HIV properties make this bactericide a promising
candidate for further investigation as a vaginal spermicide/microbicide [109].
G1-S4 or G2-S16 are another class of microbicides with anti-HIV-1 and HSV-2 activity
where their potential contraceptive activity has been investigated. A study reported that a
promising contraceptive from the combination of G1-S4 or G2-S16 platycodin D, which
induced 100% immobilization of the sperm in 30 s without showing any toxicity and
vaginal epithelium damage after 7 consecutive days (in vivo, mice) [110].
Other common detergent-type vaginal spermicide includes p-menthanyl-phenyl-
polyoxyethylene (8,8) ether, or menfegol, which is available in a foaming tablet formulation
and isooctyl-phenyl-polyoxyethylene-(9) ether, or octoxynol-9, which was removed from
the US market due to failure in providing new studies required by FDA [111].
4.2.2. Sulfhydryl Binding Agents
Anaerobic energy metabolism, spermatozoa motility, and defense against reactive
oxygen species, which are essential to the survival of both sperm and anaerobic microbes,
such as Trichomonas vaginalis in the host, depending on the availability of free thiols. Thus,
sulfhydryl binding agents (oxidants) are an option for the design of dual-purpose sperm
immobilizing agents [
112
,
113
]. These agents interact with accessible thiols on sperm and
T. vaginalis, resulting in lipid peroxidation, insufficient axonemal phosphorylations, and,
consequently, loss of motility and viability. Sulfhydryl binding agents exert their damaging
effect by oxidation, alkylation, or formation of mercaptides on the sperm membrane [
92
].
Mammalian spermatozoa, with a high content of polyunsaturated fatty acids in their
membrane as well as low concentrations of scavenging enzymes in their cytoplasm, are
particularly prone to oxidation damage [
114
]. Hydrogen peroxide, O-iodobenzoate, and
hydroquinone are known to destroy the tertiary protein structure by converting the thiol
group of cysteine to disulfide linkages. Phenyl mercuric acid is another mercaptide forming
agent [
87
,
115
]. Thirty thiourea derivatives were synthesized in a study carried out by
D’Cruz et al. In their chemical structures, one of the nitrogen atoms of the thiourea was
attached either to a phenyl, heterocyclic or alicyclic moiety through an ethyl bridge and the
other nitrogen atom was attached to a substituted pyridyl ring [
116
]. They reported that
phenyl and cyclohexanyl-substituted thiourea derivatives show anti-HIV and spermicidal
activities [
116
]. In another study by Dwivedi et al., various products of disulfide esters

Sci. Pharm. 2021,89, 3 9 of 17
of dialkylaminocarbothioic acid were synthesized, and some exhibited active spermicidal
effect [117].
4.2.3. Natural Products and Their Derivatives
The spermicidal efficacy of many natural substances has been evaluated to develop
new vaginal spermicides. For example, curcumin, a plant-derived diferuloylmethane com-
pound, offers sperm-immobilizing effect, as well as anti-HIV property [
118
]. Allitridum, an
active compound in garlic, was studied as an inhibitor to sperm mobility
in vitro
[
119
]. This
study showed an evident spermicide effect of allitridum at the 7.5 mg/mL concentration.
Various alkaloids, such as quinine, showed an inhibitory effect on spermatozoa cells, which
was dose dependent. Figure 2shows the chemical structures of curcumin and allitridum.
Immotilin, a protein isolated from an earthworm, rapidly immobilizes and kills human
spermatozoa without disturbing other cells [
120
]. Nisin, a cationic peptide, is produced by
a group of Gram-positive bacteria that belongs to Lactococcus and Streptococcus species [
121
].
Nisin is known for its spermicidal and antibacterial activities [
122
]. Intravaginal administra-
tion of Nisin (200
µ
g) resulted in complete inhibition of sperm motility and, subsequently,
fertilization prevention. The repetitive intravaginal application of Nisin at the dose of
200
µ
g for 14 continuous days did not cause any abnormalities in vaginal epithelial cells in
rats. In addition, no histopathological irregularities in vaginal tissue or any change in blood
and serum biochemical profiles were observed [
88
,
122
,
123
]. In addition to these natural
products, microorganisms are also known to delay sperm motility either by agglutination
or by secretion of extracellular substances. For instance, Staphylococcus aureus showed a
spermicidal effect. In one study, Staphylococcus aureus was encapsulated in a carbopol based
vaginal gel. The gel released about 80% of Staphylococcus aureus within 30 min that could
completely restrain human spermatozoa within the 20 s, at a dose of 200
µ
g/mL [
124
]. It
appears that Staphylococcus aureus contains a sperm-agglutinating factor that attaches to
specific receptors on human spermatozoa and changes the morphology of spermatozoa,
inducing agglutination [
125
]. Many other natural substances have been reported as a
natural spermicide. For example, tartaric acid exhibited the highest spermicide effects
among other components such as nonoxynol-9, benzalkonium chloride, and verapamil [
85
].
Furthermore, another study investigated the spermicide effects of different natural compo-
nents, such as lemon juice, pineapple juice, and apple juice, in which lemon juice showed
higher sperm immobilization exhibited [
126
]. Moreover, other natural compounds such
as bivittoside D [
127
], saponins [
128
], tannins [
129
] have been investigated as spermicidal
compounds.
Figure 2.
Chemical structures of curcumin and allitridum, natural substances evaluated for their
spermicidal activities.
4.2.4. Other Synthetic Products
Bis(cyclopentadienyl) complexes of vanadium or vanadocenes (Figure 3) are a new
class of contraceptive agents that quickly inhibit the mobility of human sperms [
130
,
131
].
The spermicidal activity of vanadocenes was reported to be 400-fold more than that of N-9,
and unlike N-9, the sperm-immobilizing activity was not disruptive to the membrane at
the ultrastructural level [
132
]. Vanadium can be found in both anionic and cationic forms
with oxidation states from
−
1 to +5. Vanadium complexes with oxidation states +4 and +5
can catalyze the production of reactive oxygen species. These species can immobilize the
spermatozoa at nanomolar to low micromolar concentrations [133,134].

Sci. Pharm. 2021,89, 3 10 of 17
Figure 3. Chemical structure of two synthetic spermicide reagents, vanadocene and iron gluconate.
Iron gluconate (Figure 3) is a synthetic reagent immobilizing the sperm tail and in-
ducing lipid peroxidation. Reactive oxygen species produced during this process result in
spermatozoa damage [135,136]. High levels of fatty acids present in human sperms make
these cells susceptible to the free radical species upon exposure to iron gluconate. This
encourages constant formation and decomposition of lipid peroxides and eventually causes
structural damage, a decline in metabolic activity, and spermicidal effect [
29
,
137
].
Han et al.
designed two different vaginal rings composed of acacia gum or non-biodegradable hy-
drogel of 2-hydroxyethyl methacrylate and sodium methacrylate. These vaginal rings
were then infused with iron gluconate and an anti-HIV agent. The release profile of each
reagent from each vaginal ring was examined, and the authors concluded that these vaginal
rings have the potential application as non-hormonal contraceptive delivery systems [
138
].
Saxena et al. also investigated the possible use of a biodegradable hydrogel impregnated
with iron gluconate as a non-hormonal contraception method [
139
]. They reported the
hydrogel composed of dextran, copolymers of polylactide, and
ε
-caprolactone releases
the iron gluconate over 16 days, and
in vivo
study on rabbits showed the effect of iron
gluconate as an efficient spermicide reagent. Recently, a pH stimuli injectable hydrogel-
based chitosan containing iron gluconate and doxorubicin hydrochloride (DOX) exhibited a
promising result [
29
]. The hydrogel showed a fast release of iron gluconate and sustainable
and controllable release of DOX from hydrogel due to the presence of pH stimuli bonds
through Schiff based reaction with amine groups and aldehyde group [140].
Green et al. reported that enzymatically generated free iodine (I
2
) is an extremely
efficient spermicidal agent [
141
]. Free I
2
also showed microbicidal and virucidal activities
at 2-5 ppm concentrations; thus, it can be useful as a dual-purpose contraceptive reagent
with no irritating side effects on tissues [
142
]. In an oxidative environment (rich-reducing
environment: vaginal and seminal fluids), alternate species, such as I
3¯
, or higher oxidation
states of iodine such as IO
¯
, I
2
O
2
, and IO
3¯
, could form during the conversion of iodide
into I
2
. These species could also be responsible for the spermicidal activity. Green et al.
suggested encapsulating precursors for I
2
formation in a vaginal delivery system (e.g.,
vaginal insert). The vaginal delivery device would release the precursor, and free I
2
will
form in situ. The pH of the vagina or semen fluid does not disturb the expression of
I
2
-mediated oxidizing activity because free I
2
is an effective oxidizing agent whether in
the elemental form at low pH or upon conversion to hypoiodate at the more alkaline
environment [141].
Jan et al. introduced a dual-purpose compound as a vaginal contraceptive capable
of preventing STDs. The compound 5-bromo-6-methoxy-5,6-dihydro-3
0
-azidothymidine-
5
0
-(p-bromophenyl methoxyalaninyl phosphate) was synthesized and proved to have an
anti-HIV function at a lower concentration compared to N-9. In addition, the spermicidal
activity of this novel agent was higher than that of N-9 when upon treatment of spermato-
zoa with this agent motility, the loss was complete within 30 min [143]. In a similar study,
the spermicidal efficacy and potential against HIV of a bromo-methoxy substituted phenyl
phosphate derivative of zidovudine were evaluated [
144
]. Unlike N-9, the spermicidal
activity of this compound was not associated with damage to epithelial cells in the vaginal
tract, and it exhibited an anti-HIV effect, hence, considered to be a unique active ingredient
for vaginal contraceptive formulations [
144
]. Figure 4illustrates the structure of these
dual-purpose contraceptives.

Sci. Pharm. 2021,89, 3 11 of 17
Figure 4. Chemical structures of zidovudine derivatives as the potential spermicides and anti-HIV agents.
Many more synthetic and natural compounds are being investigated as new spermi-
cides and anti-STDs reagents. For example, recent extraction of Asiatic acid from Shorea
robusta (tree) induced instantaneous immobilization of rat spermatozoa
in vitro
[
145
],
whereas synthesis of 3,3-bis (5-methoxy-1H-indol-3-yl) indolin-2-one resulted in significant
spermicidal activity [
146
]. All the mentioned spermicides can be exerted in various intrav-
aginal delivery formulations including, jelly, hydrogel, creams, vaginal rings, and implants.
Although these vaginal delivery systems containing spermicides may not be as effective as
other contraceptive methods (e.g., hormonal contraceptive and copper-based IUD), they
are still in the dawn of their development, and some appear to have great potential. It is
important to note that currently, using spermicides as the only method of contraception has
some weaknesses. Relatively high failure rate and risk of urinary tract infection in women
who apply them regularly are some of the drawbacks. Many studies have been carried out
on the potential application of spermicide as anti-STDs such as chlamydia, gonorrhea, or
HIV. Some of these studies suggest an increased risk of these infections when using some
effective spermicides (e.g., detergents such as N-9) since these types of spermicides irritate
the vaginal epithelium and cause small tears that allow HIV and other infectious agents to
enter [147].
5. Conclusions
Vagina, with a smooth and immobile surface with specific permeability properties,
makes it a suitable route for placement and delivery of drugs such as contraceptives in
a controlled manner compared to the traditional oral form. The present article provides
a review of the several methods of vaginal delivery of contraceptives, which either are
currently in the market or are in the design and development stage. We emphasized the
challenges and potentials for the delivery of contraceptives through the vagina compared
to the conventional route for the contraceptive administrations and summarizing the
continuing interests toward the design and the development of new techniques, which
are safe and affordable to most women and have no environmental impact. Further
investigation of vaginal contraceptive methods with minimizing the side effect is required
to fulfill woman’s needs that can be fitted into the real lives of the women who need them.
Moreover, regarding the high demand for contraceptives worldwide, cost-effectiveness
and availability of a contraceptive product should be considered.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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