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ISSN: 1071-7544 (print), 1521-0464 (electronic)
Drug Deliv, Early Online: 114
! 2014 Informa Healthcare USA, Inc.. DOI: 10.3109/10717544.2014.928760

REVIEW ARTICLE

Advanced topical drug delivery system for the management of vaginal

candidiasis
Himmat Singh Johal, Tarun Garg, Goutam Rath, and Amit Kumar Goyal

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Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India

Abstract

Keywords

Vaginal candidiasis or vulvovaginal candidiasis (VC) is a common mucosal infection of vagina,

mainly caused by Candida species. The major symptoms of VC are dyspareunia, pruritis, itching,
soreness, vagina as well as vulvar erythema and edema. Most common risk factors that lead to
the imbalance in the vaginal micro biota are the use of antibiotics, pregnancy, diabetes
mellitus, immuno suppression as in AIDS or HIV patients, frequent sexual intercourse,
spermicide and intra-uterine devices and vaginal douching. Various anti-fungal drugs are
available for effective treatment of VC. Different conventional vaginal formulations (creams,
gels, suppositories, powder, ointment, etc.) for VC are available today but have limited efficacy
because of lesser residence time on vaginal epithelium due to self-cleansing action of vagina.
So to overcome this problem, an extended and intimate contact with vaginal mucosa is desired;
which can be accomplished by utilizing mucoadhesive polymers. Mucoadhesive polymers have
an excellent binding capacity to mucosal tissues for considerable period of time. This unique
property of these polymers significantly enhances retention time of different formulations on
mucosal tissues. Currently, various novel formulations such as liposomes, nano- and
microparticles, micro-emulsions, bio-adhesive gel and tablets are used to control and
treat VC. In this review, we focused on current status of vaginal candidiasis, conventional
and nanotechnology inspired formulation approaches.

Bio-adhesive polymers, liposomes,

nanotechnology, novel drug delivery
systems, vaginal candidiasis

Introduction
Vaginal candidiasis (VC) often referred to as vulvovaginal
candidiasis, is a common mucosal infection of vagina, mainly
caused by Candida species (Alexander et al., 2004) and
alleged to be the second most prevalent mucosal infection
after bacterial vaginosis. It is a far-flung infectious disease
affecting about 75% of women of reproductive age (Song
et al., 2004). In the United States alone, annually 13 millions
of cases of VC are observed which further results in
10 million gynecologic office visits (Francois et al., 2003).
In 2002 in United States, women spend over half a billion
dollars on the medication for the treatment of VC, and about
half of this amount was spend on over the counter medicines
(Jyotsana et al., 2010). This is despite the fact that most of the
women may wrongly diagnose VC as bacterial vaginosis
(De Blaey & Polderman, 1980). The major symptoms of VC
are dyspareunia, pruritis, itching, soreness, signs of vagina
and vulvar erythema and edema (Lee, 1990; Francois et al.,
2003). Candida species, especially Candida albicans is
responsible for VC. It is a dimorphic commensal organism
that domiciliation on skin, mucosa and gastrointestinal tract

Address for correspondence: Amit Kumar Goyal, ISF College of

Pharmacy, Moga, Moga, Punjab 142001, India. Email: amitkumargoyal
1979@gmail.com

History
Received 5 May 2014
Revised 23 May 2014
Accepted 23 May 2014

of 3050% of normal healthy individual. Candida albicans is

not a pathogen, but when local or systemic defense mechanism of the host got afflicted, Candida spp. can induce
oropharyngeal, esophageal or VC (Woolfson et al., 2000).
Under normal healthy conditions, lactobacillus in vagina
produces lactic acid, which act as buffer and maintains the pH
of vagina in the range 45 (acidic) and bacteriocins and
hydrogen peroxide (H2O2), which resist the overgrowth of
pathogenic microbes. In certain ill conditions, when this
balance gets disturbed, there occurs excessive overgrowth of
Candida sp. and diminution or depletion Lactobacillus spp.
Following the overgrowth, there are two crucial elements
responsible for the developments of VC are vaginal epithelium colonization and transformation of asymptomatic
(saprophytic phase) to symptomatic (pathogenichyphal
phase). Most common risk factors that lead to the imbalance
in the vaginal micro biota are the use of antibiotics,
pregnancy, diabetes mellitus, immuno suppression as in
AIDS or HIV patients, frequent sexual intercourse, vaginal
douching, spermicide and intra-uterine devices (Gagandeep
et al., 2014). Most commonly used drugs for VC are
Fluconazole, Clotrimazole, Metronidazole, Miconazole,
Econazole, Ticonazole, Voriconazole, and Isoconazole.
In pharmaceutical literature, vagina is described as slightly
S-shaped fibro muscular, collapsible tubular organ of
approximately 610 cm length that extends from cervix of
the uterus to the vestibule of the external genitalia

H. S. Johal et al.

Drug Deliv, Early Online: 114

(Washington et al., 2000; Woolfson et al., 2000) and has two

main functions: (1) Serves as receptacle for penis during
sexual intercourse and carries sperm to the uterus and
fallopian tubes. (2) As a birth canal for the passage of the
baby during labor. The vagina comprises of three different
cell layers: epithelial layer (superficial layer), lamina propria
or tunica, muscular coat (D Amati et al., 2003). Overall of
1015 layer cell turnover is expected in the time period of 7 d
(Sjoberg et al., 1988). A brief description of vaginal anatomy
and physiology is presented in Table 1.

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Pathophysiology of vaginal candidiasis

A normal healthy micro floral balance of Lactobacillus sp.
and Candida sp. exists in vagina. When this balance gets
disturbed due to certain risk factors, there occurs excessive
growth of Candida sp. (Virulent). This is followed by cascade
of reactions that finally leads to damage to vaginal epithelium
and then symptoms get precipitated and VC occurs (Figure 1).
Adhesion to vaginal epithelia
The initial and critical step toward fungal infections is the
adhesion of Candida to epithelial cells. Candida albicans
interacts by colonization and proliferation on epithelial cells
followed by invasion, dissemination and damage. Cell wall
components of Candida play a key role in adhesion process.
Different cell wall protein adhesion candidates are:
The Als (agglutinin-like sequence) family: Till date 8 ALS
genes have been recognized ALS 1ALS 7 and ALS 9, that
are involved in adhesion. N terminus of ALS protein is
involved in ligand binding (Loza et al., 2004; Rauceo et al.,
2006; Liu & Filler, 2011). Study of ALS-deleted mutants have
variable effect on adhesion like expression of C. albicans
ALS1 or ALS5 genes in non-adhesive, ALS4 deletion
decreases C. albicans adherence to endothelial cell.

Hypha-associated genes: Hyphal wall protein (Hwp 1),

major protein on hyphal cell wall. Its N-terminal domain
serves as a substrate for epithelium transglutaminases. Thus, a
strong covalent linking occurs between Hwp and epithelium
proteins. Eap1, and Int1, also involved in adhesion but their
binding ligands are unknown.
Integrin am b2-like adhesins: Different ligands, including
iC3b, fibrinogen, factor X, urokinase receptor, CD14, CD23,
CD54 (ICAM-1), CD102 (ICAM-2), CD242 (ICAM-4),
heparin, haptoglobin, kininogen, and various microbial proteins (Haas & Plow, 1994). Out of these molecules, only
ICAM-1 and -2 are widely expressed on endothelial cells.
Integrin av b3 and avb5-like adhesins: av b3 like adhesion
has been shown to bind to vitronectin (Spreghini et al., 1999;
Santoni et al., 2001), but other ligands for av b3 include
CD31 (PECAM-1), Fibronectin, fibrinogen, thrombospondin,
von Willebrand factor, and RGD sequence peptides (Haas &
Plow, 1994). CD31 is expressed by endothelial cells and could
act as a direct ligand for Candida adhesion avb5
vitronectin, RGD sequence peptides but lack epithelium
specific binding ligand (Jouault et al., 2006).
Transmigration vaginal epithelium
After adhesion, next step is the migration across vaginal
epithelium. Different mechanism through which Candida
migrates is:
Induced endocytosis: Two Candida invasions, ALS 3 and
SSA 1 (SSA 1 is a member of the heat Shock protein (HSP)
70 family that is expressed on the cell surface). Present in
hyphal cell wall and induce endocytosis. These binds to
E- cadherin, then tyrosine phosphorylation occurs that leads
to microfilament rearrangement and then leads to pseudopod
formation and subsequent engulfment into the cell through
clathrin mediated actin-dependent mechanism.

Table 1. Anatomy and physiology of vagina.

Vaginal physiology

Characteristics

Epithelium

Stratified,
Non-keratinized squamous

Vaginal secretion

Vagina does not possess any gland (Paavonen,

1982). Vaginal fluid comprises of exudates
from blood vessels, secretion from fallopian
tubes, peritoneal, uterine, Bartholins and
Scenes gland (Francois et al., 2003)
Range of 3.54.5
(average 4.2)

pH

Micro flora

Vagina has a complex micro-ecological system

Description
 Thickness is higher in postmenopausal women than premenopausal women
 25 layered thick estrogen content act as a dominant physical barrier
 Have numerous folds, known as Rague (Hussain & Ahsan, 2005);
which helps in easy incorporation of different formulations and enhances
absorption of drugs by providing distentibility, support, increasing surface
area (Choudhury et al., 2011).
 Fluid provide moisture
 Solubilize solid dosage formulations in vagina
 Volume and composition of vaginal fluid varies with age, infection, sexual
arousal (Masters & Johnson, 1966)
 Lactobacillus sp. produces lactic acid from glycogen, which helps in
maintaining healthy acidic conditions in vagina
 Varies with age (new born 45, pre-puberty 7, puberty 57, child
bearing 45, pregnancy 35, menopause 67 and post menopause 77.4).
 Ionization of ionic drug alter with slight shift in vaginal pH; thus changes
stability, solubility and absorption of drugs
 Lactobacillus is the predominant flora in vagina
 It produces lactic acid, H2O2, bacteriocins, thus maintains acidic vaginal
environment and also resist growth of pathogenic micro-organisms
 Composition of vaginal flora varies with menstrual cycle, gestation, use of
contraceptives, frequency of sexual intercourse, etc.
 Candida sp. concentration reaches peak level in pre-menstrual period.

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Figure 1. Pathophysiology of vaginal candidiasis.

Figure 2. Diagrammatic description of vaginal colonization of Candida spp.

Active penetration: Fungi must be viable and changes to

hyphal form during or after the penetration. Sap enzymes
primarily contribute to active penetration. Sap (Secreted
aspartic proteinases) 5 degrade E- cadherin of epithelial cell
and violate integrity of vaginal epithelium, thereby enabling
hyphal penetration into epithelial cells.
Damage: Once Candida goes across vaginal epithelium, it
cusses severe damage by apoptosis and necrosis. However,
exact mechanism behind this is yet to be revealed.

Figure 2 represents diagrammatic description of vaginal

colonization of Candida Spp. Table 2 discusses the different
ligand specific adhesion and invasions involved in adhesion
and transmigration across vaginal epithelium.

Prevalence of vaginal candidiasis

VC has a wide geographical distribution all over the world
(Table 3). On the basis of various research papers it can be

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H. S. Johal et al.

Drug Deliv, Early Online: 114

of VC, proper microscopic identification of virulent sp.

should be done. Non-azole anti-fungal drugs like Boric acid
and Flucytosine can be used for non-albicans species
(Ogunshe et al., 2008; Vermitsky et al., 2008; Abruquah,
2012).

concluded that C. albicans is the most dominant and prevalent

sp. in females with VC as it has an excellent binding capacity
for mucus membrane. Non-albicans species are contributing
to VC for a far lesser extent. VC with positive samples was
observed to occur on higher levels on USA and UK while
other countries had significant lesser number of positive
samples. Among all positive samples, occurrence of
C. albicans sp. was much higher than non-albicans sp.
Among non-albicans sp., C. glabrata was the most common
fungi found in subjects vagina. This vast variation was
observed in females which are illiterate, high school education, married, having diabetes mellitus (Alli et al., 2011;
Faraji et al., 2012), frequent sexual intercourse, oral contraceptives, spermicides (Alli et al., 2011), etc.
A concerning trend was observed in prevalence of
Candida sp. in different age groups. With increasing age,
a drastic fall in albicans sp. was observed; however, there
is a significant increase in distribution of non-albicans sp.
among which C. glabrata was the dominant one. Increase
in number of C. glabrata was also observed in elderly
diabetic patients (Vermitsky et al., 2008). This can be
justified, as continuous use of azole agents leads to development of resistance in C. glabrata, which is characterized
by higher colonization of C. glabrata in vaginal epithelium
as compared to C. albicans. Thus for effective treatment

Factor affecting vaginal drug absorption

(Stewart-Tull, 1964; Hussain & Ahsan, 2005;
Mathiowitz et al., 2013)
Like other mucosal routes, drug administrated via vaginal
route is absorbed by three major ways: (1) transcellularly;
mediated via concentration-dependent gradient (2) paracellularly; through tight junctions present in between the cells
(3) vesicular or receptor-mediated transport as remarked
by Ilium and Richardson. Absorption of drug from vagina
follows two main steps: drug dissolution in vaginal lumen and
membrane penetration. So any factor influencing physiology
of vagina and formulation aspects like drug dissolution and
membrane transport will potentially alter the absorption
profile of drug from vaginal drug delivery systems (Garg
et al., 2014a). Different vaginal physiological factors that
influence drug absorption in vaginal cavity are discussed in
Table 4.

Available therapies for vaginal candidiasis

Various anti-fungal drugs are available for effective
treatment of VC. The treatment is initiated in symptomatic
women because they have 80% of Candida colonization
(Syed & Braverman, 2004). The endeavor of the treatment
is to prevent over-growth of Candida that precipitates
symptoms. Almost 37 d are sufficient for effective
results. Formulation other than oral, are usually administered
at night to prevent any leakage or removal from vagina.
There is no evidence available favoring any specific formulation or any particular azole agent. However in case of
severe infection, oral preparations may not provide symptomatic relief. In that case low-potency steroids as topical
formulations should be used (Cejtin & Mason, 2000).
Different oral and topical therapies available for VC are
given in Table 5.
While these therapies are quite effective, but
still associated with number of limitations like side effects,
drug interaction, contraindication, etc., as presented in
Table 6.

Table 2. Ligand specific adhesion and invasions involved in adhesion

and transmigration across vaginal epithelium.
Interaction of
Candida with
epithelium

Candidates

Adhesion

Als 1-7, 9
Hwp 1
Eap1
Int1
Integrin am b2-like
adhesins
Integrin av b3 like
adhesins
N-linked mannosyl
residues
O-linked mannosyl
residues
Phospholipomannan
Mannosides
ALS 3 and SSA 1
Sap enzymes

Transmigration

Ligand
N- cadherin
transglutaminases
Unknown
Unknown
ICAM-1 and -2
CD31 (PECAM-1),
Mannose receptor (MR)
Toll-like receptor 4
(TLR-4)
TLR-2
galectin-3
E- cadherin,
E- cadherin,

Table 3. Worldwide distribution of various Candida sp. responsible for

vaginal candidiasis.
Candida
Country

Total no.
of subjects

Albicans
(%)

Glabrata
(%)

Parasilosis
(%)

Krusei
(%)

Tropicalis
(%)

IOWA
USA
Nigeria
Iran
Pakistan
India
Australia
UK
Brazil

593
93 775
106
605
250
350
275
548
404

70
88.9
36.8
26.28
12
17.42
15.63
86.86
33.16

18.8
7.9

0.82
3.2
2.5
4.3
2.7
1.2

5
1.7
5.6
0.33
4
0.5
1.09
0.5
1.2

2
1.4
1.88
4.29
1.2
0.8

0.1
1.2

0.008
10.3
0.33
8.4
1.4
0.3
0.7
1.2

Other sp.
(%)
1.6

4.13
3.2
0.5

0.9
-

References
(Richter et al., 2005)
(Vermitsky et al., 2008)
(Ogunshe et al., 2008)
(Shafik et al., 2007; Faraji et al., 2012)
(Khan & Baqai, 2010)
(Jindal et al., 2007)
(Pirotta & Garland, 2006)
(El-Din et al., 2001; Dias et al., 2011)
(Sobel et al., 2004)

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Table 4. Factor affecting vaginal drug absorption.

Factors
Physiological factors

Sub-types

Drug-related features

Vaginal epithelium thickness

 Higher the epithelium thickness lesser will be permeability and vice versa; thus
absorption varies.
 Example: as in case of steroids (Vermesh et al., 1988) and estrogen.
 In guinea pigs, in early disastrous stage, Vidarabine has shown a 5100 times
more permeability coefficient as compared to that in oestrous stage (Hwang
et al., 1977).
 Poorly water soluble drugs are more frequently absorbed when fluid volume is
high.
 However this condition may remove drug from vaginal cavity thus reducing drug
absorption (Owen et al., 1999).
 Thick mucus is less permeable and vice versa.
 It act as permeability barrier for most of the drugs (Johnson et al., 1992).
 It can be exploited for bioadhesive delivery systems
 For pH-sensitive drugs and drugs which are weak electrolyte, alteration in vaginal
pH may alter drug ionization, solubility, stability and subsequent drug
release(Katz & Dunmire, 1993).
 Lipophilic steroids like progesterone and estrone have higher permeability as
compared to hydrophilic steroids i.e. hydrocortisone and testosterone (Robinson
& Bologna, 1994).
 Lipophilic drugs of low molecular weight are readily absorbed then high
molecular weight hydrophilic or lipophilic drugs.
 As vaginal fluid have some water content so it favors absorption of drugs having
certain solubility in water (Hwang et al., 1976).
 Drugs like peptide, weak electrolyte are frequently absorbed in their unionized
form (Brannon-Peppas, 1993).

Vaginal fluid

Cervical mucus
pH

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Physicochemical factors

Lipophilicity
Molecular weight
Solubility
Degree of ionization

Table 5. Different available therapies for VC (Faro, 1994; Carr et al.,

1998; Watson & Pirotta, 2011; Newson, 2013).
Agent
Clotrimazole

Miconazole

Terconazole

Ticonazole
Nystatin
Butoconazole
Ketoconazole
Fluconazole
Itraconazole

Formulation
1% cream
100 mg vaginal tablet
100 mg vaginal tablet
500 mg vaginal tablet
2% cream
100 mg, vaginal suppository
200 mg, vaginal suppository
1200 mg vaginal suppository
80 mg vaginal suppository
0.4% cream, 5 g,
0.8% cream, 5 g,
6.5% ointment, 5 g,
2% cream
100 000 IU, vaginal tablet,
2% cream,
200 mg oral tablet
150 mg oral capsule
100 mg oral capsule

Dose
5 g, intravaginal
for 7 to 14 d
100 mg  7 d
200 mg  3 d
500 mg  single dose
5 g, intravaginal for 7 d
100 mg 7 d
200 mg  3 d
1200 mg  single dose
80 mg  3 d
5g7d
5g3d
5g  single dose
5g3d
100 000 IU,  14 d
5 g,  3 d
400 mg  5 d
150 mg  single dose
200 mg  3 d

Conventional topical intravaginal delivery systems

Creams and gels
Creams and gels as intravaginal delivery systems are used to
deliver contraceptives and anti-bacterial agents (Garg &
Goyal, 2014a). However these systems are messy in use,
uncomfortable and because of non-uniformity and leakage,
exact dose can never be provided. The worthy properties of
vaginal creams and gels are acceptability; feasibility and nontoxic, non-irritant nature towards vaginal mucosa. Vaginal
creams of metronidazole and clindamycin are found to be as
efficacious as the orally administered drugs for treatment of

bacterial vaginosis (Mcgregor et al., 1998). Oxytocin,

dinoprostone and misoprostol used for cervical ripening and
labor induction, can be administered in gel form. Shetty et al.
studied efficacy of dinoprostone vaginal gel against oral tablet
for induction of labor and observed significant difference
there. Several researchers are comparing efficacy of vaginal
gel with oral products for misoprostone, and the results
obtained leads to conflicting outcome. Hall et al. reported
that orally given misoprostone is far more safe and effective in
labor induction against when it is vaginally administered.
However, Shetty et al. concluded that among vaginally and
orally administered misoprostone, vaginal delivery was the
most effective. Vaccines can also be delivered intravaginal in
the form of gel.
Pesseries and suppositories
A variety of vaginal medications are available in form of
pesseries and suppositories. They are designed in such a way
to melt in vaginal cavity and release active medicament in
controlled manner. Suppositories are used for localized
delivery of drugs like anti-septic, anti-fungal and contraceptives. Primarily, they are used to deliver drugs like
dehydroepiandrosterone Sulphate (Yamashita et al., 1991)
for cervical ripening, prior to birth; miconazole for VC
(Vukovich et al., 1977; Abrams & Weintraub, 1983) and
progesterone for hormonal replacement therapy. Different
techniques for preparation of suppositories are hand-molding,
pour-molding or by automatic machine (Brannon-Peppas,
1993; Hussain & Ahsan, 2005) where drug is dispersed in
suppository base, e g. cocoa butter. Pesseries are known to
deliver prostaglandin E2 (PGE2) for cervical ripening and
labor induction. A semi-crystalline hydrogel of cross linked
polyethylene oxide swells in saturated solution of PGE2 to
give final product, pesseries.

H. S. Johal et al.

Drug Deliv, Early Online: 114

Table 6. Drug associated limitations for anti-fungal therapy.

Anti-fungal drug
Fluconazole

Itraconazole

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Clotrimazole

Ticonazole
Ketoconazole

Side-effect
 Nausea, vomiting, abdominal pain,
and diarrhea, have been reported in
approximately 5% of patients
(Ernest, 1992).
 Skin rash, acne, itch, headache,
GI upset(Sobel et al., 1995)
 Abnormal liver function in 5.1% of
patients, Hepatotoxicity in AIDS
patient(Gearhart, 1994)
 Nausea, headache, dizziness(Stein &
Mummaw, 1993) increased level of
transaminase enzyme
 Reversible peripheral neuropathy
(Hay, 1993) and reversible changes
in liver function with low frequency
 Vaginal burning, sensitive clitoris in
(5%) Patients(Fong, 1992)

 Local pruritis, local burning, vaginal

irritation. recurrent candidiasis
(30%)(Stein et al., 1986)
 Hepatotoxicity, alcohol intolerance,
anorexia, increased appetite, headache,
dizziness, insomnia hepatitis, jaundice,

Drug interaction

Contra-indications

 Cisapride
 Erythromycin, non-sedating antihistamines,
diuretics raise fluconazole levels.
 Dilantin, oral hypo-glycemic drugs benzodiazepines; theophylline and warfarin level can
get elevated.
 Cimetidine may limit efficacy of fluconazole.

Renal and hepatic dysfunction

Pregnancy





























Heart disease

Quinidine
Pimozide
Dofetilide
Modazolam
Nisoldipine
Ergotamine
Cholecalciferol
Acetaminophen
Montelukast
Gabapentin
Furosemide
Diphenhydramine
Aspirin
Cyclosporine,
Methotrexate
Prednisone
Alprazolam
Midazolam
Triazolam
Quinidine
Amlodipine
Felodipine
Nicardipin
Phenytoine
Nifedipine
Cyclosporine
Tacrolimus

Vaginal tablets, powder and ointment

Vaginal tablets contain same components as that of conventional oral tablets like binders, disintegrants and other
excipients. These are advantageous over the other dosage
form as have ease of manufacture and insertion. Usually
deliver prostaglandins and anti-fungal drugs like Itraconazole,
Clotrimazole, etc. Highly hydrophobic drugs are not suitable
candidates for vaginal tablets as they have poor absorption.
However, use of penetration enhancers like surfactants, bile
salts can overcome this problem. Sometimes mucoadhesive
polymers can be incorporated to enhance vaginal residence
time. Polystyrene sulfonate (PSS) when formulated as vaginal
tablet, have higher anti-microbial effect against HIV and HSV
and is neither cytotoxic nor it inhibit vaginal flora (Kast
et al., 2002). Vaginal powder is prepared by dissolving
Hydroxypropyl cellulose in water with continuous heating.
This mixture is then slightly cooled and bisphosphonate was
added. This final mixture was then lyophilized. Vaginal
ointment comprises of an aqueous phase and oil phase. Drug
was dissolved in the aqueous phase and the oil phase was
incorporated into it with mixing (Kaur et al., 2014).
Vaginal ring
Vaginal rings are circular device inserted in the vagina
to achieve controlled release of the active medicament.

Hepatic dysfunction

Hypersensitivity, diabetes
Liver disease, hypersensitivity

These are approximately 5 cm in diameter and have 45 mm

of cross-sectional diameter. These are generally polymeric
rings in which the drug is homogeneously dispersed. These
offer several advantages: user controlled, deliver drug
continuously and do not interfere with coitus. From the
surface of the ring, drug release at faster rate as compared to
the inner layer of ring. This may provide an initial burst
release of the drug followed by sustained release for several
days. In order to achieve constant release, two types of system
are developed for vaginal rings: sandwich and reservoir type.
In sandwich type, a narrow layer of drug is placed between
non-medicated central core and non-medicated outer band. In
reservoir type, central core having the drug is encapsulated
with drug-free polymer layer (Garg & Goyal, 2012).
Commonly used polymers are poly (dimethylsiloxane) or
silicone devices. Moreover in the recent years, elastomeric
polymer like ethylene vinyl acetate and styrene are extensively used, as it have increased flexibility, improved optical
properties, greater adhesion and increased impact and punch
resistance (Novak et al., 2003). Vaginal rings are most
commonly employed for hormonal replacement therapy and
contraceptives delivery. To deliver contraceptive, rings are
placed in vagina for 21 d followed by 1 week ring free for
menstrual cycle to take place. NuvaRing is a common
example of vaginal ring available in U.S market to deliver
contraceptives. It is transparent, flexible ring containing

DOI: 10.3109/10717544.2014.928760

etonogestrel and ethinyl estradiol and releases 120 mg/d of

former and 15 mg/d of later one over a period of 3-week.
Femring and Estring are employed for the hormonal replacement therapy. Dapivirine also known as TMC 120 is given
in the form of ring acting as potent microbicide against
transmission of STIs and HIV. Plastic rings are sometimes
used to hold and support suppositories in position in vagina.

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Limitations of conventional vaginal formulations

These conventional vaginal delivery systems are somewhat
effective; however, they still offer several disadvantages
which we need to encounter in order to deliver anti-fungal
therapy in an efficacious way. Disadvantages associated are:
 Leakage and messiness as in case of creams and gel
 Uncomfortable
 Efficacy is quite low as gels may not provide an exact
dose because of non-uniformity and leakage
 Low retention to the vaginal epithelium
 Poor patient compliance
 Frequent administration of drug is required
 Prolonged duration of therapy
 Low bioavailability
 Drug release pattern is inappropriate (Parnami et al.,
2013; Singh et al., 2014).

Novel approaches in vaginal formulations

Different conventional vaginal formulations for VC are
available today but have limited efficacy because of lesser
residence time on vaginal epithelium due to self-cleansing
action of vagina. This leads to frequent administration of the
formulation, which ultimately cause inconvenience to the
user. So to overcome this problem, an extended and intimate
contact with vaginal mucosa is desired; which can be
accomplished by utilizing mucoadhesive polymers.
Mucoadhesive polymers have an excellent binding capacity
to mucosal tissues for considerable period of time (Kataria
et al., 2014). This unique property of these polymers
significantly enhances retention time of different formulations
on mucosal tissues. Thus, controlled release can be fruitfully
achieved and in turn frequent administration of dosage forms
is prevented. Several bio-adhesive polymers are available like
polycarbophil, hydroxypropylcellulose, polyacrylic acid, chitosan, carbopol, etc.
Vaginal bio-adhesive tablets
Method for preparation of vaginal bio-adhesive tablets is
similar to those of normal tablet; however, they differ in
composition of excipients as the former have a single or
combination of bio-adhesive polymer and the latter one is
devoid of it. In case of evaluation of these tablets, additional
parameters are included like swelling index, bio-adhesion
time and bio-adhesive strength. The very first bio-adhesive
tablet prepared was of Bleomycin, antibiotic; containing
polymers like hydroxy propyl cellulose (HPC) and poly
acrylic acid (PAA) or Carbopol-934. It was observed that
with increasing amount of HPC, in-vitro release rate increases
and increment in concentration of PAA, water absorption
property rises. 5-Flurouracil and Carbaquinone, potent

Drug delivery system for vaginal candidiasis

anti-cancer drugs were also formulated in the tablet form

(Brannon-Peppas, 1993). Various anti-fungal agents are
formulated in form of bio-adhesive tablets are mentioned in
Table 7.
Vaginal liposome
Liposomes are the spherical vesicle, characterized on their
lipid composition, size, number of lamellae, and inner/outer
phases (Garg & Goyal, 2014b). Because of biocompatibility,
stability and structural versatility, these have been extensively
used for different therapies (Goyal et al., 2013). For having
high stability with good mucoadhesive strength, positively
charged vesicles are preferred over negative ones; as mucus
membrane is negatively charged (Garg et al., 2014b). Before
1990, liposomes were used for parenteral and skin delivery
but later on there was a drastic shift in their use in vaginal
drug delivery. Jain et al. utilized liposomes for vaginal
delivery of progesterone (1997). Foldvari et al. developed
interferon alpha liposomes for treating genital papilloma virus
infections. Pavelic et al. developed Lecithin liposomes of
Clotrimazole, metronidazole and chloramphenicol for treating
fungal infections; then tested for in-vitro stability in pre- and
post- menopausal environment, as well as for in-situ stability
in cow vaginal mucosa. In order to enhance stability, better
release characteristics and overall applicability of these drugs,
author incorporated these liposomes in bio-adhesive carbopol
hydrogels. In-vitro release testing performed in vaginal fluid
stimulant ensured controlled release of all three drugs (Pavelic
et al., 1999). Ning et al. also reported controlled release of
Clotrimazole from proliposomes for vaginal therapy. Poorly
soluble anti-fungal drug, Amphotericin B was successfully
administered in vagina when formulated as thermo-sensitive
gel of poloxamers 407 and 188 having drug-loaded cationic
liposomes (Kang et al., 2010). Curcumin, a well-known antioxidant and anti-inflammatory agent when formulated in form
of liposomal gel against vaginal inflammation; overall antiinflammatory activity was significantly enhanced as revealed
by in-vitro studies (Basnet et al., 2012). Liposomal preparations loaded with anti-fungal agents are represented in
Table 8.
Vaginal micro-emulsions
In recent times, micro emulsion serves as an efficient
candidate for vaginal delivery of proteins, peptides and antifungal drugs, because of their long term stability, ease of
preparation and high solubilization capacity. Micro-emulsion
based vaginal gel system has been efficiently used to deliver
different anti-fungal drugs as given in Table 9.
Vaginal bio-adhesive suppositories
Another novel approach towards successful vaginal delivery
is the concept of bio-adhesive suppositories. To deliver
anti-miotic agent, Clotrimazole into vagina, suppositories of
semi-synthetic solid triglycerides were prepared having bioadhesive polymers viz. polycarbophil, hydroxypropylmethylcellulose and hyaluronic sodium salt. The author reported that
these polymer increased residence time of suppositories in
vagina by modifying adhesion force, liquefaction time and

H. S. Johal et al.

Drug Deliv, Early Online: 114

Table 7. Vaginal bio-adhesive tablets loaded with anti-fungal agent.

Active drug

Bio-adhesive polymer system

Comments

Clotrimazole

Chitosan-Thioglycolic acid Conjugate

(TGA)

Econazole nitrate

Carbopol 941/ NaCMC (1:1)

Clotrimazole

Carbopol 934P/
Sodium alginate (2:1)
Carbopol 934P/ HPC (1:9)

The polymeric conjugates have 26-time longer

adhesion time as compared to unmodified
polymer.
Moderate swelling
Good bio-adhesion for much longer duration
Retarded release profile of the drug
Releases the drug for extended period of 24 h
Significant bio-adhesion property
Excellent swelling,
Controlled release of drug(95% for 24 h)
In-vivo study in rats showed high vaginal
residence time (17% drug still retained after 24 h.)
Slowly released 72% of the drug over 12 h.
Good swelling
Excellent bio-adhesiveness
High in-vitro anti-fungal activity
Bio-adhesion time more than 12 h
Sustained release (more than 94% in 10 h.)

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Ketoconazole
(bio-adhesive
effervescent tablet)
Clotrimazole

Mixture of NaCMC and HPMC

Ketoconazole
effervescent tablet

HPMC K4M: Chitosan (1:1)

effervescent (sodium bicarbonate
and citric acid at the
mole ratio of 3:1)
Combination of HPMC
K4M:Carbopol 934P
Effervescent mixture (sodium
bicarbonate and citric acid at the
mole ratio of 3:1)
Combination Chitosan: HPMC
K15 M(3:1)

Sertaconazole
effervescent tablet

Clotrimazole
Clotrimazole

Eudragit
RL-100

Reference
(Kast et al., 2002)
(Ameen)
(Sharma et al., 2006)
(Wang & Tang, 2008)

(Bhat & Shivakumar, 2010a)

(Patel & Patel, 2010)

Controlled release (more than 80%) in 12 h.

Excellent bio-adhesive strength
High in-vitro anti-fungal activity

(Patel et al., 2012)

Extended release profile( 98% for 30 h)

Good bio-adhesive strength
Good swelling index
Excellent in-vivo bio-adhesive strength and time
Sustained release profile of 98% after 24 h.
Excellent in-vitro anti-fungal activity

(Dangi et al., 2011)

(Gupta et al., 2013)

Table 8. Anti-fungal agents formulated as vaginal liposomes.

Active drug

Bioadhesive polymer system

Clotrimazole

Carbopol
Carbopol

Amphotericin B
Metronidazole
(Elastic liposomes)

Poloxamer 407 and 188

Carbopol
Carbopol

Comments
Sustained release profile
Significant in-vivo activity in rats
Controlled release was achieved
High in-situ stability in cows vaginal mucosa
Good in-vitro anti-fungal activity
Controlled release for 24 h
Controlled release was achieved
High in-situ stability in cows vaginal mucosa

permanence of drug at expected site without any adverse

effect. The developed formulation showed controlled release
profile.
Vaginal bio-adhesive gel
A marketed bio-adhesive gel, Replens R of polycarbophil;
used to lubricate and to retain moisture of vagina. The
formulation maintains healthy acidic pH in vagina and
remains over there for 34 d (Lee et al., 1996; Hwang
et al., 1977). Another bio-adhesive gel named Prochieve TM
is used in hormonal replacement therapy. Later on, concept of
hydrogel was introduced which provides excellent controlled
release profile of most drugs. Hydrogels can be defined as a
three-dimensional, cross-linked hydrophilic polymeric network which can absorb significant amount of water (Singh
et al., 2010). These are insoluble in water because of crosslinked structure and can imbibe water up to 1020 times of its
molecular weight and become swollen (Kim et al., 1992;

Reference
(Ning et al., 2005)
(Pavelic et al., 2001)
(Kang et al., 2010)
(Vanic et al., 2013)
(Pavelic et al., 2001)

Peppas et al., 2000). Hydrogel swells under the influence of

different stimuli-like temp, magnetic field, sound, electric
field, etc. and then drug releases from swelled hydrogel in
controlled manner (Garg et al., 2013). Different anti-fungal
drugs formulated in form of bioadhesive gel are given in
Table 10.
Vaginal micro particles (microspheres, microcapsules)
In the recent time, micro particles systems have also
employed for designing vaginal delivery system. With
addition of mucoadhesive polymers, these systems were
made bio-adhesive so as to gain intimate prolonged contact
with vaginal mucosa for controlled drug delivery (Garg et al.,
2012). Ketoconazole was formulated as bio-adhesive microcapsules and incorporated in tablet for vaginal delivery.
Dissolution studies of these microcapsules attest sustained
release of the drug. Different anti-fungal drugs formulated in
form of microparticles are given in Table 11.

Drug delivery system for vaginal candidiasis

DOI: 10.3109/10717544.2014.928760

Table 9. Micro-emulsion based vaginal gel loaded with anti-fungal agents.

Formulation

Bio-adhesive polymer

Animal
model

Clotrimazole

Micro emulsion
based vaginal gel

Carbopol ETD-2020

In-vitro

Sertaconazole

Micro emulsion
based vaginal gel

Carbopol 940

In-vitro

Miconazole nitrate

Micro emulsion
based gel

Polycarbophil

In-vitro

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Drug

Comments

References

High in-vitro bio-adhesion time

Excellent in-vitro anti-fungal
activity as compared to
marketed formulation
Controlled release profile of drug
(more than 85% in 12 h.)
Excellent anti-fungal activity
Good bio-adhesive and
retention properties
Controlled release of 99% in 8 h.
High bio-adhesive strength
Excellent in-vivo anti-fungal
activity in mice
Good in-vitro anti-fungal activity

(Bachhav & Patravale, 2009)

(Patel & Patel, 2012)

(Bhalekar et al., 2009)

Table 10. Bio-adhesive gel loaded with different anti-fungal agents.

Active Drug

Delivery system

Metronidazole

Bio-adhesive gel
Bio-adhesive gel

Bioadhesive Polymer

Comments

Combination of chitosan and

xanthan gum
Combination of Xanthan gum
and HPMC-K4M

Controlled release profile

Good in-vitro anti-fungal activity
Sustained release for 6 h.
Excellent in-vitro anti-fungal
activity
Initial high burst for 2min followed
by sustained release for 7 h
Sustained release for 6 h.
Good in-vitro anti-fungal activity
Improved treatment of vaginal
candidiasis
Sustained release for 12 h.

Nonoxynol-9

Bio-adhesive gel

Carbopol934P

Clotrimazole

Bio-adhesive gel

Itraconazole

Thermo-sensitive
vaginal gel
Thermo-sensitive
vaginal gel

Combination of Xanthan gum

and HPMC-K4M
Poloxamer 407- HPMC

Miconazole nitrate
Miconazole nitrate
Clotrimazole

Thermo-sensitive gel
Ion-sensitive gel

Clotrimazole:
Cyclodextrin complex

Thermo-sensitive gel

Pluronic
F127, carbopol 934 and
polycarbophil
PEG-4000
Carbopol 934, HPMC and
sodium alginate

Serves as controlled release carrier

Excellent in-vivo anti-fungal
activity in mice and zero order
release for 8 h
Sustained release for 92 h

Pluronic F127- HPMC

Reference
(Yellanki et al., 2010)
(Ahmad et al., 2008)
(Lee et al., 1996)
(Ahmad et al., 2008)
(Karavana et al., 2012)
(Hani & Shivakumar)
(Bhat & Shivakumar, 2010b)
(Dhanaraj)
(Bilensoy et al., 2006)

Table 11. Different anti-fungal vaginal micro particle formulations.

Drug
Clotrimazole

Formulation type
Microspheres based
vaginal gel

Bio-adhesive
polymer

Animal model

Carbopol 934P.

In-vitro

Metronidazole Microencapsulated
bio-adhesive vaginal gel

Carbopol 974

In-vivo
New Zealand
rabbits

Clotrimazole

Combination of In-vitro
HPMC and
Carbopol

Spray dried microspheres as

bio-adhesive vaginal tablet

Cyclodextrin in vaginal therapy

Cyclodextrin complexation was primarily used to increase
bioavailability of poorly soluble drugs by incorporating them

Comments
Good control release pattern
(99% in 12 h)
Higher bio-adhesion and
retention time in vagina
Excellent in-vitro anti-fungal
activity
Extended release of drug
(100% release for 36 h)
Formulation was non-irritant to
vagina of New Zealand rabbits
Significant vaginal bio-adhesion
time
Sufficient bio-adhesive strength
with controlled release up to
24 h

References
(Hani et al.)

(Bhowmik et al., 2009)

(Gupta et al., 2013)

in cyclodextrin complexes (Patel & Rajesh). However, several

studies advocate the use of Cyclodextrin for improving
vaginal drug delivery. Hydroxypropyl-b-cyclodextrin formulation having Itraconazole was found to have good drug

10

H. S. Johal et al.

Drug Deliv, Early Online: 114

Table 12. Recently developed vaccines against VC.

Category/source

Antigen

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Subunits and glyco 65-kDa mannoprotein

conjugates
(MP65)

Animal
model
Rat

Underlying immunity
Anti-MP65 antibodies

Secretory aspartyl
Rat
proteinase (SAP)2
Recombinant N-teminus Mice
of Als 3p (rAls 3p)
Candida surface
Mice
mannan

Anti- SAP 2 antibodies

Octa-b- 1, 3-glucan
epitope

Mice

Serum and vaginal antib-glucan IgG antibodies

Peptide

Hepcidin 20 (Hep-20)

In-vitro Antimicrobial activity

Idiotypes

Killer-toxin neutralizing Rat

m Ab KT4
Mycograb (anti-Hsp-90 Human
antibodies)

Antibodies
Antigen-pulsed
cells
Whole cell or
cell extract

Anti- rAls 3p antibodies

MAb B6 and MAb B6.1

Fungicidal antibodies
Fungicidal

Dendritic cell pulsed

with Candida yeasts
or yeast RNA
Heat killed Candida
cells with novel
mucosal adjuvant
LT(R192G)

Mice

Activation of T-helper 1

Mice

C. albicans Mannan
extract- Bovine
serum albumin
conjugate

Mice

Delayed hypersensitivity
responses and Increased
levels of
Immunoglobulin G
(IgG)
IgG and IgM antibodies

solubility and excellent mucoadhesive property. Vaginal

cream having Itraconazole complexed with b-cyclodextrin
was well tolerated and remained in vagina for several days.
Hydroxypropyl-b-cyclodextrin complex was reported to
increase solubility of Amphotericin B; when both were
formulated as thermo-sensitive, pH-sensitive gel, controlled
release was successfully achieved. Cyclodextrin complexes
were also successfully employed in anti-viral therapy to
deliver anti-HIV agents (Yang et al., 2008). Chang Yun et al
(2002) fabricated Clotrimazole-loaded cyclodextrin complex
by using combination of poloxamers (P) 407, 188, and
polycarbophil (PC). The results showed that controlled release
of drug was achieved and exhibit excellent in-vivo anti-fungal
activity in female rats (Yun Chang et al., 2002).
Other novel approaches against VC
With continuous use of anti-fungal agents for VC, subsequent
failure of therapy was observed. This is due to development of
resistant by Candida sp., so further prolongation of the
therapy will be ineffective. In spite of that, a new concept of
genetically engineered antibody was introduced, which successfully encounter this limitation (Garg et al., 2011).
Different vaccines having modified antigens are introduced

Mechanism of action
Inhibit fungal adhesion
to epithelial cells
mediated by MP65
and SAP 2
Inhibit fungal adhesion
mediated by Als 3
Degrade b-1, 2-mannotriose (cell wall
component of
fungus)
Degrade b-1, 2-mannotriose
(cell wall component
of fungus)
Release b-glactosidase
that cleave
b-glycoside linking
in fungal cell wall
Unknown
Degrade Hsp-90 (cell
wall component of
fungus)
Immunity provided by
IL-4,IL-6,IL-10,
IL-12 P70
Release of cytokines
that degrade fungal
cells

References
(Sandini et al., 2007)

(De Bernardis et al., 2002,

2007, 2012)
(Spellberg et al., 2006)
(Han et al., 1998)

(Torosantucci et al., 2005,

2009; Pietrella et al., 2010)
(Del Gaudio et al., 2013)

(Polonelli et al., 1997)

(Pachl et al., 2006)
(Bacci et al., 2002)
(Cardenas-Freytag et al., 1999)

Degrade fungal cell wall (Han et al., 1999)

mannan
(mannoprotein)

that produce C. albicans specific antibodies that either have

fungicidal activity or inhibit adhesion of Candida to epithelial
cells as described in Table 12. Different techniques employed
for generating monoclonal antibodies are Hybridoma cell
production, Recombinant antibody engineering technique,
complementary-determining region (CDR) engraftment,
Cambridge Antibody Technology (CAT) (De St Groth &
Scheidegger, 1980), etc. Vaccine consists of diseases causing
micro-organism either in dead or partly killed form which will
stimulate immune system to recognize it as foreign microbe
and act against it by producing antibodies. Antibodies are
Y-shaped protein produced by plasma cells and utilized by
immune system to recognize and neutralize foreign particles
like bacteria or fungi. Monoclonal antibodies are the monospecific antibodies produced from single parent immune cell
by different techniques like hybridoma, recombinant technique, etc. Idiotypic is a shared characteristic of immunoglobulin or T cell receptors (TCR). Idiotypic describes
distinctive sequence and region that makes any immunoglobing/TCR unique from others of the same type which is its
variable region. Variable region has a specific amino-acid
sequence that determines its antigen binding affinity
and therefore the idiotope of the molecule. IgG or T cell
receptor having shared idiotope is the same idiotype

Drug delivery system for vaginal candidiasis

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(Miller et al., 1982). The main component of these vaccines

can be whole Candida cell or its cell extract, antibodies,
idiotypes, glycoconjugate and its subunits, human peptide,
antigen-pulsed cell, etc. Method for production these different
antigens are discussed below
 Human Peptide Hepcidin 20: Human liver derived
Hepticin-20 has a significant anti-fungal activity and is
either purchased or extracted from human source. This
peptide release b-glycosidase that cleaves b-Glycoside
linking in fungal cell wall.
 Candida surface mannan complex: Candida surface
mannan was obtained by extracting yeast cell with
b-mercaptoethanol and then encapsulated in multilamillar liposomescomposed of phosphatidylcholine and cholesterol in ratio 3.2:1. After immunization antibodies
specific to b 1, 2-mannotriose (cell wall component of
Candida) is produced, and exerts their anti-fungal
activity (Han et al., 1998). This mannan extract may
complexed with Bovine serum albumin, and immunization leads to production of IgG and IgM antibodies that
degrade Candida cell wall mannan (mannoprotein; Han
et al., 1999).
 Dendritic cells pulsed with fungal RNA: Candida cells
were ruptured through repeated thawing and freezing on
liquid nitrogen. Hot extraction buffer (a 1:1 mixture of
phenol and 0.1 M LiCl, 100 mM Tris-HCl (pH 8), 10 mM
EDTA, and 1% SDS at 80  C) and then a mixture
((24:1, v/v) of chloroform and isoamyl alcohol) was
added to the cells. Followed by centrifugation at
10 000 rpm at 4  C and water phase was mixed with
equal volume of 4M lithium chloride. This mixture was
again centrifuged at 10 000 at 4  C and the RNA gets
precipitated. Obtained RNA pellet was dissolved in water
and precipitated using sodium acetate and ethanol at
20  C. Dendritic cells (DCs) were either extracted from
bone-marrow of spleen. Spleen cells were subjected to
overnight plastic adherence to remove macrophages, then
reacted with 100 ml of anti-mouse CD11c mAbs (against
CD11c present on macrophage surface) conjugated with
Micro Beads followed by magnetic separation. Bone
marrow DCs, were obtained from femur of mice and
seeded for 6 d in six-well plates in 3 ml IMDM (Iscoves
Modified Dulbeccos Medium) with 10% FCS (fetal calf
serum), 50 mM 2-ME(2-mercaptoethanol), 50 mg/ml gentamicin sulfate, 2000 U/ml GM-CSF (granulocyte-macrophage colony-stimulating factor), and 1  103 U/ml IL-4.
On day 3, non-adherent cells were replaced with mixture
of GM-CSF and interleukin-4. On day 6, DCs were
isolated from non-adherent cells and incubated at 37  C
for 3 h. RNA (25 mg in 250 ml Opti-MEM medium) and
DOTAP (50 mg in 250 ml Opti-MEM medium (minimum
essential media)) was mixed in 12  75-mm polystyrene
tubes and then 2 ml of it was added to DC and incubated
for 37  C for 24 h. IL-4 Immunization leads to activation
of T-helper 1 thus initiating immune response against
Candida by releasing cytokines IL-4,IL-6,IL-10,IL-12
P70 (Bacci et al., 2002).
 Human domain antibodies: A complex procedure was
adopted to yield Human domain antibodies against
virulent traits of Candida (De Bernardis et al., 2007).

11

In brief, the author uses genetically modified Antibody

variable domains (domain antibodies [DAbs]) that have
individual heavy-chain (VH) or k-chain (Vk) variable
domains and lacks the Fc region. From Phage expression
libraries, Human DAbs against 65-kDa mannoprotein
(MP65) or the secretory aspartyl proteinase (SAP)2 of
C. albicans (mono-specific DAbs) or against both fungal
antigens (heterodimeric, bispecific DAbs) were generated. A significant inhibition of fungal adherence
(mediated by MP65 and SAP)2) and complete clearance
of vaginal infection of fungus was observed using both
mono- and bi-specific DAbs in rat vagina.
B-glucan-conjugate vaccine for VC: Donatella et al.
formulated b-glucan-conjugate in human compatible
MF59 adjuvant and anti-fungal activity was assessed in
murine model (Pietrella et al., 2010). The infection was
monitored using genetically engineered, luminescent
C. albicans strain and then Cfu was measured. The
mice were immunized with this conjugate and then a
prominent fall in Cfu of C. albicans was observed. This
anti-fungal activity was due to production of serum and
vaginal anti-b-glucan IgG antibodies. This antibody
recognizes octa-b- 1, 3-glucan epitope which is present
in hyphal cell wall protein that mediates fungal adhesion
and invasion (Torosantucci et al., 2009). Then in-vivo
imaging techniques confirm excellent anti-fungal activity. Antonella et al. reported good protection against VC
in mice by formulating b-glucan (preparation from the
brown alga Laminaria digitata) conjugate with diphtheria
toxoid CRM197 (carrier protein). This conjugate produces anti-b-glucan IgG antibodies which provide protection against Candida sp. (Torosantucci et al., 2005).
Recombinant ALS vaccine for VC: Ibrahim et al.
developed vaccine of recombinant N-terminus of Als 1p
(rAls 1p) for protection of mice against disseminated and
mucosal candidiasis. The vaccine enhances cell-mediated
immunity rather than humoral and improves survival of
mice during candidiasis (Ibrahim et al., 2005). Latter on
they formulated another vaccine of recombinant
N-teminus of Als 3p (rAls 3p) against disseminated and
mucosal Candidiasis. The vaccine proved to as effective
as rAls 1p in disseminated Candidiasis and more effective
in Mucosal (vaginal) Candidiasis (Spellberg et al.,
2006).
Candida albicans mannan extractprotein conjugates:
Vaccine having C. albicans Mannan (fungal cell wall
constituent) extract- Bovine serum albumin conjugate
was assessed for its anti-fungal activity in mice. The
vaccine was administered intraperitoneal (i.p) followed
by i.v. administration of viable Candida spp. Mice
developed both IgG and IgM antibodies specific for the
cell surface of Candida yeast cells and exerts its antifungal activity (Han et al., 1999). Table 12 represents the
recently developed vaccines against VC.

Conclusion
Although much of research work has been done to deliver
anti-fungal drugs safely and effectively for VC, various
conventional dosage forms are available like creams, gel,

12

H. S. Johal et al.

suppositories, etc. But have numerous limitations like

systemic side-effects, lesser residence time, etc. To overcome
these limitations, a novel concept of bio-adhesive formulations was introduced. While this delivery system successfully
encountered most of the disadvantages of conventional
dosage forms, but there continuous use has led to significant
resistance in Candida against azole agents. However now a
day, vaccines are employed for anti-fungal therapy and they
have been proved to be a good and potential alternative for
VC. But this delivery system still needs to be exploited, in
order to develop a novel, ideal, effective delivery system
against all Candida spp. and to protect and maintain integrity
of epithelial cells.

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Acknowledgement
Authors Amit K Goyal (under IYBA scheme; BT/01/IYBA/
2009 dated 24/05/2010) thankful to Department of
Biotechnology (DBT), New Delhi, India.

Declaration of interest
The authors declare no conflicts of interests. The authors
alone are responsible for the content and writing of this
article.

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