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International Journal of Biopharmaceutics
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IJB
VESICULAR OCULAR DRUG DELIVERY SYSTEM: PRECLINICAL
AND CLINICAL PERSPECTIVE OF DRUGS DELIVERED VIA
NIOSOMES
Nida Akhtar *
School of Pharmaceutical Sciennces, IFTM University, Lodhipur Rajput, Moradabad- 244001, Uttar Pradesh, India.
ABSTRACT
An eye is the most precious and easily accessible organ of the body. It possesses easy route to local drug delivery
and is a way to non-invasive clinical treatment of ocular diseases. Ocular delivery in spite of possessing various advantages
has the limitation of poor bioavailability and low permeability across the cornea thus, limiting the efficacy of drugs.
Therefore, various carrier systems have been developed to overcome these limitations. Most recently, niosomes have been
developed as efficient vesicular carrier for ophthalmic drug delivery. Large numbers of drugs of various therapeutic
categories have been incorporated in these vesicles. These systems exhibited enhanced permeability required for the
treatment of ocular diseases, initiating a new era in vesicular research for ocular delivery. Various reports show promising
future of niosomes for topical, transdermal, ocular delivery of various therapeutically active agents more effectively and
providing better in vivo data thus suggesting the need of the clinical testing of these carriers for their widespread utility. So,
to evaluate its safety and efficacy, various preclinical and clinical studies were conducted. The present review focuses on the
preclinical and clinical perspective of delivery of various drugs through niosomal vesicular carriers illustrating enhanced
safety and efficacy by designing these carriers.
Key words: Corneal permeability, Drug delivery, In Vivo study, Niosomes, Ocular, Vesicles.
INTRODUCTION
Eye is considered as the window of our soul. It
is a unique organ of our body anatomically as well as
physiologically. It possesses easy access to local drug
delivery and is a way to non-invasive clinical treatment
of ocular diseases. Topical drug delivery is ought to be
the most preferable route to eyes as the systemically
acting drug are not readily accessible through it. But this
route becomes complicated by the effective removal
processes of the eye which removes the foreign particles
and also by the precorneal barrier which includes
Corresponding Author
Nida Akhtar
E-mail: [email protected]
blinking reflex, tear turnover and low permeability across
the cornea (Rathore KS et al., 2009). About 5% of dose
instilled into the eyes reaches the intraocular tissues due
to various factors like pre-corneal drainage and less
permeability of corneal epithelium cells. The systemic
route can overcome this but due to the presence of bloodaqueous barrier and blood-retinal barrier, it ultimately
leads to high loading dose at the target site. The high
dose and dosing frequency causes unavoidable systemic
side effects like stomach upset and disturbed GI motility
(Modi KA et al., 2012). The main purpose of
pharmacotherapeutics is to achieve the effective drug
concentration, at the desired site of action for a sufficient
time period to elicit the desired pharmacological
response. Ocular dosage forms possessed poor
bioavailability due to the production of tears, transient
residence time and impermeability across corneal
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Nida Akhtar. et al. / International Journal of Biopharmaceutics. 2013; 4(1): 38-48.
epithelium (Kaur et al., 2012). To treat ocular diseases,
topical and localized approaches in the form of solution,
suspensions and ointments are more preferred in the
treatment of ocular diseases but they suffer from the
drawback of poor ocular bioavailability (Sahoo et al.,
2008).
In ocular drug delivery system, scientist faced
many challenges due to unique anatomical and
physiological structure of eye. There are two barriers
namely, static and dynamic barriers that limit the ocular
drug delivery. Static barrier is composed of different
segments of eye such as cornea, sclera, retina and bloodretinal barriers whereas dynamic barriers consists of
choroidal and conjunctival
blood flow, lymphatic
clearance, and tear dilution. These barriers ultimately
affect the bioavailability of various drug delivered via
this route. In the new era, various new concepts of drug
delivery such as iontophoresis, liposomes, niosomes,
bioadhesive gels, ocular insert, contact lenses etc has
been developed to overcome the problems related with
these barriers These formulation based approaches have
considered to be sufficient enough in achieving the
maximum drug concentration at specific site of eye for
the targeted drug delivery. Ocular drug delivery system
possessed major disadvantage of rapid and extensive
elimination of conventional eye drops after instillation
from the eye, which results in the loss of drug. Only
limited amount drug penetrates into the corneal layer and
reaches the internal tissue of eye. The main region of
drug loss includes lachrymal drainage and drug dilution
by tears. This in turn reduces the ocular bioavailability of
drug and leads to unwanted toxicity and adverse effects
(Sikander et al., 2012).
Ocular drug delivery systems are designed to
treat the eye diseases locally and are thereby developed
to overcome all the disadvantages of conventional dosage
forms such as ophthalmic solutions. The eye drop dosage
form though easy to instil but suffers from the drawback
that the majority of the drug present in get immediately
diluted in the tear film as soon as the eye drop is instilled
into the cul-de-sac and is rapidly drained away from the
precorneal cavity by constant tear flow. Therefore, only
1.2% of the instilled dose is available to the aqueous
humour. Frequent dosing frequency of drugs thus,
becomes necessary to achieve the therapeutic
concentration at the targeted site which often results in
corresponding increase in local and systemic side effects.
So, various Novel ophthalmic drug delivery systems have
been developed and still are in progress to overcome all
the disadvantages of conventional ophthalmic dosage
forms (Ratnam et al., 2011). The main motive behind the
development of novel drug delivery system to the eye is
to improve the ocular dosage forms that have been
developed so far and thereby improving the therapeutic
efficacy (Prabhu et al., 2010).
In this new era of research, the drug delivery
through vesicles has gained lot of attention due to its
prominent advantage in improving bioavailability and
reducing dose frequency (Modi KA et al., 2012). These
are the water-filled colloidal particles and their wall
consists of amphiphilic molecules in a bilayer
conformation where hydrophilic drugs are enclosed
within the aqueous environment and lipophilic drugs are
entrapped in the vesicle bilayer. Most commonly, these
vesicles are composed of phospholipids or non-ionic
surfactants (Akhtar 2012). Vesicular drug delivery tends
to localize and maintain drug concentration at its desired
site of action. The rate of drug penetration depends on the
physicochemical properties of the drug like, solubility,
particle size, polymorphic form etc. VDDS generally
includes liposomes and niosomes as most preferred
ocular drug delivery system (Modi KA et al., 2012). The
concept of targeted drug delivery is designed to achieve
the drug concentration at the desired site of action
(Lohumi et al., 2012).
Ideal properties of controlled ocular drug delivery
system
Ideal properties of controlled ocular drug
delivery system include controlled drug delivery at the
desired targeted site, appropriate corneal penetration.
Reduced dosing frequency, increased corneal contact and
retention time. It bypasses various anatomical and
physiological barriers such as tear secretion, nasolacrymal drainage, enhanced patient compliance etc
(Modi and Shelat, 2012).
Advantages of Ocular Drug Delivery Systems
Various advantages of ocular drug delivery
system are as such ease of convenience, self medication,
improved patient compliances, and enhanced penetration
of hydrophilic and low molecular weight drugs. Rapid
absorption and fast onset of action, it avoids hepatic first
pass metabolism.
Disadvantages of Ocular Drug Delivery Systems
Various disadvantages associated with ocular
drug delivery system are as follows: Limited
permeability across the cornea, drainage of the
administered dose into the lachrymal duct, leads to
systemic side effects and short term therapeutic effect
due to eye blinking results in frequent dosage regimen
(Kumar et al., 2011).
VESISULAR OCULAR DRUG DELIVERY
In the past few years, development of vesicles as
a recently formulated novel carrier in the drug delivery
has gained lot of attention among the scientists working
for the development of novel drug delivery system. A
novel drug delivery system should accomplish two
purposes i.e. it must deliver the drug at a predetermined
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rate and should release the drug at the specific site of
action in therapeutically active concentration (Rajera et
al., 2011). Drug delivery via vesicles provides prolonged
as well as controlled drug delivery at the targeted corneal
surface. Thus, a vesicle acts as prominent carrier system
for ophthalmic drug delivery (Kute et al., 2010). Drug
entrapped within the vesicular membrane can be easily
administered in the form of eye drops. Vesicular drug
delivery systems entrap the drug molecule within the
lipid bilayer or surfactant vesicles. Thereby, increasing
the drug concentration at the site of action with sustained
drug delivery, resulting in enhanced bioavailability
(Prabhu et al., 2010). In the new era of research, vesicles
are considered as a recently developed carrier in ocular
drug delivery. Vesicles in spite of providing prolonged
and controlled action at the corneal surface of an eye also
prevent the metabolism of the drug by the enzymes that
are present at the tear/corneal epithelial surface.
Therefore, vesicles represent a prominent carrier for an
ophthalmic delivery of variety of drugs used in the
treatment of ocular diseases (Paul et al., 2010).
Vesicles used in ophthalmic include liposome
and niosomes specifically. Liposome act as carrier
system for the delivery of variety of drug molecules,
proteins, nucleotides, enclosing them with a great
potential for their application in ophthalmic (Kute et al.,
2010).
Liposomes have been studied by various authors
to be efficient in delivering the drug (Table No. 1)
through the intravitreal route to the posterior region of
the eye (Bejjani et al., 2003). For example, Gaudana et al
had formulated ganciclovir loaded liposome and
performed in vivo pharmacokinetic study in rabbits,
concluding that liposome results in enhanced transcorneal
permeation and higher ocular tissue distribution
(Gaudana et al., 2009). Thus, the significant advantage of
liposome is their ability to come in an intimate contact
with the corneal and conjunctival surfaces, thereby,
increasing the probability of ocular drug absorption. It is
proposed that they increase the residence time as well as
drug absorption (Kute et al., 2010). The major
disadvantages associated with liposome are chemical
instability, oxidative degradation of phospholipids to
overcome these limitations of liposome; niosomes are
being developed (Patel 2011). They possess various
advantages over liposomes such as higher chemical
stability, enhanced skin penetration and lower cost as
compared to liposome (Prabhu et al., 2010).
NIOSOMES A NOVEL ELASTIC OCULAR
VESICULAR CARRIER
Niosomes are the bilayered vesicular carriers
consisting of non-ionic surfactants. They can entrap both
lipophillic and hydrophilic drugs within the vesicular
membrane (Saini 2012). This type of non-ionic vesicles
was first introduced by Handjani (Tangri 2011).They are
formed by the hydration of non-ionic surfactant
molecules (Rajera et al., 2011). It acts by reducing the
systemic drainage and improving the residence time,
which further enhances the ocular bioavailability of drug
(Saini 2012). These may be multilamellar or unilamellar,
composed of an aqueous region enclosed by the bilayer
of surfactant molecules. It is composed of two major
components i.e. non-ionic surfactants and the additives
(cholesterol and charged molecules). The presence of
cholesterol provides the rigidity to the bilayer and is an
important constituent of the cell membrane. Its presence
in niosomes affects fluidity and permeability across the
bilayer (Verma 2011) (Fig.1). The main objective behind
the development of niosomes is to control the drug
release, modify its distribution pattern as well as
targeting the drug delivery to the desired site. It is now
being studied as an alternative to liposome (Verma
2011). Niosomes represents itself as a prominent drug
carrier and has found to be effective enough to reduce the
adverse effects of the drug and thus improve the
therapeutic effectiveness of a drug in the treatment of
various diseases (Gopalakrishnan 2012). It has been
employed in delivering drugs via various routes such as
intramuscular, intravenous, topical, transdermal and nasal
etc (Tarekegn et al., 2010) (Table No. 2).
Method of Preparation
Niosomal vesicles were prepared by various
methods such as ether-injection method, hand shaking
method, sonication, reverse phase evaporation, micro
fluidization and emulsion method.
Advantages of Niosomes
As a drug delivery system niosomes possess
various advantages such as better patient compliance,
better therapeutic effect as compared to conventional
formulations. It can deliver wide variety of drugs, as it
can entrap both hydrophilic and lipophilic drugs.
Controlled and sustained drug delivery of drugs,
improved bioavailability as compared to conventional
dosage forms. Niosomes can be used specifically in
targeted drug delivery. More stable than liposomes.
Enhanced permeability across the skin (Verma 2011).
Niosomes acts in similar ways to Liposome by
prolonging the release of entrapped drug and changing
the organ distribution and its metabolic stability.
Entrapment of various antineoplastic agents in these
vesicles has been reported in the literature to reduce the
drug related toxic side effects, and on the other hand
increasing the anti-tumour efficacy. They can be used in
targeting the drug delivery as well as to control its release
(Akhilesh et al., 2012).
Evaluation of Niosomes
Niosomes were evaluated by various parameters
such as percent entrapment efficiency, shape and
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morphological study (TEM), in vitro release study, tissue
distribution/ in vivo study, ocular irritation test, stability
study, membrane rigidity and vesicular surface charge
(Verma 2011).
PRECLINICAL AND CLINICAL ASPECTS OF
DRUGS DELIVERED VIA NIOSOMAL CARRIERS
To determine the clinical efficacy and safety of
the ethosomal carriers loaded with drug, various authors
have performed preclinical and clinical studies on this.
Given below is a view of various drugs such as antiglaucomatic,
antibacterial,
antiviral
and
antiinflammatory drugs delivered through niosomal vesicular
carriers focusing mainly on preclinical and clinical
studies.
BRIMONIDINE TARTRATE
Prabhu et al formulated and evaluated
Brimonidine tartrate loaded niosomes for in vitro and in
vivo intra ocular pressure lowering activity. In vivo intra
ocular pressure lowering activity of the selected niosomal
preparations were conducted on male albino rabbits. For
this, three rabbits were divided into three groups, each
group containing one rabbit. To observe this activity,
acute glaucoma was firstly induced in the rabbits by
infusing 5% dextrose solution through the marginal ear
vein and then the basal intraocular pressure was
measured by tonometer. The formulation containing drug
(20 µl, drug equivalent to pure drug solution 0.2%) were
administered to rabbits in three different levels. In Level
1: Selected formulation was administered 30 min.before
administering dextrose solution. Level 2 contains
administering formulation as well as dextrose solution
together whereas level 3 involves the administration of
niosomal formulation containing drug 30 min. after the
dextrose solution was infused. Change in Intraocular
pressure was measured by tonometer after every 30 min.
till the difference in pressure between both controlled and
treated eye read zero. All the observations were done in
triplicate and mean was then taken. After every treatment
washout period of 3 days was given to each rabbit.
Ocular hypotensive activity was calculated as the
intraocular pressure difference between treated and
controlled eye of the same rabbit. Niosomes showed
better reduction in intraocular pressure due to the better
partitioning of drug between vesicle and eye corneal
surface. However, it was observed that delivery of drug
via niosomes enhance the local drug concentration at the
corneal surface. Prolonged contact time at the desired site
of action also improves the bioavailability of the drug.
Thus, ocular drug delivery via niosomes modifies the rate
as well as extent of absorption, which ultimately results
in reducing the intraocular pressure. Thereby, exhibiting
the controlled ocular drug delivery (Prabhu et al., 2010).
Sathyavathi et al had formulated niosomal in
situ gel incorporating Brimonidine Tartrate for ocular
drug delivery and evaluated for entrapment efficiency,
vesicle shape, size, in vitro release studies, in vivo
activity and stability studies. The present study was
investigated for the effective treatment of the ocular
disease called „glaucoma‟. Niosomes were designed by
the authors by taking various ratios of span series and
cholesterol. In vivo intra ocular pressure lowering activity
was conducted in male albino rabbits under this study,
four groups were designed, each containing 3 rabbits.
The drug formulation was instilled into the rabbit‟s eye
and the changed in ocular pressure were measured by
tonometer before, after 30 min. of the administration and
then after every hour in the period of 8 hr. Until the
pressure difference between controlled and treated eye
reached zero. Selected formulations were then instilled
into the corneal surface of the one eye and the contra
lateral eye was denoted as a “control”. The ocular
hypotensive activity was then measured. It was revealed
by the authors that niosomal gel showed better antiglaucoma activity as compared to niosomal and marketed
drops. Thus, it was concluded that niosomal represented
itself to a better system as compared to conventional eye
drops with improved bioavailability and increased
precorneal residence ability (Sathyavathi et al., 2012).
Maiti et al had formulated nanovesicular
formulation of brimonidine tartrate for the treatment of
glaucoma and evaluated them for in vivo efficacy and eye
irritation test. The intraocular pressure measurement
study was conducted by the authors on normotensive
albino rabbits (2-3 kg). The animals were divided into
two groups, containing six rabbits in each group. Group
1st were treated with vesicles whereas Group 2nd was
treated with the marketed formulation. The intraocular
pressure was measured at different intervals with a
standardized tonometer. 50-μl single dose of 0.1%
brimonidine preparation was instilled into the left eye of
the corneal surface of each rabbit, first after 30 min and
then after every 1 h interval. The intraocular pressure was
measured up to 7.5 h. The right eye was used as a control
in all the experimental animals. Marketed formulation
showed a difference of 16.55 ± 0.69 mmHg intraocular
pressure, whereas optimized vesicular formulation
showed a lower value 2.85 ± 0.67 mmHg at 3.5 h. Thus it
was observed that the tested niosomal formulation
demonstrated intraocular pressure-lowering activity more
significantly for a prolonged period of time in
comparison to a marketed formulation. It was revealed by
the authors that the vesicles increased the absorption of
drug by altering the corneal permeability of drug. To
evaluate the ocular irritancy effects of optimized
niosomal formulations, Eye Irritation Test was conducted
by the authors on three healthy albino rabbits. Niosomal
formulation (single dose, 100-μl ) was instilled into the
conjunctival sac of left eye of each animal and the
untreated eye served as a control. Each animal was
observed for any ocular reactions (corneal ulceration,
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conjunctival redness, and conjunctival edema), visually
by using slit lamp at various time intervals upto 72 hrs.
Selected formulations did not showed any sign of irritant
effect. Further, a confirmatory test was also conducted on
another two animals. It was further examined that
animals did not showed any ocular lesion in 3 days of
study. Thus, it was concluded by the authors that the
optimized niosomal formulation were non-irritant and
safe for the ocular delivery (Maiti et al, 2011).
OFLOXACIN
Ofloxacin encapsulated niosomes were designed
and characterized for improved ocular delivery by Gupta
et al. Niosomes were prepared by taking non-ionic
surfactant, Span 60, in various proportions and evaluated
for various parameters such as morphological characters,
entrapment efficiency, in vitro release studies, stability
study determination minimum inhibitory concentration
(MIC), ocular irritation test and in vivo study. Preclinical
evaluation was done by performing ocular irritation test
as well as in vivo study. The optimized formulation was
tested on six rabbits, by incorporating it in the cul-de-sac
of the left eye. No sign of irritation, inflammation or
abnormal discharge were observed in the rabbits.
Niosomes (F5) were found to be free from any
undesirable irritant effect on cornea, iris and conjunctiva
up to 24 hrs. after its application as reported by the
author. Thus, it is considered to be an appropriate system
for ophthalmic drug delivery. In vivo study was also
conducted by the authors in male rabbits (Orytolagus
cuniculus) to evaluate the ocular bioavailability of the
drug released from the niosomes (F5). Retention time of
the standard drug solution was compared with the sample
extracted from the aqueous humour. It was revealed by
the authors that increase in retention time in aqueous
humour was observed with the samples due to the
increased contact time of the formulations in the cornea
as well due to improved permeability of the drug caused
by the niosomes. Thus, the authors concluded that, the
niosomal systems represent a system that is capable
enough in delivering ofloxacin in a controlled manner
efficiently, with improved corneal penetration and
bioavailability (Gupta et al., 2010).
DICLOFENAC SODIUM
Diclofenac sodium loaded niosomes were
developed by Karthikeyan and characterized for in vivo
drug release and ocular irritation test. Male albino rabbits
were used by the authors to evaluate in vivo activity.
Niosomal preparations were compared with the control
formulation. It was reported by the authors that the
concentration of diclofenac delivered via niosomes were
higher in aqueous humour as compared to the eye drop
solution. Niosomal preparations showed Cmax 4.731
µg/ml, Tmax 200 min. and AUC value 513.46 as compared
to control which showed Cmax, Tmax, AUC 3.155 µg/ml,
80 min., 351.74 respectively. The ocular irritancy test
was done in rabbits to evaluate the preparations for any
irritation, redness or inflammation. So, it was observed
that the niosomal suspensions did not possess any sign or
irritation or redness as compared to the control
preparation. Thus, it was revealed by the authors that the
niosomes were considered to be a safe vesicular system
for the effective ocular drug delivery (Karthikeyan 2009)
NALTREXONE
Nanosized niosomal vesicles encapsulating
naltrexone have been developed and optimized by
Abdelkader et al with the objective to evaluate the
conjunctival as well as corneal tolerance ability of
naltrexone and its ingredients. To accomplish this
objective, niosomal vesicle of naltrexone hydrochloride
was designed by taking the combination of different
surfactants or lipids at various concentrations.
Specifically for the treatment of diabetic keratopathy. To
test the conjunctival and corneal toxicity, hen‟s egg testchorioallantoic membrane (HET-CAM), bovine corneal
opacity and permeability (BCOP) test as well as corneal
histopathological test were combined. Four selected
niosomal formulations subjected to 10 days old HETCAMs were found to be not showing any irritant effect.
Whereas sodium cholate (an ingredient) showed some
irritation, which have been observed to be eliminated by
incorporating it in niosomes. Thus, it was concluded by
the authors that, niosomes possessed better ocular
tolerability and less ocular irritation. Thereby, ought to be
an effective system for safe and effective drug delivery
across the cornea (Abdelkader et al., 2012).
FLUCONAZOLE
Kaur et al had formulated and evaluated elastic
surfactant based niosomal vesicular carriers loaded with
fluconazole for effective ocular delivery. Niosomes of
fluconazole were designed by the authors to prolong the
drug release as well as to enhance its effect. These
vesicles were prepared by using sorbitan (spans) with an
edge activator by ether injection method and
characterized for vesicular size, shape, and entrapment
efficiency, ex vivo corneal permeability and safety test. It
was observed by the authors that niosmal formulation
showed improved permeability as compared to the
marketed formulation. The prepared vesicles were also
found to be more stable under stability study of two
months. Safety studies were reported as genotoxicity
(Ames test), cytotoxicity (MTT assay), and eye irritation
revealed that the niosomes loaded with fluconazole were
safe. Thus, exhibiting itself an effective carrier for the
ocular drug delivery (Kaur et al., 2004).
FLUPIRTINE MALEATE
Patidar had developed niosomes enclosing
flupirtine maleate to enhance the permeability of the drug
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across the cornea and characterized them for
morphological characters, entrapment efficiency, in vitro
drug release, stability study and ocular irritation test.
Ocular irritation test was performed by the authors and
pupil size, redness as well as irritancy was observed with
respect to time. This test was done on rabbit‟s eyes, by
instilling the niosomal suspension drops in right eye.
Comparison has been made between right and left eye. It
was revealed from this study that niosomal preparations
showed no sign of redness or any other inflammation. In
vivo trigeminal neuralgia test (Nociceptive test)/eye
wiping test was done to evaluate the drug release. In this
test, seven groups of animals were taken, each containing
six rats. Control group and standard group were
compared for the results. Where control group animals
were supplied with the 5 M NaCl and number of wipes
was counted, followed by the wipes showed by the pretreated groups in which standard solution and the
prepared formulations were instilled. Pre-treated groups
were then compared with that of the control and standard
group. It was reported by the authors that the doseresponse relationships between control and standard
groups with the pre-treated group were significant as
measured by applying one-way ANOVA. Thus, it was
concluded that niosomes loaded with flupirtine maleate,
can significantly deliver the drug with reduced dosing
frequency as well as side effect. Thereby, representing
itself a prominent safe and effective vesicular carrier for
ocular delivery (Patidar 2012).
GENTAMICIN
Niosomes encapsulating gentamicin were
reported by Abdelbary for controlled ophthalmic drug
delivery. These vesicles were prepared by using different
surfactants by thin film hydration method and then
evaluated for entrapment efficiency, photo microscopy,
particle size analysis, in vitro drug release and ocular
irritancy test. Formulation F4, F6, F12 were subjected to
ocular irritancy test, to check either for any redness,
inflammation or increased tear production, by instilling
the selected preparations (50 µl) in the eyes of albino
rabbits. In all, nine- albino rabbits were used and each
formulation was incorporated in the conjunctival sac of
the eyes of three rabbits. Contra lateral eye was used as a
control. The study was done for 48 hrs. It was reported
that, no sign of redness or inflammation was observed
with any of the three niosomal formulations. Thus, it was
signified by that niosomes constitute themselves as an
effective ophthalmic vesicular carrier for the application
of gentamicin sulphate (Abdelbary 2008).
CHLORAMPHENICOL
Yasin et al had designed niosomes of
chloramphenicol
and
compared
it
with the
chloramphenicol eye drop, for the effective treatment of
conjunctivitis. Niosomes were prepared by ether injection
method and evaluated for particle size, zeta potential,
viscosity, entrapment efficiency, and stability study, in
vitro and in vivo studies. In vivo study was conducted on
twelve rabbits divided into two groups, each containing
six rabbits. Ist group was treated with ophthalmic drops
of chloramphenicol and second group with niosomal
suspensions loaded chloramphenicol. Sample (aqueous
humour) was drawn periodically up to 8 hrs and analyzed
by HPLC (High performance liquid chromatography) and
the study was done in duplicate. For the comparative
study, 12 rabbits were used, after conjunctivitis was
developed in the, treatment was commenced. 6 rabbits
were treated chloramphenicol drops whereas remaining 6
with niosomal suspension. Drops were given in the form
of 2 drops in every 2 hrs in Ist two days and then every 2
drops in every 4 hrs. for 3 days, based on the data
obtained from in vivo study. Niosomal suspensions were
then administered every 6 hrs in Ist two days and then 2
drops in every 12 hrs. for further 3 days. Result was then
recorded by visualizing the sign of conjunctivitis and the
recovery of the rabbits. It was observed from both the
studies that, each group of rabbits showed similar
recovery pattern from conjunctivitis. But, niosomal
suspensions exhibited better treatment efficacy with less
toxic effect as compared to commercial drops. Thereby,
improving the patient compliance. No sign of irritation or
redness was observed with the Niosomes containing
chloramphenicol. Thus, it is concluded that Niosomes
were appropriate as a carrier for the treatment of
conjunctivitis for ophthalmic sustained release (Yasin et
al., 2012).
ACETAZOLAMIDE
Acetazolamide encapsulated niosomes as
ophthalmic carriers were prepared Guinedi et al and
evaluated for entrapment efficiency, size, shape and in
vitro drug release, stability study and ocular irritancy test.
It was reported by the authors that niosomal formulations
niosomal lowered the intraocular pressure (IOP) in
rabbits as compared to free drug solution. Whereas under
ocular irritation test carried out for 40 days, the
histopathological examination of the corneal tissues of
rabbits instilled with niosomal formulations showed
slight reversible irritation in the substantia propria of the
eye and no other major modification in tissues were
observed. Thus, it was concluded that, Niosomes loaded
with acetazolamide exhibited an effective and safe
delivery system for the ocular drug delivery (Guinedi et
al., 2005).
Aggarwal et al had formulated Niosomes of
acetazolamide, with the objective to enhance the topical
bioavailability as well as the corneal permeability of
acetazolamide. Niosomes encapsulating acetazolamide
were prepared by reverse phase evaporation method,
coated with carbopol. In vivo pharmacodynamic studies
performed in male albino rabbits, reported reduction in
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intraocular pressure by 33%. The selected niosomal
formulation exhibited four times higher concentration as
compared to the dorzolamide (Dorzox, a topical marketed
product). In this study, authors had compared the aqueous
humor disposition of the drug from the selected
bioadhesive coated niosomal formulation with the
aqueous suspension of the 1 % w/v drug. The
concentration of acetazolamide absorbed in the aqueous
humor from both control and selected niosomal
formulation was determined by microdialysis. The peak
concentration of amount of drug absorbed in the aqueous
humor via niosomal formulation was reported to be twice
of that obtained via control suspension, after 20 min. of
instillation. Thus, depicting the fact that enhanced
penetration was achieved with niosomal formulation.
Therefore, it was revealed that Niosomes were effective
in enhancing the bioavailability of acetazolamide,
effective in the treatment of glaucoma (Aggarwal et al.,
2007).
LEVOFLOXACIN
Raghuwanshi et al had formulated Niosomes
encapsulated with Levofloxacin for Ophthalmic
Controlled Delivery and evaluated them for microscopy,
percent entrapment efficiency, in vitro release study,
ocular irritation test. The irritation or damaging effect of
the selected niosomal formulations were tested on six
rabbits by instilling the formulations in the lower cul-desac of the left eye of the rabbits, to observe for any
redness or inflammation produced by the preparations.
From this study, it was reported that none of the selected
preparations showed any sign of redness or inflammation.
Thus, it was demonstrated by the authors that Niosomes
were efficient in prolonging the drug release with
reduced side effects, representing itself as a prominent
efficient carrier in ocular drug delivery (Raghuwanshi et
al., 2012).
CYCLOPENTOLATE
Saettone et al had performed preliminary studies
on niosomal vesicles enclosed with cyclopentolate. In
vitro absorption study was conducted on rabbit using its
cornea and in vivo mydriatic activity was also performed
by the authors. It was reported by the authors that in in
vitro study, the vesicles buffered at pH 5.5 showed an
increased permeation of drug across as compared to a
reference buffer solution. In the pharmacodynamic study,
Niosomes possessed enhanced bioavailability than the
reference solution. Thus, from these two studies, it was
concluded by the authors that non-ionic surfactant
vesicles (niosomes) enhanced the absorption of the
cyclopentolate by altering the permeability across
conjunctiva and sclera (Saettone et al., 1996).
TIMOLOL MALEATE
Kaur et al had developed bioadhesive niosomes
enclosing timolol maleate and evaluted their
pharmacokinetic and pharmacodynamic activity for
ocular drug delivery. Male albino rabbits were used for
the study to evaluate the timolol maleate concentration in
aqueous humor. After instillation of one drop of both
timolol maleate solution (TMS) as well as drug loaded
bioadhesive niosomes, the drug concentration was
measured by microdialysis method. It was observed by
the authors that peak concentration of drug in aqueous
humor from bioadhesive niosomal formluation was
almost 1.7 times of that of control drug solution. Thus,
from the study it was confirmed that niosomal vesicles
exhibited sustained controlled ocular drug delivery (Kaur
et al., 2010).
Table No. 1
Ocular delivery of variety of drugs via Liposomes
Drug
Therapeutic category
Conclusion
Improved therapeutic efficacy, effective in the
Idoxuridine
Anti-viral
treatment of Herpetic Keratitis
Ganciclovir
Anti-viral
Improved efficacy with no side effects
Acyclovir
Anti-viral
Enhanced penetration and better drug release
Levofloxacin
Antibacterial
Improved residence time
Ciprofloxacin
Antibacterial
Higher drug concentration
Acetazolamine
Anti-glaucomatic
Improved efficacy in glaucoma treatment
Chloramphenicol
Antibacterial
Enhanced antibacterial activity
Fluconazole
Antifungal
Tacrolimus
Immuno suppressant
Ciprofloxacin
Antibacterial
Latanoprost
Anti-glaucomatic
Enhanced antifungal activity.
More effective and safer as compared to free
drug.
Reduced toxicity of ciprofloxacin for safe
delivery.
Sustained delivery with enhanced intraocular
pressure lowering effect.
Reference
Smolin et al. (1981)
Cheng et al.(2000)
Law et al. (2000)
Danion et al. (2007)
Budai et al. (2007)
Hathout et al. (2007)
Mahmoud et al.
(2008)
Habib et al. (2010)
Zhang et al. (2010)
Jain and Shastri
(2011)
Natarajan et al.
(2012)
45
Nida Akhtar. et al. / International Journal of Biopharmaceutics. 2013; 4(1): 38-48.
Table No. 2
Delivery of drugs via Niosomes with their reported preclinical and clinical studies
Route of
Preclinical and
Drug
Inference
delivery
clinical study
In vivo absorption
Methotrexate
Oral
Enhanced absorption
study
Bioavailability & in
Enhanced bioavailability
Flurbiprofen and
Oral &
vivo anti- inflammatory
& effective antiPiroxicam
transdermal
activity
inflammatory activity
Erythromycin
Topical
In vivo CLSM
Enhanced penetration
Sumatriptine
In vitro release & exEnhanced nasal absorption
Nasal
Succinate
vivo study
& prolonged release.
In vitro permeation
Enoxacin
Topical
Enhanced permeation
study
Insulin became active and
In vivo Hypoglycaemic
Insulin
Vaginal
therapeutically effective
activity
for vaginal delivery,
Controlled drug delivery
Propylthiouracil
Topical
In vitro drug release
from Niosomes
Increased drug absorption
in vitro skin
and bioavailability as
Minoxidil
Topical
penetration and
compared to commercial
permeation study
formulation
In vitro permeation
Prolonged drug release
Rofecoxib
Topical
study
with improved permeation.
In vivo
Enhancement in the %
Clobetasol
pharmacodynamic
Topical
reduction in paw oedema
Propionate
study (antiexhibited by niosomal gel.
inflammatory activity).
Enhanced permeation and
In vitro permeation &
better anti-inflammatory
Lornoxicam
Transdermal
in vivo inflammatory
activity as compared to
activity.
solution of drug.
In vivo
hepatoprotective
Improved hepatoprotective
Silymarin
Hepatic
activity &
efficiency & was found to
histopathological
be safe.
study.
Fig. 1. Diagrammatic view of Niosomal vesicular carrier.
Reference
Azmin et al. (1985)
Reddy and Udupa
(1993)
Jayaraman et al. (1996)
Gayatri et al. (2000)
Fang et al. (2001)
Ning et al. (2005)
Suwakul et al. (2008)
Balakrishnan et al.
(2009)
Das and Palei (2011)
Lingan et al. (2011)
Singla et al. (2012)
El-Ridy et al. (2012)
46
Nida Akhtar. et al. / International Journal of Biopharmaceutics. 2013; 4(1): 38-48.
CONCLUSION
Niosomes have been considered safe and
effective as a recently advanced vesicular carrier for
ocular delivery of variety of therapeutically active drugs.
The preclinical and clinical studies conducted on
niosomes, confirmed the fact that they are capable in
enhancing the corneal permeability as well as lowering
the intraocular pressure required for the treatment of
various ocular disease. The clinical evaluation studies on
niosomes are still in progress for targeted drug delivery.
Encapsulation of drug in niosomal vesicles provides a
novel approach towards drug delivery system and new
attempts have also been in action to enhance the drug
delivery potential of niosomes can by using novel
concepts like proniosomes, discomes and aquasome, to
further explore its widespread utility in the new era of
research.
CONFLICT OF INTERESTS
The author declared no conflict of interest.
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