Academic Sciences

International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491

Vol 5, Issue 2, 2013

Review Article

IN SITU HYDROGEL: DIFFERENT APPROACHES TO OCULAR DRUG DELIVERY

SAVITA GAMBHIRE*, KARUNA BHALERAO, SUSHMA SINGH
Department of pharmaceutics, Dr. L. H. Hiranandani College of pharmacy, Ulhasnagar-421003, Maharashtra, India.
Email: savitagambhire@gmail.com
Received: 07 Feb 2013, Revised and Accepted: 25 Mar 2013
ABSTRACT
Ophthalmic drug delivery is one of the more interesting and challenging endeavor facing the pharmaceutical scientist. The conventional ophthalmic
drug delivery systems like solution, suspensions and ointments show drawbacks such as increased pre-corneal elimination, high variability in
efficiency and blurred vision respectively.
To overcome these drawbacks there are considerable efforts directed towards newer drug delivery system for ophthalmic administration. Newer
research in ophthalmic drug delivery system is directed towards amalgamation of several drug delivery technologies, that includes to build up
systems which is not only extend the contact time of the vehicle at the ocular surface, increase corneal absorption of drug, but at the same time slow
down the removal of the drug..
In situ forming ophthalmic hydro-gels are liquid upon instillation undergoes phase transition in the ocular cul-de-sac to form visco elastic gel and
this provides a response to environmental changes. The factors considered during the formulation of in situ Hydrogel like temperature modulation,
pH change, and presence of ion. The choice of a particular in situ Hydrogel depends on its intrinsic properties and envisaged therapeutic use. In situ
forming ophthalmic gelling system provides ease of administration and reduces frequency of administration, improve patient compliance and
comfort.
Keywords: In-situ gel, Temperature triggered, Ion triggered, PH triggered.

INTRODUCTION
Ophthalmic drug delivery is one of the most interesting and challenging
for the pharmaceutical scientist. The anatomy, physiology, and
biochemistry of the eye render this organ exquisitely impervious to
foreign substances. The challenge to the formulator is to circumvent the
protective barriers of the eye without causing permanent tissue damage.
The development of newer, more sensitive diagnostic techniques and
therapeutic agents render urgency to the development of more
successful ocular delivery system[1].
There are most commonly available ophthalmic preparations such
as drops and ointments about 70% of the eye dosage formulations in
market. But these preparations when instilled into eye they are
rapidly drained away from the ocular surface due to blinking tear
flow and lachrymal nasal Drainage of the eye. Only a small amount of
drug is available for its therapeutic effect

resulting in frequent dosing application to the eye. So overcome to

these problems newer Pharmaceutical ophthalmic formulation such
as in-situ gel, nanoparticle, liposome, nanosuspension,
microemulsion, intophoresis and ocular inserts have been
developed in last three decades increase the bioavailability of the
drug as a sustained and controlled manner[2].
Anatomy and function of eye
The eye is a spherical structure with a wall made up of three
layers; the outer part sclera, the middle parts choroid layer,
Ciliary body and iris and the inner section nervous tissue layer
retina[2]. The cornea; lens and vitreous body are all transparent
media with no blood vessels; oxygen and nutrient are
transported to this non vascular tissue by aqueous humor. The
aqueous humor has a high oxygen tension and about the same
osmotic pressure as blood[1].

Fig. 1: Anatomy of eye Fig. 2: Anatomy of cornea

In figure 2. Anatomy of cornea, the cornea is covered by a thin
epithelial layer continuous with the conjunctiva at the cornea
sclerotic junction, its posterior surface is covered by a layer of
Endothelium.The eye is constantly cleansed and lubricated by the
lachrymal apparatus which consist of four structure[3]

1.

Lachrymal glands

2.

Lachrymal canals

3.

Lachrymal sac

4.

Naso lachrymal duct

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Int J Pharm Pharm Sci, Vol 5, Issue 2, 27-36
Lachrymal fluid in human has a normal volume of 7 l and it is an
isotonic aqueous solution of sodium chloride (pH-7.4).The rate of
blinking varies widely from one person to another, but
approximately 20 blinking per minute. During each blink movement
the eyelid are closed for a short period of about 0.3 sec.The aqueous
humor in humans has a volume of approximately 300l that fills in
the anterior chamber of the eye (in fort of the lens).The aqueous
humor is secreted by the ciliary process and flows out of the anterior
chamber at a turnover rate of approximately 1%/min.In clinical
practice the anterior segment of the eye(cornea, conjunctiva, sclera)
can be treated with topical ocular eye drops, the most commonly
used dosage form in ocular drug treatment. Unfortunately the eye
drops are rapidly drained from the ocular surface and, therefore, the
time for drug absorption is only a few minutes and bioavailability is
very low, typically less than 5%[4].

paracellular drug permeation [34]. Therefore, lipophilic drugs have

typically at least an order of magnitude higher permeability in the
cornea than the hydrophilic drugs [37].Despite the tightness of the
corneal epithelial layer, transcorneal permeation is the main route
of drug entrance from the lacrimal fluid to the aqueous humor.In
general, the conjunctiva is more leaky epithelium than the cornea
and its surface area is also nearly 20 times greater than that of the
cornea [38,39]. Drug absorption across the bulbar conjunctiva has
gained increasing attention recently, since conjunctiva is also fairly
permeable tothe hydrophilic and large molecules [40]. Therefore, it
may serve as a route of absorption for larger bio-organic compounds
such as proteins and peptides. Clinically used drugs are generally
small and fairly lipophilic. Thus, the corneal route is currently
dominating. In both membranes, cornea and conjunctiva, principles
of passive diffusion have been extensively investigated, but the role
of active transporters is only sparsely studied.

The barriers

III) Blood-ocular barriers

I) Drug loss from the ocular surface

The eye is protected from the xenobiotics in the blood stream by

blood-ocular barriers. These barriers have two parts: blood-aqueous
barrier and blood-retina barrier the anterior blood-eye barrier is
composed of the endothelial cells in the uvea. This barrier prevents
the access of plasma albumin into the aqueous humor, and limits
also the access of hydrophilic drugs from plasma into the aqueous
humor. Inflammation may disrupt the integrity of this barrier
causing the unlimited drug distribution to the anterior chamber. In
fact, the permeability of this barrier is poorly characterised. The
posterior barrier between blood stream and eyeis comprised of
retinal pigment epithelium (RPE) andthe tight walls of retinal
capillaries [31,34]. Unlike retinal capillaries the vasculature of the
choroid has extensive blood flow and leaky walls. Drugs easily gain
access to the choroidal extravascular space, but thereafter
distribution into the retina is limited by the RPE and retinal
endothelia. Despite its high blood flow the choroidal blood flow
constitutes only a minor fraction of the entire blood flow in the body.
Therefore, without specific targeting systems only a minute fraction
of the intravenous or oral drug dose gains access to the retina and
choroid. Unlike blood brain barrier, the blood-eye barriers have not
been characterised in terms of drug transporter and metabolic
enzyme expression.

After instillation, the flow of lacrimal fluid removes instilled

compounds from the surface of the eye. routes of drug kinetics refer
to following processes: 1) transcorneal permeation from the
lacrimal fluid into the anterior chamber, 2) non-corneal drug
permeation across the conjunctiva and sclera into the anterior uvea,
3) drug distribution from the blood stream via blood-aqueous
barrier into the anterior chamber, 4) elimination of drug from the
anterior chamber by the aqueous humor turnover to the trabecular
meshwork and Sclemm's canal, 5) drug elimination from the
aqueous humor into the systemic circulation across the bloodaqueous barrier, 6) drug distributionfrom the blood into the
posterior eye across the blood-retina barrier,7) intravitreal drug
administration, 8) drug elimination from the vitreous via posterior
route across the blood-retina barrier, and 9)drug elimination from
the vitreous via anterior route to the posterior chamber. though the
lacrimal turnover rate is only about 1 l/min the excess volume of
the instilled fluid is flown to the nasolacrimal duct rapidly in a
couple of minutes [33].Another source of non-productive drug
removal is its systemic absorption instead of ocular absorption.
Systemic absorption may take place either directly from the
conjunctival sac via local blood capillaries or after the solution flow
to the nasal cavity [32,33]. Anyway, most of small molecular weight
drug dose is absorbed into systemic circulation rapidly in few
minutes. This contrasts the low ocular bioavailability of less than 5%
[33].Drug absorption into the systemic circulation decreases the
drug concentration in lacrimal fluid extensively. Therefore, constant
drug release from solid delivery system to the tear fluid may lead
only to ocular bioavailability of about 10%, since most of the drug is
cleared by the local systemic absorption anyway [36].

Classification Of Ocular Drug Delivery System:

Ocular drug deliveries consist of following types of dosage forms:
1). Semisolid -Gel, Ointment
2). Solid -Ocular Inserts.
3). Liquid Solution, Suspension

II) Lacrimal fluid-eye barriers

Corneal epithelium limits drug absorption from the lacrimal fluid
into the eye [31]. The corneal barrier is formed upon maturation of
the epithelial cells. They migrate from the limbal region towards the
center of the cornea and to the apical surface. The most apical
corneal epithelial cells form tight junctions that limit the

4). Intraocular Implant, Injections

Types of Ocular Gel:
I.
II.

Organogel
Hydrogel

Table 2: General classification of gel [5]

Class
Organo
gel
Hydrogel

Description
Hydrocarbon type
Animal/vegetable fat,
Hydrophilic
Organic Hydrogel
Natural /synthetic gum

Advantages of Ocular In Situ Hydrogel:

I.
II.
III.

Reduced dose concentration.

Reduced dosing frequency.
Improved patient acceptability.

Examples
Aluminium Stearate,
Carbowax.

Advantage
1) Template vehicle.
2) Chemical Stability.
3) Process Benefits.
1) Biodegradable.
2)Environmental
sensitive.
3) Biocompatible.

Sodium CMC,PF127,
Veegum.

IV.
V.
a.
b.

Limitation
1)Greasy property.
2) If impurity present then no
gelling.
1)Expensive
2)Difficulty in sterilization.

Generally more comfortable than insoluble or soluble insertion.

Increased bioavailability due toIncreased precorneal residence time.
Decreased nasolacrimal drainage of the drug.

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Int J Pharm Pharm Sci, Vol 5, Issue 2, 27-36
VI.

Chances of undesirable side effects arising due to systemic

absorption of the drug through naso-lacrimal duct are reduced6.
VII.
Easy to manufacture and hence less complex process and
reduces cost of Manufacturing7.
Limitation of Ocular in Situ Hydrogel:
I.
II.
III.

Blurred vision.
Matted eyelids.
Limited values in terms of improvement of bioavailability[8].

OCULAR IN SITU HYDROGEL

A more desirable dosage form is one that can deliver drug in a
solution form, create little to no problem of vision and need be
dosed no more frequently than once or twice daily. In situ activated
gel forming systems are those which are when exposed to
physiological conditions will shift to a gel phase. This new concept of
producing a gel in situ was suggested for the first time in the early
1980s. Gelation occurs via the cross-linking of polymer chains that
can be achieved by covalent bond formation (chemical cross-linking)
or non-covalent bond formation (physical cross-linking)[9][10].
The progress that has been made in gel technology is in the
development of a droppable gel. Insitu gel-forming systems can be
described as low viscosity solutions that undergo phase transition in
the conjunctival cul-de-sac to form viscoelastic gels due to
conformational changes of polymers in response to the physiological
environment. The rate of in situ gel formation is important because
between instillation in the eye and before a strong gel is formed; the
solution or weak gel is produced by the fluid mechanism of the eye
[10].
Gel forming ophthalmic solution have been developed and approved
by FDA for Timolol Maleate this is used to reduce elevated intra
ocular pressure (IOP) in the management of Glaucoma. Timolol
maleate ophthalmic solution initially developed, require a twice a
day dosage for most patient. With in situ gel IOP lowering capacity
extended from 12 to 24 hrs and thus requires only once a dosing.
This extended duration of efficacy was demonstrated for both gels
forming product in controlled clinical trial. The first gel forming
solution, TIMOLOLXE uses the polysaccharide gellan gum and
reported in situ in response to the higher ionic strength of tear fluid
(U.S Patent4, 861,460), alternative ion sensitive system have been
patented, The second product (Timolol maleate) uses the
polysaccharide xanthum gum as the gelling agent and is reported to
gel in contact with tear fluid, At least in part due to presence of tear
protein Lysozyme (U.S. patent 6, 174,524)[11].
Mechanism Of In Situ Gel Formation
Sol to gel phase transition ocular in Hydrogel due to:
I.
II.
III.

Physical stimuli: It includes change in temperature, electric

field, light.
Chemical stimuli: It includes change in pH and ion activation
from biological fluid.
Biochemical stimuli: It includes change in glucose level.

Physical, Chemical and Toxicological properties of Hydrogel:

groups. Hydrophobic groups collapse in the presence of water, thus

minimizing their exposure to the water molecule. As a result, the
hydrogels will swell much less compared to hydrogels containing
hydrophilic groups. Swelling of environmentally-sensitive Hydrogel
can be affected by specific stimuli. Swelling of temperature-sensitive
Hydrogel can be affected by changes in the temperature of the
swelling media. There are many other specific stimuli that can affect
the swelling of other environmentally-responsive Hydrogel[12].
II) Dynamics of swelling
The swelling kinetics of hydrogels can be classified as diffusioncontrolled (Fickian) and relaxation-controlled (non-Fickian)
swelling. When water diffusion into the Hydrogel occurs much faster
than the relaxation of the polymer chains, the swelling kinetics is
diffusion-controlled[12].
III) Mechanical properties
Mechanical properties of hydrogels are very important for
pharmaceutical applications. For example, the integrity of the drug
delivery device during the life time of the application is very important to
obtain FDA approval, unless the device is designed as a biodegradable
system. A drug delivery system designed to protect a sensitive
therapeutic agent, such as protein, must maintain its integrity to be able
to protect the protein until it is released out of the system. Changing the
degree of cross linking has been utilized to achieve the desired
mechanical property of the Hydrogel. Increasing the degree of cross
linking of the system will result in a stronger gel. However, a higher
degree of cross linking creates a more brittle structure. Hence, there is an
optimum degree of cross linking to achieve a relatively strong and yet
elastic Hydrogel. Copolymerization has also been utilized to achieve the
desired mechanical properties of hydrogels. Incorporating a comonomer that will contribute to H-bonding can increase the strength of
the Hydrogel.[12]
IV) Cytotoxicity and in vivo toxicity
Cell culture methods, also known as cytotoxicity tests, can be used to
evaluate the toxicity of hydrogels. Three common assays to evaluate
the toxicity of hydrogels include extract dilution, direct contact and
agar diffusion. Most of the problems with toxicity associated with
hydrogel carriers are the untreated monomers, oligomers and
initiators that leach out during application. Therefore, an
understanding the toxicity of the various monomers used as the
building blocks of the Hydrogel is very important[12].
VARIOUS APPROACHES OF INSITU GELATION
The poor bioavailability and therapeutic response exhibited by
conventional ophthalmic solutions due to rapid pre corneal
elimination of the drug may be overcome by the use of in situ gelforming systems that are instilled as drops into the eye and undergo
a solgel transition in the cul-de-sac.
Various approaches are used
I.
II.
III.

Temperature triggered in situ Hydrogel

pH triggered in situ Hydrogel
Ion activated in situ Hydrogel

I) Factors affecting swelling of Hydrogel

I) TEMPERATURE TRIGGERED IN SITU HYDROGEL

I) Cross linking Ratio

Temperature-sensitive hydrogels are probably the most commonly

studied class of environment-sensitive polymer systems in drug
delivery research. The use of biomaterial whose transitions from
sol-gel is triggered by increase in temperature is an attractive way to
approach in-situ formation The ideal critical temperature range for
such system is ambient and physiologic temperature, such that
clinical manipulation is facilitate and no external source of heat
other than that of body is required for trigger gelation [7].

The cross linking ratio is one of the most important factor that affect
the swelling of Hydrogel. It is defined as the ratio of moles of cross
linking agent to the moles of polymer repeating units. The higher the
crosslinking ratio, the more cross linking agent is incorporated in
the Hydrogel structure. Highly cross linked Hydrogel have a tighter
structure, and will swell less compared to the same hydrogels with
lower cross linking ratios. Cross linking hinders the mobility of the
polymer chain, hence lowering the swelling ratio[12].
II) Swelling Ratio
The chemical structure of the polymer may also affect the swelling
ratio of the hydrogels. Hydrogels containing hydrophilic groups
swell to a higher degree compared to those containing hydrophobic

Three main strategies are exists in engineering of thermo responsive solgel polymeric system. Temperature-Sensitive Hydrogel Are Classified
Into:[7]
i.
ii.
iii.

Negatively Thermo Sensitive Hydrogel

Positively Thermo Sensitive Hydrogel
Thermally Reversible Hydrogel

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Int J Pharm Pharm Sci, Vol 5, Issue 2, 27-36

Fig. 3: Schematic representation of the viscosity change on the ocular surface when using ophthalmic in situ gelling systems[13].
i) Negative temperature-sensitive hydrogels
Negative temperature-sensitive hydrogel have a lower critical
solution temperature (LCST) and contract upon heating above the
LCST. Polymers with low critical temperature (LCST) transition
between ambient and physiologic temperature is used for this
purpose. One of the most extensively investigated polymers that
exhibit useful LCST transition is poly (Nisopropylacrylamide)
(PNIPAAm). PNIPAAm is a water soluble polymer at its low LCST,
but hydrophobic above LCST, which result on precipitation of
PNIPAAm from the solution at the LCST. Pluronics are poly (ethylene
oxide)-poly(propylene oxide)-poly (ethylene oxide) (PEO-PPOPEO)
triblock co-polymer that are fluid at low temperature, but forms
thermo responsible gel when heated as a consequences of a
disorder-order transition in micelle packing which makes these
polymers suitable for in situ gelation.

(ethylene oxide)-b-poly (propylene oxide)-b-poly (ethylene oxide)

(Pluronics, Tetronics, poloxamer). Polymer solution is a free
flowing liquid at ambient temperature and gels at body temperature.
Polymer solution is a free flowing liquid at ambient temperature and
gels at body Temperature
iii) Thermally reversible hydrogels
Thermo reversible gels can be prepared with naturally occurring
polymers. Most natural polymer aqueous solutions form a gel phase
when their temperature is lowered. Classic examples of natural
polymers exhibiting a solgel transition include gelatin and
carrageenan, Chitosan. At elevated temperatures; these polymers
adopt a random coil conformation in solution. Upon cooling, a
continuous network is formed by partial helix formation[12].
Thermo reversible gels, there remains an important drawback
associated with their use; the risk of gelation before administration
by increase in ambient temperature during packing or storage[7].
Polymer use in temperature triggered in situ hydrogel
I.

Poloxamer (e.g. pluronic F127,poloxomer-407)

II.
Cellulose derivative: Methyl cellulose(MC), Hydroxy propyl
methyl cellulose(HPMC),
a.
III.
I)

Fig. 4: A plot of typical thermo sensitive polymer solution

behavior[41].
ii) Positive temperature sensitive hydrogel
A positive temperature sensitive hydrogel has an upper critical
solution temperature (UCST), such hydrogel contracts upon cooling
below the UCST. Polymer networks of poly (acrylic acid) (PAA) and
polyacrylamide (PAAm) or poly (acryl amide-co-butyl methacrylate)
have positive temperature dependence of swelling[14].The most
commonly used thermo reversible gels are these prepared from poly

Ethyl (hydroxyethyl) cellulose

Xyloglucan
Poloxamer

Structure of PEO-PPO-PEO (Poloxamer).[16]

Poloxamer is a nonionic surfactant composed of polyoxyethylenepolyoxypropylene Copolymers in a concentration ranging from 2030%. At low concentrations (10-410-5 %) they form
Monomolecular micelles, but higher concentrations result in multi
molecular aggregates consisting of a hydrophobic central core with
their hydrophilic poly oxy ethylene chains facing the external
medium[15]. Micellization occurs in dilute solutions of block
copolymers in selected solvents above the Critical micellar
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Int J Pharm Pharm Sci, Vol 5, Issue 2, 27-36
concentration, at a given temperature. Due to the PEO/PPO ration of
2:1, when these molecules are immersed into the aqueous solvents,
they form micellar structures above critical micellar concentration [7].
Mechanism of gelation
The gelation mechanism of Poloxamer ( Fig.5. Schematic illustration
of micellar phases formed by the Pluronics with increasing
temperature.[16]) solutions has been investigated extensively, but is
still being debated. Ultrasonic velocity, light-scattering and small
angle neutron scattering measurements of aqueous Poloxamer
solutions have clearly indicated a micellar mode of association.
Micelle formation occurs at the critical micellization temperature as

a result of PPO block dehydration. With increasing temperature,

micellization becomes more important, and at a definite point,
micelles come into contact and no longer move. In addition, the
formation of highly ordered structures, such as cubic crystalline
phase, has been proposed as the driving force for gel formation, but
this hypothesis has been questioned recently. Thus, packing of
micelles and micelle entanglements may be possible mechanisms of
Poloxamer solution gelation with increased temperature.
Furthermore, it has suggested that intra molecular hydrogen bonds
might promote gelation. The Poloxamers are reported to be well
tolerated and non-toxic even though large amounts (25-30%) of
polymers are required to obtained a suitable gel[16].

Fig. 5: Schematic illustration of micellar phases formed by the Pluronics with increasing temperature.[16]
(Pluronic F127) was found to gel at a concentration of 20 wt. % at 25
C, which is less than that of the other members of the Poloxamer
series. At room temperature (25 C), the solution behaves as a mobile
viscous liquid, which is transformed into a semisolid transparent gel at
body temperature (37 C)[14].
Potential drawbacks
Potential drawback of Poloxamer gels include their weak mechanical
strength, rapid erosion (i.e. dissolution from the surface), and the
non biodegradability of PEO-PPO-PEO, which prevents the use of

high molecular weight polymers that cannot be eliminated by renal

excretion. To circumvent the biodegradability issue, new polymers
were synthesized by linking together a few (usually 3) Poloxamer
407 monomers via degradable carbonate linkage.As the carbonate
linkages were hydrolyzed under physiological conditions, the
hydrogel degraded into soluble Poloxamer 407 units and carbonate.
Variation of the polymer concentration enabled modification of the
gels dissolution time (2580 days).
Various poloxamer grades are available some of them which used in
ophthalmic drug delivery system as follows: Table-1 poloxamer grades

Table 1: Poloxamer grades

Nonproprietary name
Poloxamer 184
Poloxamer 185
Poloxamer 407

Commercial grade
L-64
P-65
F-127

HLB value
1218
1218
1823

pH of 2.5% w/v aqueous solution

57.5
67.4
67.4

As Gelling agent concentration 1550%; AS In situ gelling agent-13-14%

ii) Cellulose derivatives
Cellulose derivatives also cause gelation E.g.: Methylcellulose and
Hydroxyl propyl methylcellulose(HPMC) are typical examples of
such polymers. At low concentrations (110 wt. %), their aqueous
solutions are liquid at low temperature, but gel upon heating.

experimentally by a sharp rise in relative viscosity. This solgel

transformation has been exploited to design in situ gelling systems.
These systems exhibited low viscosity at 23 C and formed soft gels
at 37 [6]
iii) Xyloglucan

Methylcellulose solutions transform into opaque gels between 40

and 50 C, whereas HPMC shows phase transition between 75 and
90 C. These phase transition temperatures can be lowered by
chemical or physical modifications. For example, NaCl decreases the
transition temperature of methylcellulose solutions to 3234 C.

When xyloglucan is partially degraded by -galactosidase, the

resultant product exhibits thermally reversible gelation in dilute
aqueous solutions. Such behavior does not occur with native
xyloglucan. Gelation is only possible when the galactose removal
ratio exceeds 35 %[17].

Similarly, by reducing the hydroxyl propyl molar substitution of

HPMC, its transition temperature can be lowered to 40 C. Gelation
of methylcellulose or HPMC solutions is primarily caused by the
hydrophobic interaction between molecules containing methoxy
substitution. At low temperatures, the macromolecules are
hydrated, and there is little polymer polymer interaction other than
simple entanglement. As the temperature is raised, the polymers
gradually lose their water of hydration, which is reflected by a
decline in relative viscosity.

The transition temperature is inversely related to polymer

concentration[18] and the galactose removal ratio[17]. For example,
the solgel transition of xyloglucan was shown to decrease from 40
to 5 C when the galactose removal ratio increased from 35 to 58%.
Xyloglucan formulations were assessed for ocular delivery of
pilocarpine; using Poloxamer 407 as a positive thermosensitive
control.

Eventually, when sufficient but not complete dehydration of the

polymer occurs, polymerpolymer associations take place, and the
system approaches an infinite network structure, as reflected

The 1.5 wt. % xyloglucan formulation enhanced the miotic response

to a degree similar to that of a 25 wt. % Poloxamer 407 gel [19].
Xyloglucan is approved for use as a food additive. However, its
relatively low transition temperature (2227 C) makes handling at
room temperature problematic.

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Table 2: Commercial grades of cellulose and relates substance
Cellulose-related substance
Hydoxypropyl Methyl
cellulose

Ethyl cellulose

Grade
Methocel
A4MP
A15-LV
A15CP
A4CP
K-Series(generally retardant for release as viscosity
increases)
Ethocel, Aqualon
Ethocel Std 4 Premium
N-7

Viscosity (mPa s)
4000
15
1500
400

pH
5.58.0 for a 1% w/v aqueous
solution

3.05.5
5.68.0

As gelling agent 1-3%

PH TRIGGERED IN SITU HYDROGEL
All the pH-sensitive polymers contain pendant acidic or basic groups
that either accept or release protons in response to changes in
environmental pH.The polymers with a large number of ionizable
groups are known as polyelectrolytes. Swelling of Hydrogel increases
as the external pH increases in the case of weakly acidic (anionic)
groups, but decreases if polymer contains weakly basic (cationic)
groups. All the pH-sensitive polymers contain pendant acidic or basic
groups that either accept or release protons in response to changes in

environmental pH.The polymers with a large number of ionizable

groups are known as polyelectrolytes. Swelling of Hydrogel increases
as the external pH increases in the case of weakly acidic (anionic)
groups, but decreases if polymer contains weakly basic (cationic)
groups[23].Gelling of the solution is triggered by a change in pH. At pH
4.4 the formulation is a free-running solution which undergoes
coagulation when the pH is raised by the tear fluid to pH 7.4. The pH
change of about 2.8 units after instillation of the formulation (pH 4.4)
into the tear film leads to an almost instantaneous transformation of
the highly fluid latex into a viscous gel[22].

Fig. 6: Schematic representation of pH dependent in situ gels[20].

Polymer use in PH triggered in situ gel
I.
Polyacrylicacid(carbopol940)
II.
Pseudo latex e.g. (CAP Latex) cellulose acetate phthalate latex,
carbomer.
I) Polyacrylicacid(carbopol940)
Cross-linked poly (acrylic acid) of high molecular weight,
commercially available as Carbopol, is widely used in ophthalmology
to enhance precorneal retention to the eye.Carbopol 934 is a
synthetic polymer composed of 62% of carboxyl groups with a high
molecular weight (approximately3106) formed by repeating units of
acrylic acid, cross-linked with either ally sucrose or allylethers of
pentaerythritol.Carbopol offers the advantage of exhibiting excellent
mucoadhesive properties when compared with other polymers. (E.g.
Cellulose derivatives and Polyvinyl Alcohol). As the concentration of
Carbopol increases in the vehicle, its acidic nature may cause
stimulation to the eye tissues. In order to reduce the total polymer
content and improve the gelling properties, an ocular drug delivery
system based on a combination of Carbopol and methylcellulose has
been developed.
Mechanism of Gelation
Carbopol is a poly acrylic acid (PAA) polymer, which shows a sol to
gel transition in aqueous solution as the pH is raised above its p Ka of
about Methylcellulose, a viscosity enhancing polymer, exhibits a sol

to gel transition in aqueous solution in the range of 5055 C. The

rheological properties of this system were investigated and sol to gel
transition occurred primarily by an increase in pH due to the
presence of Carbopol; the temperature-mediated effect occurred
only at very low shear rates.They have also developed a similar
delivery system by a combination of Carbopol and hydroxyl propyl
methyl cellulose. For both systems it was found that a reduction in
the Carbopol concentration without compromising the in situ gelling
properties as well as overall rheological behaviors can be achieved
by adding a suitable viscosity enhancing polymer[6].
II) Pseudo Latex
PSEUDO LATEX coagulates within a few seconds when placed in the
cul-de-sac since the lacrymal fluid has a pHof 7.2. The pH of the ungelled formulation is 4.4 and is therefore sufficient to keep the
dispersion in a stable form. The PH change of 2.8 units after
instillation due to the surrounding tear fluid leads to an almost
instantaneous transformation of the highly fluid latex into a viscous
gel. The partially gelified polymeric dispersion shows the surface of
the latex particles starting to dissolve. They cannot be washed out of
the cul-de-sac by the lachrymal fluid and they form a micro reservoir
in situ with a high viscosity[4].
Eg.Cap Latex
First preliminary investigations of pHsensitive nano-particulate
systems (latex) for ophthalmic administration began in the early
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Int J Pharm Pharm Sci, Vol 5, Issue 2, 27-36
1980s. The choice of this polymer was determined by the
compatibility of the polymer with the active compound, the ability of
the CAP latex to be a free-running solution at pH 4.2 and a gel at 7.2,
and finally, the latex stability at relatively low pH which is a
prerequisite to ensuring the stability of pilocarpine. The gelation
capacity of CAP latexes has been visualized in vitro by scanning
electron microscopy and in vivo in rabbits by incorporating
methylene blue in ophthalmic formulations. The efficacy of a
preparation based on pseudo latex has been evaluated by measuring
pharmacological responses and precorneal residence time by
scintillography. This technique has clearly demonstrated the
superiority of CAP latex over a solution to prolong the corneal
residence time of pilocarpine. Finally, it is important to note that
irritation tests on Rabbits including examination of the cornea, the
iris and the conjunctiva have demonstrated that the investigated
pseudo latexes did not induce irritation. However, a sensation of
discomfort seems to be unavoidable after the coagulation of the
solution in the cul-de-sac as is the case for any semisolid
Preparation[6].
ION ACTIVATED IN SITU HYDROGEL
Gelling of the solution triggered by a change in ionic strength, It is
assumed that the rate of gelation depend on the osmotic gradient
across the surface of the gel. It is therefore likely that the osmolality
of the solution might have an influence on the rate of the sol to gel
transition occurring in the eye. The aqueous polymer solution forms
a clear gel in the presence of the mono or divalent cations typically
found in the tear fluids. The electrolyte of the tear fluid and
especially Na, Ca and Mg cations are particularly suited to initiate
gelation of the polymer when instilled as a liquid solution in the
conjunctival cul-de-sac [42].
Polmers Use In Ion Activated In Situ Gelation:
I.
II.

Gellerite gellan gum,

Alginates.

I) Gellan Gum
Gellan gum (Gelerite) is a linear, anionic hetero polysaccharide
secreted by the microbe Sphingomonas elodea (formerly known as
Pseudomonas elodea). The polysaccharide can be produced by
aerobic fermentation and then isolated from the fermentation broth
by alcohol precipitation. The polymer backbone consists of glucose,
glucuronic acid, and rhamnose in the molar ratio 2:1:1.These are
linked together to give a tetra-saccharide repeat unit The native
polysaccharide is partially esterified with L-glycerate and acetate,
but the commercial product Gelerite has been completely deesterified by alkali treatment.
Gelerite (deacetylated gellan gum) is one of the most interesting in
situ gelling polymers that has been tested since it seems to perform
very well in humans. Gelerite has been granted regulatory approval
as pharmaceutical excipient and is marketed by Merck in a
controlled-release glaucoma formulation called Blocarden Depot
(Timoptic). [6]

Mechanism of Gelation
Formulations with the Gelerite can be administered to ocular
mucosa as low viscosity solution. On contact with cations in tear
fluid the Formulation will form a clear gel. This is caused by cross
linking of the negatively charged polysaccharide helices by
monovalent and divalent cations (Na+, K+, Ca+). In an ion free
aqueous medium, Gelrite forms double helices at room temperature.
This Solution has a viscosity close to that of water and the helices
are only weakly associated with each other (by van der Waals
attraction). When gel-promoting cations are present, some of the
helices associate into cation-mediated aggregates, which cross-link
the polymer. On heating the polysaccharide in an ion free
environment, the polysaccharide becomes a disordered coil.
However, on heating a sample with cations present, the non
aggregated helices melt out first, and the aggregated helices melt out
at a higher temperature in a second transition.
The divalent ions such as magnesium or calcium were superior to
monovalent cations in promoting the gelation However the
concentration of sodium in tears (2.6 g/L) is quite sufficient to
induce the gelation.Corneal contact time of formulations based on
gellan gum has been investigated using two main methods, which
are fluorometry and -scintigraphy[6]
II) Alginate
Alginate with a high guluronic acid content will improve the gelling
properties and reduce the total polymer to be introduced into the
eye. The alginate forms 3-dimensional ionotropic hydrogel matrices,
generally by the preferential interaction of calcium ions with the G
moieties resulting in the formation of in homogeneous gel. The
characteristic properties of these hydrogels, such as mechanical
strength and porosity, are dependent upon the G: M ratios, type of
ionic cross linker (bio or poly-valent cations), concentration and
viscosity of the initial alginate solution. Calcium-cross linked
alginate gels show good mechanical properties even when prepare
from relatively low solution concentrations of the polymer,
0.5%w/v, and they can physically entrap a whole array of molecules,
and sustain their release. Alginates of a pharmaceutical grade and
which comply with all the quality requirements in the European and
US Pharmacopoeias can be obtained from several manufacturers.
Moreover, alginates were approved by the regulatory authorities
such as the Food and Drug Administration, for human use as wound
dressing material and as food additives [6].
Sodium alginate, the sodium salt of Alginic acid, is a natural
hydrophilic polysaccharide containing two types of monomers, b-Dmannuronic acid (M) and a-L-guluronic acid (G).The polymer forms
three-dimensional hydrogel matrices and the high G content alginate
forms a low viscosity, free-flowing liquid at concentrations suitable for
gel formation in the lachrymal fluid. Sodium Alginate was chosen as a
vehicle for ophthalmic formulations since it exhibits several favorable
biological properties such as biodegradability and non-toxicity. A
prolonged precorneal residence of formulations containing Alginic
acid was looked for, not only based on its ability to gel in the eye but
also because of its mucoadhesive properties[30].

Formulation approach for the drug with polymer

Table 3: Formulation approach
1.

Drug
Ofloxacin[21]

2.

Aceclofenac[22]

3.

Moxifloxacin[23]

4.

Leofloxacin[24]

5.
6.

Ketorolac
Tromomethamine[25]

Polymer
Polyacrylic Acid(Carbopol 940)With HPMC
(Methocel E5m0lv)
Carbopol940
With HPMC
PoloxomerF127,
PoloxomerF68,
Carbopol 934NF,
MC E461.
Carbopol 940,
HPMC.
Gelerite

System
PH Triggered In Situ Gelling System
PH Triggered In Situ Gelling
System
PH Triggered In Situ Gelling System

PH Triggered In Situ Gelling

System
Ion Activated In Situ Gelling System

33

Gambhire et al.
Int J Pharm Pharm Sci, Vol 5, Issue 2, 27-36
7.

Diclofenac[26]

8.

Fluconazole[27]

9.

Baicalin[28]

10.

Cartelol[29]

11.
12.
13.

Indomethacin[29]
Ofloxacin[29]
Ciprofloxacin[30]

Sodium Alginate,
HPMC,HPC,HEC,
Carbopol.
Chitosan(Deacetylated),
Poloxomer407.
Carbopol 974p(0.3%W/V)
HPMC E4M(0.6%W/V)
Alginic Acid,
HEC.
Alginate Gel.
Sodium Alginate.
Chitosan, Poloxamer.

PH Triggered In Situ Gelling System

Temperature Triggered In Situ Gelling System

PH Triggered In Situ Gelling System
Ion Activated In Situ Gelling System
Ion Activated In Situ Gelling System, Long Acting.
Ion Activated In Situ Gelling System,
Temperature Triggered In Situ Gelling System

PATENT AVAILABLE
Patent available on in situ ocular hydrogel:
Table 4: Patent available
S. No.
1.

Patent no.
US2011/0003816 A1

2.

US2011/0028477 A1

3.

US2011/0082221 A1

4.

US2010/0069482 A1

5.

US2010/0267664 A1

6.

US2010/0234336A1

7.

US2010/0216700A1

8.

US2008/0132444 A1

9.

US2006/0094643 A1

10.

US2005/0129771 A1

11.

US2004/0137069 A1

12.

US67030339
B2/2004

13.
14.

US2003/0077302
US6511660B1/2003

15.

US6583124B2/2003

16.

US5492937/1996

17.

US005371108A/1994

18.

US32969/1989

19.

US4738851/1988

Petent name
Ophthalmic composition
Halder et al.
Stable ophthalmic formulation
Aleo et al.
In situ gelling system as a sustained delivery for
front of eye. Haug et al.
Gel useful for delivery of ophthalmic drug.
Longo et al.
Ophthalmic composition containing,
polysaccharide-borate gelling system.
Asgharian et al.
Ophthalmic compositions
Xia et al.
Methods of treating ocular disorders. Li et al.
Ocular agent delivery system
Li et al.
Composition of hyaluronic acid and method of use
Svirkin et al.
Ophthalmic composition containing a
polysaccharide /borate gelling system
Asgharian et al.
Piperazine ophthalmic gel
Takruri et al.
reversible gelling system for ocular drug
delivery,
Xia et al.
Diclofenamide suspension gel,claus herz et al.
Ophthalmic drug delivery formulation and
method for preparing same
Lin et al.
Ophthalmic composition containing
galactomannarn polymers and borate.
Asgharian et al.
Gel forming liquid carrier composition
Bogentoft et al.
Dry eye treatment process and solution
Korb et al.
Injectable viscoelastic ophthalmic gel
Trager et al.
Controlled release ophthalmic gel formulation
Schoenwald et al.

Comment
Ophthalmic composition of beta blocker and polymeric
vehicle.
Stable formulation suitable for treatment of glaucoma and
ocular hypertension
Ophthalmic formulation used as vehicle for sustained
delivery using alginate and excipient.
Gel formulation containing a buffer and polymer for treating
the diseases of eye.
Composition useful as artificial tears and lubricant and also
useful for topical delivery in eye.
An aqueous ophthalmic composition containing carboxy
containing poly anionic polymer to maintain viscosity.
Treatment of ocular disorders using emulsions and molecular
dispersions in form of gel for hydrophobic drug.
Novel ocular drug delivery agent containing emulsion
emulsions and gel using hydrophobic agent.
Composition use for the treatment of dryness of eye.
Composition form the gel /partial gel upon instillation in to
eye.
Aq.gel for ophthalmic formulation as a vehicle for treatment
of myopia.
Ophthalmic aq.gel containing propylene oxide and ethylene
oxide and hpmc.
It is an ophthalmic gel for treating glaucoma.
Novel ophthalmic drug delivery formations containing
mixture of carbopol and pluronic.
This composition containing gelling amount of
galactomannarn polymers and borate.
A carrier composition is liquid at or below room temperature
form a high viscosity layer or gel at body temperature
Applying gel of oil and wax over the eye, then disperse in
aqueous phase.
For ophthalmic surgical and treatment procedure.
Controlled release gel contain sodium carboxy methyl
cellulose and colloidal magnesium aluminum silicate

EVALUATION OF OCULAR IN SITU HYDROGEL

1. Physical parameters:

The insitu gel formulations is evaluated for clarity, pH measurement,

gelling capacity, drug content, rheological study, invitro diffusion
study, isotonicity, in vivo ocular testing in rabbits and accelerated
stability studies. The pH of In-situ gel solution should be 7.4 for all
the formulations. The formulation should have an optimum viscosity
that will allow for easy instillation into the eye as a liquid (drops),
which would undergo a rapid soltogel transition (triggered by pH,
temperature or ion exchange).[43]

The In-situ gel solution is tested for clarity, pH, gelling capacity, and
drug content estimation[43].
2. Gelling capacity
The gelling capacity is determined by placing a drop of the
formulation in a vial containing 2.0 ml of freshly prepared simulated
tear fluid and visually observed. The time taken for its gelling is
noted.[43].
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Gambhire et al.
Int J Pharm Pharm Sci, Vol 5, Issue 2, 27-36
3. Rheological studies

6. Isotonicity evaluation

The viscosity measurements can be calculated using Brookfield

viscometer, Cone and Plate Viscometer. [43]

Isotonicity is important characteristic of the ophthalmic

preparations. Isotonicity should be maintained to prevent tissue
damage or irritation of eye. All ophthalmic preparations undergo
isotonicity testing, Formulations mixed with few drops of blood and
observed under microscope at 45X magnification and compared
with standard marketed ophthalmic formulation[43].

4. In vitro drug release studies

In vitro release study of Insitu gel solution is carried out by
using Franz diffusion cell. The formulation placed in donor
compartment and freshly prepared simulated tear fluid in
receptor compartment. Between donor and receptor
compartment dialysis membrane is placed (0.22m pore size).
The whole assembly is placed on the thermostatically controlled
magnetic stirrer. The temperature of the medium is maintained
at 37C 0.5C. 1ml of sample is withdrawn at predetermined
time interval of 1hr for 6 hrs and same volume of fresh medium
is replaced. The withdrawn samples are diluted in a volumetric
flask with respective solvent to specific volume and analyze by
UV spectrophotometer at respective nm using reagent blank. The
drug content is calculated using the equation generated from
standard calibration curve then the % cumulative drug release
(%CDR) is calculated. The data obtained is further subjected to
curve fitting for drug release data. [43].
5. Texture analysis
The consistency, firmness and cohesiveness of insitu gel are assessed
by using texture profile analyzer which mainly indicated gel strength
and easiness in administration in vivo. Higher values of adhesiveness
of gels are needed to maintain an intimate contact with mucus
Surface[43].

7. Ocular irritancy test

The Draize irritancy test is designed for the ocular irritation potential of
the ophthalmic product prior to marketing. According to the Draize test,
the amount of substance applied to the eye is normally 100l placed into
the lower cul de sac with observation of the various criteria made at a
designed required time interval of1hr, 24hrs, 48 hrs, 72hrs, and 1week
after administration. Three rabbits (male) weighing 1.5 to 2kg are used
for the study. The sterile formulation is instilled twice a day for a period
of 7 days, and a crossover study is carried out (a 3 day washing period
with saline was carried out before the crossover study). Rabbits are
observed periodically for redness, swelling, watering of the eye.[43].
8. Accelerated stability studies
Formulations are placed in ambient colour vials and sealed with
aluminium foil for a short term accelerated stability study at 402 C and
755% RH as per International Conference on Harmonization (ICH)
states Guidelines. Samples are analyzed every month for Clarity, pH,
gelling capacity, drug content, rheological evaluation, and in vitro
dissolution. The storage conditions and the lengths of studies chosen
should be sufficient to cover storage, shipment, and subsequent use. [43].

Table 5: Stability condition

General case Study
Long term*
Intermediate**
Accelerated

Storage condition
25C 2C/60% RH 5% RH or 30C 2C/65% RH 5% RH
30C 2C/65% RH 5% RH
40C 2C/75% RH 5% RH

Minimum time period covered by data at submission

12 months
6 months
6 months

*It is up to the applicant to decide whether long term stability studies are performed at 25 2C/60% RH 5% RH or 30C 2C/65% RH 5% RH.
**If 30C 2C/65% RH 5% RH is the long-term condition, there is no intermediate condition.
Drug substances intended for storage in a refrigerator Study:
Table 6: Stability condition for drug substance intended for storage in a refrigerator
Drug substances intended for storage in a
refrigerator Study
Long term
Accelerated

Storage condition

Minimum time period covered by data at

submission
12 months
6 months

5C 3C
25C 2C/60% RH 5% RH

It is considered unnecessary to continue to test a drug substance through 6 months when a significant change has occurred within the first 3
months.[44]
9. Sterility studies
The test for sterility is an important aspect for ophthalmic
preparations. The test for sterility is intended for detecting the
presence of viable forms of bacteria, fungi and yeast in or on sterilized
preparations is carried out according to pharmacopoeial method[43].
10. Sol-Gel transition temperature and gelling time
For in situ gel forming systems incorporating thermo reversible
polymers, the sol-gel transition
Temperature may be defined as that temperature at which the phase
transition of sol meniscus is first noted when kept in a sample tube at a
specific temperature and then heated at a specified rate. Gel formation
is indicated by a lack of movement of meniscus on tilting the tube[7].
CONCLUSION
Ophthalmic drug delivery system is burgeoning field in which most
of the researchers are taking challenges to combat various problems
related to this delivery. Steady advancement in the understanding of
principles and processes governing ocular drug absorption and
disposition and continuing technological advances have surely

brought some improvements in the efficacy of ophthalmic delivery

systems. The primary requirement of a successful controlled release
product focuses on increasing patient compliance which the insitu
gels offer. Exploitation of polymeric insitu gels for controlled release
of various drugs provides a number of advantages over conventional
Dosage forms. Sustained and prolonged release of the drug, good
stability and biocompatibility characteristics make the in situ gel
dosage forms very reliable. Use of biodegradable and water soluble
Polymers for the insitu gel formulations can make them more
acceptable and excellent drug delivery systems
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