Chapter - 1.

Introduction

In situ gel are the solution or suspension that undergo gelatin

after reducing the particular site due to contact with body fluid or
physicochemical change (i.e. PH, temperature, ionic, concentration, Uv
radiation, presence of specific molecules, or ions external, triggers etc.)
(Temperature & ionic condition (Ca2+) in tear fluid cause a transition
of aqueous solution of gellan into the gel state) In-situ forming gels
process the formulation is liquid when instilled into the eye which
undergoes gel formation rapidly in the cul-de-sac (a blind pouch or
cavity that is closed at one end) of the eye in response to environmental
changes in a particular physico-chemical parameter (such as pH,
temperature, or ion sensitivity) that regulate the drug's prolonged and
controlled release are among the factors that affect gel formation. Drug
content, clarity, pH, gelling ability, viscosity, in vitro drug release tests,
texture analysis, sterility testing, isotonicity evaluation, accelerated
studies, and irritancy test were all examined for these systems.
Incompatibilities between drugs and polymers were discovered using
FT-IR spectroscopy.[3] Numerous novel dosage forms have been
developed, including insitu gel, collagen shield, minidisc, ocular film,
ocusert, nanosuspension, nanoparticulate system, liposomes, noisome,
dendrimers, and ocular iontophoresis. Because of the limitations of the
ocular route, such as non-productive absorption, drainage, induced
lacrimation, tear turnover, and drug penetration to the cornea,
developing ophthalmic drug delivery systems has always been
difficult. The well-established route of administration for treating many
eye illnesses such dryness, conjunctivitis, keratitis, eye fever, etc. is
topical application of medications to the eye. Utilising polymers, which
play a crucial role in delivering drugs to the pre and intra ocular
tissues, new methods have been investigated for drug delivery to the
eye. [4] Through such tenacious efforts, the bioavailability of ocular
drugs has been increased, and their therapeutic effects have been
prolonged. Smart polymeric systems have shown to be effective ways
to distribute the medications. After administration, these polymers go
through a sol-gel transition. Prior to administration, they are in a
solution phase, but under physiological conditions, they gel. The
medications' corneal permeability and residence time in the cul-de-sac

1
can be increased to increase their ocular bioavailability. [5].
Temperature, pH, an electric field, a magnetic field, and light are just a
few of the physical and chemical factors that influence in situ gel
formation. The properties of the formulation alter in response to an
external stimulus (such as temperature and pH), which is how stimuli
responsive polymers crudely mimic biological systems. To create in
situ gels, both organic and synthetic polymers can be utilised. Thus, in
situ gels can be administered orally, topically, intraperitoneally,
rectally, vaginally, and via injection. [6, 7]. This paper provides a succinct
overview of in situ gels and several in situ gelling system techniques.
Additionally, various smart polymer types, how they form gels from
sol forms, and assessments of polymeric in situ gels
Anatomy and function of the eye
The outside layer of the eye is called the sclera, the middle layers
are the choroid layer, the ciliary body, and the iris, and the inner layer
is the retina, which is made up of nerve tissue. Apart from the cornea,
which is clear at the front and allows light to enter the eye, the sclera, a
thick fibrous coating, protects the white interior tissues of the eye.
Numerous blood vessels that changed at the front of the eye as the
pigmented iris, the coloured part of the eye (blue, green, brown, hazel,
or grey), are found in the choroid layer, which is located in the sclera
the front of the eye's clear, translucent bulging cornea, which transmits
images to the back of the nerve system. The mature cornea is a
vascular tissue with a radius of about 7-8mm that receives nutrients
and oxygen from blood vessels at the junction of the cornea and sclera
as well as from lachrymal fluid and aqueous humour. The five layers
that make up the cornea—the epithelium, the bowman's layer, the
stroma, the Descemet’s membrane, and the endothelium—are the
principal routes by which drugs permeate the eye. The corneal
epithelium is the primary barrier to drug absorption into the eye, in
contrast to many other epithelial tissues (such as the intestine, nasal,
bronchial, and tracheal), which are comparatively impervious. The
epithelium is squamous stratified, with a thickness of roughly 50-100
m and 5–6 layers of cells. The basal cells are tightly packed, creating a
barrier that is efficient against dust particles and the majority of
bacteria as well as for drug absorption. The primary route for drugs to

2
pass the corneal epithelium is through the transcellular or paracellular
pathway. While hydrophilic drugs prefer the paracellular pathway
(passive or altered diffusion through the intercellular spaces of the
cells), lipophilic drugs prefer the transcellular route.

Fig 01 Anatomy of the eye

Ocular absorption of drug

Topical injection of ophthalmic dose formulation drops into the lower
cul-de-sac is the typical technique of ocular medication delivery. Due
of the eye's fast outflow of eye drops
The precorneal area returns to maintain a resident volume of around 7 l
during blinking reflux. Drug passive transport across the cornea is
fueled by the drug concentration that is present in precorneal fluid.
However, for most lipophilic drugs, the stroma is the rate-limiting step,
whereas the epithelium is the predominant rate-limiting barrier for
hydrophilic drugs.The conjunctiva can withstand molecules up to
20,000 Da, while the cornea can withstand molecules up to 5,000 Da.
Drug loss through the conjunctiva is a significant route for drug
clearance as it is 2–30 times more permeable for pharmaceuticals than
the cornea. Precorneal tear film is a thin liquid layer that covers the
exposed area of the eye. Depending on the measurement technique, the
film thickness ranges from 3 to 10 mm, with a resident volume of
roughly 10 l. In healthy eyes, the tear fluid's osmolality is kept between
310 to 350 m Osm/kg by proteins and monovalent and divalent

3
inorganic ions such Na+, K+, Cl-, and HCO3-. The average pH of
healthy
Bicarbonate ions, proteins, and mucus all work as buffers to the tear’s
fluid [2]. Tears have a rheological behaviour that is non-Newtonian and
have a viscosity of roughly 3 m Pas. The tear film's average surface
tension value is around 44.

Fig 2: Absorption routes of a topically applied ophthalmic drug

Property
Fenoprofen is an anti-inflammatory analgesic used to treat mild to
moderate pain in addition to the signs and symptoms of rheumatoid
arthritis and osteoarthritis. An anti-inflammatory analgesic and
antipyretic highly bound to plasma proteins.

4
Chapter - 2. Drug
Profile

Nonsteroidal anti-inflammatory drug

Fenoprofen is a propionic acid derivative that has anti-
inflammatory, analgesic, and antipyretic properties. It has fewer side
effects than other non-selective NSAIDS, but its anti-inflammatory
properties are weaker. It is unsuitable for conditions where
inflammation is predominant, such as acute gout.
Fenoprofen is about as effective as naproxen, and flurbiprofen may be
slightly more effective. Both are associated with slightly more
gastrointestinal side effects than ibuprofen
Class of drug
Fenoprofen is in a class of medications called NSAIDs. It works by
stopping the body's production of a substance that causes pain, fever,
and inflammation
Drug Profile
Parameter Description
Drug name Fenoprofen
Brand Names Fenortho, Nalfon
Synonyms Fenoprofen Fénoprofène Fenoprofeno Fenoprofenum
Molecular weight Average: 242.2699
melting point 3.2.4
molecular formula C15H14O3
Chemical name 2 Methyl-2(3-phenoxyphenyl) Propanoic acid
Chemical
structure

BCS class class II

Half life plasma half-life is approximately 3 hours
Protein binding 99% to albumin

5
Dose 1-2 Drop (0.05 millilitre)

Chemistry: -
Fenoprofen is in the propionic acid nonsteroidal anti-inflammatory agent.
Fenoprofen is a viscous oil, with a boiling point between 168-171 o C The
solubility of the calcium salt is 8 mg/ml in methanol and 2.5 mg/ml in
water.

Advantages of ophthalmic in situ gels over conventional

dosage forms
1. Increased accurate dosing. To overcome the side effects of pulsed
dosing produced by conventional systems.
2. To provide sustained and controlled drug delivery.
3. To increase the ocular bioavailability of the drug by increasing the
corneal contact time. This can be achieved by effective adherence
to the corneal surface.
4. To provide targeting within the ocular globe to prevent the loss to
other ocular tissues.
5. To circumvent the protective barriers like drainage, lacrimation,
and conjunctival absorption.
6. To provide comfort, better compliance to the patient and to
improve the therapeutic performance of the drug.
7. To provide better housing of delivery system

These conventional eye drops have some following

disadvantages
1. Poor bioavailability, because of rapid precorneal elimination,
conjunctival absorption drainage by gravity and normal tear
turnover.
2. Frequent instillation of medication leads to poor patient
compliance.

6
3. Systemic absorptions of drug and additives through nasolacrimal
duct may result in undesirable effect.
4. Amount of drug delivered during application may vary. The drop
size of ocular medication is not uniform and dose delivered is
generally not correct [25,26,27]

Pharmacodynamics
Fenoprofen is a propionic acid derivative with analgesic, anti-
inflammatory and antipyretic properties. Fenoprofen inhibits
prostaglandin synthesis by decreasing the enzyme needed for
biosynthesis. In patients with rheumatoid arthritis, the anti-
inflammatory action of Fenoprofen has been evidenced by relief of
pain, increase in grip strength, and reductions in joint swelling,
duration of morning stiffness, and disease activity (as assessed by both
the investigator and the patient). In patients with osteoarthritis, the
anti-inflammatory and analgesic effects of Fenoprofen have been
demonstrated by reduction in tenderness as a response to pressure and
reductions in night pain, stiffness, swelling, and overall disease activity
(as assessed by both the patient and the investigator). These effects
have also been demonstrated by relief of pain with motion and at rest
and increased range of motion in involved joints. In patients with
rheumatoid arthritis and osteoarthritis, clinical studies have shown
fenoprofen to be comparable to 03
aspirin in controlling the aforementioned measures of disease activity,
but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus
occurred less frequently in patients treated with Fenoprofen than in
aspirin-treated patients. It is not known whether fenoprofen causes less
peptic ulceration than does aspirin. In patients with pain, the analgesic
action of fenoprofen has produced a reduction in pain intensity, an
increase in pain relief, improvement in total analgesia scores, and a
sustained analgesic effect.
Pharmacokinetics

7
 Fenoprofen completely absorbed after oral administration [17]
with peak plasma levels occurring at 1 hour Plasma concentration is
related to dosage in the range 15 to 150 mg and peak plasma
concentration is about 12μg/ml after a 100 mg dose and is usually
attained 1.5 to 3 hours after ingestion [18,19]. Fenoprofen is 99% bound to
human serum albumin [20,21]. F undergoes rapid oxidative metabolism
and is excreted primarily in the urine as both glucuronide and sulphate
conjugates and approx. 20% of drug eliminated unchanged [20,21]. There
are no known active metabolites in humans and there is no evidence of
dose dependent alterations of pharmacokinetics or of drug
accumulation in plasma after multiple dose administration. The
elimination half-life is about 3.5 hours during repeated doses [22].
Gastric emptying rate is found notably higher in fed state [23].
Fenoprofen gastrointestinal tolerance is considered better than other
NSAIDs i.e., indomethacin and aspirin, and comparable to naproxen
and ibuprofen. It has shown no problematic or irreversible hepatotoxic,
carcinogenic, or teratogenic effects. Hypertensive and renal effects are
probably similar to other NSAIDs.
Mechanism of action
Fenoprofen exact mode of action is unknown, but it is thought that
prostaglandin synthetase inhibition is involved. Fenoprofen has been
shown to inhibit prostaglandin synthetase isolated from bovine seminal
vesicles.
Absorption
Rapidly absorbed under fasting conditions, and peak plasma levels of
50 µg/mL are achieved within 2 hours after oral administration of 600
mg doses.
Metabolism
About 90% of a single oral dose is eliminated within 24 hours as
fenoprofen glucuronide and 4'- hydroxyfenoprofen glucuronide, the
major urinary metabolites of fenoprofen.

8
Toxicity
Symptoms of overdose appear within several hours and generally
involve the gastrointestinal and central nervous systems. They include
dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache,
ataxia, tinnitus, tremor, drowsiness, and confusion. Hyperpyrexia,
tachycardia, hypotension, and acute renal failure may occur rarely
following overdose. Respiratory depression and metabolic acidosis
have also been reported following overdose with certain NSAIDs.

9
Chapter - 3. Research
Methodology

Fusion method
Suitable when ointment base contains number of solid ingredients of
different melting point
Procedure: -
1. Ointment base are melted in decreasing order of their melting
point
2. Highest melting point should be melted first, low melting
point next.
3. This avoids over heating of substances of low melting point
4. Incorporate medicament slowly to the melted mass
5. Stir thoroughly until mass cools down and homogeneous
product is formed.
6. Liquid ingredients or aqueous substance should be heated to
the same temperature as the melted bases before addition.

Precautions: -
1. Stirring is done continuously- homogeneous mass
2. Vigorous stirring should be avoided to prevent entrapment of
air
3. Rapid cooling should be avoided to get a uniform product.
4. To remove the dust or foreign particles strain through muslin
cloth

Stability of ointments: -
1. The ointment should remain stable from the time of
preparation to the time when whole of it is consumed.

10
 2. On long storage the ointments lead to microbial growth
therefore a suitable preservative must be added to inhibit the
growth.
3. Ingredients like wool fat and its derivatives lead to
oxidation.so antioxidant may be added to protect the active
ingredients from oxidation.
4. Humectants such as glycerin, propylene glycol and sorbitol
may be added to prevent the loss of moisture from
preparation.
5. Ointment must be stored at an optimum temperature
otherwise separation of phase may take place.

Packaging of ointments: -
 Ointment jars
1. Made of colourless or coloured glass
2. Amber coloured for light sensitive preparation
3. With screw caps
4. With impermeable liners

 Collapsible tube
1. Made of tin or plastic
2. Supplied with the applicator

 Storage
1. Store in a well closed container and in cool place
2. Protect from high temperature direct sunlight
3. Prevent the loss of volatile constituents
4. High temperature softens or melt base
5. Separation of phases may take place
 Chemical Constituent
1. Fenoprofen (Drug)
2. HPMC-IP 0.25%W\V
3. Phenylmercuric nitrate -IP 0.002W\V

11
 (As Preservative)
4. Aqueous buffered vehicle Q.S

12
Chapter - 4. Research Envisaged and Plan of
work

AIM AND OBJECTIVES

AIM: Change the bioavailability of Fenoprofen and study about
Formulation Development & characterization of novel in
situ ocular gels
Objective: -
1. Preparation and evaluation of in situ gelling system of
Fenoprofen
2. Provides an increased ocular residence time resulting in
prolonged delivery of drug in ocular cavity
3. To improve ocular bioavailability of drug.
4. For better patient compliance
5. Improve ocular retention, viscosity, and gel strength of in situ
gel.

PLAN OF WORK
1. Procurement of drug
2. Formulation developments
A. Preformulation study
a. Different Scanning Calorimetry
b. Fourier transform infrared spectroscopy
B. Preparation of in situ gel
C. Optimization of in situ gel
D. Evaluation of the formulation
a. Determination of visual appearance, clarity, pH, and Drug Content
b. In vitro gelation studies
c. Rheological studies
d. In vitro drug release study
e. antimicrobial efficacy Studies
f. Ocular irritation studies
g. Sterility testing

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 h. Stability studies

 Literature survey
(Research and review articles, Books, websites)
Chapter - 5
Conclusion

 CONCLUSION:
Development of ophthalmic drug delivery system has proved to be
beneficial as compared to the conventional drug delivery. Likewise, it
is also challenging enough to establish successful ophthalmic drug
delivery systems. However, the persistent attempts towards
advancement in the understanding of principles and processes
governing ocular drug absorption and disposition have led to the
improvements in the efficacy of ophthalmic delivery systems. One
such novel approach is development of in-situ ocular gels. Sustained
and prolonged release of the drug, good stability and biocompatibility
characteristics make the in-situ gel dosage forms very reliable. The
evaluation of in-situ gels can be carried out based on the parameters
like gelling capacity, rheological studies, in-vitro drug release studies,
drug-polymer interaction study, thermal analysis, antibacterial activity,
and ocular irritancy test. Use of biodegradable and water-soluble
polymers for the insitu gel formulations can make them more
acceptable and excellent drug delivery systems. Insitu activated gel‐
forming systems seemed to be favoured as they can be administered in
drop form and produce appreciably less inconvenience with vision.
Moreover, they provide better sustained release properties than drops.

14
This type of dosage forms is used now a day in combat glaucoma, dry
eye syndrome, Sjogren’s syndrome, ARMD, trachoma etc.

15
References

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