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Introduction
The eye is a sensory organ that converts light to an
electric signal that is treated and interpreted by the
brain. Briefly, the eye ball is covered by three layers:
an outer fibrous protective layer (sclera and cornea), a
middle vascular layer(choroid),and an inner nervous
layer (retina). The cornea is a clear, transparent, thin
avascular tissue that is composed of five layers:
epithelium, bowmans‘s layer, stroma, Descemet‘s
membrane and endothelium. The stroma is the only
hydrophilic layer. The eye is generally divided into two
parts: the anterior and the posterior segments. The
anterior segment includes the cornea, sclera, ciliary
body, and the lens; these structures delimit a cavity: the
anterior chamber filled with the aqueous humor. The
posterior segment includes all the structures between Fig. 1: Anatomy of human eye
the lens and the optic nerve that delimit a cavity: the The eye possesses efficient protective mechanisms like
vitreous filled with an aqueous gel (the vitreous reflex blinking, lachrymation, and drainage, while lid
humor). closure protects the eye from external aggression.
Tears permanently wash the surface of the eye and
exert an anti-infectious activity through the lysozyme
* Corresponding Author: and immunoglobulins they contain. Finally, the
E-mail: vnus.jun25@gmail.com lachrymal fluid is drained down the nasolacrimal
pathways. All these protective mechanisms are
responsible for te rapis and extensive procorneal loss of
topically applied ophtalmic drugs 1-5.
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Ophthalmic Disorders Endophthalmitis
Eye Infections It is severe form of intraocular inflammation (purulent
Eyes can get infections from bacteria, fungi or viruses. uveitis) involving ocular cavities & inner coats of
Eye infections can occur in different parts of the eye eyeball. Causative organisms include Streptococci,
and can affect just one eye or both. Common eye E.coli, Pseudomonas, etc. Accordingly, the
infections are Conjunctivitis, Corneal ulcers & armamentarium of available antimicrobials used in the
Endophthalmitis. prevention and treatment of these infections includes
Conjunctivitis antivirals, antifungals, and antibacterials. Common
Conjunctivitis is swelling (inflammation) or infection topical antibacterials used in the treatment of ocular
of the membrane lining the eyelids (conjunctiva).It is infectious diseases include sulfonamides,
characterized by cellular infiltration and exudation. aminoglycosides, polymyxin-based combinations, and
Staphylococcus aureus is the most common cause of Fluoroquinolones.
bacterial conjunctivitis and blepharo-conjunctivitis. The fluoroquinolones represent an expanding class of
Many other organisms like Haemophilus influenza, broad-spectrum antibacterials which cover a host of
Streptococcus pneumoniae also cause conjunctivitis. Gram-negative and anaerobic species responsible for
Conjunctivitis can be classified as (1) Infective – ocular infections. These antibacterials have gained
Acute, Sub acute & Chronic (2) Allergic conjunctivitis. popularity in the ophthalmology field since they have
Corneal ulcers / Keratitis been shown to be equivalent to combination therapy in
Inflammation of cornea (Keratitis) is characterized by the treatment of many ocular infections.
corneal edema, cellular infiltration & ciliary Fluoroquinolones are also effective against a variety of
congestion. Being the most anterior part of eyeball, Gram-positive organisms, including Streptococcal and
cornea is exposed to atmosphere & hence prone to get Staphylococcal species; however, resistance is
infected easily.Bacterial corneal ulcers are the most emerging among some of these organisms. 6, 7, 8The
commonly caused by virulent organism. Common classification (Table 1.1) and mechanism of action of
bacteria associated with corneal ulceration are fluoroquinolones are given below.
Staphylococcus aureus, Pseudomonas pyocyanea,
E.coli, Proteus etc.
· Norfloxacin
3 RD
· Ciprofloxacin Having antipseudomonal activity against
GENERATION
· Levofloxacin gram negative bacilli.
· Ofloxacin
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Mechanism of action of Fluoroquinolones concentration of a drug at the active site for the
Fluoroquinolones act by inhibiting two enzymes appropriate duration. 14
involved in bacterial DNA synthesis, both of which are Ocular disposition and elimination of a therapeutic
DNA topoisomerases that human cells lack and that are agent is dependent upon its physicochemical properties
essential for bacterial DNA replication, thereby as well as the relevant ocular anatomy and physiology.
enabling these agents to be both specific and A successful design of a drug delivery system,
bactericidal. 10 therefore, requires an integrated knowledge of the drug
DNA topoisomerases are responsible for separating the molecule and the constraints offered by the ocular
strands of duplex bacterial DNA, inserting another route of administration. The various approaches that
strand of DNA through the break, and then resealing have been attempted to increase the bioavailability and
the originally separated strands. DNA gyrase the duration of the therapeutic action of ocular drugs
introduces negative superhelical twists in the bacterial can be divided into two categories. The first one is
DNA doublehelix ahead of the replication fork, thereby based on the use of sustained drug delivery systems,
catalyzing the separation of daughter chromosomes. which provide the controlled and continuous delivery
This activity is essential for initiation of DNA of ophthalmic drugs. The second involves maximizing
replication and allows for binding of initiation proteins. corneal drug absorption and minimizing precorneal
Topoisomerase IV is responsible for decatenation that drug loss. 15
is, removing the interlinking of daughter chromosomes Ideal ophthalmic drug delivery must be able to sustain
thereby allowing segregation into two daughter cells at the drug release and to remain in the vicinity of front of
the end of a round of replication. Fluoroquinolones the eye for prolong period of time. Consequently it is
interact with the enzyme-bound DNA complex (i.e., imperative to optimize ophthalmic drug delivery; one
DNA gyrase with bacterial DNA or topoisomerase IV of the ways to do so is by addition of polymers of
with bacterial DNA) to create conformational changes various grades, development of in situ gel or colloidal
that result in the inhibition of normal enzyme activity. suspension or using erodible or non erodible insert to
As a result, the new drug– enzyme–DNA complex prolong the precorneal drug retention. 16
blocks progression of the replication fork, thereby Routes of ocular drug delivery
inhibiting normal bacterial DNA synthesis and There are several possible routes of drug delivery into
ultimately resulting in rapid bacterial cell death. 11 the ocular tissues. (Figure 2) The selection of the route
Older fluoroquinolones exhibit a relatively consistent of administration depends primarily on the target
pattern with respect to specificity of enzyme inhibition tissue.
in different types of bacteria. The newer fourth
generation fluoroquinolones like moxifloxacin,
gatifloxacin have a dual-binding mechanism of action,
inhibiting both DNA gyrase and topoisomerase IV, in
Grampositive species. 12
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the mucous membrane that lines the ducts and the properties such as flexibility, structure,
lachrymal sac; only a small amount reaches the nasal biocompatibility, and hydrophilicity, three dimensional
passage. 22 matrices, hydrogels, are being extensively used as drug
Barriers for ocular delivery delivery carriers. 25
A. Drug loss from the ocular surface Advantages of polymeric drug delivery
After instillation, the flow of lacrimal fluid removes
Reduce toxic effects on the healthy tissue and reach
instilled compounds fromthe surface of the eye. Even
sites that are conventionally Inaccessible due to the
though the lacrimal turnover rate is only about 1 μl/min
presence of various barriers17 by targeted drug delivery.
the excess volume of the instilled fluid is flown to the
Increase the half-life of drugs, preventing their rapid
nasolacrimal duct rapidly in a couple of minutes.
degradation, and reduce the rate of elimination, thus
Another source of non-productive drug removal is its
maintaining drug concentration within a therapeutically
systemic absorption instead of ocular absorption.
effective window.
Systemic absorption may take place either directly
from the conjunctival sac via local blood capillaries or Reduce the amount of drug required to achieve
after the solution flow to the nasal cavity. therapeutic efficacy.
B. Lacrimal fluid-eye barriers Cut down the number of repeated invasive dosage
Corneal epithelium limits drug absorption from the required for certain conditions and thus helps to
lacrimal fluid into the eye. The corneal epithelial cells improve patient‘s compliance and offers better living.
form tight junctions that limit the paracellular drug A. In situ hydrogels
permeation. Therefore, lipophilic drugs have typically Hydrogels are polymeric networks that absorb large
at least an order of magnitude higher permeability in quantities of water while remaining insoluble in
the cornea than the hydrophilic drugs. In general, the aqueous solutions due to chemical or physical
conjunctiva is leakier epithelium than the cornea and crosslinking of individual polymer chains. They
its surface area is also nearly 20 times greater than that resemble natural living tissue more than any other class
of the cornea. of synthetic biomaterials due to their high water
C. Blood-ocular barriers content; furthermore, the high water content of the
The eye is protected from the xenobiotics in the blood materials contributes to their biocompatibility. 26
stream by blood-ocular barriers. These barriers have Hydrogels show minimal tendency to adsorb proteins
two parts: blood-aqueous barrier and blood-retina from body fluids because of their low interfacial
barrier. The anterior blood-eye barrier is composed of tension. Further, the ability of molecules of different
the endothelial cells in the uvea (The middle layer of sizes to diffuse into (drug loading) and out of (drug
the eye beneath the the sclera. It consists of the iris, release) hydrogels allows the possible use of dry or
ciliary body, and choroid). swollen polymeric networks as drug delivery systems
This barrier prevents the access of plasma albumin into for oral, nasal, buccal, rectal, vaginal, ocular and
the aqueous humor, and also limits the access of parenteral routes of administration. 27
hydrophilic drugs from plasma into the aqueous humor. These are polymers endowed with an ability to swell in
The posterior barrier between blood stream and eye is water or aqueous solvents and induce a liquid–gel
comprised of retinal pigment epithelium (RPE) and the transition.28
tight walls of retinal capillaries. Unlike retinal Currently; two groups of hydrogels are distinguished,
capillaries the vasculature of the choroid has extensive namely preformed and in situ forming gels. Preformed
blood flow and leaky walls. Drugs easily gain access to hydrogels can be defined as simple viscous solutions
the choroidal extravascular space, but thereafter which do not undergo any modifications after
distribution into the retina is limited by the RPE and administration. The use of preformed hydrogels still
retinal endothelia.17,23. has drawbacks that can limit their interest for
Polymeric drug delivery for ophthalmic ophthalmic drug delivery or as tear substitutes. They do
Hydrogels are one of the upcoming classes of polymer- not allow accurate and reproducible administration of
based controlled release drug delivery systems. 24 quantities of drugs and, after administration; they often
Polymeric drug delivery systems have been extensively produce blurred vision, crusting of eyelids, and
studied in order to solve the potential problems lachrymation.
associated with drugs or bioactive molecules including Thus in situ hydrogels can be instilled as eye drops and
toxicity, site dependence, low effectiveness, poor undergo an immediate gelation when in contact with
solubility, short half life, rapid degeneration and rapid the eye. In situ-forming hydrogels are liquid upon
clearance from the body. Considering various instillation and undergo phase transition in the ocular
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cul-de-sac to form viscoelastic gel and this provides a B. Smart hydrogels
response to environmental changes. Three methods ―Smart‖ hydrogels, or stimuli-sensitive hydrogels, are
have been employed to cause phase transition on the very different from inert hydrogels in that they can
surface: change in temperature, pH, and electrolyte ―sense‖ changes in environmental properties such as
composition. pH and temperature and respond by increasing or
Increase in solution viscosity by using polymers decreasing their degree of swelling. The volume-
improves retention of product on the corneal surface. changing behavior of ‗smart‘ hydrogels is particularly
More recently, the approach to improve precorneal useful in drug delivery applications as drug release can
retention is based on the use of mucoadhesive be triggered upon environmental changes.
polymers. The principle for use of bioadhesive vehicles These ―intelligent‖ or ―smart‖ polymers play important
relies on their ability to interact with the mucin-coating role in drug delivery since they may dictate not only
layer present at the eye surface. The polymers chosen where a drug is delivered, but also when and with
to prepare ophthalmic hydrogels should meet some which interval it is released. The stimuli that induce
specific rheological characteristics. It is generally well various responses of the hydrogel systems include
accepted that the instillation of a formulation should physical (temperature) or chemical (pH, ions) ones. 29
influence tear behavior as little as possible. Because In this, polymers may undergo phase transition in
tears gave a pseudoplastic behavior, pseudoplastic presence of various ions. Gellan gum commercially
vehicles would be more suitable as compare to available as Gelrite® is an anionic polysaccharide that
Newtonian formulations, which have a constant undergoes in situ gelling in the presence of mono- and
viscosity independent of the shear rate, whereas divalent cations, including Ca2+, Mg2+, K+ and Na+.
pseudoplastic solution exhibit decreased viscosity with Gelation of the low-methoxy pectins can be caused by
increasing shear rate, thereby offering lowered divalent cations, especially Ca2+. Mechanism and
viscosity during blinking and stability of the tear film examples of stimuli sensitive hydrogels are given in
during fixation. 29, 30 Table 1.3. 32, 33, 34
Drug release from hydrogels:
As discussed in the previous sections, hydrogels have a Table 1.3: Stimuli sensitivity of hydrogels
unique combination of characteristics that make them
useful in drug delivery applications. Due to their External
Mechanism Examples
hydrophilicity, hydrogels can imbibe large amounts of stimuli
water. Therefore, the molecule release mechanisms
from hydrogels are very different from hydrophobic Formulation is
polymers. Both simple and sophisticated models have liquid at
been previously developed to predict the release of an room temperature
active agent from a hydrogel device as a function of (20° – 25° C) which
time. These models are based on the rate limiting step undergoes gelation Poloxamer/Pluronics
for controlled release and are therefore categorized as with contact to Co-polymers of
diffusion, swelling & chemically controlled mechanism body fluids (35° –
polyethylene oxide
(Fig. 5). 37°C) PEO
Co-polymers of
Temperature
Temperature polypropylene oxide
increases the
PPO
degradation of
polymer chain Polyester
which leads to Xyloglucan
formation of Cellulose derivatives
hydrophobic
domains and
transition of an
aqueous liquid to
hydrogel network
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