This presentation concisely describes the ophthalmic drug delivery system.

1. Ophthalmic drug deliveryOphthalmic drug delivery
systemsystem
Compiled by:
Priyanka D. Dabir
Assistant Professor
Department of Pharmaceutics
Gokhale Education Society’s
Sir Dr. M.S. Gosavi College Of Pharmaceutical
Education & Research, Nashik-422005
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2. ContentsContents
 Introduction
 Anatomy & physiology of eye
 Physiology of vision
 Ophthalmic drug delivery system & dosage forms
Optimum characters of ophthalmic drug delivery system
Target sites in ocular drug delivery
Routes of ophthalmic drug delivery
Constraints to ocular drug delivery
Barriers to ocular drug delivery
Mechanisms of ocular drug absorption
Fate of formulation administered through eye
Ophthalmic dosage forms
 Approaches for bioavailability enhancement
 Formulation consideration in ophthalmics
 References
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3. IntroductionIntroduction
 Ophthalmic preparations are sterile dosage forms, essentially free
from foreign particles, suitably compounded and packed for
instillation into the eye. Ophthalmic preparation can be in the
form of aqueous or oily solution, suspension, ointment, gel, and
certain solid dosage form.
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4. Anatomy and physiology of human eyeAnatomy and physiology of human eye
 Owing to its design, human eye represents a gateway to the process
called vision. The human eye is comprised of layers and internal
structures, each of which performs distinct functions. The human eye is
composed of two segments:
 The anterior segment consists of: Aqueous humour, Pupil, Iris, Ciliary
muscle.
 The posterior segment consists of: Sclera, Conjunctiva, Cornea, Lens,
Vitreous humour, Retina, Choroid layer, Optic nerves.
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5. Physiology of visionPhysiology of vision
The physiological activities involved in the normal functioning of the eyes
are:
 Maintenance of clear ocular media,
 Maintenance of normal intraocular pressure,
 The image forming mechanism,
 Physiology of binocular vision,
 Physiology of pupil, and
 Physiology of ocular motility.
 Physiology of vision,
Physiology of vision is a complex phenomenon which is still poorly
understood.
The main mechanisms involved in physiology of vision are:
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6. 6
Ophthalmic drug delivery system & dosage forms
Liquid Semisolid Solid
Eye Drops
•Solutions
•Suspensions
Ointments
Aqueous gels
Inserts
Minitablets
 Injections
 Irrigating
solutions
Optimum characters of ophthalmic drug delivery system:
Prolong contact time with corneal tissue.
Simplicity of instillation for the patient.
Non irritative and comfortable form.
Appropriate rheological properties and concentrations of the viscous system.
Not require dosing above 1-2 times a day.

7. Target sites in ocular drug delivery
 In eye drug is administered at various site such as corneal, conjunctival and scleral
for better achievement of bioavailability and required effects related with the
therapy.
7
Sr.
no.
Target Site Salient Features
1 Cornea  Bowman’s capsule is lipophilic, allows diffusion of small
lipophilic molecules. Stroma is hydrophilic, allows diffusion
of hydrophilic and larger molecules.
2 Conjunctiva  Main barrier for drug absorption, allows absorption of
hydrophilic and large molecules. Absorption of peptides is
less due to enzymatic degradation.
3 Sclera  Some drugs (β-blockers) diffuse readily. Trans-scleral
iontophoresis is used for intra-vitreal administration.
4 Aqueous
humor
 Drugs absorbed through cornea discharge through
aqueous humor into systemic routes.
5 Vitreous
humor
 Drug absorbed through sclera and conjunctiva discharge
through vitreous humor into systemic routes.

8. Routes of ophthalmic drug delivery
8
Route Dosage Forms Advantages Disadvantages
Topical Solutions,
Suspensions,
Ointments,
Gels etc.
Ease of
administration
Poor bioavailability, suitable
only for anterior segment,
blurring vision.
Sub
conjunctival
Injectables Delivery of large
molecular size
drugs, sustained
release of drug
Patient non-compliance,
suitable for only water
soluble drugs.
Retrobulbar Injectables
(used for
anesthetization)
- Perforation of globe, patient
non- compliance.
Peribulbular Injectables
(used for
anesthetization)
Avoidance of
perforation of globe
Non-compliance in
pediatrics patients and
patient with mental
disorders.
Intraviteral Injectables Sustained delivery
of drug to posterior
segment of the eye
Patient non-compliance.

9. Constraints to Ocular drug deliveryConstraints to Ocular drug delivery
 Drainage from the precorneal area -reduces the ocular contact time and
bioavailability
 Systemically absorption of drug- inhibits the local corneal action
 High tear turnover rate(16 % per minute) - remove drug solution from
the conjunctival cul-de-sac
 Corneal membrane barrier - does not allow drugs to cross easily,
 Prolonging Ocular residence of drug will help in increasing bioavailability
 Barriers for ocular delivery
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Conjunctiva Cornea Sclera
Surface Area (cm2
) 17.65 ± 2.12 1.04 ± 0.12 16 – 17
Thickness (mm) - 0.57 0.4-0.5
Structural Composition • Mucus
membrane
• Epithelium
• Vasculature
5 Layers:
•Epithelium
•Bowman’s membrane
•Stomata
•Descemet’s membrane
•Endothelium
• Collagen fibers
• Water
• Proteoglycans
• Monopolysaccharides
• Elastic fibers
• Fibroblast

10. Barriers to ocular drug delivery
1. Drug loss from the ocular surface
After instillation, the flow of lacrimal fluid removes instilled compounds from the
surface of the eye. Even though the lacrimal turnover rate is only about 1 μl/min
the excess volume of the instilled fluid is flown to the nasolacrimal duct rapidly in
a couple of minutes.
2. Lacrimal fluid-eye barriers
Corneal epithelium limits drug absorption from the lacrimal fluid into the eye.
The corneal epithelial cells form tight junctions that limit the paracellular drug
permeation. Therefore, lipophilic drugs have typically at least an order of
magnitude higher permeability in the cornea than the hydrophilic drugs. In
general, the conjunctiva is leakier epithelium than the cornea and its surface
area is also nearly 20 times greater than that of the cornea.
3. Blood-ocular barriers
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
humour, and also limits the access of hydrophilic drugs from plasma into the
aqueous humour. The posterior barrier between blood stream and eye is
comprised of retinal pigment epithelium (RPE) and the tight walls of retinal
capillaries.
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11.  Losses of administered amount due to
 Rapid clearance by lachrymation and tear turnover.
 Non- productive absorption through conjunctiva.
 Drainage through nasolacrimal drainage.
 Nasolacrimal Drainage System:
 The nasolacrimal drainage system consists of three parts:
 Secretory system: The secretory system consists of basic secretors that
are stimulated by blinking and temperature change due to tear evaporation
and reflex secretors that have an efferent parasympathetic nerve supply
and secreted in response to physical or emotional stimulation.
 Distributive system: The distributive system consists of the eyelids and the
tear meniscus around the lid edges of the open eye, which spread tears
over the ocular surface by blinking, thus preventing dry areas from
developing.
 Excretory system: The excretory part of the nasolacrimal drainage system
consists of the lacrimal puncta, the superior, inferior and common
canaliculi; the lacrimal sac; and the nasolacrimal duct.
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12. 12
Nasolacrimal Drainage System

13.  Topical delivery into the cul-de-sac is, by far,
the most common route of ocular drug delivery.
Adsorption from this site may be corneal or
noncorneal.
 Corneal Permeation:
Corneal absorption represents the major
mechanism of absorption for most therapeutic
entities. Topical absorption of these agents,
then, is considered to be rate limited by the
cornea. The anatomical structures of the cornea
exert unique differential solubility requirements
for drug candidates.
 Non-corneal Permeation:
The noncorneal route of absorption involves
penetration across the sclera and conjunctiva
into the intraocular tissues. This mechanism of
absorption is usually non-productive, as drug
penetrating the surface of the eye beyond the
corneal-scleral limbus is taken up by the local
capillary beds and removed to the general
circulation.
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Mechanisms of ocular drug absorptionMechanisms of ocular drug absorption

14. Fate of formulation administered through eyeFate of formulation administered through eye
 The general process of absorption into the eye from the precorneal area (dose site)
following topical ocular administration is quite complex.
 The classical sequence of events involves drug instillation, dilution in tear fluid,
diffusion through mucin layer, corneal penetration (epithelium, stroma,
endothelium), and transfer from cornea to aqueous humour. Following absorption,
drug distributes to the site of action e.g., iris-ciliary body.
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15. Ophthalmic dosage formsOphthalmic dosage forms
 Ophthalmic preparations are sterile products essentially free from foreign
particles, suitably compounded and packaged for instillation in to the eye.
The following dosage forms have been developed to ophthalmic drugs.
 These can be classified on the basis of their physical forms as follows:
1. Liquids: Solutions, suspensions
2. Solids: Ocular inserts, contact lenses
3. Semi-solids: Ointments, Gels
 Eye tissues can be accessed directly with relative ease using topical eye
drops. However, the loading and ocular absorption of drugs are limited
using traditional solution and suspension formulations, particularly for
compounds with low aqueous solubility. For such compounds, delivery to
the posterior ocular tissues, including the retina and choroid, can be
particularly problematic. The need for formulations that increase the
topical ocular absorption of poorly soluble compounds remains largely
unmet which leads to the development of various newer approaches for
ophthalmic drug delivery.
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16. Viscosity enhancers:
 Viscosity-increasing polymers are
usually added to ophthalmic drug
solutions on the premise that an
increased vehicle viscosity should
correspond to a slower elimination from
the preocular area, which lead to
improved precorneal residence time
and hence a greater transcorneal
penetration of the drug into the anterior
chamber.
 The polymers used include polyvinyl
alcohol (PVA), polyvinylpyrrolidone
(PVP), methylcellulose, hydroxyethyl
cellulose, hydroxypropyl
methylcellulose (HPMC), and
hydroxypropyl cellulose.
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Approaches for the enhancement of ocular bioavailabilityApproaches for the enhancement of ocular bioavailability

17. Penetration enhancers
 The transport characteristics across the cornea can be maximized by increasing
the permeability of the corneal epithelial membrane.
 So, one of the approaches used to improve ophthalmic drug bioavailability lies
in increasing transiently the permeability characteristics of the cornea with
appropriate substances known as penetration enhancers or absorption
promoters.
 It has disadvantages like ocular irritation and toxicity. The transport process
from the cornea to the receptor site is a rate-limiting step, and permeation
enhancers increase corneal uptake by modifying the integrity of the corneal
epithelium.
 Eg. Cetyl pyridinium chloride, benzalkonium chloride, Parabens,Tween 20,
saponins.
 Classified as:
1. Calcium chelators
2. Surfactants
3. Bile acid and salts
4. Preservative
5. Glycoside
6. Fatty acids
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18. Eye ointments
 The medicinal agent is added to the
base either as a solution or as a
finely micronized powder.
 Upon instillation in the eye,
ointments break up into small
droplets and remain as a depot of
drug in the cul-de-sac for extended
periods.
 Ointments are therefore useful in
improving drug bioavailability and
in sustaining drug release.
 Although safe and well-tolerated by
the eye, ointments suffer with
relatively poor patient compliance
due to blurring of vision and
occasional irritation.
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19. Gel
 It has advantage like reduced systemic
exposure. Despite the extremely high
viscosity, gel achieves only a limited
improvement in bioavailability, and the
dosing frequency can be decreased to once a
day at most.
 The high viscosity, however, results in
blurred vision and matted eyelids, which
substantially reduce patient acceptability.
 The aqueous gel typically utilizes such
polymers as PVA, polyacrylamide,
poloxamer, HPMC, carbomer, poly methyl
vinyl ether maleic anhydride, and hydroxy
propyl ethyl cellulose.
 The release of a drug from these systems
occurs via the transport of the solvent into
the polymer matrix, leading to its swelling.
The final step involves the diffusion of the
solute through the swollen polymer, leading
to erosion/dissolution.
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20. Liposomes
 Liposomes are the microscopic vesicles
composed of one or more concentric lipid
bilayers, separated by water or aqueous
buffer compartments.
 Liposomes possess the ability to have an
intimate contact with the corneal and
conjunctival surfaces, which increases
the probability of ocular drug absorption.
 This ability is especially d It provides the
sustained release and sitespecific
delivery. Liposomes are difficult to
manufacture in sterile preparation.
 It has limitation like low drug load and
inadequate aqueous stability & is
undesirable for drugs that are poorly
absorbed, the drugs with low partition
coefficient.
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21. Niosomes
 Niosomes are bilayered
structural vesicles made up of
nonionic surfactant which are
capable of encapsulating both
lipophilic and hydrophilic
compounds.
 Niosomes reduce the systemic
drainage and improve the
residence time, which leads to
increase ocular bioavailability.
 They are nonbiodegradable and
nonbiocompatible in nature.
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22. Nanoparticles/nanospheres
 These are polymeric colloidal particles,
ranging from 10 nm to 1 mm, in which
the drug is dissolved, entrapped,
encapsulated, or adsorbed.
 Encapsulation of the drug leads to
stabilization of the drug. They
represent promising drug carriers for
ophthalmic application.
 They are further classified into
nanospheres (small capsules with a
central cavity surrounded by a
polymeric membrane) or nanocapsules
(solid matricial spheres).
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23. Microemulsion
 Microemulsion is stable
dispersions of water and oil,
facilitated by a combination of
surfactant and co-surfactant in
a manner to reduce interfacial
tension.
 Microemulsion improves the
ocular bioavailability of the
drug and reduces frequency of
the administration.
 These systems are usually
characterized by higher
thermodynamic stability, small
droplet size (~100 nm), and
clear appearance.
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24. In situ-forming gel
 The droppable gels are liquid upon instillation, and they undergo a phase transition
in the ocular cul-de-sac to form a viscoelastic gel, and this provides a response to
environmental changes.
 It improves the patient acceptance. It prolongs the residence time and improves
the ocular bioavailability of the drug.
 Parameters that can change and trigger the phase transition of droppable gels
include pH, temperature, and ionic strength.
 Examples of potential ophthalmic droppable gels reported in the literature include
gelling triggered by a change in pH - CAP latex cross linked polyacrylic acid and
derivatives such as carbomers and polycarbophil, gelling triggered by temperature
change - poloxamers methyl cellulose and Smart Hydrogel™, gelling triggered by
ionic strength change – Gelrite and alginate.
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25. Ocular inserts
 The ocular inserts overcome this disadvantage by providing with more controlled,
sustained, and continuous drug delivery by maintaining an effective drug
concentration in the target tissues and yet minimizing the number of applications.
 It reduces systemic adsorption of the drug. It causes accurate dosing of the drug.
 It has disadvantages like patient incompliance, difficulty with self-insertion, foreign
body sensation, and inadvertent loss from the eye.
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26. Implants
 The goal of the intraocular implant design is to provide prolonged activity with
controlled drug release from the polymeric implant material.
 Intraocular administration of the implants always requires minor surgery. In
general, they are placed intravitreally, at the pars plana of the eye (posterior to the
lens and anterior to the retina).
 Although this is an invasive technique, the implants have the benefit of:
(1) by-passing the blood-ocular barriers to deliver constant therapeutic levels of
drug directly to the site of action,
(2) avoidance of the side effects associated with frequent systemic and intravitreal
injections, and
(3) smaller quantity of drug needed during the treatment.
 The ocular implants are classified as non biodegradable and biodegradable devices.
Non biodegradable implants can provide more accurate control of drug release and
longer release periods than the biodegradable polymers do, but the non
biodegradable systems require surgical implant removal with the associated risks.
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27. Iontophoresis
 Ocular iontophoresis has gained significant interest recently due to its noninvasive
nature of delivery to both anterior and posterior segment.
 Iontophoresis is a non invasive method of transferring ionized drugs through
membranes with low electrical current.
 The drugs are moved across the membranes by two mechanisms: migration and
electro-osmosis. Ocular iontophoresis is classified into transcorneal, corneoscleral,
or trans-scleral iontophoresis.
 It has ability of modulate dosage (less risk of toxicity), a broad applicability to
deliver a broad range of drugs or genes to treat several ophthalmic diseases in the
posterior segment of the eye, and good acceptance by patients. It may combined
with other drug delivery systems.
 It has disadvantage like no sustained half-life, requires repeated administrations,
side effects include mild pain in some cases, but no risk of infections or ulcerations,
risk of low patient compliance because the frequent administrations that may be
needed.
 OcuPhor™ system has been designed with an applicator, dispersive electrode, and a
dose controller for transscleral iontophoresis (DDT). This device releases the active
drug into retina-choroid as well.
 A similar device has been designed called Visulex™ to allow selective transport of
ionized molecules through sclera.
 Examples of antibiotics successfully employed are gentamicin, tobramycin, and
ciprofloxacin, but not vancomycin because of its high molecular weight.
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28. 28

29.  Approaches for the enhancement of ocular bioavailability are:
 Based on the use of the drug delivery system, which provide the controlled and continuous delivery
of ophthalmic drugs.
 Based on maximizing corneal drug absorption and minimizing precorneal drug loss
 These are summarized as:
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Approach Advantages Limitations
Penetration
Enhancers
Ease of formulation due to compatibility
with wide range of excipients.
Accumulation in cornea affecting clear vision.
Alteration of permeability of blood vessels in
the uveal tract.
Irritation of eye and nasal mucosa.
Suspension Retention in lower cul-de-sac for
prolonged period.
Non-uniformity of dosing.
Formation of non-dispersible cake.
Polymorphic changes of drug.
Ointments Retention in lower cul-de-sac for
prolonged period.
Slower diffusion of drug.
Blurred vision.
Non esthetic.
Gels Retention in lower cul-de-sac for
prolonged period.
Slower diffusion of drug.
Difficulty in administration.
Blurred vision.
Mucoadhesive
dosage forms
Retention in lower cul-de-sac for
prolonged period.
Poor compliance.
Blurred vision.
Liposomes Biodegradable.
Non toxic.
Available in more than one dosage forms.
Limited stability.
Limited drug loading capacity.
Expensive.

30. Approach Advantages Limitations
Niosomes Non-toxic.
Available in more than one dosage forms.
Limited stability.
Limited drug loading capacity.
Expensive.
Micro and
Nanoparticles
Enhance bioavailability.
Available in more than one dosage forms.
Retention in lower cul-de-sac for prolonged
period.
Suitability for only small dose drugs.
Difficulty in formulation.
Expensive.
Micro emulsion Enhanced patient compliance.
Best for drugs with slow dissolution.
Good stability.
Rapid precorneal elimination.
Ocular inserts Controlled rate of release.
Prolonged delivery.
Irritation.
Need of skilled personnel for administration.
Abrasion of cornea.
Expensive.
Contact lenses Correction of vision.
Sustained delivery of drugs.
Low precision of dosing.
Expensive.
Iontophoresis Fast delivery.
Painless and safe drug delivery system.
Delivery at the desired ocular tissue.
Increased ocular retention time.
Difficulty of insertion.
Patient non-compliance.
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31. Formulation consideration in ophthalmicsFormulation consideration in ophthalmics
 Sterility
 Preservatives
 Clarity
 Stability
 pH adjustment and buffers
 Tonicity
 Viscosity modifiers
 Additives
Stabilizers
Surfactant
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32. Sterility
 Probably the most important property of ophthalmic
formulations is that they must be sterile.
 The USP XXII-NF XVII (2003) lists five methods of
achieving sterility:
1. Steam sterilization at 121°C.
2. Dry-heat sterilization.
3. Gas sterilization using ethylene oxide (due to
environmental concerns the use of ethylene oxide is
being phased out wherever possible).
4. Sterilization using ionizing radiation e.g. radioisotope
decay (gamma radiation) and electron beam radiation.
5. Sterilization by filtration.
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33. Preservatives
The selection of a preservative for ophthalmic solutions is not an easy task, with
very few candidates to choose from:
The following criteria are important for selection of preservative:
 Board spectrum of activity against both Gram-positive and Gram-negative
organisms and fungi.
 The agent should rapidly kill virulent organisms.
 Satisfactory chemical and physical stability over a wide range of pH and
temperature.
 Compatibility with formulation components and container materials.
 Nontoxic and non irritating during use.
33
Sr. no. Preservatives Conc. range
1 Quaternary ammonium compounds 0.004-0.02
0.01 most common
2 Organic mercurials 0.001-0.01
3 Parahydroxy benzoates 0.1 maximum
4 Chlorobutanol 0.5

34.  Clarity
 The official definition of ophthalmic solutions requires that they be free of
particulate matter.
 Solution clarity is usually achieved by filtration, either with a clarifying filter or as
part of a sterile filtration procedure.
 The degree of clarity of the finished product can be monitored by means of
various instruments capable of detecting any light scattering or blockage
resulting from the presence of particulate matter.
34
Sr.
no.
Particle size (µm) Proposed limit (Particles per ml)
1 ≥10 ≤50
2 ≥25 ≤5
3 >50 None allowed

35. Stability
 The stability of the active ingredient in an ophthalmic
solution depends upon the chemical nature of the active
ingredient, pH manufacturing procedure, type of additives,
and type of container.
 The maintenance of a pH that is consistent with acceptable
stability is often in conflict with a pH that would provide
optimum corneal penetration of the drug in question and
optimum patient acceptance of the product.
35

36. pH adjustment and buffers
 The adjustment of ophthalmic solution pH by the
appropriate choice of a buffer is one of the most important
formulation considerations.
 Buffers may be used in an ophthalmic solution for one or
more of the following reasons; to maintain the physiologic
pH of the tears upon administration of formulation in order
to minimize tearing and patient discomfort, to optimize the
therapeutic activity of the active ingredient by altering
corneal penetration through changes in the degree of
ionization; and to optimize product stability.
 The tear fluid pH is reported to be vary between 6.9 and
7.5.
36

37. Tonicity
 The hypertonic solution placed in the eye tends to draw
solvent (water) from its surroundings in order to dilute the
instilled solution.
 In this case, water flows from the aqueous layer through
the cornea to the eye surface.
 Conversely, a hypotonic solution could result in the
passage of water from the site of application through the
eye tissues.
 In this case, the epithelial permeability is increased;
allowing water to flow into the cornea, the corneal tissues
swells, and drug concentration on the ocular surface is
temporarily increased.
37

38. Viscosity modifiers
 The viscosity of ophthalmic solutions is often increased in
order to prolong the corneal contact time, decrease the
drainage rate, and increase the bioavailability of the active
ingredient.
 The polymers used to increase viscosity may also lower the
frictional resistance between the cornea and the eyelid
which occurs with each blink, thereby exerting a lubricating
effect that may be of benefit for some patients.
38

39. Additives
• Stabilizers
• The use of stabilizers is permitted in ophthalmic solutions when
necessary. Epinephrine hydrochloride undergoes oxidative degradation
and an antioxidant such as sodium bisulphate or metabisulfite is
commonly added up to a 0.3% concentration. Epinephrine borate
stabilization requires special consideration, and mixtures of ascorbic
acid and acetyl-cysteine or sodium bisulphite and 8-hydroxyquinoline
have been used for this purpose.
• Surfactant
• The addition of surfactants to ophthalmic solutions is permitted, even
though their use is greatly restricted. The toxicity of surfactants is on
the order:
Anionic > cationic > non-ionic
Non-Ionics are used in low concentration to increase the dispersion
of suspended drugs, such as steroids, and thereby improve solution
clarity. The ability of these compounds to bind and thereby
inactivate certain preservatives coupled with their irrational
potentials, limits their use to low concentrations.
39

40. ReferencesReferences
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 Khurana, A.K. Comprehensive Ophthalmology. 4th
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Sci Drug Res. 2009; 1(1): 1-5.
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Published by Controller of Publications. Delhi Vol. II. 1996; 736.
 Guyton, A.C.; Hall, T.E. Textbook of Medical Physiology. 11th
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 Nirmal, H. B.; Bakliwal, S. R.; Pawar, S. P. In Situ Gel : New Trends in Controlled and
Sustained Drug Delivery System.Int.J. PharmTech Res. 2010, 2 (2), 1398-1408.
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