ocular drug delivery

ocular drug delivery system

1. Masters of pharmacy, Pharmaceutical technology (Pharmaceutics)
Subject- Advances in drug delivery (MPT-103T)
Lesion no- 4, Ocular drug delivery systems By- Drx JAYESH M RAJPUT
Points: -
1) Ocular drug delivery system.
Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases. Eye is the most
easily accessible site for topical administration of a medication. Ideal ophthalmic drug delivery must be able to
sustain the drug release and to remain in the vicinity of front of the eye for prolong period of time. Due to
accessibility of the eye surface, topical administration of ophthalmic medications is the most common method for
treating conditions affecting the exterior eye surface. The unique anatomy and physiology of the eye renders it
difficult to achieve an effective drug concentration at the target site. So, efficient delivery of a drug through the
protective ocular barriers with minimization of its systemic side effects remains a major challenge. Ocular
delivery systems, such as a ointment, suspensions, micro-and nanocarriers and liposomes, have been
investigated during the past two decades focusing two main strategies: -
To increase the corneal permeability and
To prolong the contact time on the ocular surface
 They are specialized dosage form designed to be instilled onto the external surface of the eye (topical),
administered inside (intraocular) or adjacent (periocular) to the eye or used in conjunction with an
ophthalmic device
 The novel approach of drug delivery system in which drug can instilled on the cul-de-sac cavity of eye is
known as ocular drug delivery system
 Cul-de-sac cavity is the space between eye lids and eye balls
 The most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments
 But these preparations when instilled into the eye are rapidly drained away from the ocular cavity due to
tear flow and lacrimal nasal drainage
 Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases
 Eye is the most easily accessible site for topical administration of a medication
 Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain in the vicinity of
front of the eye for prolong period of time
 The newest dosage forms for ophthalmic drug delivery are gels, gel-forming solutions, ocular inserts,
intravitreal injections and implants.
Difference between ophthalmic and ocular drug delivery system
Sr.no Ophthalmic DDS Ocular DDS
1 Conventional system Novel system
2 Old concept New concept
3 Addition of preservatives Do not add preservatives

2. 4 High dosing frequency Low dosing frequency
5 Minimum release rate of drug Maximum release rate of drug
6 Limited flexibility Extreme flexibility
7 Minimum absorption rate Maximum absorption rate
8 Minimum bioavailability Maximum bioavailability

Major classes of drugs used are
 Miotics- e.g. Pilocarpine HCL
 Mydriatics- e.g. Atropine
 Cycloplegics- e.g. Atropine
 Anti-inflammatory- e.g. Corticosteroids
 Anti-infective (antibiotics, antiviral and antibacterial)
 Anti-glaucoma drugs- e.g. Pilocarpine HCL
 Surgical adjuncts- e.g. Irrigating solutions
 Diagnostic drugs-e.g. Sodium fluorescin
 Anesthetics- e.g. Tetracaine
Composition of eye
 Water- 98%
 Solid-1.8%
 Organic elements
Protein-0.67%
Sugar-0.65%
NaCL-0.66%
 Other mineral element- sodium, potassium and ammonia- 0.79%
 Artificial tear- the solution intended to rewet hard lenses in situ are referred has rewetting solutions or
artificial tear.
Lacrimal nasal drainage

3. Anatomy of the human eye

Mechanism of ocular drug absorption
Topically applied drug can be absorbed from, two routes: -
 Corneal absorption
 The outermost layer, the epithelium is the rate-limiting barrier
 Transcellular transport is the major mechanism of ocular absorption for lipophilic drugs
 Small ionic and hydrophilic molecules appear to gain access to the anterior chamber through paracellular
pathway.
 Non-corneal absorption
 It involves penetration across the sclera and conjunctiva into the intraocular tissues
 This mechanism of absorption is usually non-productive, as drug penetrating is taken up by the local capillary
beds and removed to the general circulation
 Significant for drug molecules with poor corneal permeability
2) Barriers of drug permeation
 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 1µl/min the
excess volume of the instilled fluid is flown to the nasolacrimal duct rapidly in a couple of minutes
 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 atleast 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.
 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 plasma albumin into the aqueous
humor. The posterior barrier between blood stream and eye is comprised of retinal pigment epithelium
(RPE) and the tight walls of retinal capillaries.

4. Or
Barriers are broadly classified as: -

1) Anatomical barriers
When a dosage form is topically administered there are two routes of entry, either through the cornea or via
the non-corneal route. The cornea is very tight multilayered tissue that is mainly composed of five sections
Epithelium, bowman’s membrane, stroma, descent’s membrane and endothelium.
Corneal cross section

Out of these it is the epithelium which acts as the principal barrier. These 5-6 layers of columnar epithelial
cells with very tight junctions create high Para cellular resistance of 12-16 KΩ.cm. it acts as a major barrier
to hydrophilic drug transport through intercellular spaces. On the other hand stroma, which consists of
multiple layers of hexagonally, arranged collagen fibers containing aqueous pores or channels allow
hydrophilic drugs to easily pass through but it acts as a significant barrier for lipophilic drugs. Thus for a
drug to have optimum bioavailability, it should have the right balance between lipophilicity and
hydrophilicity. The remaining layers are leaky and do not act as significant barriers. Non-corneal route by
passes the cornea and involves movement across conjunctiva and sclera. This route is important for large
especially and hydrophilic molecules such as peptides, proteins and siRNA (small or short interfering RNA).
The conjunctiva is more permeable than cornea especially for hydrophilic molecules due to much lower
expression of tight junction proteins relative to corneal epithelium. High vascularity of the limbal area
renders this route not suitable for drug delivery as the blood vessels remove a large fraction of absorbed
dose. Only a small fration of the dose reaches the vitreous.

2) Physiological barriers
o The eye’s primary line of defense is its tear film
o Bioavailability of topical administered drugs is further reduced by precorneal factors such as
solution drainage, tears dilution, tear turnover, and increased lacrimation.
o The lacrimal fluid is an isotonic aqueous solution containing a mixture of proteins (such as lysozyme)
as well as lipids
o Following topical application, lacrimation is significantly increased leading to dilution of
administered dose
o This in turn lowers drug concentration leading to diminished drug absorption
o Rapid clearance from the precorneal area by lacrimation and through nasolacrimal drainage and
spillage further reduces contact time between the tissue and drug molecules
o This in turn lowers the exact time for absorption leading to reduced bioavailability

5. o The average tear volume is 7-9 µL with a turnover rate of 16% per minute
o Thus drugs administered as eye drops need to be isotonic and non irritating to prevent significant
precorneal loss
3) Blood-ocular barrier
o The blood-ocular barrier normally keeps most drugs out of the eye. However inflammation breaks
down this barrier allowing drugs and large molecules to penetrate into the eye
4) Blood- aqueous barrier
o The ciliary epithelium and capillaries of the iris
5) Blood- retinal barrier
o Non-fenestrated capillaries of the retinal circulation and the tight junctions between retinal
epithelial cells preventing passage of large molecules from chorio-capillaries into the retina

Drug and dosage form related factors: -
 The physicochemical properties of drug molecule become even more important in the case of ocular drug
delivery because of the complex anatomical and physiological constrains
 The rate of absorption from the administered site depends highly on the physical properties of drug molecule
(solubility, lipophilicity, degree of ionization and molecular weight) and ocular tissue structure
 Solubility: - solubility is dependent on the pKa of the drug and pH of the solution. With these parameters one can
determine the ratio of ionized to unionized molecules
 Usually unionized molecules can readily permeate biological membranes example: - the permeability of
unionized Pilocarpine is almost two fold greater than that of its ionized form.

6.  The corneal epithelium bears a negative charge at the pH of lachrymal fluid and hence cationic species tend to
penetrate at a faster ratio their anionic counterparts.
 Lipophilicity: - lipophilicity and corneal permeability display sigmoidal relationship
 This is because of the diffential permeability of the different layers of cornea towards lipophilic drugs. As
previously mentioned, lipophilic drug tend to permeate easily through the epithelial layers of cornea
 But the hydrophilicity of the inner layer of cornea (stroma) requires higher hydrophilicity for optimal permeation
 Partition coefficient (Log P) value ranging from 2-4 is found to result in optimum corneal permeation.
 Molecular weight and size: - the weight and size of a molecules play a critical role in deciding its overall
permeability through paracellular route
 The diameter of the tight junctions present on corneal epithelium is less than 2 nm
 Molecules having molecular weight less than 500 Dalton are able to permeate readily
 The paracellular permeability is further limited by the pore density of corneal epithelium.
Molecular weight and size
 The conjunctiva has larger paracellular pore diameter thus allowing permeation of larger molecules such as
small and medium size peptides (5000-10000 Daltons)
 Permeation across sclera occurs through the aqueous pores and molecular size of the solute can be the
determining factor
 Example: - sucrose (molecular weight- 342 Daltons) permeates 16 times faster than inulin (molecular weight
5000 Daltons)
 Sclera permeability is approximately half of conjunctiva but much higher than cornea.

3) Methods to overcome barriers
I. 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), polyvinyl pyrrolidone (PVP), methylcellulose (MC),
hydroxyl ethyl cellulose, hydroxyl propyl methyl cellulose (HPMC), and hydroxyl propyl cellulose.
II. 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
 E.g., cetyl pyridinium chloride, benzalkonium chloride, parabens, tween 20, saponins

7.  Classified as:-
Calcium chelators, surfactants, bile acid and salts, preservative, glycoside, fatty acids
III. Eye ointments
 The medical 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 the 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.
IV. 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 hydroxyl 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
V. 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 provides the sustained release and site specific delivery. Liposomes are difficult to
manufacture in sterile preparation
 It has limitation like low drug load and inadequate aqueous stability and is undesirable for drugs that are
poorly absorbed, the drugs with low partition coefficient.
VI. Niosomes
 Niosomes are bilayered structural vesicles made up of non-ionic 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 non biodegradable and non biocompatible in nature.
VII. 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)
VIII. Microemulsion

8.  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
IX. 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.



X. 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.

9. XI. 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
intravitrally, 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: -
 By-passing the blood-ocular barriers to deliver constant therapeutic levels of drug directly to the
site of action
 Avoidance of the side effects associated with frequent systemic and intravitreal injections, and
 Smaller quantity of drug needed during the treatment
 The ocular implants are classified as non biodegradable devices. Non-biodegradable implants can provide
more accurate control of drug release and longer release periods that the biodegradable polymers do, but
the non biodegradable systems require surgical implant removal with the associated risks
XII. Iontophoresis
 Ocular Iontophoresis has gained significant interest recently due to its non invasive 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, corneosceral, or trans-scleral Iontophoresis
 It has ability to modulate dosages (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

10. Approaches for the enhancement of ocular bioavailability
Based on the use of the drug delivery system, which provide the controlled and continuous delivery of opthalmic drugs.
Based on maximizing corneal drug absorption and minimizing precorneal drug loss, these are summarized as: -
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 formulation
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 form
Limited stability, limited drug loading
Capacity, expensive.
Niosomes Non-toxic
Available in more than one dosage
Form
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 of
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 in insertion, patient
non-compliance

11. Formulation considerations in ophthalmics
A. 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: -
Steam sterilization at 121 degree, dry-heat sterilization, gas sterilization using ethylene oxide (due to
environmental concerns the use of ethylene oxide is being phased out wherever possible), sterilization using
ionizing radiation e.g., radioisotope decay (gamma radiation) and electron beam radiation, sterilization by
filtration.
B. Preservatives
The selection of a preservative for ophthalmic solutions is not an easy task, with very few candidates to choose
from: -
Sr no Preservatives Conc. range
1 Quaternary ammonium compounds 0.004-0.02
2 Organic mercurial’s 0.01- most common
3 Parahydroxy benzoates 0.001- 0.01
4 Chlorobutanol 0.5

The following criteria are important for selection of preservative: -
 Bard 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
 Non-toxic and non-irritating during use
C. Clarity
o The official definition of ophthalmic solutions requires that they be free of particulate matter
o Solution clarity is usually achieved by filtration, either with a clarifying filter or as part of a sterile filtration
procedure
o 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.
Sr no Particle size (µm) Proposed limit (particles per ml)
1 ≥10 ≤50
2 ≥25 ≤5
3 ˃50 Not allowed

12. D. 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.
E. pH adjustment and buffers
o the adjustment of ophthalmic solution pH by the appropriate choice of a buffer is one of the most
important formulation considerations
o 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 the corneal
penetration through changes in the degree of ionization; and to optimize product stability
o the tear fluid pH is reported to be vary between 6.9 and 7.5
F. Tonicity
o The hypertonic solution placed in the eye tends to draw solvent (water) from its surroundings in order to
dilute the instilled solution
o In this case, water flows from the aqueous layer through the cornea to the eye surface
o Conversely, a hypotonic solution could result in the passage of water from the site of application through
the eye tissues
o 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.
G. Viscosity modifiers
o The viscosity of ophthalmic solutions is often increase in order to prolong the corneal contact time,
decrease the drainage rate, and increase the bioavailability of the active ingredient
o 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.
H. Additives
o Stabilizers
o The use of stabilizers is permitted in ophthalmic solutions when necessary. Epinephrine hydrochloride
undergoes oxidative degradation and an oxidant 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
o Surfactant
o The addition of surfactants to ophthalmic solutions is permitted; even through 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.
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