Ophthalmic drugdelivery system

Ocular Drug Delivery
System
:Prepared By:
Dr. Yamini D. Shah
Roshni S. Vora
L. M. College of Pharmacy, Ahmedabad,
Gujarat, India

 To review and study ocular drug delivery system.
 To study various factors affecting ocular absorption.
 To know various approaches ot improve drug absorption.
 To study mechanism of drug absorption.
 They are specialized dosage forms 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 most commonly employed ophthalmic dosage forms are
solutions, suspensions, and ointments. 2

 But these preparations when instilled into the eye are rapidly
drained away from the ocular cavity due to tear flow and lachrymal
nasal drainage.
 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.
3

Major classes of drugs used are
 Miotics e.g. pilocarpine Hcl
 Mydriatics e.g. atropine
 Cycloplegics e.g. atropine
 Anti-inflammatories e.g. corticosteroids
 Anti-infectives (antibiotics, antivirals and antibacterials)
 Anti-glucoma drugs e.g. pilocarpine Hcl
 Surgical adjuncts e.g. irrigating solutions
 Diagnostic drugs e.g. sodiumfluorescein
 Anesthetics e.g. tetracaine
4

 Water - 98%,
 Solid -1.8%,
 Organic element
 Protein - 0.67%,
 sugar - 0.65%,
 NaCl - 0.66%
 Other mineral element
 sodium, potassium and ammonia - 0.79%.
5

 Human eye
Diameter 23 mm
Structure comprises of three layers
1.Outermost coat : The clear, transparent cornea and the white, opaque
sclera
2.Middle layer : The iris anteriorly, the choroid posteriorly, and the
ciliary body at the intermediate part
3.Inner layer : Retina (extension of CNS)
Cornea
Epithelium-stroma-endothelium (fat-water-fat structure)
Penetration of the drug depends on Oil-water partition coefficient7

 Fluid systems in eye
1. Aqueous humor
 Secreted from blood through epithelium of the ciliary body.
 Secreted in posterior chamber and transported to anterior chamber.
2. Vitreous humor
 Secreted from blood through epithelium of the ciliary body.
 Diffuse through the vitreous body.
 Lacrimal glands
 Secrete tears & wash foreign bodies.
 Moistens the cornea from drying out.
9

 The sclera : The protective outer layer of the eye, referred to as the
“white of the eye” and it maintains the shape of the eye.
 The cornea : The front portion of the sclera, is transparent and allows
light to enter the eye. The cornea is a powerful refracting surface,
providing much of the eye's focusing power.
 The choroid : is the second layer of the eye and lies between the
sclera and the retina. It contains the blood vessels that provide
nourishment to the outer layers of the retina.
 The iris : is the part of the eye that gives it color. It consists of muscular
tissue that responds to surrounding light, making the pupil, or circular
opening in the center of the iris, larger or smaller depending on the
brightness of the light. 10

 The lens is a transparent, biconvex structure, encased in a thin
transparent covering. The function of the lens is to refract and
focus incoming light onto the retina.
 The retina is the innermost layer in the eye. It converts
images into electrical impulses that are sent along the optic
nerve to the brain where the images are interpreted.
 The macula is located in the back of the eye, in the center of
the retina. This area produces the sharpest vision.
11

Non-Corneal
Absorption
• Penetration across Sclera & Conjuctiva into Intra Ocular
tissues
• Non-Productive: because penetrated drug is absorbed by
general circulation
Corneal
Absorption
• Outer Epithelium: rate limiting barrier, with pore size
60å,Only access to small ionic & lipohilic molecules
• Trans cellular transport: transport between corneal
epithelium & stroma.
12

1. Inflow & outflow of lacrimal fluids.
2. Efficient naso-lacrimal drainage.
3. Interaction of drug with proteins of lacrimal fluid.
4. Dilution with tears.
5. Corneal barriers
6. Physico-chemical properties of drugs
7. Active ion transport at cornea,
8. Limited and poor corneal permeability
9. Metabolism
14

Factors affecting drug availability:
1. Rapid solution drainage by gravity, induced lachrymation, blinking
reflex, and normal tear turnover.
 The normal volume of tears = 7 ul,
 The blinking eye can accommodate a volume of up to 30 ul without
spillage,
 The drop volume = 50 ul
2. Superficial absorption of drug into the conjunctiva and sclera and
rapid removal by the peripheral blood flow
15

16
3. Low corneal permeability (act as lipid barrier)
 Transport of hydrophilic and macromolecular drugs
occurs through scleral route.
 Lipophilic agents of low molecular weight follow
transcorneal transport by passive diffusion.
4. Metabolism
Enzymatic biotransformation
Esterases, oxidoreductases, Peptidases, Glucuronide
Sulfate transferases, Lysosomal enzymes

Poor
Bioavialability
Protective
mechanism (short
residence time)
Blinking
Reflex lacrimation,
Nasolacrimal drainage
Anatomy of eye
Barrier properties of
cornea
17

1. Viscosity enhancers
2. Eye ointments
3. Gel
4. Prodrug
5. Penetration enhancers
6. Liposomes
7. Niosomes
8. Nanosuspension
9. Microemulsion
10. Nanoparticles/nanospheres
11. In situ-forming gel 18

 Enhancement of bioavailability
1. Increase in viscosity of formulation leads to decrease in
drainage.
2. Slows elimination rate from the precorneal area and enhance
contact time.
3. Generally hydrophilic polymers, eg. Methyl cellulose,
polyvinyl alcohols, polyacrylic acids, sodium carboxy methyl
cellulose, carbomer is used.
4. A minimum viscosity of 20 cp is needed for optimum corneal
absorption. 19

 Use of penetration enhancers
1. Act by increasing corneal uptake by modifying the integrity
of the corneal epithelium.
2. Substances which increases the permeability characteristics of
the cornea by modifying the integrity of corneal epithelium are
known as penetration enhancers.
 Modes of actions
1. By increasing the permeability of the cell membrane.
2. Acting mainly on tight junctions.
20
e.g. Caprylic acid, sodium caprate, Azone

 PRODRUGS
1. Prodrugs enhance corneal drug permeability through
modification of the hydrophilic or lipophilicity of the drug.
2. The method includes modification of chemical structure of the
drug molecule, thus making it selective, site specific and a safe
ocular drug delivery system.
3. Drugs with increased penetrability through prodrug formulations
are epinehrine, phenylephrine, timolol, pilocarpine.
21

 USE OF MUCOADHESIVES IN OCULAR DRUG DELIVERY
1. Polymereric mucoadhesive vehicle: Retained in the eye due to
noncovalent bonding with conjuctival mucine.
2. Mucine is capable of picking of 40-80 times of weight of water.
3. Thus prolongs the residence time of drug in the conjuctival sac.
4. Mucoadhesives contain the dosage form which remains adhered to
cornea until the polymer is degraded or mucus replaces itself.
 Types
1. Naturally Occurring Mucoadhesives - Lectins, Fibronectins
2. Synthetic Mucoadhesives - PVA,Carbopol, CMC 22

 Phase Transition System
1. Solution that are liquid in the container and thus can be
instilled as eye drop becomes gel on contact with the tear
fluid and provide increased contact time with the
possibility of improved drug absorption and increased
duration of therapeutic effect.
2. Liquid-gel phase transition-dependent delivery system vary
according to the particular polymer employed and their
mechanism for triggering the transition to a gel phase in the
eye take advantage of change in temperature, pH, ion
sensitivity, or lysozymes upon contact with tear fluid.
23

POLYMER MECHANISM
Lutrol FC – 127 and
Poloxamer 407
Viscosity increased when their
temperature raised to eye
temperature.
Cellulose acetate phthalate
latex
Coagulates when its native pH
4.5 raised by tear fluid to pH
7.4
Gelrite Forms clear gel in the
presence of cations
24
EXAMLE OF POLYMER

OCULAR DELIVERY
SYSTEMS
CONVENTIONAL VESICULAR
CONTROLED RELEASE
PARTICULATE
o IMPLANTS
o HYDROGELS
o DENDRIMERS
o IONTOPORESIS
o COLLAGEN SHIELD
o POLYMERIC
SOLUTIONS
o CONTACT LENSES
o CYCLODEXRIN
o MICROONEEDLE
o MICROEMULSION
S
o NANO
SUSPENSION
o MICROPARTICLES
o NANOPARTICLES
o LIPOSOMES
o NIOSOMES
o DISCOMES
o PHARMACOSOMES
ADVANCED
o SCLERAL PLUGS
o GENE DELIVERY
o Si RNA
o STEM CELL
o SOLUTION
o SUSPENSION
o EMULSION
o OINTMENT
o INSERT
o GELS
25

LIQUIDS
Solutions
Suspensions
Powders for
reconstitution
Sol to gel
systems
SEMISOLIDS
Ointments
Gels
26
SOLID
Ocular inserts
Contact lenses
INTRAOCULAR
DOSAGE FORM
Injections
Irrigating
solutions
Implants

Good corneal penetration.
Prolong contact time with corneal tissue.
Simplicity of instillation for the patient.
Non irritative and comfortable form.
Appropriate rheological properties.
Inert and stable.
27

o Drugs which are active at eye or eye surface are widely
administered in the form of Solutions, Emulsion and Suspension.
o Various properties of eye drops like hydrogen ion concentration,
osmolality, viscosity and instilled volume can influence retention
of a solution in the eye.
o Less than 5 % of the dose is absorbed after topical administration
into the eye.
o The dose is mostly absorbed to the systemic blood circulation via
the conjunctival and nasal blood vessels. 28

Advantages And Disadvantages Of Eye Drops
Dosage form Advantages Disadvantages
Solutions 1. Convenience
2. Usually do not interfere
with vision of patient.
1. Rapid precorneal elimination.
2. Non sustained action.
3. To be Administered at frequent
intervals.
Suspension 1. Patient compliance.
2. Best for drug with slow
dissolution.
3. Longer contact time
1. Drug properties decide
performance loss of both
solutions and suspended
particles.
2. Irritation potential due to the
particle size of the drug.
Emulsion 1. Prolonged release of
drug from vehicle
1. Blurred vision.
2. patient non compliance.
29

• Prolongation of drug contact time with the external ocular
surface can be achieved using ophthalmic ointment vehicle.
• The ointment base is sterilized by heat and appropriately
filtered while molten to remove foreign particulate matter.
30
Ointment base is
sterilized by heat and
filtered while molten
to remove foreign
particulate matter.
It is then placed into a
sterile steam jacketed to
maintain the ointment
in a molten state and
excipients are added
The entire ointment
may be passed
through a previously
sterilized colloid mill

• Advantages
1. Longer contact time and greater storage stability.
2. Flexibility in drug choice.
3. Improved drug stability.
• Disadvantages
1. Sticking of eyes lids.
2. Blurred vision.
3. Poor patient compliance
4. Interfere with the attachment of new corneal epithelial cells to their
normal base. 31

• Gels
1. Ophthalmic gels are composed of mucoadhesive polymers that
provide localized delivery of an active ingredient to the eye. Such
polymers have a property known as bioadhesion.
2. These polymers are able to extend the contact time of the drug
with the biological tissues and there by improve ocular
bioavailability.
Advantages
1. Longer contact time and Greater storage stability.
Disadvantages
1. Blurred vision but less then ointment. And Poor patient compliance.
32

 Liposomes are biocompatible and biodegradable lipid vesicles made
up of natural lipids and about 25 –10 000 nm in diameter.
 They are having an intimate contact with the corneal and
conjunctival surfaces which is desirable for drugs that are poorly
absorbed, the drugs with low partition coefficient, poor solubility or
those with medium to high molecular weights and thus increases the
probability of ocular drug absorption.
 Vesicle composed of phospholipid bilayer enclosing aqueous
compartment in alternate fashion. It is Biodegradable, Non-toxic in
nature.
33

 Types : 1. MLV
2. ULV-SUV(upto 100 nm)
3. LUV(more than 100 nm)
 Polar drugs are incorporated in aqueous compartment while
lipophilic drugs are intercalated into the liposome membrane.
 Phospholipids used- Phosphotidylcholine, Phosphotidic acid,
Sphingomyline, Phosphotidyleserine, Cardiolipine.
34

ADVANTAGES
Drugs delivered intact to
various body tissues.
Liposomes can be used
for both hydrophilic and
hydrophobic drug.
Possibility of targeting and
decrease drug toxicity.
The size, charge and other
characteristics can be altered
according to drug and
desired tissue.
DISADVANTAGES
Their tendency to be up
taken by reticular endothelial
system.
They need many
modification for drug delivery
to special organs.
Costly.
Stability problem and
oxidative degradation.
Requires special packaging
and storing facility. 35

 The major limitations of liposomes are chemical instability,
oxidative degradation of phospholipids, cost and purity of natural
phospholipids.
 To avoid this niosomes are developed as they are chemically stable
as compared to liposomes and can entrap both hydrophobic and
hydrophilic drugs.
 Niosomes are non-ionic surfactant based multilamellar (>0.05µm),
small unilamellar (0.025-0.05µm) or large unilamellar vesicles
(>0.1µm) in which an aqueous solution of solute(s) is entirely
enclosed by a membrane resulted from organization of surfactant
macromolecules as bilayers.
37

 They are non toxic and do not require special handling
techniques.
 Niosomes are nonionic surfactant vesicles that have potential
applications in the delivery of hydrophobic or amphiphilic drugs.
 STRUCTURAL COMPONENTS USED
• Surfactants (dialkyl polyoxy ethylene ether non ionic
surfactant)
• Cholesterol.
38

 The vesicle suspension being water based offers greater patient
compliance over oil based systems.
 Since the structure of the niosome offers place to accommodate
hydrophilic, lipophilic as well as ampiphilic drug moieties, they
can be used for a variety of drugs.
 The characteristics such as size, lamellarity etc. of the vesicle can be
varied depending on the requirement.
 The vesicles can act as a depot to release the drug slowly and offer a
controlled release.
39

 They are osmotically active and stable.
 They increase the stability of the entrapped drug.
 Improves therapeutic performance of the drug by protecting it
from the biological environment and restricting effects to target
cells, thereby reducing the clearance of the drug.
Drawbacks
 Physical instability.
 Aggregation.
 Leaking of entrapped drug.
40

 This term is used for pure drug vesicles formed by the amphiphilic
drugs.
 The amphiphilic prodrug is converted to pharmacosomes on dilution
with water.
 Since many drugs are also amphiphiles, they can form the vesicles.
Advantages
 Drug metabolism can be decreased.
 Controled release profile can be achieved.
41

• Soluble surface active agents when added in critical amount to
vesicular dispersion leads to solubilization or breakdown of vesicles
& translates them into mixed micellar systems
e.g: Egg yolk phosphatidyl choline liposomes by the addition
of non ionic surfactants of poly oxy ethylene cetyl ether till the
lamellar and mixed lamellar coexist
Advantages
• Minimal opacity imposes no hinderance to vision
• Increased patient compliance
• Zero order release can be easily attained 42

1. No difficulty of insertion as in the case of ocular inserts.
2. No tissue irritation and damage as caused by penetration enhancers.
3. Provide patient compliance as there is no difficulty of insertion as
observed in the case of inserts.
4. The vesicular carriers are biocompatable and have minimum side effects.
5. Degradation products formed after the release of drugs are biocompatable.
6. They prevent the metabolism of drugs from the enzymes present at
tear/corneal epithelium interface.
7. Provide a prolong and sustained release of drug.
43

OCULAR
INSERTS
NONERODABLE
OCUSERT
SOFT CONTACT
LENSES
ERODABLE
SODI
COLLAGEN SHIELDS
44
OCUFIT SR

 OCUSERT
 The Ocusert therapeutic system is a flat, flexible, elliptical
device designed to be placed in the inferior cul-de-sac between
the sclera and the eyelid and to release Pilocarpine continuously
at a steady rate for 7 days.
 The device consists of 3 layers…..
1. Outer layer - ethylene vinyl acetate copolymer layer.
2. Inner Core - Pilocarpine gelled with alginate main polymer.
3. A retaining ring - of EVA impregnated with titanium di oxide
45

• ADVANTAGES
 Reduced local side effects and toxicity.
 Around the clock control of drug.
 Improved compliance.
• DISADVANTAGES
 Retention in the eye for the full 7 days.
 Periodical check of unit.
 Replacement of contaminated unit
 Expensive.
47

48
 The solid inserts absorb the aqueous tear fluid and gradually erode
or disintegrate. The drug is slowly leached from the hydrophilic
matrix.
 They quickly lose their solid integrity and are squeezed out of the
eye with eye movement and blinking.
 Do not have to be removed at the end of their use.
 Three types :
1. Lacriserts
2. Sodi
3. Minidisc

• LACRISERTS
 Sterile rod shaped device made up of hydroxyl propyl cellulose
without any preservative.
 For the treatment of dry eye syndromes.
 It weighs 5 mg and measures 1.27 mm in diameter with a length
of 3.5 mm.
 It is inserted into the inferior fornix.
• SODI (Soluble ocular drug inserts)
 .Small oval wafer.
 Sterile thin film of oval shape.
 Weighs 15-16 mg. 49
Lacriserts

• Minidisc
 Countered disc with a convex front and a concave back
surface.
 Diameter – 4 to 5 mm.
• Composition
 Silicone based prepolymer-alpha-w-dis (4-methacryloxy)-butyl
poly di methyl siloxane. (M2DX)
 M-Methyl a cryloxy butyl functionalities.
 D – Di methyl siloxane functionalities.
 Pilocarpine, chloramphenicol.
50
Minidisc

• Contact lenses can be a way of providing
extended release of drugs into the eye.
• Conventional hydrogel soft contact lenses have
the ability to absorb some drugs and release
them into the post lens lachrymal fluid,
minimizing clearance and sorption through the
conjunctiva.
• Their ability to be a drug reservoir strongly
depends on the water content and thickness of
the lens, the molecular weight of the drug, the
concentration of the drug loading solution and
the time the lens remains in it.
51

Type Advantages Disadvantages
Erodible inserts Effective.
Flexiblility in drug type
& dissolution rate.
Need only be introduced
into eye & not removed.
Patient discomfort.
Requires patient
insertion.
Occasional product.
Non-erodible
inserts
Controlled rate of
release.
Prolonged delivery.
Flexibility for type of
drug selected.
Sustained release.
Patient discomfort.
Irritation to eye.
Tissue fibrosis.
52

1. Implants have been widely employed to extend the release of drugs
in ocular fluids and tissues particularly in the posterior segment.
2. Implants can be broadly classified into two categories based on their
degradation properties:
(1) Biodegradable
(2) Nonbiodegradable
1. With implants, the delivery rate could be modulated by varying
polymer composition.
2. Implants can be solids, semisolids or particulate-based delivery
systems.
53

 For chronic ocular diseases like cytomegalo virus (CMV)
retinitis, implants are effective drug delivery system. Earlier
non biodegradable polymers were used but they needed
surgical procedures for insertion and removal.
 Presently biodegradable polymers such as Poly Lactic Acid
(PLA) are safe and effective to deliver drugs in the vitreous
cavity and show no toxic signs.
54

In Iontophoresis direct current drives ions into cells or tissues. For
iontophoresis the ions of importance should be charged
molecules of the drug.
 If the drug molecules carry a positive charge, they are driven into
the tissues at the anode; if negatively charged, at the cathode.
 Requires a mild electric current which is applied to enhance
ionized drug penetration into tissue.
 Ocular iontophoresis offers a drug delivery system that is fast,
painless, safe, and results in the delivery of a high concentration of
the drug to a specific site.
55

• Ocular iontophoresis delivery is not only fast, painless and safe but it can
also deliver high concentration of the drug to a specific site.
• Ocular iontophoresis has gained significant interest recently due to its
non-invasive nature of delivery to both anterior and posterior
segment.
• Iontophoretic application of antibiotics may enhance their bactericidal
activity and reduce the severity of disease
• Can overcome the potential side effects associated with intraocular
injections and implants.
• Iontophoresis is useful for the treatment of bacterial keratitis.
56

Dendrimer
• Dendrimers can successfully used for different routes of drug
administration and have better water-solubility, bioavailability and
biocompatibility.
Microemulsion
 Microemulsion is dispersion of water and oil stabilized using
surfactant and co- surfactant to reduce interfacial tension and usually
characterized by small droplet size (100 nm), higher thermodynamic
stability and clear appearance.
 Selection of aqueous phase, organic phase and surfactant/co-
surfactant systems are critical parameters which can affect stability of
the system. 58

 Nanosuspensions have emerged as a promising strategy for the
efficient delivery of hydrophobic drugs because they enhanced
not only the rate and extent of ophthalmic drug absorption but
also the intensity of drug action with significant extended
duration of drug effect.
 For commercial preparation of nanosuspensions, techniques
like media milling and high-pressure homogenization have
been used.
59

Advance System
• Design of Punctal Plug
1. Punctal plugs are placed in the tear duct (punctum) to release
a variety of drugs.
2. Currently targeting the treatment of glaucoma and ocular
hypertension
60

• Design of Replenish Mini Pump
1. Micro-electromechanical system that delivers continuous or
bolus-targeted drugs to both the anterior and posterior
segments.
2. Refillable drug reservoir (via 31 gauge needle) that is
capable of storing and delivering up to 12 months.
61

• Design of ODTx
1. Non-biodegradable implant that is comprised of multiple
sealed reservoirs containing individual doses of drugs.
2. Implant is injected into the vitreous.
3. Drug is released by creating an opening via laser.
62

• I-vation™
1. A solid triamcinolone acetnoide implant, can delivery up to
24 months.
2. Phase I showed positive outcome, phase 2 was terminated
before completion.
3. Also, has polysaccharide-based matrix for protein delivery
(eureka™ duet)
63

• Vitrasert®
1. (Ganciclovir-CMV retinitis) and Retisert® (fluocinolone
acetonide-chronic non infectious uveitis).
2. Are FDA approved
3. These devices are solid sustained-release devices, typically
made of PLGA, capable of delivering drug for up to 30
months.
64

Ophthalmic drugdelivery system

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Ophthalmic drugdelivery system