OCULAR DRUG DELIVERY SYSTEM

PRESENTED BY: SOMNATH NAVGIRE

M. PHARM II: (PHARMACEUTICS)
DEPARTMENT OF PHARMACEUTICAL
SCIENCES, RASHATRASANT TUKDOJI
MAHARAJ NAGPUR UNIVERSITY,
NAGPUR.



1
IDEAL OPHTHALMIC DELIVERY SYSTEM
Good corneal penetration.

Prolong contact time with corneal tissue.

Simplicity of instillation for the patient.

Non irritative and comfortable form

Appropriate rheological properties

OCULAR DRUG DELIVERY SYSTEMS
ADVANCED
DELIVERY SYSTEMS
Scleral plugs
Gene therapy
Stem cell

CONTROLLED
DELIVERY SYSTEMS
Implants
Hydrogels
Dendrimers
Iontophorosis
Polymeric solution
Penetration enhancers
Contact lenses
Nano suspensions
Micro emulsions
Cyclodextrins
Phase transition
systems
Mucoadhesive


PARTICULATE
SYSTEMS
Nano particles
Micro particles
VESICULAR
DELIVERY SYSTEMS
Liposomes
Neosomes
Pharmacosomes
discomes
RETRO METABOLIC
DELIVERY SYSTEMS
Softdrug approach
Chemical delivery systems
SOLUTIONS
GELS
OINTMENTS
SUSPENSIONS
EYE DROPS
CONVENTIONAL
DOSAGE FORMS



LIMITATIONS OF CONVENTIONAL
DRUG DELIVERY

Rapid precorneal elimination
Solution drainage by gravity
Frequent instillation is necessary
Conjuctival absorption



ADVANTAGES OF AVANCED
DUG DELIVERY
Sustained and/or controlled drug
release
Site-specific targeting
Protect the drug from chemical or
enzymatic hydrolysis
Increasing contact time and thus
improving bioavailability
Better patient compliance.


4

Factors Affecting Intraocular Bioavailability:
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. Limited and poor corneal permeability
6. Metabolism
NOVEL OCULAR DRUG DELIVERY SYSTEM
OBJECTIVES :
To prolong the pre ocular retention
To reduce the frequency of administration
To provide controlled, continuous drug delivery
To avoid or minimize the initial drug concentration
peak in the aqueous humour
To avoid periods of under-dosing that may occur
between eye drop instillation.
APPROACHES TO IMPROVE
OCULAR DRUG DELIVERY
ENHANCEMENT OF BIOAVAILABILITY
VISCOSITY IMPROVER
Solution Viscosity Solution Drainage.
Enhances viscosity of the formulation.
Slows elimination rate from the precorneal area and enhance contact
time.
Generally hydrophilic polymers- e. Methyl cellulose, polyvinyl
alcohols, polyacrylic acids, sodium carboxy methyl
cellulose,carbomer is used
A minimum viscosity of 20 cst is needed for optimum corneal
absorption.
USE OF PENETRATION ENHANCERS: Act by
increasing corneal uptake by modifying the integrity of the
corneal epithelium
Substances which increases the permeability
characteristics of the cornea by modifying the integrity of
corneal epithelium are known as penetration enhancers.
Modes of actions
By increasing the permeability of the cell membrane.
Acting mainly on tight junctions.

Classification
Calcium chelators :
e.g. EDTA
Surfactants :
e.g. palmiloyl carnitine, sodium caprate, Sodium dodecyl
sulphate
Bile acids and salts :
e.g. Sodium deoxycholate, Sodium taurodeoxycholate,
Taurocholic acid

10
11
Preservatives :
e.g. Benzalkonium chloride
Glycosides :
e.g. saponins, Digitonon
Fatty acids :
e.g. Caprylic acid
Miscellaneous :
e.g. Azone, Cytochalasins
PRODRUGS
Prodrugs enhance corneal drug permeability through modification
of the hydrophilic or lipophilicity of the drug.
The method includes modification of chemical structure of the drug
molecule, thus making it selective, site specific and a safe ocular
drug delivery system.
Drugs with increased penetrability through prodrug formulations are
epinehrine, phenylephrine, timolol, pilocarpine
USE OF MUCOADHESIVES IN OCULAR DRUG
DELIVERY
Polymereric mucoadhesive vehicle: Retained in the eye due to
non-covalent bonding with conjuctival mucine.
Mucine is capable of picking of 40-80 times of weight of water.
Thus prolongs the residence time of drug in the conjuctival sac.

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, carboxy methyl
cellulose, cross-linked polyacrylic acid

Drugs incarporated in to this are pilocarpine, lidocaine,
benzocaine and prednisolone acetate.





13
Mechanism of mucoadhesion
The polymer undergoes swelling
in water,
Entanglement of the polymer
chains with mucin on the epithelial
surface.
The un-ionized carboxylic acid
residues on the polymer form
hydrogen bonds with the mucin.
The water-swellable yet water-
insoluble systems are preferred
14
PHASE TRANSITION SYSTEM
PHASE TRANSITION SYSTEM
PHASE TRANSITION SYSTEM
POLYMERS

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
PHASE TRANSITION SYSTEM
18
PARTICULATE SYSTEM FOR OCULAR DRUG DELIVERY
NANOPARTICLES:
For water soluble drugs.
Size:10-1000nm
Drug is Dispersed, Encapsulated, or Absorbed
Produced by Emulsion Polymerization
Chemical initiation, Gamma irradiation, Visible light.
Polymerization is carried out by :
Emulsifier stabilizes polymer particle
Polymer used are Biodegradable.
E.g. :- Nanoparticle of Pilocarpine enhances Mitotic
response by 20-23%.

Advantages of nanoparticles
Sustained drug release and prolonged therapeutic activity
Site-specific targeting
Higher cellular permeability
Protect the drug from chemical or enzymatic hydrolysis
Efficient in crossing membrane barriers -blood retinal
barrier
Act as an inert carrier for ophthalmic drugs
Poly alkyl cyano acrylate(PACA) nanoparticles and
nanocapsules improve corneal penetration of hydrophilic
and lipophilic drugs.
Poly- -caprolactone(PECL) nanocapsules increase ocular
penetration of lipophilic drugs such as
metipranolol,betaxolol.


20
VESICULAR SYSTEM FOR
OCULAR DRUG DELIVERY
LIPOSOMES
22
Vesicle composed of phospholipid bilayer enclosing aqueous
compartment in alternate fashion.
Biodegradable, Non-toxic in nature.
Types :1.MLV
2.ULV-SUV(upto 100 nm)
LUV(more than 100 nm)
Polar drugs are incorporated in aqeous compartment while
lipophilic drugs are intercalated into the liposome
membrane
Phospholipids used- Phosphotidylcholine, Phosphotidic acid,
Sphingomyline, Phosphotidyleserine,Cardiolipine
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 OF
LIPOSOMES
Their tendency to be uptaken by
RI system.
They need many modification
for drug delivery to special
organs.
Cost .
23
Degradation and Drug Release Of
Liposomes
24
1. Endocytosis
2. Fusion
Niosomes are non-ionic surfactant based
multilamellar(>0.05m),small unilamellar(0.025-0.05m) or large
unilamellar vesicles(>0.1m) in which an aqueous solution of
solute(s) is entirely enclosed by a membrane resulted from
organization of surfactant macromolecules as bilayers
STRUCTURAL COMPONENTS USED
Surfactants (dialkyl polyoxy ethylene ether non ionic surfactant)
Cholesterol.
NEOSOMES
ADVANTAGES:
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.
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.
DISADVANTAGES
Physical instability, Aggregation, Leaking of entrapped drug,
Fusion,a
PHARMACOSOMES
The vesicle formation takesplace not only just by association of
phospholipids but also by amphiphilic molecular association
Since many drugs are also amphiphiles, they can form the
vesicles
Advantages:
Drug metabolism can be decreased
Controled release profile can be achieved
DISCOMES
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
Advantages of vesicular systems

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


IONTOPHORESIS
Iontophoresis is the process in which direct current drives ions into
cells or tissues.

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.

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.

Iontophoresis
CYCLODEXTRINS:
Cyclodextrins (CDs) forming inclusion complexes with many guest
molecules. And aqueous solubility of hydrophobic drugs can be
enhanced without changing their molecular structure and their
intrinsic ability to permeate biological membranes.

They increase corneal permeation of drugs and increase ocular
bioavailability of poorly water soluble drugs. Applied in the form of
eye drops.
DENDRIMERS:
These are macromolecular compounds made up of a series of
branches around a central core. Their nanosize, ease of preparation,
functionalization and possibility to attach multiple surface groups
provides suitable alternative vehicle for ophthalmic drug delivery.

This system can entrap both hydrophilic and lipophilic drugs into
their structure.
MICROEMULSION
They can be easily prepared through emulsification method,
easily sterilized, and are more stable and have a high capacity for
dissolving drugs.
The presence of surfactants and co-surfactants in microemulsion
increase the dug molecules permeability, thereby increasing
bioavailability of drugs. they act as penetration enhancers to
facilitate corneal drug delivery

NANOSUSPENSIONS
It is consist of pure, hydrophobic drugs (poorly water soluble),
suspended in appropriate dispersion medium..
It offer advantages such as more residence time and avoidance of
the high tonicity created by water-soluble drugs, their performance
depends on the intrinsic solubility of the drug in lachrymal fluids
after administration. Thus, they controlled its release and increase
ocular bioavailability.
Ocular Control Release System: Ophthalmic Inserts
Definition:- Solid or Semisolid in nature,
- Placed in lower Fornix
- Composed of Polymeric vehicle containing drug.
Desired Criteria For Control Release Ocular Inserts.
Comfort
Ease of
handling
Reproducibility
of release
kinetics
Sterility Stability Ease of mfg.

Advantages
1. Accurate dosing.
2. Absence of preservative.
3. Increase in shelf life due to
absence of water.
Limitations
1. Perceived by patient as foreign body.
2. Movement around the eye.
3. Occasional loss during sleep or
while rubbing eyes.
4. Interference with vision.
5. Difficulty in placement & removal.
CONTROLLED RELEASE
OCULAR DEVICES
INSERTS:
Ophthalmic inserts are solid devices intended to be placed in
the conjunctival sac and to deliver the drug at a comparatively
slow rate
Increased ocular permeation with respect to
standard vehicles, hence prolonged drug activity
and a higher drug bioavailability;
Accurate dosing -theoretically, all of the drug is
retained at the absorption site;
Capacity to provide, in some cases, a constant rate of drug
release;
INSOLUBLE INSERTS
OCUSERTS:
Flexible, oval inserts
Consists of a medicated core reservior prepared out of hydrogel
polymer sandwiched between two sheets of transperant
lipophilic,rate controlling polymer like ethylene/vinyl acetate
copolymer membrane.

CONTACT LENS :
The most widely used Material is poly-2-hydroxyethylmethacrylate.
Its copolymers with PVP are used to correct eyesight , hold and
deliver drugs.
Controlled release can be obtained by binding the active ingredient
via biodegradable covalent linkages.


SOLUBLE OCULAR INSERTS

LACRISERT:
It is a sterile ophthalmic insert use in treatment of dry eye
syndrome.
The insert is composed of 5mg of HPC in rod-shaped form about
1.27 mm diameter by about 3.5 m long

MINIDISC:
It is made up of counter disc with convex front & concave back
surface in contact with eye ball.
Composition: silicon based pre polymer
Hydrophillic or hydrophobic.
COLLAGEN SHIELDS
Collagen is the structural protein of bones, tendons, ligaments and
skin and comprises more than 25% of the total body protein in
mammals.
Collagen shields have been used in animal model and in
humans (eg. Antibiotics, antiviral etc.,) or combination of these
drugs often produces higher drug concentration in the cornea and
aqueous humor when compared with eye drops and contact lens
They are manufactured from porcine scleral tissue, which bears a
collagen composition similar to that of human cornea.
They are hydrated before being placed on the eye and the drug is
loaded with the collagen shield simply by soaking it in the drug
solution.
They provide a layer of collagen solution that lubricates the eye.
INTRAOCULAR INJECTIONS

Micro needle used to deliver drug to posterior segment as an
alternative to topical route.

It shows excellent in vitro penetration into sclera and rapid
dissolution of coating solution after insertion. In-vivo drug level was
found to be significantly higher than the level
observed following topical drug administration.

To deliver anti-infective, corticosteroids and anesthetic product to
achieve higher therapeutic condition intraocularly, FDA approved
intraocular Injections includes miotics, viscoelastics, and anti-viral
agents for intravitreal injection
INTRAOCULAR IMPLANTS

It employed to extend the release in ocular fluids and tissues
particularly in the posterior segment. It may be biodegradable and
non-biodegradable.

With implants, the delivery rate could be modulated by varying
polymer composition.

Implants can be in the form of solid, semi-solid or particulate based
delivery systems. These implants have been applied in the treatment of
diseases affecting both anterior and posterior segments of the eye.

Implant containing gancyclovir or, anti-neoplastic agents is release
drug over a 5 to 8 months.
RETROMETABOLIC DELIVERY
SYSTEM
Combination of SAR and SMR Retrometabolic drug design (RMDD)
Metabolic activation of inactive delivery forms: chemical delivery systems
CDS Drug
inactive active
Alkyl oxime datives oximes(enzymes located in iris-celiary
body)
Metabolic deactivation of specifically designed active species:soft drugs
SD Mi
Active inactive metabolites
hydrocartisone spirothiazolidine
RMDD represent novel, systemic approach to achieve these goles include
two distinct methods aimed to increase the therapeutic index
SOFT DRUG design
CHEMICAL DELIVERY SYSTEM design

The chemical delivery systems(CDSs)- chemical compounds
produced by synthetic chemical reaction(s) forming covalent
bonds between the drug(D) and specifically designed carrier
and other moieties. At least one chemical bond needs to be
broken for active compound (D) to be released. The release of
active compound from CDSs takes pace by enzymatic or
hydrolytic cleavage.
The basic principle of retrometabolic drug design approaches
is that the drug metabolism considerations should actually be
involved at a very early stage of the design process- not as an
after thought inorder to explain some of the behaviours of the
drug
SAR+SMR=RETROMETABOLIC DRUG DELIVERY
SYSTEM
Drug targeting by CDSs
1.enzymatic physical chemical
based targeting
2.site specific-enzyme activated
targeting
3.receptor based chemical
targeting
Drug targeting by soft drugs
1.soft drug analogs
2.activated soft coompounds
3.active metabolite type soft drugs
4.controlled release of endogenous
soft compounds
5.Inactive metabolic approach
CONCLUSION
The main efforts in ocular drug delivery is to prolong the residence time of
drugs

The development of ophthalmic drug delivery systems is easy because we
can easily target the eye to treat ocular diseases

the eye has specific characteristics such as eye protecting mechanism, which
make ocular delivery systems extremely difficult.

The most widely developed drug delivery system is represented by the
conventional and non-conventional ophthalmic formulations to polymeric
hydrogels, nanoparticle, nanosuspensions, microemulsions, iontophorosis and
ocular inserts.

In future an ideal system should be able to achieve an effective drug
concentration at the target tissue for an extended period of time, while
minimizing systemic exposure and the system should be both comfortable and
easy to use.
REFERENCES
Ophthalmic drug delivery system: Challenges and approaches
PB Patel, DH Shastri, PK Shelat, AK Shukla
Controlled drug delivery Concepts and Advances, by S.P. Vyas and Roop K.
Khar, page no.: 383 410.
Ansels Pharmaceutical dosage forms and drug delivery systems, by Loyd V.
Allen, Nicholas G. Popovich and Howard c. Ansel page no.: 661 663.
Advances in Controlled and Novel drug delivery, edited by N.K. Jain, page no.:
219 223.
. http://www.pharmainfo.net/reviews/recent advances in opthalmic drug delivery
system.