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1. SUBCONJUNCTIVAL
DRUG DELIVERY
SYSTEM (STRATEGIES)
ATHAR SHAMIM
M.PHARM 2nd
SEM
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2. CONTENTSCONTENTS
• INTRODUCTION
• ANATOMY AND PHYSIOLOGY OF EYE
• BARRIERS
• FORMULATION CONSIDERATIONS
• IDEAL CHARACTERISTICS
• DRUG DELIVERY SYSTEMS
• EVALUATION
• ADVANTAGES AND DISADVANTAGES
• CONCLUSION
• REFERENCES
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3. INTRODUCTION
• Eye diseases are commonly encountered in day to day life, which are
cured or prevented through the conventionally used dosage forms
like eye drops, ointments, etc., Ocular drug delivery systems are
intended for installation into the cul-de-sac, i.e., the space between
the eye ball and the eye lids. Delivery to the internal parts of the eye
still remains troublesome due to the anatomical and protective
structure of the eye. Drugs may be delivered to the eye through the
application of four primary modes of administration: topical,
systemic, intravitreal, and periocular.
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4. ANATOMY AND PHYSIOLOGY OF
EYE
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5. Eye and lacrimal drainage systemEye and lacrimal drainage system
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6. ROUTES OF DRUG DELIVERY INROUTES OF DRUG DELIVERY IN
EYEEYE
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7. BARRIERS FOR DRUG
ABSORPTION
Precorneal Constraints
It include –
• Solution drainage
• Lacrimation
• Tear dilution
• Tear turnover
• Conjunctival absorption
Corneal constraints
• Cornea as rate limiting barrier
• Anatomy of cornea
1.Outer-
Epithelium(lipophilic),
2.Middle-
Stroma(hydrophilic),
3.Inner-
Endothelium(lipophilic
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8. OCULAR ABSORPTION 8
Corneal Absorption
Depend upon physicochemical
properties of drug
Only access to small ionic &
lipophilic molecules
Outer Epithelium: rate limiting
barrier
Trans cellular transport:
transport between corneal
epithelium & stroma
e.g. pilocarpine
Non-Corneal
Absorption
Penetration across Sclera &
Conjunctiva into Intra
Ocular tissues
Non-Productive: because
penetrated drug is absorbed
by general circulation.
Minor pathway
Important for drug with low
corneal permeability
e.g. inulin

9. GENERAL PATHWAY FOR OCULARGENERAL PATHWAY FOR OCULAR
ABSORPTIONABSORPTION
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10. FORMULATION CONSIDERATIONS
• Physicochemical characteristics of drug and
polymers.
• Buffering capacity and pH.
• Instillation volume.
• Osmotic pressure.
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11. Ideal characteristics of ocular drug
delivery system
• Good corneal penetration.
• Prolong contact time with corneal tissue.
• Non irritative and non toxic.
• Good rheological properties.
• Non greasy
• Patient compliance.
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12. 12DRUG DELIVERY SYSTEMS TO EYE:
IMPLANTS
DENDRIMERS
IONTOPHORESIS
MICROEMULSION
MICRONEEDLE
NANOSUSPENSION
CONTACT LENSES

13. APPROACHES TO IMPROVE DRUG
DELIVRY
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
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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 cst is needed for optimum corneal
absorption.

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 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.
e.g. Caprylic acid, sodium caprate, Azone

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 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.

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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

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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.

19. EYE DROP
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.
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20. •OINTLENTS AND GELS
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Prolongation of drug contact time with the external ocular surface can be
achieved using ophthalmic ointment vehicle,flaxibality in drug
choice,improved drug stability but, the major drawback of this dosage form
like, blurring of vision and blinking of eyelids can limits its use. These
products will stay on eyes longer than eye drops.
•INSERTS
Ocular insert are sterile preparation that prolong residence time of drug with a
controlled release manner and negligible or less affected by naso-lacrimal
damage. The ocular inserts maintain an effective drug concentration in the
target tissues and yet minimize the number of applications.

21. OCUSERTOCUSERT
 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
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22. • ADVANTAGESADVANTAGES
 Reduced local side effects and toxicity.
 Around the clock control of drug.
 Improved compliance.
• DISADVANTAGESDISADVANTAGES
 Retention in the eye for the full 7 days.
 Periodical check of unit.
 Replacement of contaminated unit
 Expensive.
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23.  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
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24. • LACRISERTSLACRISERTS
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.
• SODISODI
Soluble ocular drug inserts.
Small oval wafer.
Sterile thin film of oval shape.
Weighs 15-16 mg.
Use – glaucoma.
Advantage – Single application. Lacriserts
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25. • MinidiscMinidisc
Countered disc with a convex front and a concave back
surface.
Diameter – 4 to 5 mm.
• CompositionComposition
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.
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26. 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.
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Type Advantages Disadvantages

27. 2.VESICULAR SYSTEMS
• LIPOSOMES: Liposomes are vesicles composed of lipid membrane enclosing
an aqueous volume. These structures are formed simultaneously when a matrix
of phospholipids are agitated in an aqueous medium to disperse the two phases.
They are having an intimate contact with the corneal and conjunctival surfaces
which is desirable for drugs that are poorly absorbed.
• NIOSOMES AND DISCOMES : Niosomes are nonionic surfactant vesicles
that have potential applications in the delivery of hydrophobic or amphiphilic
drugs. Discomes are discoidal vesicles and may act as potential drug delivery
carriers by releasing the drug in a sustained manner at the ocular site.
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•PHARMACOSOMES: Drugs possessing a free carboxyl
group or an active hydrogen atom can be esterified to the
hydroxyl group of a lipid molecule, thus generating an
amphiphilic prodrug. This amphiphilic prodrug is converted to
pharmacosomes on dilution with water. pharmacosomes show
greater shelf stability, facilitated transport across the cornea,
and a controlled release profile.

29. 3.CONTROLLED RELEASE
• IMPLANTS: implants are effective drug delivery system for chronic
ocular diseases like cytomegalovirus (CMV), retinitis. Intravitreal implants
of fluocinolone acetonide were developed for the treatment of posterior
segment.
• DENDRIMERS: Dendrimers are repetitively branched molecules and can
be successfully used for ocular drug administration and have better water-
solubility, bioavailability and biocompatibility.
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•IONTOPHORESIS: Iontophoresis is a noninvasive technique for ocular
drug delivery. In iontophoresis the drug solution is in contact with the cornea
in an eye-cup bearing an electrode and the diffusion of drug occurs by
electrical potential difference.
•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. They reduce the frequency of administration as
compared to the conventional systems.

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•NANOSUSPENSION: 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.
•CONTACT LENSES: Water soluble drugs soaked in drug solutions
can be absorbed through Contact lenses. The drug saturated contact
lenses are placed in the eye which releases the drug in eye for a long
period of time. For prolongation of ocular residence time of the drugs,
hydrophilic contact lenses can be used.

32. 4.PARTICULATE SYSTEMS (NANOPARTICLES
AND MICROPARTICLES)
• Nanoparticles are prepared using bioadhesive polymers to provide
sustained effect to the entrapped drugs. An optimal corneal penetration of
the encapsulated drug was reported in presence of bioadhesive polymer
chitosan.
• Microemulsions have a transparent appearance, with thermodynamic
stability and a small droplet size in the dispersed phase (aqueous and
nonaqueous phase) (<1.0μm). Microspheres of poly lacto gylcolic acid
(PLGA) are prepared for topical ocular delivery.
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33. 5.ADVANCED DRUG DELIVERY
SYSTEMS
• Several kinds of viruses including adenovirus, retrovirus,
adeno-associated virus, and herpes simplex 140virus, have
been manipulated for use in gene transfer and gene therapy
applications. The advanced delivery systems such as gene
delivery, SiRNA, stem cells that prolong the contact time of
the dosage form with the surface of the eye and facilitate non-
invasive administration.
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6. Microneedle:
Microneedle had shown prominent in vitro penetration into sclera and
rapid dissolution of coating solution after insertion while in vivo drug
level was found to be significantly higher than the level observed
following topical drug administration like pilocarpine.
7. Mucoadhesive Polymers:
They are basically macromolecular hydrocolloids with plentiful
hydrophilic functional groups, such as hydroxyl, carboxyl, amide and
sulphate having capability for establishing electrostatic interactions
A mucoadhesive drug formulation for the treatment of glaucoma was
developed using a highly potent beta blocker drug, levobetaxolol (LB)
hydrochloride and partially neutralized poly acrylic acid (PAA).

40. Evaluation of ocular drug delivery
system
• Thickness of the film.
• Drug content.
• Irritancy test.
• Percentage moisture loss.
• In vitro drug release.
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41. ADVANTAGES
• Localized drug delivery is possible.
• Drops are easy to apply and have good patient acceptance.
• Intravitreal , periocular sub-conjuctival injections improve drug absorption
and have no systemic toxicity.
• Micro particles , Nanoparticles, liposomes increase half life of drug.
• ocular inserts increased ocular residence releasing drugs at a slow
and constant rate.
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42. DISADVANTAGES
• Physical instability of the dosage form.
• Frequent administration reqired with conventional
systems.
• Leaking of entrapped drug.
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43. REFERENCES
• Text book of pharmaceutical sciences by Remington.
• Novel and controlled drug delivery by N.K Jain.
• Patel Vishal, Agrawal Y.K. CURRENT STATUS AND
ADVANCED APPROACHES IN OCULAR DRUG DELIVERY
SYSTEM, Journal of Global Trends in Pharmaceutical
Sciences, Vol.2, Issue 2, pp -131-148.
• www.vision-care-guide.com
• www.google/images/eye/anatomy& physiology
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