occular drug delivery system

1. By – PANKAJ VERMA
M.Pharm 1st year
Roll No. 27/MPH/18
DEPARTMENT OF PHARMACEUTICS

2. INDEX
 INTRODUCTION
 ANATOMY OF EYE
 MECHANISM OF DRUG ABSORPTION
 BARRIERS TO DRUG PERMEATION
 METHODS TO OVERCOME BARRIERS
 CONVENTIONAL DRUG DELIVERY SYSTEMS
 NOVEL DRUG DELIVERY SYSTEMS
 CONCLUSION

3. INTRODUCTION
Ophthalmic drug delivery is one of the most interesting
and challenging field facing the pharmaceutical
scientist . The anatomy, physiology and biochemistry of
the eye render this organ exquisitely impervious to
foreign substances . The challenge to the formulator is
to circumvent the protective barriers of the eye without
causing permanent tissue damage.

4.  The bioavailability of ophthalmic drugs is very poor due to
efficient protective mechanisms of the eye.
 Blinking, reflex lachrymation, and drainage rapidly remove
drugs, from the surface of the eye.
 To overcome these, two approaches can be followed.
 The first involves using alternate delivery routes to
conventional ones allowing for more direct access to
intended target sites.
 Second approach involves development of novel drug
delivery systems providing better permeability, treatability
and controlled release at target site.
 Combination of both these approaches are being utilized
and optimized in order to achieve optimal therapy with
minimal adverse effects.

6. Diseases
Anterior segment
occupies approx
one -third of the
eye.
Eye
Anterior segment
cornea, conjunctiva,
aqueous humor, iris,
ciliary body and lens
glaucoma, allergic
conjunctivitis, anterior
uveitis and cataract
posterior segment
choroid, retinal pigment
epithelium, neural retina,
optic nerve and vitreous
humor.
age-related macular
degeneration (AMD)
and diabetic
retinopathy

7. MECHANISM OF DRUG ABSORPTION
CORNEAL ROUTE
Lipophilic drugs
follow Transcellular
pathway
Hydrophilic drug
follow paracellular
pathway
NON-CORNEAL
ROUTE
Significant for
hydrophilic drugs

8. MECHANISM OF OCULAR DRUG
ABSORPTION
Topically applied drug can be absorbed from, two routes:
(1)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.
(2) NON-CORNEAL ABSORPTION:
 It involves penetration across the sclera and conjunctiva into the
intraocular tissues.
 This mechanism of absorption is usually nonproductive, 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.

9. BARRIERS OF DRUG
PERMEATION
PRECORNEAL
DRAINAGE OF DRUG
SOLUTION
LACRIMATION
TEAR DILUTION
DYNAMIC
LYMPHATIC FLOW
BLOOD FLOW IN
CONJUCTIVA AND
CHOROID
STATIC
CORNEAL EPITHELIUM
SCLERA/CONJUCTIVA
CHOROID AND RETINAL
PIGMENT EPITHELIUM

10. BARRIERS TO OCULAR DRUG DELIVERY
 Delivery of ocular drugs to the targeted ocular tissues
and maintenance of required therapeutic drug
concentration is very difficult due to presence of
various precorneal , dynamic and static barriers.
 As a result ocular bioavailability is usually only 1%-7%
of the applied dose.
 These barriers can also be classified as anatomical
barriers and physiological barriers.

11. ANATOMICAL BARRIERS
(1)Cornea
 The cornea is mainly composed of five sections:
Epithelium, bowman’s membrane, stroma, descemet’s
membrane and endothelium.
 Epithelium acts as the principal barrier.
 Stroma,consists of multiple layers of hexagonally
arranged collagen fibers containing aqueous pores or
channels.
 It allow hydrophilic drugs to easily pass through but it
acts as a significant barrier for Lipophilic drugs.

12. (2) SCLERA AND CONJUCTIVA
 The conjunctiva is more permeable than cornea especially for hydrophilic
molecules.
 High vascularity renders this route not suitable for drug delivery as the
blood vessels remove a large fraction of absorbed dose. Only a small fraction
of the dose reaches the vitreous.
(3) BLOOD –OCULAR BARRIERS
 These barriers have two parts: blood-aqueous humor barrier and blood-
retina barrier.
 The anterior blood-ocular barrier is composed of the endothelial cells in the
uvea. This barrier limits the access of hydrophilic drugs from plasma into
the aqueous humor.
 Inflammation may disrupt the integrity of this barrier.
 The posterior barrier between blood stream and eye is comprised of retinal
pigment epithelium (RPE) and the tight walls of retinal capillaries
 Therefore, only a minute fraction of the intravenous or oral drug dose gains
access to the retina.

13. PHYSIOLOGICAL BARRIERS
 Nasolachrimal drainage of drug solution
 Reflex blinking
 Increased lacrimation and tear turnover
 Tear dilution
 Metabolism
 Non -productive absorption

15. Factors affecting intraocular
bioavailability
 Inflow and outflow of lachrimal fluids.
 Efficient nasolachrimal drainage.
 Interaction of drug with proteins of lachrimal fluids.
 Corneal barriers.
 Dilution with tears.
 Physiochemical properties of a drug.

16. PHYSIOCHEMICAL PROPERTIES OF
DRUGS
The rate of absorption from the administered site depends
on the physical properties of drug molecule.
(1)Solubility:
 Usually unionized molecules can readily permeate
biological membranes.
 In case of ionized species, their charge can also affect
permeability across the cornea.
 The corneal epithelium bears a negative charge at the pH
of lachrymal fluid and hence cationic species tend to
penetrate at a faster rate to their anionic counterparts.

17. (2)LIPOPHILICITY:
 Different layers of cornea show differential permeability towards
Lipophilic drugs.
 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.
(3) MOLECULAR WEIGHT AND SIZE:
 The molecules having diameter less than 2 nm easily permeate.
 molecular weight should be less than 500 Dalton to permeate readily
through cornea.
 The conjunctiva has larger paracellular pore diameter thus allowing
permeation of larger molecules such as small and medium size
peptides (5000-10000 Daltons).
 Scleral permeability is approximately half of conjunctiva but much
higher than cornea.

18. Methods to overcome barriers
To overcome barriers in ocular drug delivery, two
Distinct yet complimentary approaches can be used:
 (1) The first involves using alternate delivery routes
to conventional ones allowing for more direct access to
intended target sites.
 (2) Second approach involves development of novel
drug delivery systems providing better permeability,
treatability and controlled release at target site.

19. Alternate drug delivery routes
(1)Intra-vitreal injection(IVI)
 It involves delivering of the drug formulation directly into the vitreous humor.
 It provides direct access to the vitreous and avoids both the cornea and also the
Scleral blood vessels.
 Formulations such as solution, suspension or a depot formulation can be
administered through this route.
 Adverse effects are retinal detachment, cataract, hyperemia and
endophthalmitis.
(2)Sub-conjunctival injections
 This injection delivers the drug beneath the conjunctival membrane that lines
the inner surface of eyelid.
 It avoids both cornea and conjunctiva allowing the drug direct access to the
sclera.
 It has lesser side effects when compared to intravitreal injections.
 Excellent route for delivering hydrophilic drugs, depot forming formulation
and macromolecules.

21. (3)Retrobulbar and peribulbar route
 Retrobulbar injection is given through eyelid and orbital fascia and it places the
drug into retrobulbar space.
 It causes minor or no change in IOP .
 Adverse effects: It may damage the optic nerve.
 Peribulbar route for drug delivery involves injections above and/or below the
globe.
 It is also a viable route for the delivery of anesthesia in cataract surgery,
 It is a safer route compared to the retrobulbar route .
 Rise in IOP have been reported.
(5)Intracameral injections
 This injection delivers drug to the anterior chamber.
 It is generally employed for anterior segment procedures such as cataract
surgery.
 It is an efficient and more cost-effective method of delivering antibiotics.

22. Ocular drug delivery
systems
Solution
Suspension
Emulsion
Ointments
Gels
Liposomes
Niosomes
Discomes
Inserts
Implants
Hydrogels
Contact lenses
Collagen shield
Microneedle
iontophoresis
Microparticle
nanoparticle
Conventional Vesicular
Control release Particulate

23. Conventional drug delivery systems
 These include eye drops containing solutions, suspension or
emulsion of drugs and eye ointments.
 These preparations when instilled in the eye are rapidly removed
from the ocular cavity by tear flow and nasolachrimal drainage.
 DISADVANTAGES :
 poor bioavailability
 frequent dosing
 interference with vision
 ADVANTAGES:
 ease of bulk scale manufacturing,
 high patient acceptability,
 drug product efficacy,
 stability and cost effectiveness.

24. Comparison between various
conventional dosage forms
Dosage form Advantages Disadvantages
solution Convenient,safe,high
patient acceptability,
non-invasive and cost
effective.
Poor bioavailability
frequent dosing, rapid
precorneal elimination
and short acting
suspension Improved drug contact
time and duration of
action
Performance depends on
the properties of drug
Emulsion
o/w emulsion is preferred
over w/o system because
of less irritation and
better ocular tolerance
Prolonged drug action,
improved precorneal
residence time and
corneal permeation
Blurred vision , poor
patient compliance
ointment Improved bioavailability
and sustain release action
Sticking of eyelids, poor
patient compliance,
blurred vision

25. NOVEL OCULAR DRUG DELIVERY
SYSTEMS
Objective
1. To Increase accurate dosing.
2. To overcome the side effects produced by conventional
systems.
3. To provide sustained and controlled drug delivery.
4. To increase the ocular bioavailability of drug by increasing the
corneal contact time.
5. To provide targeting within the ocular globe so as to prevent
the loss to other ocular tissues.
6. To overcome the protective barriers like drainage, lacrimation
and conjunctival absorption.
7. To provide comfort, better compliance to the patient and to
improve therapeutic performance of drug.

26. VESICULAR SYSTEMS
(1)LIPOSOMES
 These are biodegradable, non-toxic and amphiphilic
delivery systems usually formulated with phospholipids
and cholesterol.
 They can be utilized for both improving the permeability
as well as sustaining the release of the entrapped drugs.
 Liposomes sustain the release of therapeutic agents into
the vitreous and retina-choroid and avoids non-targeted
tissues (sclera and lens).
 Limitations : chemical instability, oxidative degradation
of phospholipids, cost and purity of natural
phospholipids.

28.  (2) Niosomes and Discomes
 These are bilayer structures which can entrap both
hydrophilic and lipophilic drugs.
 These nonionic surfactant bilayer exhibit low toxicity
and are chemically stable.
 Niosomes are also used in their modified form, i.e.,
discosomes in ophthalmology. Discosomes contains
non-ionic surfactant.
 These vesicles fit better in the cul-de-sac of the eye and
are not drained into systemic circulation because of
their large size.
 They have high entrapment efficiency.

30. Control release systems
(1)Implants
 Implants are devices that control drug release by utilizing
various degradable or non-biodegradable polymeric
membranes. .
 Polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA) are
most commonly used non-biodegradable implant polymers.
 Advantage: low burst effects,
 Disadvantage : the implants need to be surgically removed.
 Biodegradable polymers such as poly lactic acid (PLA), poly
glycolic acid (PGA) are safe but undergo enzymatic and/or
non-enzymatic hydrolysis.
 It leads to bulk erosion of encapsulated drug rather than
surface erosion.

31. (2)Contact lenses
 Contact lenses can absorb water-soluble drugs when
soaked in drug solutions.
 They are placed in the eye for releasing the drug for a long
period of time.
 They can be used to prolong the ocular residence time of
the drugs.
(3)Artificial tear inserts(lacrisert)
A rod shaped pellet of hydroxy propyl cellulose without
preservative.
 This device is designed as a sustained release artificial tear
for the treatment of dry eye disorders.

32. (4) Microneedles
 It is used to deliver drug to posterior ocular tissues.
 It may reduce the risk and complications associated with
intravitreal injections such as retinal detachment, hemorrhage,
cataract.
 It may help to avoid blood retinal barrier and deliver therapeutic
drug levels to retina/choroid. These needles help to deposit
drug or carrier system into sclera or into the narrow space
present between sclera and choroid called “suprachoroidal space.
 For intraocular delivery of drug microneedles surface coated
with drugs
 By use of microneedles, nanoparticles suspensions and
microparticles were also delivered into sclera by microneedles.

33. (5)Ocular iontophoresis
Iontophoresis is the process in which direct current
drives ions into cells or tissues.
 When iontophoresis is used for drug delivery, the ions
of importance are 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.
 Ocular iontophoresis offers a drug delivery system
that is fast, painless and safe; and results in the
delivery of a high concentration of the drug to a
specific site.

34.  (6) collagen shields
 It has excellent biocompatibility and safety ,
biodegradability and weak antigenecity.
 The shields are hydrated before they are placed on the eye,
having been stored in a dehydrated state. Typically the
drug is loaded into the drug solution for a period of time
prior to application.
 They often produce some discomfort and interfere with
vision.
 (7) ocusert
 It is a flat, flexible, elliptical device designed to be placed in
the inferior cal-de-sac between sclera and the eyelid to
release the drug in a sustained manner.

35. Particulate system
Nanoparticles and microparticles
 Particulate polymeric drug delivery systems include micro and
nanoparticles.
 The upper size limit for microparticles for ophthalmic administration is
about 5-10 mm. Above this size, a scratching feeling in the eye can
result after ocular application.
 Microspheres and nanoparticles represent promising drug carriers for
ophthalmic application.
 The binding of the drug depends on the physicochemical properties of
the drugs, as well as of the nano- or micro-particle polymer.
 Particulates such as nanoparticles, nanocapsules, micro emulsions,
nanosuspensions improved the bioavailability of ocularly applied
drugs.

36. CONCLUSION
 In the past two decades, ocular drug delivery research accelerated
towards developing a novel, safe and patient compliant formulation
and drug delivery devices/techniques, which may surpass these
barriers and maintain drug levels in tissues.
 advances are modulation of conventional topical solutions with
permeation and viscosity enhancers.
 Various nanoformulations have also been introduced.
 These novel devices and/or formulations may help to surpass ocular
barriers and associated side effects with conventional topical drops.
 Also, these novel devices and/or formulations are easy to formulate,
no/negligibly irritating, possess high precorneal residence time, sustain
the drug release, and enhance ocular bioavailability of therapeutics.
 Further improvements are needed to achieve effective and highly
patient compliant therapies.