CONTENTS : Introduction Physiology of the Eye Ideal characteristics of OCDDS Advantages Of Ocular Drug Delivery System Disadvantages Of Ocular Drug Delivery System Mechanism of drug absorption Barriers in Ocular Drug Delivery System INTRODUCTION : The eye is a complex organ made up of diversified cells with specified protective mechanism. Ocular administration of drug is primarily associated with the need to treat opthalmic diseases. Several type of dosage form can be applied as the delivery systems for the ocular delivery of the drugs but the most prescribed dosage form is the eye drop solutions . Presence of Barriers make it difficult to deliver drugs in therapeutic amounts as intended sites. IDEAL CHARACTERISTICS OF OCDDS : Sterility Isotonicity Buffer / pH adjustment Less Irritation Precorneal residence time Minium protein binding ADVANTAGES OF OCDDS : Increased residence time and bioavilability Increase accurate dosing Quick absorption and effect Better patient compliance To provide sustained and controlled drug delivery Self administration of drug possible DISADVANTAGES OF OCDDS : Dosage form cannot be terminated During Emergency Occasional loss during Sleep or while Rubbing Eye Insertion techniques are difficult Short contact time of drug solution and eye surface Instability of dissolved drug 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. 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. 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 a very tight multilayered tissue that is mainly composed of five sections: -Epithelium, -Bowman’s membrane, -Stroma -Descemet’s membrane and - Endothelium. Corneal Route Out of five layers it’s the epithelium which acts as the principal barrier . It acts as a major barrier to hydrophillic drug transport throgh intercellular spaces. On the other hand stroma , 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

1. BARRIERS OF DRUG PERMEATION OF
OCULAR DRUG DELIVERY SYSTEM
Presented By :
Tanvi D.Mhashakhetri
M.Pharm 1st Sem
Department of
Pharmaceutics
Guided By :
Dr. Nilesh M. Mahajan
Professor and Head Department
of Pharmaceutics
Dadasaheb Balpande College Of Pharmacy ,
Besa , Nagpur – 440037
2022-2023
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2. CONTENTS :
• Introduction
• Physiology of the Eye
• Ideal characteristics of OCDDS
• Advantages Of Ocular Drug Delivery System
• Disadvantages Of Ocular Drug Delivery System
• Mechanism of drug absorption
• Barriers in Ocular Drug Delivery System
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3. INTRODUCTION :
• The eye is a complex organ made up of diversified cells with
specified protective mechanism.
• Ocular administration of drug is primarily associated with the need
to treat opthalmic diseases.
• Several type of dosage form can be applied as the delivery systems
for the ocular delivery of the drugs but the most prescribed dosage
form is the eye drop solutions .
• Presence of Barriers make it difficult to deliver drugs in
therapeutic amounts as intended sites.
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4. PHYSIOLOGY OF THE EYE :
Fig 1 : Internal structure of the Eye
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5. IDEAL CHARACTERISTICS OF OCDDS :
• Sterility
• Isotonicity
• Buffer / pH adjustment
• Less Irritation
• Precorneal residence time
• Minium protein binding
5

6. ADVANTAGES OF OCDDS :
• Increased residence time and bioavilability
• Increase accurate dosing
• Quick absorption and effect
• Better patient compliance
• To provide sustained and controlled drug delivery
• Self administration of drug possible
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7. DISADVANTAGES OF OCDDS :
• Dosage form cannot be terminated During Emergency
• Occasional loss during Sleep or while Rubbing Eye
• Insertion techniques are difficult
• Short contact time of drug solution and eye surface
• Instability of dissolved drug
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8. MECHANISM OF DRUG ABSORPTION
Corneal Route
Lipophilic drugs follow
Transcellular pathway
Hydrophilic drug follow
Paracellular pathway
Non-Corneal Route
Significant for
hydrophilic drugs
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9. MECHANISM OF OCULAR DRUG ABSORPTION :
Topically applied drug can be absorbed from , two routes :
1) CORNEALABSORPTION :
• 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.
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10. 10
2) NON-CORNEALABSORPTION:
• 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.

11. BARRIERS IN OCCULAR DRUG DELIVERY SYSTEM :
• Corneal route
• Non Corneal route
Anatomical
Barriers
• Cornea and anterior segment Barrier
• Sclera and Bruch’s choroid complex
• Retina and Blood – retinal Barrier
Physiological
Barriers
• Blood Aqueous Barrier
• Blood Retinal Barrier
Blood –Ocular
Barriers
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12. 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 a very tight multilayered tissue that is mainly
composed of five sections:
-Epithelium,
-Bowman’s membrane,
-Stroma
-Descemet’s membrane and
- Endothelium.
Corneal cross section
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13. Corneal Route
• Out of five layers it’s the epithelium which acts as the principal barrier .
• It acts as a major barrier to hydrophillic drug transport throgh
intercellular spaces.
• On the other hand stroma , 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.
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14. Non Corneal Route
• Non-corneal route involves movement across conjunctiva
and sclera.
• This route is important especially for large and hydrophilic
molecules such as peptides, proteins and siRNA (small or
short interfering RNA).
• The conjuctiva is more permeable than cornea especially
for Hydrophilic molecule .
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15. Physiological Barriers
• Drugs can be delivered into the eye via anterior or posterior
segment routes depending on the target site.
• Each layer of the ocular tissues has special characteristics and
Posses a different barriers.
Cornea and Anterior segment Barriers
• Epithelial cells become flatter during maturation and eventually
form tight intercellular junctions with a tiny paracellular pore .
• The paracellular pore diameter of 2.0nm resulting tight
diffusion barrier for drug absorption .
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16. • Only molecules with a molecular radius of less than 5.5 A° or a
Molecular weight of 500 Da are generally able to penetrate across
The corneal epithelium .
• Corneal permeability is also heavily affected by the charge of the
solute.
• Conjuctiva is a thin translucent
vascularized mucus membrane
• It can be divided into three portions :
-Bulbar conjuctiva
-conjuctival fornix
- Palpebral conjuctiva
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17. • In humans , conjuctiva occupies a 17 fold larger surface area than
the cornea.
• The intercellular spacing in conjuctival epithelium is wider than
the corneal epithelium .
• Being 3.0 nm in the bulbar and 4.9 nm in the palpebral conjuctiva
• Thus , the permeability of drugs across conjuctiva is greater than
cornea .
• However, drug absorption through conjuctiva is still minimal
Due to presence of blood capillaries and lymphatics .
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18. Anterior segment Drug Delivery Barriers
Epithelial Tight Junction
• The stratified epithelium consist of a basal layer of columnar cells
, two to three layers of wing cells and one or two outer layers of
squamous cells .
• The tight junction act as a barrier for permeation of drug molecule
via paracellular route .
• Extracellular and Intracellular calcium level in tight junctions
Influence the permeability.
• The pores of corneal epithelium are negatively charged at
physiological pH , hence negatively charged molecule permeate
slowly compared to positively charged molecule.
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19. Reflex Blinking
• A normal eye dropper delivers 25–56 μL of the topical
formulation with an average volume of 39 μL.
• However, an eye can transiently hold up to 30 μL, and the rest is
lost either by nasolacrimal drainage or reflex blinking (5–7
blinks/min).
• It significantly decreasing the overall drug available for
therapeutic action.
Metabolism in Ocular Tissue
• Drugs containing aromatic hydrocarbons are metabolized in the
pigmented epithelium and ciliary body to their corresponding
epoxides and phenols.
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20. • It further metabolized by other enzymes present in the eye .
Tear Turnover
• A significant impediment to topical ocular delivery is tear
turnover.
• An increase in the volume of cul-de-sac occurs that leads to reflex
blinking and increased tear secretion.
• Loss of the solution occurs due to tear turnover and nasolacrimal
drainage until the tear volume in the conjunctiva cul-de-sac
returns to a normal range (7–9 μL) .
• The initial first order drainage rate of eye drops from the ocular
surface is 1.2 μL/min in humans and 0.5–0.7 μL/min in rabbits.
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21. Nasolacrimal Drainage
• The lacrimal drainage system in human adults serves as a
channel for tearflow from the eye to the nasal cavity.
• The pathway consists of the puncta, canaliculi, lacrimal sac,and
nasolacrimal duct.
• Histologically, the walls of the lacrimal
sac and the nasolacrimal duct are
vascularized and hence are potential
sites for systemic
drug absorption.
• After topical application,the eye drop
Solution initially mixes with lacrimal fluid.
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22. Efflux pumps
• The efflux protein are located either on the apical or basolateral
cell membranes .
• These proteins restrict or enhance drug absorption.
There are primarily two major efflux pumps that are responsible for
drug resistance:
(a) P-glycoprotein, which restricts entry of amphipathic compounds,
both in normal and cancer tissue.
• The contact time of the drug with ocular tissues is approximately
1–2 min due to the constant production of lacrimal fluid.
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23. • P-glycoprotein 1 (P-gp), also known as MDR1, is a ATP
dependent efflux pump.
• It is located on the apical surface of polarized cells and is
responsible for decreasing drug accumulation in multidrug-
resistant cells.
b) Multidrug Resistant Protein (MRP) which is known
to efflux organic anions and conjugated compounds.
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24. Sclera and Bruch-choroid complex
• The human sclera has large surface area and mainly consists of
an Extracellular matrix .
• Scleral permeability depends upon drug MW, with
macromolecule exhibiting lower permeability than small
molecule .
• Transscleral permeability is influenced by the charge of the
molecule.
• Positively charged molecule have lower permeability across
the sclera than those with negative charges.
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25. • Bruch’s-choroid complex possess a more critical barrier to
drug delivery by the transscleral route than the sclera itself .
• Due to binding of solute to the tissue thereby forming a slow
release drug depot in the BC complex .
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26. Retina and Blood-Retinal barrier
• The retina is a thin transparent tissue which forms the innermost
layer of the eye and adheres to the choroid.
• It consists of the outer RPE and the inner neural retina.
• The RPE is a monolayer of polarized cells while the neural retina
is composed of nine layers with the inner limiting membrane
(ILM), mainly comprised of extracellular matrix (ECM) proteins.
• The BRB mainly hinders substance diffusion from the systemic
circulation into the retina.
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27. • It is divided into the inner and outer BRB.
• The inner BRB is composed of retinal capillary endothelial
(RCE) cells which possess intercellular tight junctions and
selectively protect the retina from foreign substances.
• The outer BRB is comprised of the RPE, which is located
between the photoreceptors and the choriocapillaries.
• Hydrophilic compounds permeate mainly through tight
junctions (paracellular route), while lipophilic drugs cross the
RPE via the transcellular route.
• Thus, only small lipophilic molecules can transfer efficiently
between choroid and retina, which limits drug delivery both in
the inward (blood to vitreous) and outward (vitreous to blood)
direction.
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28. Blood Ocular Barrier
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.
Blood-aqueous barrier:
• The ciliary epithelium and capillaries of the iris.
• The aqueous humor is protected by the blood aqueous
barrier(BAB) .
• Two discrete cellular layers the endothelium of the iris –cilliary
blood vessels and the non pigmented ciliary epithelium form the
BAB .
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29. Blood-retinal barrier:
Non-fenestrated capillaries of the retinal circulation and tight
junctions between retinal epithelial cells preventing passage
of large molecules from chorio-capillaris into the retina.
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30. References
1. Yie W. chein , Novel Drug Delivery Systems , Second Edition,
page no. 269-272 .
2. Di Haung , Ying-Shan Chen , Ilva D. Rupenthal , Advanced
Drug Delivery Reviews , page no. 4-7 .
3. Rinda Devi Bachu , Pallabitha Chowdhury , Zahraa H. F. Al-
Saedi , Pradeep K. Karla 2 and Sai H. S. Boddu , Ocular Drug
Delivery Barriers , Page no. 2-4.
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31. THANK YOU
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