BARRIERS OF DRUG PERMEATION OF OCCULAR DRUG DELIVERY SYSTEM

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 1 st 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 1

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 2

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. 3

4. PHYSIOLOGY OF THE EYE : Fig 1 : Internal structure of the Eye 4

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 6

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 7

8. 8

9. 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. 9

10. 10 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.

11. BARRIERS IN OCCULAR DRUG DELIVERY SYSTEM : 11

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 12

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. 13

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 . 14

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 . 15

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 16

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 . 17

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. 18

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. 19

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. 20

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. 21

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. 22

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. 23

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. 24

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 . 25

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. 26

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. 27

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 . 28

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. 29

30. References Yie W. chein , Novel Drug Delivery Systems , Second Edition, page no. 269-272 . Di Haung , Ying-Shan Chen , Ilva D. Rupenthal , Advanced Drug Delivery Reviews , page no. 4-7 . 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. 30

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