OCULAR DRUG DELIVERY SYSTEM 1

PRESENTED BY: PRANAY MITTAL
M.PHARM 1st SEMESTER
DEPARTMENT OF PHARMACEUTICS
SCHOOL OF PHARMACEUTICAL
EDUCATION AND RESEARCH
JAMIA HAMDARD, NEW DELHI.

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CONTENTS:

 Introduction

 Difference between Ophthalmic and Ocular Drug Delivery System

 Major classes of drugs used are

 Composition of Eye

 Lacrimal nasal drainage

 Barriers in ocular absorption

 Anatomy and Physiology of eye

 Routes of Drug Administration

 Mechanism of Ocular absorption

 Ideal characteristics of Ocular drug delivery

 Various Formulations of Ocular drug delivery

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Introduction

DEFINITION

 “They are specialized dosage forms designed to be instilled onto the external surface of the eye (topical), administered

inside (intraocular) or adjacent (periocular) to the eye or used in conjunction with an ophthalmic device”.

 “The Novel approach of drug delivery system in which drug can Instilled on the cull de sac cavity of eye is known as

Ocular drug delivery system”.

 cull de sac cavity: the space between eye lids and eye balls.

 The most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments.

 But these preparations when instilled into the eye are rapidly drained away from the ocular cavity due to tear flow and

lacrimal nasal drainage.

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 Ocular administration of drug is primarily associated with the need to treat

ophthalmic diseases.

 Eye is the most easily accessible site for topical administration of a medication.

 Ideal ophthalmic drug delivery must be able to sustain the drug release and to

remain in the vicinity of front of the eye for prolong period of time.

 The newest dosage forms for ophthalmic drug delivery are: gels, gel-forming

solutions, ocular inserts , intravitreal injections and implants.

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Difference between Ophthalmic and Ocular
Drug Delivery System

Sr.No. Ophthalmic DDS Ocular DDS

1. Conventional System Novel System

2. Old Concept New concept

3. Addition of Preservatives No addition of Preservatives

4. High Dosing Frequency Low Dosing Frequency

5. Minimum release rate of drug Maximum release rate of drug

6. Limited flexibility Extreme flexibility

7. Minimum absorption rate Maximum absorption rate

8. Minimum bioavaibility Maximum bioavaibility

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Composition of eye

 Water – 98%

 Solid -1.8%

 Organic element

Protein – 0.67%

Sugar – 0.65%

NaCl – 0.66%

 Other mineral element: Sodium, Potassium and Ammonia – 0.79%.

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Lacrimal
Nasal
Drainage

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BARRIERS IN OCULAR ABSORPTION

 It includes

Precorneal constraints Corneal constraints

 Solution Drainage 3 Layers :

 Lacrimation Epithelium

 Tear Dilution Endothelium

 Tear turnover Inner stroma

 Conjunctival Absorption

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Anatomy
and
Physiolog
y of Eye

PHYSIOLOGY OF EYE 12

 The eye consists of transparent cornea, lens, and vitreous body without blood vessels. The oxygen and

nutrients are transported to this non-vascular tissue by aqueous humor which is having high oxygen and

same osmotic pressure as blood. The aqueous humor in human is having volume of 300 µl that fills the

anterior chamber of the eye which is in front of lens.

 The cornea is covered by a thin epithelial layer continuous with the conjunctiva at the corneasclerotic

junction. The main bulk of cornea is formed of criss-crossing layers of collagen and is bounded by elastic

lamina on both front and back. Its posterior surface is covered by a layer of endothelium. The cornea is richly

supplied with free nerve endings. The transparent cornea is continued posteriorly into the opaque white

sclera which consists of tough fibrous tissue. Both cornea and sclera withstand the intra ocular tension

constantly maintained in the eye.

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 The eye is constantly cleansed and lubricated by the lacrimal apparatus which consists of four structures.

lacrimal glands,

lacrimal canals,

lacrimal sac,

nasolacrimal duct

 The lacrimal fluid secreted by lacrimal glands is emptied on the surface of the conjunctiva of the upper eye lid at a turnover

rate of 16% per min. It washes over the eye ball and is swept up by the blinking action of eye lids.

 Muscles associated with the blinking reflux compress the lacrimal sac, when these muscles relax; the sac expands, pulling the

lacrimal fluid from the edges of the eye lids along the lacrimal canals, into the lacrimal sacs.

 The lacrimal fluid volume in humans is 7 µl and is an isotonic aqueous solution of bicarbonate and sodium chloride of pH 7.4.

It serves to dilute irritants or to wash the foreign bodies out of the conjunctival sac. It contains lysozyme, whose bactericidal

activity reduces the bacterial count in the conjunctival sac.

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Routes of Drug Delivery In Eye

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Ideal characteristics of ophthalmic 19

drug delivery systems.

 Good corneal penetration.

 Maximizing ocular drug absorption through prolong contact time with corneal tissue.

 Simplicity of instillation for the patient.

 Reduced frequency of administration.

 Patient compliance.

 Lower toxicity and side effects.

 Minimize precorneal drug loss.

 Nonirritative and comfortable form(viscous solution should not provoke lachrymal secretion and
reflex blinking).

 Should not cause blurred vision.

 Relatively nongreasy.

 Appropriate rheological properties and concentrations of the viscous system.

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Enhancement of Bioavailability

 Increase in viscosity of formulation leads to decrease in drainage.

 Slows elimination rate from the precorneal area and enhance contact time.

 The polymers used include polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP),

methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC),

hydroxypropyl cellulose, polyacrylic acids, sodium carboxy methyl cellulose, carbomer.

 A minimum viscosity of 20 cst is needed for optimum corneal absorption.

Use of Penetration Enhancers:
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 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.

 The preservative agents used in most ophthalmic solutions and suspensions serve as potential drug penetration
enhancers. Ex: 0.01% benzalkonium chloride( Swanson et al.,1968)

 Increase in penetration of fluorescein in normal eye has been found in presence of chlorhexidine gluconate and
benzalkonium chloride. (toxic effect endothelium degeneration when prolong administration of topical
medications containing BAC).

 Another approach is concept of ion-pair formation which results in altered drug species with respect to ionic
size, diffusivity and partitioning behaviour.

Ex: a)Extent and rate of penetration of sodium cromoglycate, a dianonic drug was altered when ion-paired with
dodecylbenzylmethylethyl ammonium chloride.

b) The in-vivo corneal uptake of chloramphenicol succinate was found to have increased when ion-paired with m-
chloro benzyl tri-methyl phosphonium chloride( Olejnik, 1986)

Prodrugs:
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 They are simple, chemically or enzymatically liable derivatives of drugs which are converted to their active parent drug typically as a result of hydrolysis

within the eye(Stella et al.,1980)

 Enzyme systems identified in ocular tissues include esterases, ketone reductase, and steroid 6-hydroxylase.

 Most ophthalmic drugs contain functional groups such as alcohol, phenol, carboxylic acid and amine that lend themselves to derivatization.

 The modification of chemical structure of drugs centres on changing the physiochemical properties of drugs such as lipophilicity, solubility and pka.

 This technology helps in improving corneal permeability of drugs and also useful in solving pharmaceutical formulations problems such as poor

solubility and stability.

 Commercially available prodrug is Dipivalyl Epinephrine (Mandell, 1978). Approach has been extended to phenylephrine (Chien and Schoenwald,

1986), terbutaline(Schoenwald, 1987) and timolol (Chang et al., 1988).

 Chang et al.,(1988) demonstrated that O-butyl timolol ester prodrug increased the ocular absorption of topically applied timolol 4-6 times in the

pigmented rabbit thereby allowing a corresponding reduction in topical dose in either instilled concentration /volume.

 A concept of double prodrug is also gaining importance where a double prodrug is a prodrug of prodrug. Jarvinen et al.,(1992) synthesized (dibenzyl)

bispilocarpates, a pilocarpine double prodrug with adequate amount of aqueous solubility, improved delivery characteristics of pilocarpine and stability.

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Mucoadhesive:

 Mucoadhesion is based on entanglement of noncovalent bonds between polymers and conjunctival mucin.

 Mucin is capable of picking of 40-80 times of weight of water.

 Commonly used polymers in these formulations are many high molecular weight polymers with different functional groups like carboxyl,

hydroxyl, amino and sulphate which are capable of forming hydrogen bonds and not crossing biological membranes. These have been

screened as possible mucoadhesive excipients in ocular delivery systems.

 The Charged polymers i.e. both anionic and cationic polymers show better mucoadhesive capacity than the non-ionic ones.

a)Anionic polymers: Sodium alginate, Poloxamer, Carbomer, Sodium Carboxy Methoxy Cellulose.

b)Cationic polymers: Chitosan.

 This formulation helps in increasing the residence time of drug in the eye.

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Nanoparticles:

 This approach is considered mainly for the water soluble drugs. Nanoparticles are particulate drug delivery systems 10-1000 nm in the size in which

the drug may be dispersed, encapsulated or absorbed.

 Nanoparticles for ODD were mainly produced by emulsion polymerization.

 Polymerization is started by chemical initiation or by irradiation with gamma rays, ultraviolet or visible light.

 The emulsifier stabilizes the resulting polymer solution.

 The materials mainly used for the preparation of ophthalmic nanoparticles are polyalkylcyanoacrylates. The pH of the polymerization medium has to

be kept below 3.

 After polymerization pH may be adjusted to the desired value. The drugs may be added, before, during or after the polymerization. The polymers used

for the preparation of ophthalmic nanoparticles are rapidly bio-degradable. Hence the nanoparticles are very promising as targeted drug carriers to

inflamed region of the eye.

E.g. :- Nanoparticle of Pilocarpine enhances Mitotic response by 20-23%.

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Liposomes:

 The potential advantages achieved with the liposomes are the control of the rate of encapsulated drug and protection of the drug

from the metabolic enzymes present at the tear corneal epithelium interface.

 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. Phospholipids commonly used are

phosphatidylcholine, phosphatidylserine, phosphatidic acid sphingomyelins, and cardiolipins. They may be multilamellar vesicles

or unilamellar depending upon the number of concentric alternating layers of phospholipid and aqueous phases.

 They can be prepared by sonication of dispersion of phospholipids, reverse phase evaporation, solvent injection, detergent

removal or calcium induced fusion. Lipophilic drugs are delivered to a greater extent to the ocular system by these liposomes.

 The drawbacks associated with the liposomes in ocular drug delivery are due to short shelf life, limited loading capacity and

obstacles such as sterilization of the preparation.

Ex: liposomal preparation of idoxuridine

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Niosomes and Discosomes:

 The major limitations of liposomes are chemical instability, oxidative degradation of phospholipids, cost and purity of natural phospholipids.

 To avoid this Niosomes are developed as they are chemically stable as compared to liposomes and can entrap both hydrophobic and hydrophilic drugs.

 They are non toxic and do not require special handling techniques.

 Niosomes are nonionic surfactant vesicles that have potential applications in the delivery of hydrophobic or amphiphilic drugs.

 Discosomes may act as potential drug delivery carriers as they released drug in a sustained manner at the ocular site.

 Discosomes are giant Niosomes (about 20 um size) containing poly-24- oxy ethylene cholesteryl ether or otherwise known as Solulan 24.

 Pharmacosomes: This term is used for pure drug vesicles formed by the amphiphilic drugs. The amphiphilic prodrug is converted to pharmacosomes

on dilution with water.

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Controlled Delivery Systems 29

1. Implants:

 For chronic ocular diseases like cytomegalovirus (CMV) retinitis, implants are effective drug delivery system.

 Presently biodegradable polymers such as Poly Lactide/glycolide are safe and effective can deliver drug over 5-6 months.

 Retisert and intravitreal implants are able to deliver drug over a 6 months period.

2. Iontophoresis:

 In it direct current drives ions into cells or tissues. For iontophoresis the ions of importance should be charged molecules of the drug.

 Positively charged of drug are driven into the tissues at the anode and vice versa.

 Ocular iontophoresis delivery is not only fast, painless and safe but it can also deliver high concentration of the drug to a specific site.

3. Dendrimer:

They can successfully used for different routes of drug administration and have better water- solubility, bioavailability and biocompatibility.

4. Microemulsion:

 It is dispersion of water and oil stabilized using surfactant and co- surfactant to reduce interfacial tension and usually3 c0haracterized

by small droplet size (100 nm), higher thermodynamic stability and clear appearance.

 Selection of aqueous phase, organic phase and surfactant/co-surfactant systems are critical parameters which can affect stability of

the system.

5. Nanosuspensions:

 They 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.

 For commercial preparation of nanosuspensions, techniques like media milling and high-pressure homogenization have been used.

6. Microneedle:

 It 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.

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Ophthalmic Inserts

 They are aimed at remaining for a long period of time in front of eyes

 These solid devices are intended to be placed in the conjunctival sac and to deliver the drug at a comparatively low rate.

 Advantages of the system:-

i)Contact time is increased

ii) Accurate dosing is possible

iii) Constant and predictable rate of drug release can be achieved

iv) Better patient compliance.

v) Increase shelf life

vi) Targeting to internal ocular tissues can be done

 Two types of ocular inserts

a) Non erodible b) Erodible

 Two types of ocular inserts

a) Non erodible b) Erodible
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i) Ocusert i) Laciserts

ii) Contact lens ii) SODI

iii) Minidisc

Non-erodible Ocular inserts

i) Ocusert: was one of the earlier ocular inserts in use. The technology used in this is an insoluble delicate sandwich
technology. In ocusert the drug reservoir is a thin disc of pilocarpine-alginate complex sandwiched between two
transparent discs of micro porous membrane fabricated from ethylene-vinyl acetate copolymer. The micro porous
membranes permit the tear fluid to penetrate into the drug reservoir compartment to dissolve drug from the
complex.

E.g. Alza-ocusert: In this Pilocarpine molecules are then released at a constant rate of 20 or 40 µg/h for 4 to 7 days.
Used in the management of glaucoma.

ii) Contact Lens:

The use of pre-soaked hydrophilic contact lenses was used for ophthalmic drug delivery. Therapeutic s3of3t lenses are

used to aid corneal wound healing in patients with infection,

corneal ulcers, which is characterized by marked thinning of the cornea.

An alternative approach to pre-soaked soft contact lenses in drug solutions is to incorporate the drug either as a

solution or suspension of solid particles in the monomer mix. The polymerization is then carried out to fabricate the

contact lenses. This technique is promising longer release up to 180 h as compared to pre-soaked contact lenses

Disadvantages of these non-erodible ocular inserts are :

a) Complexity and difficulty of usage is noticed particularly in self administration.

b)Tolerability in the eye is poor, due to rigidity, size or shape.

c)Foreign body sensation and they are to be removed at the end of the dosing period.

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Erodible ophthalmic insert: 35

a) Lacisert: It is a sterile rod shaped device made up of hydroxyl propyl cellulose without any preservative is

used for the treatment of dry eye syndromes. It weighs 5 mg and measures 12.7 mm in diameter with a length

of 3.5 mm.

Lacisert is useful in the treatment of keratitis whose symptoms are difficult to treat with artificial tear alone. It is

inserted into the inferior fornix where it imbibes water from the conjunctiva and cornea, forms a hydrophilic film

which stabilizes the tear film and hydrates and lubricates the cornea. It dissolves in 24 hours.

b) SODI: Soluble Ocular Drug Insert is a small oval wafer developed for cosmonauts who could not use eye drops

in weightless conditions. It is sterile thin film of oval shape made from acrylamide, N- vinylpyrrolidone3 an6d

ethylacrylate. It weighs about 15-16 mg.

It is used in the treatment of glaucoma and trachoma. It is inserted into the inferior cul-de-sac and get wets and

softens in 10-15 seconds. After 10-15 min the film turns into a viscous polymer mass, after 30-60 minutes it turns

into polymer solutions and delivers the drug for about 24hours.

c) Minidisc: The minidisc consists of a contoured disc with a convex front and concave back surface in the

contact with the eyeball. It is like a miniature contact lens with a diameter of 4-5mm. The minidisc is made up of

silicone based prepolymer-α-omega-bis (4-methacryloxy) butyl polydimethyl siloxane. Minidisc can be hydrophilic

or hydrophobic to permit extend release of both water soluble and insoluble drugs.

New Ophthalmic Drug Delivery System:
The NODDS is a method of presenting drugs to the eye within a water soluble drug loaded film. It provides accura3te7, reproducible

dosing in an easily administered preservative free form. These systems were developed with two primary objectives:

a. To provide a sterile, preservative-free, water soluble, drug loaded film to the eye

b. It serves as a unit-dose formulation for the delivery of a precise amount of drug to the ocular surface.

The basic design of NODDS consists of three components-

-Water soluble, drug-loaded film (flag) attached via

-Thin, water soluble membrane film, to

-Thicker, water-soluble, handle film.

All the three films are made using the same grade of polyvinyl alcohol (PVA) in aqueous medium, but at three different

concentrations. The NODDS is approximately 50mm in length, 6mm in width, the flag (drug loaded film) is semi circular in shape

and has an area of 22 sq.mm and a thickness of 20 µm and a total weight of 500 µg of which 40% can be drug.

On contact with the tear film in the lower conjunctival sac, the membrane quickly dissolves releasing the flag into the tear film.

The flag hydrates allowing diffusion and absorption of the drug. For easy handling the handle film is sandwiched between the

paper strips before the whole unit is sealed in a moisture free pouch. By this system an eight fold greater bioavailability was

observed compared to the conventional eye drop.

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