Rashesh K., Kotecha Dan Mangi Ravi K., 2013, Advances in Opthalmic Drug Delivery System, Pharma...

Vol - 4, Issue - 4, Supl – 1, Sept 2013 ISSN: 0976-7908 Kotecha et al

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PHARMA SCIENCE MONITOR

AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

ADVANCES IN OPTHALMIC DRUG DELIVERY SYSTEM

Kotecha Rashesh K.*, Mangi Ravi K.

Parul Institute of Pharmacy, P.O. Limda, Ta. Waghodia, Dist. Vadodara – 391760, Gujarat, India.

ABSTRACT Eye is the most complicated and sophisticated organ of the body, so it is important that give the special attention to the eye diseases. Ocular drug delivery has been a major challenge for researchers due to its unique anatomy and physiology which contains various types of barriers such as different layers of cornea, sclera and retina as well as blood aqueous and blood–retinal barriers, choroidal and conjunctival blood flow etc. These barriers are inherent and unique to ocular anatomy and physiology making it a challenging task for drug delivery scientists. Ophthalmic drug delivery systems are classified as conventional and non-conventional drug delivery systems. Nanosuspension, nanoparticle, in situ gel, liposomes, and microemulsions have been investigated to overcome various barriers. Noninvasive methods designed to deliver drugs to intraocular regions, mainly for the treatment of posterior segment diseases. INTRODUCTION

Eye is a unique and very valuable organ. This is considered a window hinge. We can

enjoy it and look at the world body [1]. Designing a drug delivery system to target a

particular tissue of the eye has become a major challenging endeavours facing for

scientists in the field [2]. Topical administration is usually ideal over systemic

administration for eye disease, before reaching the anatomical barrier of the cornea, any

drug molecule administered by the ocular route firstly crosses the precorneal barriers.

These are the first barriers that slow the penetration of drug into the eye and consist of the

tear film and the conjunctiva [3].

The drug in suitable type of dosage form, upon instillation, stimulates the protective

physiological mechanisms, i.e., tear production, which exert a difficult defense against

ophthalmic drug delivery. Another serious problem of the elimination of topically

administered drugs from the precorneal area is the nasal cavity, as the nasal mucosal

membrane has greater surface area and higher permeability compared to that of the

cornea [3]. Normal dropper used with conventional ophthalmic solution delivers about 50-

75μl per drop and drops quickly drain until the eye is back to normal resident volume of

7μl. As a result of this drug loss in front of the eye, very small amount of drug is



available to enter the cornea and inner tissue of the eye [4]. Actual corneal permeability of

the drug is relatively low and very small corneal contact time (about 1-2 min) in humans

for instilled solution usually less than 10%. Therefore only small amount of drug actually

penetrates the cornea and reaches intraocular tissue [3].

Many ophthalmic drug delivery systems are available. These are classified as

conventional and nonconventional (newer) drug delivery systems. Most commonly

available ophthalmic preparations are eye drops and ointments about 70% of the eye

dosage formulations in market. But these preparations when instilled into the cul-de-sac

are rapidly drained away from the ocular cavity due to tear flow and lachrymal nasal

drainage. Only a small amount is available for its therapeutic effect [5].

The following characteristics are required to optimize ocular drug delivery systems.

A good corneal penetration.

A prolonged contact time of drug with corneal tissue.

Simplicity of installation and removal for the patient.

A non-irritative and at ease form (the viscous solution should not irritate

lachrimation and reflex flashing).

Appropriate rheological properties and concentration of viscolyzer [6].

ANATOMY AND PHYSIOLOGY OF EYE

The eye is a spherical structure with a wall made up of three layers; the outer part sclera,

the middle parts choroid layer, Ciliary body and iris and the inner section nervous tissue

layer retina [7].

Aqueous Humour: The aqueous humour is a jelly-like substance located in the anterior

chamber of the eye [8].

Choroid: The choroid layer is located behind the retina and absorbs unused radiation.

Ciliary Muscle: The ciliary muscle is a ring-shaped muscle attached to the iris. It is

important because contraction and relaxation of the ciliary muscle controls the shape of

the lens [9].

Cornea: The cornea is the most anterior part of the eye, in front of the iris and pupil. It is

the most densely innervated tissue of the body, and most corneal nerves are sensory

nerves, derived from the ophthalmic branch of the trigeminal nerve. Five layers can be

distinguished in the human cornea: the epithelium, Bowman’s membrane, the lamellar



stroma, Desçemet’s membrane and the endothelium [10]. The main barrier of drug

absorption into the eye is the corneal epithelium, in comparison to many other epithelial

tissues (intestinal, nasal, bronchial, and tracheal) that is relatively impermeable. The

transcellular or paracellular pathway is the main pathway to penetrate drug across the

corneal epithelium. The lipophilic drugs choose the transcellular route whereas the

hydrophilic one chooses paracellular pathway for penetration [7].

Sclera: The sclera is a tough white sheath around the outside of the eye-ball. This is the

part of the eye that is referred to by the colloquial terms "white of the eye” [8].

Retina: The retina may be described as the "screen" on which an image is formed by

light that has passed into the eye via the cornea, aqueous humour, pupil, lens, then the

hyaloid and finally the vitreous humour before reaching the retina. The retina contains

photosensitive elements (called rods and cones) that convert the light they detect into

nerve impulses that are then sent onto the brain along the optic nerve [8].

Conjunctiva: The conjunctiva is involved in the formation and maintenance of the

precorneal tear film and the protection of the eye. It is a thin, vascularized mucous

membrane that lines the posterior surface of the eyelids and outer regions of the cornea

[11].

ROUTES OF OCULAR DRUG DELIVERY

Fig. 1: Different Routes for Ocular Drug Delivery [8]



Topical route:

Generally topical ocular drug administration is accomplished by eye drops, but they have

only a short contact time on the eye surface. The contact and duration of drug action can

be prolonged by formulation design (e.g. gels, gelifying formulations, ointments, and

inserts) [12]. During the short contact of drug on the corneal surface it partitions to the

epithelium and in the case of lipophilic compounds it remains in the epithelium and is

slowly released to the corneal stroma and further to the anterior chamber [13]. After eye

drop administration the peak concentration in the anterior chamber is reached after 20–30

min, but this concentration is typically two orders of magnitude lower than the instilled

concentration even for lipophilic compounds [14]. From the aqueous humor the drug has

an easy access to the iris and ciliary body, where the drug may bind to melanin. Melanin

bound drug may form a reservoir that is released gradually to the surrounding cells,

thereby prolonging the drug activity [1].

Fig. 2: Topical administration to retina: Cornea as a barrier [8]

Sub-conjunctival administration:

Traditionally sub-conjunctival injections have been used to deliver drugs at increased

levels to the uvea. Currently this mode of drug delivery has gained new momentum for



various reasons. The progress in materials sciences and pharmaceutical formulation have

provided new exciting possibilities to develop controlled release formulations to deliver

drugs to the posterior segment and to guide the healing process after surgery (e.g.

glaucoma surgery) [7]. The development of new therapies for macular degeneration

(antibodies, oligonucleotides) must be delivered to the retina and choroid [15, 16]. After

subconjunctival injection drug must penetrate across sclera which is more permeable than

the cornea. Permeability of sclera is not dependent on drug lipophilicity [1].

Periocular and intravitreal administration:

Even though it is not very patient compliant, these routes are employed partly to

overcome the inefficiency of topical and systemic dosing to deliver therapeutic drug

concentrations to the posterior segment. In addition, systemic administration may lead to

side effects making it a less desirable delivery route for geriatric patients. The periocular

route includes subconjunctival, subtenon, retrobulbar, and peribulbar administration and

is comparatively less invasive than intravitreal route. The drug administered by periocular

injections can reach the posterior segment by three different pathways like transscleral

pathway, systemic circulation through the choroid and the anterior pathway through the

tear film, cornea, aqueous humor, and the vitreous humour [17].

BARRIER TO EYE

Drug loss from the ocular surface

The flow of lacrimal fluid removes instilled compounds from the surface of the eye after

instillation. Even though the lacrimal turnover rate is only about 1 μl/min the excess

volume of the instilled fluid is flown to the nasolacrimal duct rapidly in a couple of

minutes. Another source of non-productive drug removal is its systemic absorption

instead of ocular absorption. Systemic absorption may take place either directly from the

conjunctival sac via local blood capillaries or after the solution flow to the nasal cavity [5].

Lacrimal fluid-eye barriers

Corneal epithelium limits drug absorption from the lacrimal fluid into the eye. The

corneal epithelial cells form tight junctions that limit the paracellular drug permeation.

Therefore, lipophilic drugs have typically at least an order of magnitude higher

permeability in the cornea than the hydrophilic drugs. In general, the conjunctiva is



leakier epithelium than the cornea and its surface area is also nearly 20 times greater than

that of the cornea [8].

Blood-ocular barriers

A number of ocular inserts were prepared utilizing different techniques to make soluble,

erodible, nonerodible and hydrogel inserts [19]. The eye is protected from the xenobiotics

in the blood stream by blood-ocular barriers. These barriers have two parts (1) blood-

aqueous barrier (2) blood-retina barrier (BRB) [5].The blood-aqueous barrier and the

Blood-retinal-barrier regulate the transport of molecules from the systemic circulation to

anterior and posterior ocular tissue, respectively. These barriers are reported to limit the

intravitreal drug levels of poorly lipid soluble antibiotics to ~10% of serum levels [19].

MECHANISM OF OCULAR DRUG ABSORPTION

Elimination of instilled dose via different routes

Several mechanisms such as a relatively impermeable corneal barrier and rapid drainage

of the instilled solution protect the eye. Lee and Robinson have shown that drugs are

mainly eliminated from the precorneal lacrimal fluid by solution drainage, lacrimation

and nonproductive absorption to the conjunctiva of the eye. These factors and the cornea

barrier limit the penetration of the topically administered drug into the eye. Only a few

percent of the applied dose is delivered into intraocular tissues, while the major part (50-

100%) of the dose is absorbed systemically. Elimination of instilled dose via different

routes [8].



Fig. 3: Elimination of instilled dose via different routes [8]

DRUG ABSORPTION

Drug absorption occurs through corneal and non-corneal pathways. Mostly non-corneal

absorption occurs by way of the nasolacrimal duct and leads to non-productive systemic

uptake, while majority of drugs transported through the cornea is taken up by the targeted

intraocular tissue. Corneal absorption is limited by drainage of the instilled solutions,

lacrimation, tear turnover, metabolism, tear evaporation, non-productive

absorption/adsorption, limited corneal area, poor corneal permeability, binding by the

lacrimal proteins, enzymatic degradation and the corneal epithelium itself. These

limitations confine the absorption window to a few minutes after administration and

reduce corneal absorption to < 5% [5].



Fig. 4: Schematic diagram of ocular distribution [5].

Ophthalmic Preparations

Conventional ophthalmic dosage forms

Liquids: Eye drops/lotion- Eye drops may be solutions or suspensions and are

comparatively convenient, safe, immediately active and acceptable to patients. An eye

drops is sterile, contains a preservative, is isotonic, has a pH of about 7.4 for the patient

comfort and has a limited shelf life after opening (if used more than one time). Eye

lotions are isotonic, sterile solutions for the irrigation of the eye, usually as a single use

first aid treatment [20].

Polymers are frequently added to ophthalmic solutions and suspensions with the aim of

increase the viscosity of the vehicle which prolongs contact with the cornea, so that

enhancing bioavailability. Generally, the high molecular weight hydrophilic polymers

such as poly vinyl alcohol, hyaluronic acid, dextran, gellan, methyl cellulose, hydroxyl

methyl cellulose are unlikely to cross the biological membrane [3].

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Ointments: While ophthalmic solutions are certainly the most preferred dosage forms,

ophthalmic ointments are still being marketed for night time applications and where

prolonged therapeutic actions are required. Major drawback of the ophthalmic ointments

is that they cause blurred vision due to refractive index difference between the tears and

the non-aqueous nature of the ointment and inaccurate dosing. Nevertheless, desirable

attributes for ointment development should include factors such as (a) they should not be

irritating to the eye (b) they should be uniform (c) they should not cause excessive

blurred vision and (d) they should be easily manufacturable. Manufacturing process for

an ophthalmic ointment includes micronization and sterilization of the active agent by dry

heat, ethylene oxide irradiation or gamma irradiation. Antimicrobial preservatives (if

required) such as chlorobutanol or parabens are dissolved in a mixture of molten

petrolatum and mineral oil and cooled to about 40°C with continuous mixing to assure

homogeneity. Sterilized and micronized active is then added aseptically to the warm

sterilized petrolatum mineral oil mixture with continuous mixing until the ointment is

homogeneous. The ointment is then filled into presterilized ophthalmic tubes [8].

Gels and mucoadhesive polymer systems: Mucoadhesive polymers can provide a

localized delivery of an active agent to a specific site in the body such as the eye. Such

polymers have a property known as bioadhesion meaning attachment of a drug carrier to

a specific biological tissue such as the epithelium and possibly to the mucosal surface of

such tissues. These polymers are able to increase the contact time of the drug with the

biological tissues and thereby improve ocular bioavailability [8].

RECENT ADVANCES AND CHALLENGES IN OCULAR DRUG DELIVERY

SYSTEM

Sol to gel systems

The new concept of producing an in situ gel was suggested for the first time in the early

1980s. It is widely accepted that increasing the viscosity of a drug formulation in the

precorneal region leads to an increased bioavailability, due to slower drainage from the

cornea. Several concepts have been investigated for the in situ gelling systems. These

systems can be triggered by pH, temperature or by ion activation. Middleton and

Robinson prepared a sol to gel system with mucoadhesive property to deliver the steroid

fluorometholone to the eye [5].



Nanosuspensions

Nanosuspensions are preferred 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. Various

techniques like media milling and high pressure homogenization have been used for

preparation of nanosuspension [21]. Nanosuspension consists of pure poorly water soluble

drug, suspended in appropriate dispersion medium.

Microemulsion

Due to their intrinsic properties and specific structures, microemulsions are a promising

dosage form for the natural defense of the eye. Because they are prepared by inexpensive

processes through auto emulsification or supply of energy and can be sterilized easily,

they are stable and have a high capacity of dissolving the drugs. The In vivo results and

preliminary studies on healthy volunteers have shown a delayed effect and an increase in

the bioavailability of the drug. The proposed mechanism is based on the adsorption of the

nanodroplets representing the internal phase of the microemulsions, which constitutes a

reservoir of the drug on the cornea and should then limit their drainage [1].

Liposomes and Niosomes

Liposomes are phospholipid-lipid vesicles for targeting drugs to the specific sites in the

body. They offer controlled and selective drug delivery and improved bioavailability and

their potential in ocular drug delivery appears greater for lipophilic than hydrophilic

compounds. liposomes are less stable than particulate polymeric drug delivery systems

[4].

In order to avoid the limitations of liposomes, such as chemical instability, oxidative

degradation of phospholipids, cost and purity of natural phospholipids, niosomes have

been developed as they are chemically stable compared to liposomes and can entrap both

hydrophilic and hydrophobic drugs [4].

Ocular inserts:

Ocular inserts are solid dosage forms and can overcome the drawbacks reported with

traditional ophthalmic systems like aqueous solutions, suspensions and ointments. The

ocular inserts maintain an effective drug concentration in the target tissues. Limited

recognition of ocular inserts has been attributed to psychological factors, such as



reluctance of patients to abandon the traditional liquid and semisolid medications and to

occasional therapeutic failures (e.g., unnoticed expulsions from the eye, membrane

rupture, etc.) A number of ocular inserts were prepared utilizing different techniques to

make soluble, erodible, nonerodible and hydrogel inserts [1]. The examples of ocular

inserts are given in Table 1.

Table1. Ocular inserts devices [1]

NAME DESCRIPTION

Soluble ocular

drug Insert

Small oval wafer, composed of soluble copolymers consisting of

actylamide, N-venyl pyrrolidone and ethyl acetate, soften on

insertion

Ocusert Flat, flexible elliptical insoluble device consisting of two layers,

enclosing a reservior, use commercially to deliver Pilocarpine for 7

days

Minidisc or

ocular

Therapeutic

system 4-5 mm diameter contoured either hydrophilic or

hydrophobic disc

Lacrisert Rose-shape device made from Hydroxy propyl cellulose use for the

eye syndrome as an alternative to tears

Bioadhesive

ophthalmic eye

insets

Adhesive rods based on a mixture of Hydroxy propyl cellulose, ethyl

cellulose, Poly acrylic acid cellulosephthalate

Gel foam Slabs of Gel foam impregnated with a mixture of drug and cetyl ester

wax in chloroform

MICRONEEDLE AND ULTRASOUND OCULAR DRUG DELIVERY SYSTEMS

All these delivery systems are noninvasive methods designed to deliver drugs to

intraocular regions, mainly for the treatment of posterior segment diseases. Researchers

have developed drug-coated microneedles with a length of 500 to 750 μm. The drug to be

delivered can be coated on the solid metal. Following administration, coated molecules

dissolve rapidly, and subsequently, microneedles are removed from the tissue. This

delivery system generates a much higher concentration compared to a free drug solution



[22]. Sodium fluorescein and pilocarpine were coated and delivered using a similar

technique. In the case of sodium fluorescein, permeation was found to be 60 fold higher,

and in the case of pilocarpine, rapid constriction of pupil was observed. Similarly,

intrascleral hollow microneedles have also been developed. This delivery system is able

to deliver microparticles, nanoparticles, and drugs in a solution with minimal invasion.

To deliver microparticles, concomitant administration of spreading enzymes such as

hyaluronidase and collagenase is also necessary. These enzymes rapidly hydrolyze the

collagenous and extracellular matrix structure of the sclera making the delivery of

microparticles feasible [23].

Similarly, ultrasound-mediated drug delivery has also received attention in recent years.

Delivery of beta-blockers such as atenolol, carteolol, timolol, and betaxolol, was

attempted with ultrasound application (20 kHz for 1 h) across cornea in the treatment of

glaucoma. Corneal permeability of these compounds has been significantly enhanced

with ultrasound.

Recently, researchers have attempted to deliver a hydrophilic molecule, sodium

fluorescein, at an ultrasound frequency of 880 kHz and intensities of 0.19–0.56 W/cm2

with exposure duration of 5 min. This study reported a tenfold enhancement in corneal

permeation with minor changes in the epithelium [24].

IONTOPHORESIS DRUG DELIVERY SYSTEM

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 [25]. If the drug molecules carry a positive charge, they are driven into the tissues

at the anode, if the drug molecules carry a negative charge; they are driven into the

tissues at the cathode. Ocular iontophoresis offers a drug delivery system that is fast,

painless and safe; and in most cases, it results in the delivery of a high concentration of

the drug to a specific site. Iontophoretic application of antibiotics may enhance their

bactericidal activity and reduce the severity of disease; similar application of anti-

inflammatory agents could prevent or reduce vision threatening side effects [26, 27]. But the

role of iontophoresis in clinical ophthalmology remains to be identified.



CONCLUSION

It can be concluded from whole study that many successes in ODDSs for prolonging

retention time and reducing dosing frequency have been achieved but the additional

system should be both comfortable and easy to use. Patient acceptance will continue to be

emphasized in the design of future ophthalmic drug delivery systems. Nanosuspension,

nanoemulsion, in situ gel, liposomes and niosomes like dosage forms are widely

employed in the field of ODDSs. Stability is a major problem in liposomes and

particulates. Advances in nanotechnology and noninvasive drug delivery techniques will

remain in the front position because they provide protective and effective therapy for the

nearly inaccessible diseases of eyes.

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For Correspondence: Kotecha Rashesh K. Email: [email protected]

Rashesh K., Kotecha Dan Mangi Ravi K., 2013, Advances in Opthalmic Drug Delivery System, Pharma...

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