AN UPDATE REVIEW ON NOVEL ADVANCED … UPDATE REVIEW ON NOVEL ADVANCED OCULAR DRUG DELIVERY SYSTEM...

www.wjpps.com

545

Rituraj et al. World Journal of Pharmacy and Pharmaceutical Sciences

AN UPDATE REVIEW ON NOVEL ADVANCED OCULAR DRUG

DELIVERY SYSTEM

*Rituraj Shivhare1, Ashish Pathak 1, Nikhil Shrivastava2, Chandraveer Singh1,

Gourav Tiwari1, Rajkumar Goyal 1

1Department of Pharmaceutics, ShriRam College of Pharmacy, S.R.G.O.C. Campus, AB

Expressway Banmore, Morena, M.P., India.

2Department of Pharmacology, ShriRam College of Pharmacy, S.R.G.O.C. Campus, AB

Expressway Banmore, Morena, M.P., India.

ABSTRACT

Eye is the most complicated and sophisticated organ of the body, so it

is important that give the especial attention to the eye diseases. For

eye diseases various drug delivery system are available but there are

various limitation like rapid drainage, loss from tear flow, eye

sensitivity due to protective anatomy and physiology of eye.

Absorption and elimination of therapeutic active agents depend upon

the physiochemical, microbiological and pharmaceutical properties of

dosage form and also depend upon the eye anatomy and physiology.

Problems which are associated with conventional ophthalmic dosage

form may reduce with new drug delivery system. New drug delivery

system improves the bioavailability, residence time, doctor and

patient complies and reduces the toxic effect, systemic side effect,

frequency of dosing and discomfort of patients. There are many new

drug delivery systems available which are applied in the eye. In this review we are focusing

on various new drug delivery system like inserts, contact lenses, mucoadhesive, collagen

shield, penetration enhancers, implants, particulate and vasicular system like liposomes,

niosomes, pharmacosomes, microemulsion, nanoparticles, iontophoresis, dendrimers and also

on more recent advanced approaches like gene therapy, aptamers, protein and peptide

therapy, oligonucliotide, siRNA, stem cell therapy and many more.

WWOORRLLDD JJOOUURRNNAALL OOFF PPHHAARRMMAACCYY AANNDD PPHHAARRMMAACCEEUUTTIICCAALL SSCCIIEENNCCEESS

VVoolluummee 11,, IIssssuuee 22,, 554455--556688.. RReevviieeww AArrttiiccllee IISSSSNN 2278 – 4357

Article Received on 15 July 2012, Revised on 22 July 2012, Accepted on 27July 2012

*Correspondence for

Author:

* Rituraj Shivhare

Department of Pharmaceutics

ShriRam College of Pharmacy.

Banmore, Morena M.P. India.

[email protected]

www.wjpps.com

546


Keywords: rapid drainage, physiochemical, microbiological, pharmaceutical properties, new

drug delivery system.

INTRODUCTION

The field of ocular delivery is one of the most interesting and challenging Endeavours facing

the pharmaceutical scientist. This is significantly improved over past few 10-20 years[1]. In

the earlier period, drug delivery to the eye has been limited to topical application,

redistribution into the eye following systemic administration or directs intraocular/periocular

injections[2]. Dosage forms are administered directly to the eye for localized ophthalmic

therapy[3]. Topical application of drugs to the eye is the well established route of

administration for the treatment of various eye diseases like dryness, conjunctiva, eye flu etc.

Therefore marketed ophthalmic dosage formulations are classified as conventional and non-

conventional (newer) drug delivery systems. There are most commonly available ophthalmic

preparations such as drops and ointments about 70% of the eye dosage formulations in

market[4]. Topical application of drugs to the eye is the most popular and well-accepted route

of administration for the treatment of various eye disorders[5].

Topical administration is generally considered the preferred route for the administration of

ocular drugs due to its convenience and affordability. Drug absorption occurs through corneal

and non-corneal pathways. Most non-corneal absorption occurs via the nasolacrimal duct and

leads to non-productive systemic uptake, while most drug transported through the cornea is

taken up by the targeted intraocular tissue. Unfortunately, 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[6].

These preparations when instilled into eye they are rapidly drained away from the ocular

surface, only a small amount of drug is available for its therapeutic effect resulting in

frequent dosing application to the eye[4]. Ophthalmic diseases are most commonly treated by

topical eye-drop instillation of aqueous products. These formulations, however, raise

technical problems (e.g., solubility, stability, and preservation) and clinical issues (efficacy,

local toxicity and compliance)[7]. It leads to development of advanced techniques for ocular

therapy those include particulate delivery system which improves the pharmacokinetic and

pharmacodynamic properties of various types of drug molecules and novel controlled drug

delivery systems such as dendrimers, microemulsions, muco-adhesive polymers, hydrogels,

www.wjpps.com

547


iontophoresis, collagenshield, prodrug approaches. Other advanced approaches for the

treatment of macular degeneration include intravitreal small interfering RNA (siRNA) and

inherited retinal degenerations involve gene therapy. The rapid progress of the biosciences

opens new possibilities to meet the needs of the posterior segment treatments. The examples

include the antisense and aptamer drugs for the treatment of cytomegalovirus (CMV) retinitis

and age-related macular degeneration, respectively, and the monoclonal antibodies for the

treatment of the age-related macular degeneration[8].

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 lachrymation

and reflex flashing).

Appropriate rheological properties and concentration of viscolyzer[10].

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[4]. 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 [3].

Fig.1: Cross section of the eye[3]

www.wjpps.com

548


The 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[12]. 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[4].

The Sclera

The sclera is hydrated and has large collagen fibrils arranged haphazardly; therefore, it is

opaque and white rather than clear. The sclera has three layers: the episclera, the outer layer;

the sclera; and the melanocytic layer, the inner lamina fusca.

The Retina

The sensory retina covers the inner portion of the posterior two-thirds of the wall of the

globe. It is a thin structure which in the living state is transparent and of a purplish-red color

due to the visual purple of the rods. The retina is a multilayered sheet of neural tissue closely

applied to a single layer of pigmented epithelial cells[13] The retina is protected and held in

the appropriate position by the surrounding sclera and cornea[12].

Aqueous Humor

Aqueous humor, contained in the anterior compartment of the eye, is produced by the ciliary

body and drained through outflow channels into the extraocular venous system. The aqueous

circulation is a vital element in the maintenance of normal intraocular pressure (IOP) and in

the supply of nutrients to avascular transparent ocular media, the lens and the cornea[13].

The 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[14].

www.wjpps.com

549


OCULAR DISORDERS

Blepharitis: An infection of lid tructures (usuallyby staphylococcus aureus) with

concomitant seborrhoea, rosacea, a dry eye and abnormalities in lipid secretions.

Conjunctivitis: The condition in which redness of eye and presence of a foreign body

sensation are evident. There are many causes of conjunctivitis but the great majority is the

result of acute infection or allergy[11]. An inflammation of the conjunctiva may be caused by

bacterial and viral infection, pollen and other allergens, smoke and pollutants.

Keratitis: an inflammation of the cornea, caused by bacterial, viral or fungal infection[14].

The condition in which patient have a decreased vision ,ocular pain, red eye, and often a

cloud / opaque cornea .It is mainly caused by bacteria ,viruses, fungi etc.

Trachoma: This is caused by the organism chalmydia trachoma is; it is the most common

cause of blindness in North Africa and Middle East[11].

Glaucoma: the build up of pressure in the anterior and posterior chambers of the choroid

layer that occurs when the aqueous humour fails to drain properly[14] More than 2% of the

population over age 40 years have this disorder in which an increased intraocular pressure

greater than 22 mg Hg ultimately compromises blood flow to retina and thus causes death of

peripheral optic nerves[11].

Iritis (anterior uveitis): commonly has as acute onset with the patient suffering pain and

inflammation of the eye[14].

ROUTES OF DRUG DELIVERY

There are three main routes commonly used for administration of drugs to the eye: topical,

intraocular and systemic. The topical route is the most common method to administer a

medication to the eye[1], but such drops are outflow quickly due to the eye blinking reflux,

and the precorneal region returns to maintain resident volume of around 7µl. The available

concentration of drug in precorneal fluid provides the driving force for passive transport of

drug across the cornea[4].The intraocular route is more difficult to achieve practically. Now

research is concentrating on the development of intravitreal injections and use of intraocular

implants to improve delivery to eye[1].

www.wjpps.com

550


Fig.2: Disadvantages and complications associated with ocular drug delivery[9].

DRUG ABSORPTION

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

absorption occurs via the nasolacrimal duct and leads to non-productive systemic uptake,

while most drug transported through the cornea is taken up by the targeted intraocular tissue.

Unfortunately, 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%[6].

Fig.3: Schematic diagram of ocular distribution1.

Ocular absorption (5% of the dose) Systemic absorption (50-100% of the dose)

Corneal Route

-small

-lipophilic drugs

Conjunctival and scleral route

-large hydrophilic drugs

Aqueous humor

Ocular tissues Elimination

Drug in tear fluid

www.wjpps.com

551


CRITICAL BARRIERS IN OCULAR THERAPEUTICS

Drug loss from the ocular surface

After instillation, the flow of lacrimal fluid removes instilled compounds from the surface of

the eye. 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[16].

Systemic absorption may take place either directly from the conjunctival sac via local blood

capillaries or after the solution flow to the nasal cavity. Anyway, most of small molecular

weight drug dose is absorbed into systemic circulation rapidly in few minutes. This contrasts

the low ocular bioavailability of less than 5%[5].

Lacrimal fluid-eye barriers

The corneal barrier is formed upon maturation of the epithelial cells. They migrate from the

limbal region towards the center of the cornea and to the apical surface[16]. The most apical

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. Despite the tightness of the corneal epithelial layer,

transcorneal permeation is the main route of drug entrance from the lacrimal fluid to the

aqueous humor[5].

Blood-ocular barriers

The eye is protected from the xenobiotics in the blood stream by blood-ocular barriers. These

barriers have two parts: blood-aqueous barrier and blood-retina barrier [5].The blood-aqueous-

barrier and the blood-retinal-barrier (BRB) 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[6].

CONVANTIONAL DRUG DELIVERY SYSTEM

The conventional ophthalmic drug delivery systems are used in today’s ocular disease

treatment and preventions are solutions, suspensions, ointments and Bioadhesive polymer

gel. In spite of significant criticisms over the efficacy and efficiency of these conventional

systems, such as limitation are such as bioavailability, sterility, dosing administration[4].

www.wjpps.com

552


Sites and methods for ocular drug delivery to the eye

Fig. 4: Sites and methods for ocular drug delivery to the eye[9].

Eye Drops

These are liquid preparation contain drug substances which are used in ocular drug delivery.

The drug substance must be active on surface of eye or internal region of eye after passage

through cornea or conjunctiva[10]. Eye drops are widely administered in the form of Solutions,

Emulsion and Suspension. Generally eye drops are used only for anterior segment disorders

as adequate drug concentrations are not reached in the posterior tissues using this drug

delivery method[2]. A considerable disadvantage of using eye drops is the rapid elimination of

the solution and their poor bioavailability[5]. Various properties of eye drops like hydrogen

ion concentration, osmolality, viscosity and instilled volume can influence retention of a

solution in the eye. Less than 5 Percent of the dose is absorbed after topical administration

into the eye. The dose is mostly absorbed to the systemic blood circulation via the

conjunctival and nasal blood vessels[8].

Ointment and Gels

Prolongation of drug contact time with the external ocular surface can be achieved using

ophthalmic ointment vehicle but, the major drawback of this dosage form like, blurring of

vision and matting of eyelids can limits its use[8]. Pilopine HS gel containing pilocarpine was

used to provide sustain action over a period of 24 hours[2].

www.wjpps.com

553


Sol to gel systems

The new concept of producing a gel in situ (e.g., in the cul-de-sac of the eye) 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[10]. Several concepts for the in situ gelling systems have been

investigated. 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].

Ophthalmic inserts

Ophthalmic inserts are aimed at remaining for a long period of time in front of the eye.

These solid devices are intended to be placed in the conjunctival sac and to deliver the drug at

a comparatively slow rate[11]. These are solid dosage forms and can overcome the

disadvantage reported with traditional ophthalmic systems like aqueous solutions,

suspensions and ointments. The ocular inserts maintain an effective drug concentration in the

target tissues[5]. Inserts are available in different varieties depending upon their composition

and applications[2].

Non erodible inserts: ocusert, contact lance.

Ocuserts are described as single, sterile, thin, and multilayered, drug impregnated, solid or

semisolid consistency devices, whose size and shape are especially designed for application

in eye. A polymeric support is must for the ocular inserts which may or may not contain the

drug. The drug is later entrapped or dispersed or the drug can be incorporated as a solution in

the polymeric supports which have advantages as they increases the residence of the drug in

the eye so a sustained release dosage form would be formulated . The drug release from the

inserts would take place by following three procedures 1) diffusion, 2) osmosis, and 3)

bioerosion[4].

Contact lenses

Contact lenses can absorb water-soluble drugs when soaked in drug solutions. These drug

saturated contact lenses are placed in the eye for releasing the drug for a long period of time.

The hydrophilic contact lenses can be used to prolong the ocular residence time of the drugs.

In humans, the Bionite lens which was made from hydrophilic polymer (2-hydroxy ethyl

methacrylate) has been shown to produce a greater penetration of fluorescein[5]. Several kinds

of polymers have been used for the preparation of these lenses. They are made up of hydro

www.wjpps.com

554


gels that absorb certain amounts of aqueous solution, because of this property they have been

found useful for drug delivery to anterior of the eye[3]. For prolongation of ocular residence

time of the drugs, hydrophilic contact lenses can be used[8].

Fig. 5: ocusert[3]

2. Erodible ophthalmic insert: The marketed devices of erodible drug inserts are Laciserts,

SODI, and Minidisc.

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[11]. This device was introduced by

Merck, Sharp and Dohme in 1981.It weighs 5 mg and measures 12.7 mm in diameter with a

length of 3.5mm.[8].

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-vinylpyrrolidone and ethylacrylate called as ABE[11]. After introduction into

cul de sacs where wetted by tear film it softens in 10-15 seconds and assumes the curved

configuration of the globe. During the following 10-15 min; the film turns into viscous

polymer mass thereafter in 30-60 min it becomes a polymer solution[8].

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

www.wjpps.com

555


minidisc is made up of silicone based prepolymer-α-ψ-bis (4-methacryloxy) butyl

polydimethyl siloxane. Minidisc can be hydrophilic or hydrophobic to permit extend release

of both water soluble and insoluble drugs[11].

Fig. 6: Non-biodegradable and biodegradable inserts[9].

B.VESICULAR SYSTEM

Liposomes

Liposomes are biocompatible and biodegradable lipid vesicles made up of natural lipids and

about 25–10000 nm in diameter. They are having an intimate contact with the corneal and

conjunctival surfaces which is desirable for drugs that are poorly absorbed, the drugs with

low partition coefficient, poor solubility or those with medium to high molecular weights and

thus increases the probability of ocular drug absorption[8]. The potential advantage achieved

with the liposome have been have been the control of the rate of encapsulated drug and

protection of drug from metabolic enzymes present at tear corneal epithelium surface. The

biodegradable and non toxic nature has stimulated interest in the use of liposome as drug

carriers in ocular delivery. Liposomes are lipid vesicles enclosing an aqueous volume. They

can be prepared by sonication of dispersed of phospholipids, reverse phase evaporation,

solvent injection and detergent removal or calcium induced fusion. Much research in the

recent years has concentrated on the methods of increasing the precorneal residence of

vesicles. Vesicles have been suspended in polymer solutions. Accumulation of drug in the

cornea could occur by endocytosis of the liposomes. In order to enhance adherence to the

corneal/conjunctival surface, dispersion of the liposomes in mucoadhesive gels or coating the

www.wjpps.com

556


liposomes with muco-adhesive polymers was proposed. Several muco-adhesive polymers

were employed are poly (acrylic acid) (PAA), hyaluronic acid (HA), chitosan, poloxame[1].

Limitations: The major limitations of liposomes are chemical instability, oxidative

degradation of phospholipids, cost and purity of natural phospholipids[8].

Niosomes and Discomes

Niosomes are nonionic surfactant vesicles that have potential applications in the delivery of

hydrophobic or amphiphilic drugs[8]. 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[2]. Vyas and co workers reported that there was about

2.49 times increase in the ocular bioavailability of timolol maleate encapsulated in niosome

as compared to timolol maleate solution. Non-ionic surface active agents based discoidal

vesicles known as (discomes) loaded with timolol maleate were formulated and characterized

for their in vivo parameters. In vivo studies showed that discomes released the contents in a

biphasic profile if the drug was loaded using a pH gradient technique[8].

Pharmacosomes

Pharmacosomes are amphiphilic lipid vesicular system possessing phospholipid complexes to

improve bioavailability of poor water soluble as well as poorly lipophilic drugs[18] . The

pharmacosomes show greater shelf stability, controlled release profile[2] . these particulate

carriers are colloidal dispersion of drugs bound covalently, electrostatically or by hydrogen

bonds to phospholipid. Depending upon the chemical structure, pharmacosomes exist as

ultrafine miceller or hexagonal aggregates.

Advantages of pharmacosomes

1. No problem of drug incorporation.

2. No risk of leakage of drug on it is covalently conjugated with lipid.

3. Predetermined maximum entrapment efficiency can be achieved as the drug is covalently

conjugated with lipid.

4. Suitable for both hydrophilic and lipophilic drug.

5. In the vesicular and miceller state the phase transition temperature of pharmacosomes

have significant effect on their interaction with membrane.

www.wjpps.com

557


Limitation:

1. Covalent bonding is required to protect the leakage of drugs.

2. Amphiphilic nature is responsible for synthesis of a compound.

3. On storage pharmacosome undergoes fusion, aggregation as well as chemical

hydrolysis[18] .

CONTROL DELIVERY SYSTEMS

Advantages of controlled ocular drug delivery systems

1. Increased accurate dosing. To overcome the side effects of pulsed dosing produced by

conventional systems.

2. To provide sustained and controlled drug delivery.

3. To increase the ocular bioavailability of drug by increasing the corneal contact time. This

can be achieved by effective adherence to corneal surface.

4. To provide targeting within the ocular globe so as to prevent the loss to other ocular

tissues.

5. To circumvent the protective barriers like drainage, lacrimation and conjunctival

absorption [19].

Mechanism of controlled sustained drug release into the eye

The corneal absorption represents the major mechanism of absorption for the most

conventional ocular therapeutic entities.

Passive Diffusion is the major mechanism of absorption for nor‐erodible ocular insert

with dispersed drug.

Controlled release can further regulated by gradual dissolution of solid dispersed drug

within this matrix as a result of inward diffusion of aqueous solution[1] .

Implants

Ocular implants have many advantages over more traditional methods of drug administration

to the eye, including delivering constant therapeutic levels of drug directly to the site of

action and bypassing the blood–brain barrier. Release rates are typically well below toxic

levels, and higher concentrations of the drug are therefore achieved without systemic side

effects[9]. For chronic ocular diseases like cytomegalovirus (CMV) retinitis, implants are

effective drug delivery system. Earlier non biodegradable polymers were used but they

needed surgical procedures for insertion and removal. Presently biodegradable polymers such

as Poly Lactic Acid (PLA) are safe and effective to deliver drugs in the vitreous cavity and

www.wjpps.com

558


show no toxic signs[2]. In general, subconjunctival implantation is used for anterior-segment

diseases, whereas intravitreal and suprachoroidal methods are typically used to treat

posterior-segment diseases[9].

Iontophoresis

Iontophoresis is a new concept in ocular drug delivery system in which charged drug

molecules are used. Positive charge drug molecules were driven into the tissue at anode and

negative charge drug molecule driven respectively at cathode. Ocular Iontophoresis is safe,

fast and easy. It is also proficient to hold high concentration of drugs at targeted tissue[10].

Ocular Iontophoresis delivery is not only fast, painless and safe but it can also deliver high

concentration of the drug to a specific site [8].

Iontophoretic technique is used to depth penetration of topically applied drug loaded

nanoparticles Iontophoresis is a method for enhancing charged drug penetration into anterior

and posterior ocular structures, by using a low electric current. The mechanisms of drug

penetration are followed by iontophoresis of electrorepulsion elecroosmosis and current-

induced tissue damage[4].

Dendrimers

Dendrimers are successfully used for different routes of drug administration and have better

water-solubility, bioavailability and biocompatibility. Vandamme and co workers have

developed and evaluated poly (amidoamine) dendrimers containing fluorescein for controlled

ocular drug delivery[2]. They determined the influence of size, molecular weight and number

of amine, carboxylate and hydroxyl surface groups in several series of dendrimers. The

residence time was longer for the solutions containing dendrimers with carboxylic and

hydroxyl surface groups[8].

Cyclodextrins

Cyclodextrins (CDs) are cyclic oligosaccharides capable of forming inclusion complexes

with many guest molecules. CD complexes are reported to increase corneal permeation of

drugs like dexamethasone, dexamethasone acetate, cyclosporine and pilocarpine resulted in

higher bioavailability than the conventional eye drops[2]. This complexation of CD does not

interrupt the biological membrane compared to conventional permeation enhancer like

benzalkonium chloride. Due to inclusion, the free drug is not available, so drugs with

www.wjpps.com

559


inherent irritant properties can be successfully delivered by this approach. CD molecules are

inert in nature and were found to be non irritant to the human and animal eye[8].

Collagen Shield

Collagen shield basically consist of cross linked collagen, fabricated with foetalcalf skin

tissue and developed as a corneal bandage to promote wound healing. Topically applied

antibiotic conjugated with the shield is used to promote healing of corneal ulcers[2]. Collagen

shields promote wound healing and perhaps more important to delivery a variety of

medications to the cornea and other ocular tissues. Collagen is structural protein of bones,

tendons ligaments and skin. Collagen comprises more than 25% of the total body portion in

mammals. It is main constituent of food grade gelatin[3]. Tear fluid makes these devices soft

and form a thin pliable film which is having dissolution rate up to 10, 24 or 72 hours.

Because of its structural stability, good biocompatibility and biological inertness, collagen

film proved as a potential carrier for ophthalmic drug delivery system. Collagen ophthalmic

inserts are available for delivery of pilocarpine to the eye[2]. Collagen shields have been used

in animal model and in humans (eg. Antibiotics, antiviral etc.,) or combination of these drugs

often produces higher drug concentration in the cornea and aqueous humor when compared

with eye drops and contact lens[19].

Microemulsion

Microemulsion has native properties and specific structures. They are prepared by auto

emulsification and straightforwardly sterilized. preparations have high capability of

dissolving the drugs and good stability. Due to these properties it has good bioavailability.

The mechanism of action of drug is absorption[10]. Due to their intrinsic properties and

specific structures, microemulsions are a promising dosage form for the natural defense of the

eye. Indeed, because they are prepared by inexpensive processes through auto emulsification

or supply of energy and can be easily sterilized, they are stable and have a high capacity of

dissolving the drugs[5]. Microemulsions were first described Hoar and Schulman.

Microemulsion is a dispersion of water and oil that formulated with surfactants and co-

surfactants in order to stabilize the surface tension of emulsion. Microemulsions have a

transparent appearance, with thermodynamic stability and a small droplet size in the

dispersed phase (aqueous and nonaqueous phase) (<1.0µm). The ophthalmic o/w

Microemusion could be advantageous over other formulation, because the presence of

surfactants and co-surfactants increase the dug molecules permeability, thereby increasing

www.wjpps.com

560


bioavailability of drugs. Due to, these systems act as penetration enhancers to facilitate

corneal drug delivery. The in-vivo experiments and preliminary studies on healthy volunteers

have occurred a delayed effect and an increase in the bioavailability of the drug. This

mechanism is based on the adsorption of the nanodroplets representing the internal phase of

the microemulsions, which act as a reservoir of the drug on the cornea and should decrease

their drainage in limit[4].

Nanosuspensions

Nanosuspensions 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[2]. Nanosuspension contains of pure,

hydrophobic drugs (poorly water soluble), suspended in appropriate dispersion medium.

Nanosuspension technology are utilized for drug components that form crystals with high

energy content molecule, which renders them insoluble in either hydrophobic or hydrophilic

media. Although nanosuspensions offer advantages such as more residence time in a cul-de-

sac and avoidance of the high tonicity created by water-soluble drugs, their performance

depends on the intrinsic solubility of the drug in lachrymal fluids after administration. Thus,

the intrinsic solubility rate of the drug in lachrymal fluid controlled its release and increase

ocular bioavailability. However, the intrinsic dissolution rate of the drug after application will

vary because of the constant inflow and outflow of lachrymal fluids[4].

Prodrugs

In the present context, prodrugs 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. 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 the drug centers on changing the physiochemical properties of drugs such as lipophilicity,

solubility and pKa[19]. The ideal Prodrugs for ocular therapy not only have increased

lipophilicity and a high partition coefficient, but it must also have high enzyme susceptibility

to such an extent that after corneal penetration or within the cornea they are either chemically

or enzymatically metabolized to the active parent compound. The partition coefficient of

ganciclovir found to be increased using an acyl ester prodrug, with substantially increased the

www.wjpps.com

561


amount of drug penetration to the cornea which is due to increased susceptibility of the

ganciclovir esters to undergo hydrolysis by esterases in the cornea[2]. The concept of double

prodrug is also gaining importance where a double prodrug is a prodrug of a prodrug[1].

Prodrug technology is generally considered as a useful technique in improving corneal

permeability of drugs[19].

Penetration Enhancers

Transport of drug across the cornea is increased by increasing the permeability through

corneal epithelial membranes. For such purpose Penetration enhancers can be used[2]. They

act by increasing corneal uptake by modifying the integrity of corneal epithelium. Chelating

agents, preservatives, surfactants and bile salts were studied as possible penetration

enhancers. But the effort was diminished due to the local toxicity associated with enhancers.

Penetration enhancers have also been reported to reduce the drop size of conventional

ophthalmic solutions especially if they do not elicit local irritation[19]. The preservative agents

used in most ophthalmic preparations serve as penetration enhancers 0.01% benzalkonium

chloride has been demonstrated by Swanson. An increase in the penetration of fluorescein in

normal eye has been found in presence of chlorohexidine gluconate and benzalkonium

chloride.The extent and rate of corneal penetration of sodium cromoglycate a dianioic drug

was altered when ion paired with dodecylbenzylmethylethyl ammonium chloride[1].

Mucoadhesive Dosage Forms

Any polymer solution /suspension placed in the eye, first encounters mucin at the cornea and

conjunctival surface. If the polymer adheres to the mucin, the interaction is referred to as

muco-adhesion, mucus on the corneal surface is provided by the goblet containing

conjunctiva that is not tightly bound so that a corneal adhesive would attach to cornea itself

and to be a true bio-adhesion[3]. Mucoadhesive dosage forms for ocular delivery still poses

numerable challenges. This approach relies on vehicles containing polymers which will

attach, via noncovalent bonds, to conjunctival mucin. Mucoadhesive polymers are typically

macromolecular hydrocolloids with several hydrophilic functional groups, such as carboxyl-,

hydroxyl-, amide and sulphate, competent of establishing electrostatic interactions. The

bioadhesive dosage form showed more bioavailability of the drug than those of conventional

dosage forms. The result is evaluated of polyacrylic acid as a bioadhesive polymer on the

ocular bioavailability of timolol. It was also used in the enhancement of ocular bioavailability

of progesterone[10].

www.wjpps.com

562


PARTICULATES (NANOPARTICLES AND MICROPARTICLES)

Particulate polymeric drug delivery systems include micro and nanoparticles. The superior

size of microparticles for ophthalmic administration is regarding 5-10 mm, above this size, a

scratching sensation in the eye can result after ocular application[10]. Nanoparticles are

prepared using bioadhesive polymers to provide sustained effect to the entrapped drugs. An

optimal corneal penetration of the encapsulated drug was reported in presence of bioadhesive

polymer chitosan. Similarly Poly butyl cyanoacrylate nanoparticles, containing pilocarpine

into collagen shields, showed greater retention and activity characteristics with respect to the

controls. Microspheres of poly lacto gylcolic acid (PLGA) for topical ocular delivery of a

peptide drug vancomycin were prepared by an emulsification/ spray-drying technique[8].

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. After optimal drug binding to these

particles, the drug absorption in the eye is enhanced significantly in comparison to eye

drops[5].

ADVANCED DELIVERY SYSTEM

Gene therapy

The idea of gene therapy is not as new as it seems. It is still developing, and requires further

efforts before it is brought to the clinic. Development of a successful strategy for gene

therapy depends on several factors. The molecular genetic basis of the disease must be

understood. A mechanism must be available to deliver the desired gene to the therapeutic site.

Gene therapy is based on strategies for delivering genes, which is accomplished by means of

gene delivery vehicles known as vectors. These vectors encapsulate therapeutic genes for

delivery to cells. Though efficient gene delivery remains a substantial obstacle to widespread

human clinical trials, many gene delivery methods are under investigation. These include

both viral and non-viral vectors. The eye is one of the most suitable targets for gene therapy.

It is easily accessible and allows local application of therapeutic agents with reduced risk of

systemic effects. In the eye, the retina is possibly the best candidate for gene therapy. The

amount of virus injected into the retina is about 1/1000 of the amount used for systemic

diseases. The blood ocular barrier within the eye separates it from the rest of the body, acting

to protect the retina and preventing the escape of large molecules into the blood stream.

Therefore, a virus delivered to the eye is unlikely to cause any systemic disease. Thus, gene

www.wjpps.com

563


therapy may become a therapeutic modality in the treatment of ocular diseases, in addition to

serving as a method for studying mechanisms of the disease pathogenesis[20].

Cell encapsulation

The entrapment of immunologically isolated cells with hollow fibres or microcapsules before

their administration into the eye is called Encapsulated Cell Technology (ECT) which enables

the controlled, continuous, and long-term delivery of therapeutic proteins directly to the

posterior regions of the eye[2]. The polymer implant containing genetically modified human

RPE cells secretes ciliary neurotrophic factor into the vitreous humour of the patients’ eyes.

ECT can potentially serve as a delivery system for chronic ophthalmic diseases like

neuroprotection in glaucoma, anti-angiogenesis in choroidal neovascularisation, anti-

inflammatory factors for uveitis[8].

Stem cell therapy

Stem cell biology is a fast-emerging field that offers promise of cell-based tools for the

treatment of a wide range of recalcitrant diseases that are not amenable to other forms of

therapy. By definition, stem cells are cells with a capacity for unlimited or prolonged self-

renewal and can produce at least one type of differentiated cell associated with the tissue. In

ophthalmology, reconstruction of the ocular surface in patients suffering from intractable

blinding ocular surface disease has become possible with the advent of techniques of ex vivo

expansion and transplantation of limbal epithelial stem cells onto the cornea.7–9 Different

groups have used different techniques and substrates to cultivate the limbal cells with almost

similar clinical outcomes of about 50 to 70 per cent success at the end of three to five years.

Another challenge in eye disease is the treatment for irreversible photoreceptor loss in many

retinal conditions. Repair of such damage by cell transplantation is one of the most feasible

types of central nervoussystem repair; photoreceptor degeneration initially leaves the inner

retinal circuitry intact and new photoreceptors need to make only single, short synaptic

connections to contribute to the retinotopic map[21].

Protein and peptide therapy

Recent developments in technology and science have provided the tool and opportunity to

expand the range of peptide- and protein-based drugs in an effort to combat poorly controlled

diseases and to increase patient quality of life. While there has been rapid progress in

molecular biology and production, progress in the formulation and development of peptide

and protein drug delivery systems has only recently begun. This can be attributed primarily to

www.wjpps.com

564


lack of knowledge about the effects of the administration route and how physicochemical and

chemical properties of peptides and proteins impact the absorption and in vivo efficacy[23].

Ocular route is not preferred route for systemic delivery of such large molecules.

Immunoglobulin G has been effectively delivered to retina by trans scleral route with

insignificant systemic Absorption[2].New approaches are currently under investigation to seek

possible solutions, such as using iontophoresis and other techniques, i.e. microneedles, which

would facilitate acceptable patient compliance and take into account life quality of the

patients [23].

Scleral plug therapy

Scleral plug can be implanted using a simple procedure at the pars plana region of eye, made

of biodegradable polymers and drugs, and it gradually releases effective doses of drugs for

several months upon biodegradation[8]. The release profiles vary with the kind of polymers

used, their molecular weights, and the amount of drug in the plug. The plugs are effective for

treating vitreoretinal diseases such as proliferative vitreoretinopathy, cytomegalovirus

retinitis responds to repeated intravitreal injections and for vitreoretinal disorders that require

vitrectomy[2].

siRNA therapy

A more recent approach for targeting mRNA is the use of small interfering RNA or siRNA.

In fact, it was shown that introducing long double-stranded RNA (dsRNA) into a variety of

hosts could trigger post transcriptional silencing of all homologous host genes and/or

transgenes. RNA interference is an antisense mechanism of action, as ultimately a single

strand RNA molecule binds to the target RNA molecule by Watson-Crick base pairing rules

and recruits a ribonuclease that degrades the target RNA. This mechanism makes feasible the

use of small double stranded siRNA in therapeutics instead of ODNs. Indeed, it has been

recently shown that unexpectedly small double-stranded RNAs (siRNAs) appear to be very

efficient agents to inhibit gene expression in mammalian cell[24]. The technology of RNA

interference (RNAi) offers the perspective for selective and on demand silencing of gene

expression. One of the critical factors that limit the experimental and therapeutic application

of RNAi in vivo is the ability to deliver intact siRNA efficiently. Although RNAi technology

has been successfully demonstrated for cell lines and primary cultures, delivery of siRNA in

mammalian tissues in vivo provides a significant challenge[25].

www.wjpps.com

565


Oligonucleotide therapy

There are many retinal diseases that lack success using conventional treatment and for which

oligonucleotides have shown strong potentialities. The anti-mRNA strategy, particularly the

use of antisense oligonucleotides has been very successful in the last ten years since many

compounds are now in clinical trial at a very advanced stage and one drug, Vitravene®,

designed for the treatment of intraocular infection by cytomegalo virsus has been marketed.

Antisense oligonucleotides are synthetic molecules that bind to specific intracellular

messenger RNA strands (mRNA). They consist of short sequences, composed of 13 to about

25 nucleotides, which are complementary to mRNA strands in a region of a coding sequence

designed as sense strand. By binding to the mRNA molecules, Antisense oligonucleotides

stop translation of the mRNA, and hence protein synthesis expressed by the targeted gene.

Among several recognized mechanisms, one commonly described is the so-called

translational arrest. In this mechanism, the single strand mRNA binds to the AS-ODNs by

Watson-Crick base pairing forming a double-helix hybrid and blocks sterically the translation

of this transcript into a protein[24].

Aptamers

Aptamers are oligonucleotides, such as ribonucleic acid (RNA) and single-strand

deoxyribonucleic acid (ssDNA) or peptide molecules that can bind to their targets with high

affinity and specificity due to their specific three-dimensional structures. Especially, RNA

and ssDNA aptamers can differ from each other in sequence and folding pattern, although

they bind to the same target. The concept of joining nucleic acids with proteins began to

emerge in the 1980s from research on human immunodeficiency virus (HIV) and adenovirus.

The use of antibodies as the most popular class of molecules for molecular recognition in a

wide range of applications has been around for more than three decades. Aptamers are widely

known as a substitute for antibodies, because these molecules overcome the weaknesses of

antibodies[22].

Ribozyme therapy

Ribozymes are small catalytic RNA molecules able of degrading target RNAs in a similar

way as restriction enzymes. The 5' and 3' ends of these ribonucleotides can recognize specific

nucleotide sequence, hybridizing by Watson-Crick base pairing complementary to the target

RNA. They also contain an intramolecular hairpin loop, which induces the cleavage of the

target RNA. The two main classes of ribozymes described are hammerhead ribozyme and

www.wjpps.com

566


hairpin ribozymes. In the case of hammerhead ribozyme, cleavage is dependent on divalent

cations, such as Mg+2, Mn+2, Ca+2, Co+2, or Cd+2. Ribozymes molecules are potentially

very efficient because, once they cleave their target, they are released from their mRNA

target and are free to hybridise with another mRNA molecule. Similary to ODN, they can

destroy multiple mRNAs in a catalytic manner[24].

CONCLUSIONS

The eye is one of the most complex and sophisticate organ as previously discussed in this

review. Many successes in anterior DDSs for prolonging retention time and reducing

administration frequency have been achieved, but Additional requirement is needed in this

field might be to improve for patient and compliance. On the other side, A few new products

of ophthalmic delivery system have been commercialized as a result of the research. The

performance of these new products, however, is still far from level of satisfaction. An ideal

ophthalmic drug delivery system should be able to achieve minimum effective drug

concentration at the target tissue of eye for prolonged period with minimizing systemic

exposure and these systems should be comfortable to use. More research required in each of

the technologies discussed in this review. For ophthalmic delivery system some formulations

are relatively easy to manufacture, but limited in their ability to provide sustain and

controlled drug release for prolong time period. Other approaches are promising with regard

to sustained and controlled drug release, but are difficult to manufacture, use and for

achieving Stability especially in case of particulates, liposomes, oligonucleotide therapy,

aptamer and other novel advanced delivery system. The novel advanced delivery systems

offer more protective and effective means of the therapy for the nearly inaccessible diseases

of eyes. The latest available targeted drug delivery systems focus on the safe and easily

localized delivery of the drugs and certain macromolecular substances like DNA, siRNA, and

protein to the internal parts of the eye.

REFERENCES

1. Thakur RR and Kashiv M. modern delivery systems for ocular drug formulation: A

comparative overview W.R.T convetional dosage form. Int J Res Pharm and Bio Sci,

2011; 2(1): 8-18.

2. Patel V and Agrawal YK. Current status and advanced approaches in ocular drug delivery

system. Journal of global trends in pharmaceutical sciences, 2011; 2(2): 131-148.

www.wjpps.com

567


3. Rathore KS, Nema RK and Sisodia SS. An overview and advancement in ocular drug

delivery systems. Int J Pharm Sci and Res, 2010; 1(10): 11-23

4. Jitendra, Sharma PK, Banik A and Dixit S. A new trend: ocular drug delivery system. Int

J of Pharm Sci, 2011; 2(3): 1-25.

5. Tangri P, and Khurana S. basics of ocular drug delivery systems. Int J Res Pharm and

Biomed Sci, 2011; 2(4): 1541-1552.

6. Haders DJ. New controlled release technologies broaden opportunities for ophthalmic

therapies. Drug delivery technology, 2008; 8(7): 48-53.

7. Lallemand F, Daull P, Benita S, Buggage R and Garrigue JS. Successfully improving

ocular delivery using the cationic nano- emulsion, novasorb. Journal of drug delivery,

2012; Article ID 604202:1-16.

8. Sireesha DS, Suriaprabha K and Prasanna PM. Advanced approaches and evaluation of

ocular drug delivery system. Ame J Pharmatech Res, 2011; 1(4): 72-92.

9. Short BG. Safety evaluation of ocular drug delivery formulation: techniques and practical

considerations. Toxicologic pathology, 2008; 36: 49-62.

10. Sikandar MK, Sharma PK and Visht S. ocural drug delivery system: An overview. Int J

Pharm Sci and Res, 2011; 2(5): 1168- 75.

11. Ratnam VG, Madhavi S and Rajesh P. ocular drug delivery: An update review. Int J

Pharm Bio Sci, 2011; 1(4): 437-46.

12. Willoughby CE, Ponzin D, Ferrari S, Lobo A, Landau K and Omidi Y. anatomy and

physiology of the human eye: effects of mucopolysaccharidoses disease on structure and

function a review. Clinical and experimental ophthalmology, 2010; 38: 2-11.

13. McCaa CS. The eye and visual nervous system: anatomy, physiology and toxicology.

Environmental health perspectives, 1982; 44: 1-8.

14. Rathore KS and Nema PK. An insight into ophthalmic drug delivery system. Int J Pharm

Sci Drug Res, 2009; 1(1): 1-5.

15. Visser L. common eye disorders in the elderly- a short review. SA Fam Pract, 2006;48(7):

34-8.

16. Pandey H, Sharma UK and Pandey AC. Eudragit- based nanostructures: A potential

approach for ocular drug delivery. Int J Res Dev Pharm L Sci, 2012; 1(2): 40-3.

17. Bodos N and Buchwald P. Ophthalmic drug design based on the metabolic activity of the

eye: soft drugs and chemical delivery systems. AAPS J, 2005;7(4): E820-33.

18. Kumar DP and Arnab D. Pharmacosomes: A potential vesicular drug delivery system. Int

Res J Pharm, 2012; 3(3): 102-5.

www.wjpps.com

568


19. Arulkumaran KSG, Karthika K and Padmapreetha J. Comparative review on

conventional and advanced ocular drug delivery formulation. Int J Pharm and Pharm Sci,

2010; 2(4): 1-5.

20. Singh VK and Tripathi P. Gene therapy in ocular diseases. Indian J Ophthalmol, 2002;

50: 173-81.

21. Vemuganti GK, Sangwan VS and Rao GN. The promise of stem cell therapy for eye

diseases. Clin Exp Optom, 2007; 90(5): 315-16.

22. Song KM, Lee S and Ban C. Aptamers and their biological applications. Sensors, 2012;

12: 612-31.

23. Degim T and Celebi N. controlled delivery of peptides and proteins. Current

pharmaceutical design, 2007; 13: 99-117.

24. Games Dos Santos AL, Bochot A and Fattal E. intraocular delivery of oligonucleotides.

Current pharmaceutical bio technology, 2005; 6: 7-15.

25. Tuchinovich A, Zoidl G and Dermietzel R. Non- viral si RNA delivery into the mouse

retina invivo. BMC ophthalmology, 2010; 10(25): 2-5.

AN UPDATE REVIEW ON NOVEL ADVANCED … UPDATE REVIEW ON NOVEL ADVANCED OCULAR DRUG DELIVERY SYSTEM...

Documents

Transcript of AN UPDATE REVIEW ON NOVEL ADVANCED … UPDATE REVIEW ON NOVEL ADVANCED OCULAR DRUG DELIVERY SYSTEM...