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248 | P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 3(2): March-April 2014

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***

ICV 5.13***

Pharmaceutical Sciences REVIEW ARTICLE……!!!

NEW ADVACEMENT: IN OCULAR DELIVERY SYSTEM

Ankita Bhatt1, Dr. Ganesh Bhatt

1, Dr. Preeti Kothiyal

2

Department of pharmaceutical science, Shri Guru Ram Rai institute of technology and science,

Patel nagar Dehradun,248001.

KEYWORDS:

Ocular insert , recent

advancement in ocular

drug delivery.

For Correspondence:

Ankita Bhatt *

Address: Department of

pharmaceutical science,

Shri Guru Ram Rai

institute of technology

and science,Patel nagar

Dehradun,248001.

Email Id:

[email protected]

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.

Many ophthalmic formulations like solutions,

suspensions, ointments suffer from the drawbacks like precorneal

elimination, high variability in efficiency and blurred vision. The

major problem associated with these conventional dosage forms is

the bioavailability of drug. The effective dose of the medication

which is administered opthalmically may be altered by varying the

strength, volume, or frequency of administration of medication or the

retention time of the medication in contact with the surface of the

eye.



INTRODUCTION:

The field of ocular delivery is one of the most interesting and challenging Endeavor’s facing the

Pharmaceutical scientist [1]

There are most commonly available ophthalmic preparations such as drops and ointments about 70% of

the eye dosage formulations in market.[2]

Ocular drug delivery systems are developed to treat eye locally, whereas past formulations were targeted to

reach systemic circulation and these are designed to overcome all the disadvantages of conventional dosage

forms such as ophthalmic solutions [3].

The eye drop dosage form is easy to instill but suffers from the

inherent draw back that the majority of the medication it contains is immediately diluted in the tear film as

soon as the eye drop solution is instilled into the cul-de-sac and is rapidly drained away from the precorneal

cavity by constant tear flow, a process that proceeds more intensively in inflamed than in the normal eyes,

and lacrimal-nasal drainage. Therefore, only a very small fraction of the instilled dose is absorbed into the

target tissues.[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]

ANATOMY AND PHYSIOLOGY OF EYE:

Eye is a spherical structure with a wall consists of three layers. Namely outer sclera, middle choroid layer,

inner retina.[7]

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. [8]

The cornea is covered by a thin epithelial layer continuous with the conjunctiva at the cornea-sclerotic

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

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 conjuctival sac. It contains lysozyme, whose bactericidal activity reduces the bacterial count in the

conjuctival sac. [9]

Figure . 1: The schematic diagram of eye

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. [10]

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[11]



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 [12]

Conjunctiva

The conjunctiva protects the eye and also involved in the formation and maintenance of the precorneal tear

film. The conjunctiva is a thin transparent membrane lies in the inner surface of the eyelids and that is

reflected onto the globe. The conjunctiva is made of an epithelium, a highly vascularised substantia

propria, and a submucosa [13]

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 aqueouscirculation 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 [14]



Figure. 2

OCULAR DRUG DELIVERY SYSTEMS:

The necessary characters of Ideal control release ocular drug delivery system are:

It should not induce a foreign-body sensation or long lasting blurring.

It should possess more local activity than systemic-effect.

It must deliver the drug to the right place, i.e. in targeting the ciliary body.

It should be easy to self-administer.

The number of administrations per day should be reduced.

The primary approaches in the design of control release ocular drug delivery system attempt to slow down

the drainage of drug by tear flow.[15]



1.Conventional ophthalmic dosage forms

1.1. Aqueous solutions- Majority of topical ophthalmic preparations available today are in the form of

aqueous solutions. A homogeneous solution dosage form offers many advantages including the simplicity

of large scale manufacture. The factors that must be taken into account while formulating aqueous solution

include selection of appropriate salt of the drug substance, solubility, therapeutic concentration required,

ocular toxicity, pKa, the effect of pH on stability and solubility, tonicity, buffer capacity, viscosity,

compatibility with other formulation ingredients as well as packaging components, choice of preservative,

ocular comfort and ease of manufacturing. Several bioavailability experiments must be conducted in order

to arrive at the optimum formulation. Corneal penetration enhancement can be achieved best by increasing

solution concentration, increasing contact time in the precorneal packet, selection of the drug with

appropriate pKa and offering optimal lipid solubility.[16]

1.2. Mucoadhesive Formulations- Mucoadhesion is based on entanglement of non-covalent bonds

between polymers and mucous. 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. [17]

1.3.Suspension: Suspensions form an important part of the ophthalmic dosage forms and offer distinct

advantages. Many of the recently developed drugs are hydrophobic and have limited solubility in water.

Formulation of a sterile, preserved, effective, stable and pharmaceutically elegant suspension is more

complex and challenging compared to conventional ophthalmic solutions. Some of the difficulties that a

formulator should overcome during the development of a suspension are non-homogeneity of the dosage

form, settling, cake formation, aggregation of the suspended particles, resuspendability, effective

preservation, and ease of manufacture. The understanding of interfacial properties, wetting, particle

interaction zeta potential, aggregation, sedimentation and rheological concepts are required for formulating

an effective and elegant suspension. [18,19]

1.4. Ointments-

While ophthalmic solutions are by far the most preferred dosage forms, ophthalmic ointments are still

being marketed for night time applications and where prolonged therapeutic actions are required. Major

disadvantage 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 .[20]



1.5 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 extend the contact time of the drug with the biological tissues and

thereby improve ocular bioavailability. The choice of the polymer plays a critical role in the release

kinetics of the drugs from the dosage form. There are several bioadhesive polymers now available with

varying degree of mucoadhesive performance.[21]

2. Non-conventional ophthalmic delivery systems

Ocular insert: Shows in Figure .3

Figure . 3

Figure. 4



Table no. 1

2.1. Non-erodible ocular inserts-

In 1975, the first controlled-release ophthalmic dosage form was marketed in United States by Alza

Corporation. The Ocusert pilocarpine ocular systems are noted for several reasons. The strength of the drug

is specified in the labeling by the rates at which they deliver pilocarpine in vivo. The Ocusert is an elliptical

shaped membrane which is soft and flexible and designed to be placed in the cul de sac between the sclera

and the eyelid and continuously release pilocarpine at a steady rate (20 μg/h and 40 μg/h) for 1 week. The

design of the dosage form is described by Urquhart in terms of an open looped therapeutic system having

three major components (a) the drug (b) a drug delivery module and (c) a platform. The drug in Ocusert is

pilocarpine base.[22]



2.2Nanoparticles-

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 ophthalmic drug delivery were mainly produced by emulsion polymerization. In this

process a poorly soluble monomer is dissolved the continuous phase which may be aqueous or organic. [23]

2.2. Prodrugs-

Prodrugs are chemical modifications of known pharmacological agents. These drugs, when administered to

biological systems, are biotransformed to the parent compound. In the past, epinephrine has been routinely

used to control ocular hypertension. A prodrug of epinephrine namely, dipivefrin (DPE) has been

developed successfully for several years.

Some key advantages of such prodrugs are

enhanced bioavailability

increased potency

lower dose

prolonged duration of action

reduce side effects and

enhanced chemical stability

The lipophilic nature of DPE is responsible for its greater bioavailability in ocular tissues, DPE at 0.1%

concentration produces intraocular pressure lowering response which is clinically comparable to 2%

epinephrine while showing greatly reduced. [24]

3.3Microspheres -

Microspheres are monolithic particles possessing a porous or solid polymer matrix, whereas microcapsules

consist of a polymeric membrane surrounding a solid or liquid drug reservoir. Nanoparticles have a particle

size in the nanometer size range below 1 μm. The definitions for these particles include nanospheres as

well as nanocapsules. In micro- or in nanocapsules the drug can be present in a liquid form, it can be

dissolved or suspended in a liquid or solid core or it may be present in the core itself. Monolithic micro- or

nanoparticles contain the drug either dissolved in the polymer matrix in form of a solid solution or

suspended in form of a solid dispersion. Alternatively the drug may be adsorbed to the particle surface. It is

important to note that the particle size for ophthalmic applications should not exceed 10 μm because with

larger sizes a scratching feeling might occur. Therefore, a reduction in particle size improves the patient

comfort during administration.[25]



3. Control drug delivery system:

Iontophoresis-

In Iontophoresis direct current drives ions into cells or tissues. Positively charged of drug are driven into

the tissues at the anode and vice versa. Deliver high concentration of drug to a specific site. By the use of

iontophoretic application of antibiotics in eye we increase their bactericidal activity as well as also reduce

the severity of disease. Application of anti-inflammatory agent can reduce vision threatening side effect.[26]

The mechanism of drug penetration are followed by iontophoresis of electrorepulsion, electroosmosis and

current-induced tissue damage.

Figure no. 5

NEW AVANCEMENTS-

1.Nonbiodegradable polymeric drug delivery systems

• I-vation. Sustained delivery of triamcinolone acetonide (TA) to the vitreous using I-vation (Surmodics

Inc.) is in development for diabetic macular edema (DME). The I-vation intravitreal implant is a titanium

helical coil coated with TA (925 μg) and the nonbiodegradable polymers poly(methyl methacrylate) and

ethylene-vinyl acetate. It is predicted that this implant will have an in vivo sustained delivery of at least 2

years. A phase 1 clinical trial in patients with DME has been completed and 24-month interim results have

been reported.1 At 24 months, 25 of 31 patients remained in the study; 11 patients (11 eyes) in the

slowrelease group, 14 patients (14 eyes) in the fast-release group. The proportion of patients demonstrating

improved visual acuity (greater than 0 ETDRS letter gain from baseline) was 64% in the slow-release



group and 72% in the fast-release group; 28.6% of patients in the fast-release group gained greater than 15

letters.

• Renexus. Encapsulated cell technology provides extracellular delivery of ciliary neurotrophic factor

(CNTF) with long-term and stable intraocular release at constant doses through a device (Renexus

[formerly NT-501], Neurotech) implanted in the vitreous. It contains human cell line of retinal pigment

epithelium (RPE), NTC-200, genetically modified to secrete recombinant human CNTF. Renexus consists

of a sealed semipermeable hollow fiber membrane capsule surrounding a scaffold of 6 strands of

polyethylene terephthalate yarn, which can be loaded with cells. The device is surgically implanted in the

vitreous through a tiny scleral incision and is anchored by a single suture through a titanium loop at one

end of the device. The semipermeable hollow fiber membrane allows the outward diffusion of CNTF and

other cellular metabolites and the inward diffusion of nutrients necessary to support the cell survival in the

vitreous cavity while protecting the contents from host cellular immunologic attack.

• ODTx. The injectable, biocompatible, nonresorbable device (ODTx, On Demand Therapeutics) contains

reservoirs designed for drug release in optimized doses for laser activation.The reservoirs are capable of

storing small- or large-molecule drugs that can be released via a standard, noninvasive laser activation

procedure. The multiple reservoir system allows ophthalmologists to control drug delivery by activating

specific reservoirs, while unactivated reservoirs remain intact. Unfortunately, clinical trials of ODTx have

not commenced.

Advantages of controlled ocular drug delivery systems[26,27]

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

systems.

To provide sustained and controlled drug delivery.

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

This can be achieved by effective adherence to corneal surface.

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

To circumvent the protective barriers like drainage, lacrimation and conjunctive absorption.

To provide comfort, better compliance to the patient and to improve therapeutic performance of

drug.

Easy convenience and needle free drug application without the need of trained personnel

assistance for the application, self medication, thus improving patient compliances compared to

parenteral routes.



Good penetration of hydrophilic, low molecular weight drugs can be obtained through the eye.

Rapid absorption and fast onset of action because of large absorption surface area and high

vascularisation. Ocular administration of suitable drug would therefore be effective in emergency

therapy as an alternative to other administration routes.

Avoidance of hepatic first pass metabolism and thus potential for dose reduction compared to oral

delivery.

Disadvantages:-Various disadvantages of ocular drug delivery system are given below.

The physiological restriction is the limited permeability of cornea resulting into low absorption of

ophthalmic drugs.

A major portion of the administered dose drains into the lacrimal duct and thus can cause

unwanted systemic side effects.

The rapid elimination of the drug through the eye blinking and tear flow results in a short duration

of the therapeutic effect resulting in a frequent dosing regimen. [27]

Conclusion:

Ocular drug delivery is difficult because of multiple barriers imposed by the eye against the entry of

xenobiotics. Over last several years, attempts have been made to improve ocular bioavailability through

manipulation of product formulation such as viscosity and application of mucoadhesive polymers. Thus

far, these approaches to prolong corneal contact time have led to modest improvement in ocular

bioavailability. Consequently, it seems logical to consider non-conventional approaches such as

nanotechnology, microspheres, appropriate prodrugs and effective delivery of gene therapy to further

enhance ocular absorption and reduce side effect.

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