Ankur Agrawal et al.

, Asian Journal of Pharmaceutical Technology & Innovation, 04 (21); 2016; 45 - 54

Asian Journal of Pharmaceutical Technology & Innovation

ISSN: 2347-8810

Review Article
Received on: 29-11-2016 Ocular Drug Delivery System & Role of Ocular
Accepted on: 09-12-2016
Published on: 15-12-2016 Inserts In Eye Disorder Treatment: A Review

Corresponding Author:
Ankur Agrawal*, Lalit Kumar Yadav, Vikash Rathour

* Ankur Agrawal,
ABSTRACT
M.Pharm, Pharmaceutics,
Assistant Professor,
Department of Pharmaceutics, Eye is the organ of human body having main function of vision.
Nagaji Institute of Pharmaceutical
Science, Ocular drug delivery is the alternative route for the systemic
Gwalior, Madhya Pradesh 474001
treatment of disease and also a route for the treatment of eye

diseases such as conjunctivitis, keratitis etc. Ocular inserts are the

one of the most useful and innovative technique for the treatment of

eye diseases by increase contact time and providing control release

of drug. This review is generated to provide an overview of ocular

drug delivery including role of ocular inserts in treatment of eye

disorders.

*Email Id- Key-words: Ocular drug delivery, ocular insert, conjunctivitis.

ankur14agrawal@gmail.com

Cite this article as:

Ankur Agrawal*, Lalit Kumar Yadav, Vikash Rathour, Ocular Drug Delivery System & Role of Ocular Inserts In Eye Disorder
Treatment: A Review,Asian Journal of Pharmaceutical Technology & Innovation, 04 (21); 45-54, 2016.

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 Ankur Agrawal et al., Asian Journal of Pharmaceutical Technology & Innovation, 04 (21); 2016; 45 - 54

INTRODUCTION
The human eye can be classified into two segments: anterior and posterior segments. The cornea,
conjunctiva, iris, ciliary body, aqueous humor and lens are includes in the anterior segment and sclera,
choroid, retina, vitreous humor are includes in the posterior segment. The outermost transparent
membrane of the eye is cornea such are the corneal epithelium, bowman's membrane, stroma,
descemet's membrane, and endothelium. The anterior segment is a fluid of the eye which contains the
source of nutrition to the crystalline lens and cornea. The iris sphincter and dilator muscles are help full
to adjust the pupil size which regulates the amount of light entering to the eye.[1, 2]

A ring-shaped muscle attached to the iris called ciliary muscles. It is important because contraction and
relaxation of the ciliary muscle controls the shape of the lens. The choroid layer is located behind the
retina and absorbs unused radiation.[3]

The retina is a multi-layered sensory, light sensitive tissue contains millions of photoreceptors or
photosensitive elements that capture light rays and convert them into electrical impulses. These impulses
travel along the optic nerve to the brain, where they are converted into an image. A jelly-like substance
known as vitreous humor, distribute between retina and lens.[1, 2]

Fig. 1: Anatomy of Eye

MANAGEMENT OF EYE DISEASES

Conjunctivitis
Bacterial conjunctivitis is an inflammation of the conjunctiva caused by bacteria.[4, 5]
Fluoroquinolones
Ciprofloxacin or Ofloxacin, Levofloxacin, Moxifloxacin, Gatifloxacin or Besifloxacin
Aminoglycosides
Tobramycin or Gentamicin
Macrolides
Erythromycin [6, 7]
Keratitis

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Bacterial keratitis is an infection and inflammation of the cornea that cause pain, reduced vision, light
sensitivity and tearing or discharge from the eye that can, in severe cases cause loss of vision. Treatment
will include third-generation quinolone drops (ciprofloxacin and ofloxacin) or fourth generation drops
(gatifloxacin or moxifloxacin).[8]
OCULAR DRUG DELIVARY
Ocular drug delivery system is a system to deliver active pharmaceutical ingredient to ophthalmic route
for local or systemic effect.
TYPES OF OCULAR DRUG DELIVARY
A multitude of ocular dosage forms are available for delivery of drugs to the eye. These can be classified
as follows:
1. Liquids: Solutions, Suspensions, Sol to gel systems, Sprays
2. Solids: Ocular inserts, Contact lenses, Artificial tear inserts, Filter paper strips
3. Semi-solids: Ointments, Gels
4. Miscellaneous: Ocular iontophoresis, Mucoadhesive dosage forms.[9]
Liquids
It is most popular and desirable state of dosage forms for the eye and drug absorption rate is fastest from
this state then the other.
Solution and suspensions
Solutions are widely used to administer drugs that must be active on the eye surface or in the eye after
passage through the cornea or the conjunctiva. The drug in the solution is in the solved state and may be
immediately active. To increase the corneal contact time of a drug substance and provide a more
sustained action we use ophthalmic suspensions.
Sol to gel system
It is a new concept of producing a gel in situ (eg. in the cul-de-sac of the eye) and widely accepted that in
the precorneal region when viscosity of a drug formulation increased so the bioavailability will also
increased, due to slower drainage from the cornea. These systems can be triggered by pH, temperature or
by ion activation.
Spray
These sprays are used in the eye for dilating the pupil or for cycloplegic examination.
Solids
The concept of using solids for the eye is based on providing sustained release characteristics.[9]
Ocular Inserts
Ophthalmic inserts are defined as sterile preparations, with a solid or a semi solid consistency, whose
size and shape are especially designed for ophthalmic application. A number of ocular inserts were
prepared utilizing different techniques to make soluble, erodible, non erodible, and hydrogel inserts.[10]
Contact lenses
Contact lenses can absorb water soluble drugs when soaked in drug solutions.
Artificial tear inserts
This device is designed as a sustained release artificial tear for the treatment of dry eye disorders.
Filter paper strips

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These strips are used to disclose corneal injuries and infections such as herpes simplex, and dry eye
disorders. The example of filter paper strips are Sodium fluorescein and rose Bengal dyes.
Semisolids
To provide sustained effects Semi-solids dosage forms are used. Ophthalmic ointment is used to prolong
drug contact time with the external ocular surface. Ophthalmic gels are composed of mucoadhesive
polymers that provide localized delivery of an active ingredient to the eye.
Miscellaneous
Ocular iontophoresis
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. If the drug molecules
carry a positive charge, they are driven into the tissues at the anode; if negatively charged, at the cathode.
Mucoadhesive dosage forms
Mucoadhesive polymers are usually macromolecular hydrocolloids with numerous hydrophilic functional
groups such as carboxyl-, hydroxyl-, amide and sulphate, capable of establishing electrostatic
interactions. The bioadhesive dosage form showed more bioavailability of the drug as compared to
conventional dosage forms.[9]
OCULAR INSERTS
Ophthalmic inserts are sterile preparations with a solid or a semisolid consistency, and whose size and
shape are especially designed for topical or systemic treatment ophthalmic inserts.[11]
Advantages over other ocular drug delivery system
 Increased ocular residence, hence a prolonged drug activity and a higher bioavailability with
respect to standard vehicles
 Possibility of releasing drugs at a slow, constant rate
 Accurate dosing
 Reduction of systemic absorption
 Better patient compliance, resulting from a reduced frequency of administration and a lower
incidence of visual and systemic side-effects
 Possibility of targeting internal ocular tissues through non-corneal routes
 Increased shelf life with respect to aqueous solutions
 Exclusion of preservatives, thus reducing the risk of sensitivity reactions
 Possibility of incorporating various novel chemical/technological approaches [12]
Characteristics required for drug
 The necessary characteristics for the material used to fabricate the ocular insert and obtain the
desired drug metering effect are dependent on the particular drug used.
 Hydrophobic polymeric materials having a relatively high affinity for the drug should be used in
forming the ocular insert. Otherwise, the drug will be rapidly released from the ocular insert and
the objective of continuous and sustained release defeated.
 However, many hydrophobic polymers having the desired drug retention and release
characteristics tend to be irritating to the eye and surrounding tissues.
 To provide compatibility with the eye and surrounding tissues. Since hydrophilic materials do not
have the drug retention characteristics needed for many drugs, it has been necessary at times in
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the past to select materials which compromise the desired comfort and tissue compatibility with
the desired retention and release characteristics for the drug.
 Should be compatible with eye and surrounding tissues.
 In most cases hydrophobic polymers are used due to which sustain release of drug is achieved.
 Should not irritate ocular tissues.
 The surface of the ocular insert in contact with the eye and surrounding tissues should be soft and
hydrophilic.
 Half life should not more.
 Protein binding should be low.
 Considerable bioavailability should be there.
Characteristics of ocular inserts
 Ocular inserts should not produce immunogenic & mutagenic reactions
 Ocular inserts are bio stable in nature & Biocompatible with tissue of eye
 They should have good mechanical strength
 Easily sterilizable
 They should not produce toxic & carcinogenic reactions
 Should be free from drug leakage
 They should be Retrievable & Release at a constant rate
 Non-interference with vision
 Successful oxygen permeability
 Ease of manufacture and low cost
 Sterility[9,13, 14, 15]
CLASSIFICATION OF OPHTHALMIC INSERTS [14, 15, 16, 17]
Based upon their solubility behavior
1. Insoluble inserts; Diffusion, osmotic and contact lens etc.
2. Soluble; Natural polymers (eg. collagen), synthetic or semi synthetic polymers (eg. cellulose
derivatives)
3. Bioerodible

Fig.2. Classification of Ocular inserts

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Insoluble ocular inserts

Diffusion
In diffusion inserts, the release of drug is based on diffusion mechanism. The diffusion systems are
designed of a central reservoir of drug enclosed in a special semi permeable or micro porous membranes,
which allow the drug to diffuse the reservoir at a precisely determined rate.
Osmotic
The osmotic inserts are generally divided into two types, in the first case the central part of the insert is
surrounded by a peripheral part. The central part can be composed of a single reservoir, which is
composed of the drug with or without an osmotic solute dispersed through a polymeric matrix, so that
the drug is surrounded by the polymer as discrete small deposits.[18] In the second case, the drug and the
osmotic solutes are placed in two separate compartments, the drug reservoir is surrounded by an elastic
impermeable membrane and the osmotic solute reservoir surrounded by a semi-permeable membrane.
The peripheral part of these osmotic inserts is comprised of a film covering made of an insoluble semi-
permeable polymer.[19] The release of drug through the osmotic insert follows the zero-order drug
release profile.[20]
Contact lenses
When contact lenses soaked in drug solutions it absorbs water-soluble drugs. Contact lenses are used to
provide extended release of drugs into the eye. In ophthalmic drug delivery systems, Contact lenses have
certainly good prospects. The contact lenses are sub-divided into five groups; rigid, semi-rigid,
elastomeric, soft hydrophilic and bio-polymeric.[9, 14, 21]
Soluble ocular inserts
Soluble ocular inserts are divided into two types
Natural polymer
The first type of soluble inserts is based on natural polymer. Natural polymer used to produce soluble
ophthalmic inserts is preferably collagen. The amount of drug loaded will depend on the amount of
binding agent present, the concentration of the drug solution into which the composite is soaked as well
as the duration of the soaking.
Synthetic and semi-synthetic polymer
The second type of soluble insert is usually based on semi-synthetic polymers (e.g., cellulose derivatives)
or on synthetic polymers such as polyvinyl alcohol. A decrease of release rate can be obtained by using
Eudragit, a polymer normally used for enteric coating, as a coating agent of the insert. Ethyl cellulose, a
hydrophobic polymer, can be used to decrease the deformation of the insert and thus to prevent blurred
vision.[17]
Bioerodible
The bioerodible inserts are composed of metrical homogeneous dispersion of a drug included or not into
a hydrophobic coating which is substantially impermeable to the drug. These inserts are formed by bio-
erodible polymers (e.g., cross-linked gelatin derivatives, polyester derivatives) which undergo hydrolysis
of chemical bonds and hence dissolution. The great advantage of these bio-erodible polymers is the
possibility of modulating their erosion rate by modifying their final structure during synthesis and by
addition of anionic or cationic surfactants. They are two in types; insoluble inserts and soluble inserts.[15,
17]

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METHOD OF PREPARATION
Solvent casting method
In this method using different ratio of drug and polymer and prepare no. of batches. Firstly, in distilled
water the polymer is dissolved. In stirring condition a plasticizer is added to this solution. The weighed
amount of drug was added to this solution and stirred to get a uniform dispersion. After mixing this
solution poured in Petridish and covered with funnel to allow slow evaporation at room temperature for
48 h. The dried films thus obtained then cut into circular pieces of definite size containing drug. The
ocular inserts were stored in a desiccators (air tight container) under ambient condition.[22]
Gelfoam disc
A gelfoam disc which diameter is ≈4 mm and 0.5 mm thickness was punched from a slab of gelfoam
sponge with a common hole punch and phenylephrine HCL 1.7 mg and tropicamide 0.6 mg were
dissolved in a solution (25 µl) of 50% (v/v) ethanol in water. The solution was placed on the Gelfoam
disc. Under vacuum for at least 72 h, the wet matrics were dried. By this method placebo devices were
also prepared but without drug. The dose of phenylephrine and tropicamide are equal to two drops each
of Mydriacyl.[23]
Mould preparation
Using appropriate amounts of polymer, drug and exicipients we prepare, polymethylsiloxane rod- shaped
silicone inserts. Into the aluminium moulds (diameter 0.9 mm, length 22.0 mm), the mixtures were
injected, and were allowed to cure at 45°C for 24 h. The resulting rubbery cylinders (diameter 0.9 mm,
length 22.0 mm) were appropriately cut to give a drug content of specific amount. The final lengths and
weights were in the range 4-12 mm and 2.7-8.0 mg, depending on insert type. The rod shaped silicon
inserts were used, as such and after poly- acrylic acid or polymethacrylic acid coating, for hydration tests
and for in vitro/in vivo drug release studies.[24]
EVALUATION PARAMETERS
Sterility study
The inserts were sterilized using gamma radiation before carrying out the eye irritancy and in vivo drug
release study. No microbial or fungal growth was seen in any of the formulations, which indicate that the
films were sterilized completely.[25]
Surface pH determination
The pH of solutions, drops, suspensions, and in situ gels is most often determined using a potentiometric
method. In this method, the pH value is determined by measuring potential difference between
electrodes placed in examined and reference solutions of known pH or between measurement electrode
and reference (calomel or silver chloride) electrode, both placed in examined preparation.[26-28]
Clarity examination
Clarity examination involves the visual assessment of formulation in suitable lighting on white and black
background. It is performed for liquid forms, with the exception of suspensions. This examination applies
to eye drops and in situ gels before and after gelling.[29, 30]
Another method of clarity examination involves transmittance measurement using a UV-Vis
spectrophotometer. This method can be employed in research on contact lenses filled with active
ingredients. The lenses are hydrated in physiological saline and placed on the surface of quartz cuvette.
The transmittance is measured afterwards from 200 to 1000 nm wavelength.[31]
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Examination of size and morphology of particles

For examination of particles’ size multiple methods are employed: optical microscopy (microscopic
particle count test), light obscuration particle count test, dynamic imaging analysis, laser diffraction
particle analyzers, electron microscopy, dynamic light scattering, coulter counter test and nanoparticle
tracking analysis.[32]
In-vivo characterization
Eye Irritancy Test (Draize Eye Test)
There are many modifications of eye toxicity/irritancy test (Draize eye test) performed for dosage forms,
that is, solutions, emulsions, ointments, solids, for example, inserts, and so forth. The most often used
animal subspecies are albino (eg. New Zealand) rabbits, which are examined and weighed before the test
and then placed in specifically adapted cages, designed so as to avoid accidental injuries. The examined
preparations are introduced to conjunctival sac or applied directly on the cornea. At first, about 0.1mL of
analyzed drug was being applied on the eyeball, but many later examinations pointed to reducing the
amount, for example, to 0.01 mL, which more reflects real situations. In the test, one eyeball, usually the
left one, is used as a control. After introducing a drug form on the eyeball, the eyelids are usually kept
closed for a few seconds, although it is not required. Sometimes sterile solutions are additionally used for
rinsing the eyeball surface. An assessment of eyeball condition before and after introducing the
formulation is done by observation of the eyeball in suitable light, often using magnifying glass or a slit
lamp, which ensures more precise evaluation. Auxiliary procedures which simplify visualization of
changes include dyeing with fluorescein and taking photos of eyeball. Moreover, the discomfort level
after application may be indicated by the number of blinkings or rubbings of the eye. The evaluation
takes place usually after 1 h, 24 h, 48 h, and 72 h from introducing a drug form on the eyeball and, if
essential, also after 7 or 21 days. Duration of examination, as well as its scheme, is individually adapted to
the analyzed formulation.[34-36]
Transcorneal Permeation Study
For transcorneal permeation study, as in the Draize eye test, healthy albino rabbits are chosen in the
number which is suitable for obtaining reliable results. The amount of active substance in aqueous humor
after introducing the formulation to conjunctival sac is marked in specified time intervals. Using a syringe
with needle, after intramuscular or intravenous anaesthetic injection which may contain, depending on
application, ketamine hydrochloride, xylazine hydrochloride, or pentobarbital sodium, a sample of
aqueous humor is taken in the amount of about 150–200 𝜇L and stored at negative temperature, for
example, −20∘C, before HPLC analysis.[37-41] At times, additional inhalation anaesthesia is used, for
example, in the form of mixture of 4% isofluraneoxygen, shortly before or during paracentesis.[38]
Regional anaesthesia, for example, in the form of xylocaine solution, may also be applied.[40] Noomwong
with associates, during performed tests, added suitable amount of 2% ZnSO4 ⋅ 7H2O solution to the taken
samples in order to salt out proteins contained in aqueous humor and then centrifuged the sample at the
speed of 10000 rpm for 1 h at the temperature of −10∘C. They used HPLC method to examine the amount
of active ingredient in the obtained supernatant [38]. On the other hand, El-Laithy et al. and associates
examined obtained samples using a spectrofluorometric method, which could have been employed due to
natural fluorescence of used drug from fluoroquinolone group, moxifloxacin.[39]

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Brand name Drug Dosage form Use

Dichol Carbahol Sterile solution/injection In ophthalmic surgery
Dexcin Dexamethasone Eye drop In eye infection
Ocupol Polymixin-B Eye drop/Ointment Corneal ulcer
Acivir eye Acyclovir Ointment Eye infection
Chloromycetin Chlorampthenicol Ointment Conjunctivitis
palmitate
Pred forte Prednisolone acetate Suspension Anti allergic
Ciplox Ciprofloxacin Eye drop Conjunctivitis
Restasis Cyclosporine Emulsion Dry eye
Refresh classic Artificial tear fluid Single use vials Dry eye
Betnisol N Betamethasone Eye drop Eye infection
Refresh tears Hydroxypropyl Eye drops Eye lubricant
methylcellulose
Geltear Carbomer Bioadhesive gel Lubricant
Timolol xe Timolol maleate In-situ gel Keratoconjuctivitis
Table: Marketed ophthalmic products[42]
CONCLUSION
Ocular delivery based formulations have great applications for local treatment of eye disease with
relatively lesser side effects as compared to other route of drug delivery. Progress in the field of ocular
drug delivery has been established recently with controlled loading and sustained release. Ocular
formulations could be more acceptable and excellent drug delivery systems if prepared by using the
biodegradable and water soluble polymers. Ocular inserts might be an alternate for the traditional
system with many of benefits and best system for the treatment of eye disease as well as systemic
disease.

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