SUBMITTED BY –RAJASHRI S.PATIL M.PHARMACY - (PHARMACEUTICS)DR.D.Y.PATIL.COLLEGE OF PHARMACY,AKURDI,PUNE

OCULAR INSERTS

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CONTENTS:

INTRODUCTIONHUMAN EYE ANATOMYIDEAL REQUIREMENTS FOR OCULAR DRUG DELIVERYMECHANISM OF OCULAR DRUG ABSORPTIONCLASSIFICATION OF OPHTHALMIC DOSAGE FORMEVALUATION OF OPHTHALMIC INSERTSSTABILITY STUDIES

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INTRODUCTIONThe eye is a unique organ, both anatomically and

physiologically, containing several widely varied structures with independent physiological functions.

One of the major barriers of ocular medication is to obtain and maintain a therapeutic level at the site of action for prolonged period of time.

The anatomy, physiology and biochemistry of the eye render this organ exquisitely impervious to foreign substances.

The challenging to the formulator is to circumvent the protective barriers of the eye without causing permanent tissue damage.

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The development of newer, more sensitive diagnostic techniques and therapeutics agents renders urgency to the development of maximum successful and advanced ocular drug delivery systems .

The therapeutic efficacy of an ocular drug can be greatly improved by prolonging its contact with the corneal surface.

Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases.

The eye is the most accessible site for topical administration of medication.

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ANATOMY & PHYSIOLOGY OF EYE

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CONT..• The eye is a spheroidal structure consisting of Outer fibrous layer:

“EYE” Sclera Choroid layer Retina Middle vascular level: Iris

Ciliary body

choroids

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o it is the tough fibrous coating.oProtects the inner layers of the eye.

o It allows light to enter the eye.o Optically transparent tissue (cornea) transmits images

to the back of the eye and covers about one-sixth of the total surface area of eyeball.

o It screens out the damaging ultraviolet wavelength in sunlight.

SCLERA

CORNEA

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The cornea has five layers anterioposteriorly:1) Epithelium and its basement membrane – stratified

squamous type of epithelium with five to six cell layers of regular arrangement.

2) Bowman’s layer – homogeneous sheet of modified stroma.3) Stroma – consists of approximately 90% of total corneal

thickness. Consists of lamellae of collagen, cells and ground substance.

4) Descemet’s membrane – the basement membrane of the endothelium.

5) Endothelium – a single layer of cells lining the inner surface of Descemet’s membrane.

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choroids consist of following parts:oBruch’s membrane – membrane on the external surface of

the retinal pigment epithelium (RPE). It consists of the basement membrane of RPE cells and choriocapillaris . Between the two layers of basement membrane are the elastic and collagenous layers. Small localised thickenings of Bruch’s membrane (which increase with age) are called drusen.

oThe choriocapillaris – a network of capillaries supplying the RPE and outer retina.

oLayer of larger choroidal blood vessels external to the choriocapillaris.

oPigmented cells scattered in the choroid external to the choriocapillaris.

Choroid

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o It is thin , semitransparent, multilayered sheet of neural tissue.o This is the “photographic film” of the eye that converts light into electrical energy

(transduction) for transmission to the brain.o It consist of two main parts: The neuroretina – All layers of the retina that are derived from the inner layer of the embryological optic cup. The RPE – Derived from the outer layer of the optic cup. It is comprised of a single layer of cells, which are fixed to Bruch’s membrane. Bruch’s membrane separates the outer retina from the choroid.

RETINA

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o The Iris is the part of eye which gives it color .o It is a thin circular disc perforated centrally by the pupil.o It consists of muscular tissue that responds to surrounding light,

making the pupil opening in the center of the iris, larger or smaller depending on the brightness of the light.

o The ciliary body is a specialized structure uniting the Iris with the choroid.

o It is attached anteriorly to the iris and the scleral spur, posteriorly it is continuous with the choroid and retina.

o The aqueous humor is an optically clear solution of electrolytes (in water) that fills the space between the cornea and the lens.

oNormal volume is 0.3 ml. Its function is to nourish the lens and cornea.

IRIS

CILIARY BODY

The Aqueous Humor

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o The vitreous consists of a three-dimensional network of collagen fibers with the interspaces filled with polymerized hyaluronic acid molecules, which are capable of holding large quantities of water and produce gel like consistency.

o It is non-vascular, colorless and transparent.oThe lens consist of elongated , stiff, prismatic cells known as lens

fibers ,very tightly packed together and divided into nucleus, cortex and capsule.

The Vitreous Body

The Lens

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•COMPOSITION OF EYE:

Water - 98%, Solid -1.8%, Organic element – Protein - 0.67%,

sugar - 0.65%, NaCl - 0.66% Other mineral element sodium,

potassium and ammonia - 0.79%.

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Drugs used in the eye:Miotics e.g. pilocarpine HclMydriatics e.g. AtropineCycloplegics e.g. AtropineAnti-inflammatories e.g. corticosteroidsAnti- infectives (antibiotics, antivirals and antibacterials)Anti- glucoma drugs e.g. pilocarpine HclAdjuncts e.g. Irrigating solutionsDiagnostic drugs e.g. sodiumfluoresceinAnesthetics e.g. Tetracaine

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IDEAL REQUIREMENTS FOR OCULAR DRUG DELIVERY:

A no. of requirements must be considered in the preparation of ophthalmic solution, suspension or ointments.

These includes : sterility ,clarity , buffer , buffer capacity and pH, tonicity , viscosity , stability , comfort ,additives , particles size , packaging and preservatives.

The ophthalmic solutions are formulated should be sterile , isotonic , and buffered for stability and comfort.

Solution must be free from foreign particles.Sterilization represents the major requirement of eye product.

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MECHANISM OF OCULAR DRUG ABSORPTION

Corneal Drug Absorption

Non-corneal Drug Absorption

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CORNEAL ABSORPTION NON-CORNEAL ABSORPTION

Depend upon physicochemical Penetration across sclera &conjunctiva prop of drug. into intra ocular tissue. Only access to small ionic & lipophilic Non Productive : bcz penetrated drug is molecule absorbed by general circulation. Trans cellular transport: transport Important for drug with low Bet corneal epithelium & stroma. Corneal permeability. Outer epithelium: rate limiting barrier. Minor pathway.

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CLASSIFICATION OF OPHTHALMIC DOSAGE FORM

LIQUID SEMISOLID SOLID INTRAOCULAR DF

SOLUTION OINTMENT INJECTION

SUSPENSION

SOL TO GEL SYS

POWDER FOR RECONSTITUTION

GEL

INSERTS

CONTACT LENSESIMPLANTS

IRRIGATING SOL

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OCULAR INSERTS

Ophthalmic inserts are defined as sterile preparations , with a thin, multilayered, drug-impregnated, solid or semisolid consistency devices placed into cul-de-sac or conjuctival sac and whose size and shape are especially designed for ophthalmic application.

It is inserted into the eye and worn under the upper or lower lid. It ensures a sustained and controlled release effect. Requirements for success- - COMFORT - EASE OF HANDLING - REPRODUCIBILITY OF RELEASE KINETICS - EASE OF MFG - NON- INTERFERENCE WITH VISION - STERILITY &STABILITY - LACK OF TOXICITY & EXPULSION

SOLID DOSAGE FORM :

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.ADVANTAGE…

Improves BA. Prolonged drug release

& better efficacy. Over comes side effects

of pulsed dosing. Accurate dose & better

therapy. Circumvent the

protective barriers like drainage etc.

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LIMITATIONS…

Ophthalmic inserts resides in their solidity

Patient discomfort Movement around eye

cause abrasion Inadvertent loss

during sleep & while rubbing eye

Difficult placement & removal

Interference with vision (in elderly)

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CLASSIFICATION:

Ocular inserts

Non –erodible

Erodible

Ocuserts

Contact lenses

lacriserts

SODI

Minidiscs

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Ocuserts:It is a flat flexible elliptical device consisting of three layers.Outer layer are consisted of ethylene vinyl-acetate enclosing

the core of gelled pilocarpine drug.A retaining ring of ethylene vinyl-acetate impregnated with

titanium dioxide for encloses the drug reservoir.

NON ERODIBLE INSERTS

27Fig : ocusert

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The release rates of the enclosed drug can be controlled by varying thickness of the covering layers ( rate controlling membranes).

The successful release behaviour of the ocusert relies on the solubility properties of the drug free base.

Eg.pilocarpine is miscible in water and organic solvents thus exhibiting both hydrophobic and lipophilic characters.

Increased contact time and thus improved bio-availability.Possibility of providing a prolonged drugrelease and a better efficacy.Administration of an accurate dose in the eye and thus a better therapy. Reduction of systemic side effects and thus reduced adverse effects.

Advantages of ocuserts

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Reduction of the no. of administration of drug and thus better patient Compliance and Comfort.

Lack of explosion.Ease of handling and insertion. Non-interference with vision and oxygen permeability. Sterility. Stability. Exclusion of preservatives.Increased shelf life with comparison to aqueous solutions

due to absence of water.

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Contact lenses : Contact lenses are circular shaped structures and the primary objective of

contact lenses is for improvement of vision.Their use has been extended as potential drug delivery devices by

presoaking them in drug solutions.The main advantage of this system is the possibility of correcting vision

and releasing drug simultaneously.ADVANTAGES:No preservationSize and shapeDISADVANTAGES:Handling and cleaningExpensive

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Types of contact lenses: Hard contact lenses Soft contact lenses Rigid gas permeable (RGP)

1) Hard contact lenses: -Made of rigid plastic resin polymethylmethacrylate-Impermeable to oxygen and moisture.

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2) Soft contact lenses :- Made of hydrophilic transparent plastic, hydroxyethylmethacrylate.- Contain 30 – 80% water so are permeable to oxygen.- Have two types: daily wear and extended wear .ADVANTAGES :1- worn for longer periods.2- do not dislodge easily.DISADVANTAGES:- have a shorter life span and the wearer must ensure that the lenses do not dry out.

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3) Rigid gas permeable: - Take the advantages of both soft and hard lenses, they are hydrophobic and oxygen permeable

ADVANTAGES OF HARD CONTACT LENSES AND RGP -Resistant to absorption of medications and environmental

contaminants.- Visual acurity.DISADVANTAGES- Require adjustment period of the wearer.- More easily dislodged from the eye.

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• Marketed preparations:

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LACRISERTS :- Lacriserts are sterile rod shaped device.- It consist of HYDROXYPROPYL CELLULOSE without any preservative.-Weight – 5 mg-Use :-in the T/T Dry eye syndrome, Keratitis SiccaDisadvantages :- The procedure is difficult to insertion .

ERODIBLE INSERTS

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• Marketed preparation of Lacriserts :

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• The SODI are small oval shaped wafers, originally developed by Soviet scientist.• The SODI is a small oval shaped wafer of

polyacrylamide incorporating a drug.• SODIs of pilocarpine and tetracycline have proved

clinically comparable with conventional eye drops for treatment of glaucoma and trachoma.

Soluble ocular drug inserts

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• Minidiscs are formulated and designed as a successful ocular inserts with the properties like comfort to patient ,lack of explusion , ease of handling and administration , non interference with vision and oxygen permeability.

• These are hydrophilic or hydrophobic.• Composition : Silicon based pre polymer.• 4-5mm in diameter.

MINIDISCS

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Uniformity of Thickness : The thickness of the insert is determined with Vernier caliper at five separate points of each inserts . for each formulation, five randomly selected inserts are tested for their thickness.Uniformity of Weight : from each batch ,five inserts are taken out and weighed individually using a digital balance.Drug Content : five ocular inserts are taken from each batch and dissolved or crushed in 10 ml of isotonic phosphate buffer pH 7.4 in a beaker and filtered into 25 ml vol. flask , make up the vol with buffer. 1 ml of the above sol is withdrawn and analysed by suitable method.

EVALUATION OF OPHTHALMIC INSERTS…

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• Surface pH : the inserts are allowed to swell in a closed petri dish at room temp for 30 min in 0.1 ml of distilled water . the swollen devices surface pH is determined by digital pH meter.• In – vitro Diffusion study: In- vitro diffusion of drug from the different ocular insert is studied using the classical standard cylindrical tube fabricated in the laboratory .A simple modification of glass tube 15 mm internal diameter and 100mm height and the diffusion cell membrane tied to one end of open cylinder , which act as a donor compartment. An ocular insert is placed inside this compartment. The diffusion cell- memb acted as corneal epithelium. The entire surface of the membrane should be in contact with the receptor compartment comprising of 25 ml of isotonic phosphate buffer ( pH 7.4 ) in a 100 ml beaker. Stirr continuously the contents of receptor compartment using a magnetic stirrer and maintain temp at 37 º cel. At specific intervals of time , 1 ml aliquot of sol is withdrawn from the receptor compartment and replaced with fresh buffer solution. The aliquot is analyzed for the drug content.

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Eye Irritancy Test :-The selected ocular inserts were sterilized using γ-radiation before eye irritancy test and in vivo drug release studies. Eye irritancy potential of a substance was determined on the basis of its ability to cause injury to the cornea, iris, and conjunctiva when a substance is applied to the eye. Testing was carried out on adult albino rabbits weighing about 2.5 to 3.5 kg of either sex.A twelve rabbits were used for testing the eye irritation potential of the ocular inserts.Ocular inserts were placed into the cul-de-sac of the rabbit while other eye served as a control.

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Microbiological studies :

The selected ocular insert were evaluated for microbiological study. The microbiological studies were carried out to ascertain the biological activity of the selected formulation against test microorganism. A Layer of nutrient agar seeded with the test organism (E. coli and S.aureus) was allowed to solidify in the Petri dish. An ocular inserts were removed from the pack and carefully placed over the agar layer at a suitable distance.The plates were then incubated at 37± 0.5˚C for 24 h. After incubation the zone of inhibition was measured around the ocular insert.

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Stability studies :Perform stability studies on ocular inserts , according to

ICH guidelines. A sufficient number of ocular inserts ( packed in aluminum foil) are stored in humidity chamber , with relative humidity of 75 % and at temperature of 40 degree cel. The samples are tested for drug content after 0, 30 , 60 , 180 days respectively.

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• Reference's : N . K.Jain, Advances in Controlled & Novel Drug

Delivery, CBS Publication, & distributor, New Delhi, pg. No.83-91

Dr. Dinesh K. Jain , Novel Drug Delivery Systems ,Nirali prakashan ,pg no. 7.1 – 7.20

www.thepharmajournal.comK. P. Sampath Kumar1*, Debjit Bhowmik, “Ocular Inserts:

A Novel Controlled Drug Delivery System”- THE PHARMA INNOVATION – JOURNAL.

www.google/images/eye/anatomy& physiology.www.pharmainfo.net/reviews/recent-advances-

ophthalmic-drug-delivery-system.

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Thank You…