OCULAR DRUG DELIVERY SYSTEMPRESENTED BY:- SUJAY SAWANT ( m.pharm )KLE’S College of pharmacy, belgaum .

INTRODUCTION TO OCULAR DRUG DELIVERY SYSTEM • Ocular administration of drug is associated with

the need to treat opthalmic diseases.• Eye is most easily accessible site for topical

administration of medication.• Ideal opthalmic drug delivery system is the one

which is able to sustain the drug release and to remain in the vicinity of front of the eye for prolonged period of time.

• Most ocular treatments call for the topical administration of opthalmically active drugs to tissue around the ocular activity.

• Most prescribed dosage form is the “Eye Drops”.

IDEAL CHARACTERISTICS OF ODDS • Good corneal penetration• Prolonged contact time with the eye• Less drainage tendency• Simplicity of instillation for patient• Non-irritating and comfortable• Appropriate rheological properties• Sterile• Free from foreign particles• Isotonic with the tear fluid• Minimum protein binding• Good bioavailability • Ideal pH should be 7.4

ANATOMY OF EYE

PHYSIOLOGY OF EYE The cornea, lens, vitreous bodies all are transparent media with no blood vessels.Thin epithelial layer covers the cornea which is continuous with the conjunctiva. Bulk of cornea is formed of cris-crossing layers of the collagen & is bounded by elastic laminae on both i.e front & back.

Eye is constantly cleaned & lubricated by the lacrimal apparatus which consists of 4 structures:1. Lacrimal glands2. Lacrimal canals3. Lacrimal sac4. Nasolacrimal duct

Lacrimal fluid secreted by the lacrimal glands is emptied on the surface of the conjunctiva of the upper eyelid .Lacrimal fluid in human has a normal volume of 7mcg.It contains enzymes ‘lysozymes’ which is bactericidal.

Composition of tear:a. Water-98.2%, b. Solids-1.8%, c. Organic elements- Proteins (0.67), NaCl (0.66%), Sugar (0.65%)

MECHANISM OF OCULAR DRUG ABSORPTION• Non- corneal absorption:Penetration across sclera & conjunctiva into intra ocular tissues.Non productive: because penetrated drug is absorbed by general circulation.• Corneal absorption:Outer epithelium: rate limiting barrier, with pore size 60a, only access to small ionic and lipophilic molecules.Trans cellular transport: transport between corneal epithelium and stroma.

DRUG PENETRATION BARRIER IN Cul-de-sac

BARRIERS AVOIDING DRUG DELIVERY

CONVENTIONAL OCULAR DRUG DELIVERY SYSTEMS TYPES OF CONVENTIONAL ODDS

Eye drops Opthalmic ointmentsOpthalmic gels Eye lotionsInserts

CATEGORIES OF DRUGS USED IN ODDS:-Miotics (pupil to contract) Mydriatics (pupil ton dilate) DiagnosticsSurgical adjunctsAnti bacterial / Anti infectives

• Eye Drops:-

Drugs which are active at eye or eye surface are widely administered in the form of Solutions, Emulsion and Suspension.

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 % 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.

3 Types:-Solutions, Suspensions, Emulsions

1. Opthalmic solution:-Sterile homogenous preparation which is free from the foreign particles, prepared for the instillation of medication into the eye.

Ex. Timolol opthalmic solution (Timoptic, Timoptic-XE), Azithromycin eye drops (Azasite)

2. Opthalmic Suspension:-Sterile disperssions of finely divided insoluble API in an aqueous solvent consisting of suitable suspending and dispersing agentIts activity is particle size dependent. So if size is optimum then optimal activity is achieved.

Ex. Tobramycin 0.3% + Dexa 0.05% (TobraDex ST) have very low settling rate

3. Emulsions:-Fine sterile dispersion of minute droplets of one liquid into another, in which it is generally not soluble or miscible.

Ex. (w/o emulsion) Cyclosporin 0.05% opthalmic emulsion (Restasis)(o/w emulsion) Fluribrophen axetil + Castor oil (Fluribrophen opthalmics) have better bioavailability and less irritation.

• OPTHALMIC OINTMENTS :-Mixture of semisolid and solid hydrocarbons (parrfins) which melts at ocular Temperature of 34 C.

When applied to inferior conjuctival sac, ointments melt quickly and the excess spread out onto the lid margin, lashes, skin of lids.

It has a therapeutic effect for 6hr.Prolongation of drug contact time with the external ocular surface can be achieved using ophthalmic ointments, but the major drawback of this dosage form such as blurring of vision & matting of eyelids can limit its use.

Ex. Tobramycin opthalmic ointment (Tobrex)

• Opthalmic gels:-Sterile semisolid cross linked system which is meant for administration of drug into the eye.

Ex. Pilocarpine gel (Pilopine HS)

• Opthalmic lotion:-Low to heavy viscosity topical preparation meant for cleansing of eyes.

Ex. Eye Drops Smile 40 EX Mild Eye Lotion

OPTHALMIC INSERTS:-

2 TYPES OF OPTHALMIC INSERTS :- Non-erodible inserts- Ocuserts & Contact lens Erodible inserts- Lacriserts, SODI, Minidisc

DESIRED CRITERIA FOR OCULAR INSERTS :- Comfortable Ease of handling & insertion Non interfering with vision & oxygen permeability Reproducibility of release kinetics Sterility Stability Ease of manufacture

NON ERODIBLE INSERTS:-1. OCUSERTSIt is medicated novel ocular drug delivery system which can be inserted into the eye.

Ex. Pilocarpine ocusert(Ocusert Pilo-20, Pilo-40)

2.CONTACT LENSES Hard contact lenses, soft contact lenses and intraocular lenses are popular for correction of refractive errors of the eye and several kinds of polymer have been used for the preparation .Therapeutic soft lenses are often used to aid corneal wound healing in patient with infection, corneal, ulcers, characterised by marked thinning of the cornea.

2 types of contact lenses :-Disposable lensesNon-disposable lenses

E.g. Bionite ® was developed by Griffin laboratory, and Soflens®, was developed by Bausch & Lomb, They used fluoresce in as a model drug. Antiviral idoxuridine (IDU), polymyxin B and pilocarpine as drug delivery by soft Conact Lenses to the eye.

ERODIBLE INSERTS:-1. LACRISERTSSterile rod shaped device made of hydroxy propyl cellulose without any preservative i.e used in the treatment of dry eye syndromes.

Advantage:-Replacement of 4 times an hour regimen by once or twice daily regimen is the benefit achieved by this dosage form.

2. SODI (SOLUBLE OCULAR DRUG INSERT)

• Sterile thin films of oval shape, which after introduction into the inferior cul-de-sac are wetted by the tear & then gets soften in 10-15 mins viscous polymer mass (10-15 mins) polymer solution (30-60 mins)

• ADVANTAGE:-SODI application has been reported to replace 4-12 drops instillation or 3-6 applications of ointment for treatment of glaucoma & trachoma

MINIDISC

• Ocular therapeutic system (OTS) consists of a countered disc with a convex front and a concave back surface in the contact with eyeball.

• It is like a mimiature contact lens with a diameter of 4-5 mm.

CONTROLLED OCULAR PILOCARPINE DELIVERY BY OCUSERT SYSTEM:-The inserted ocusert in cul-de-sac, dissolved in lacrimal fluid, penetrating into system by zero order kinetics.

It can be given by the following equation:- (dQ/dt)r = Dp.Km.(Cr-Ct) hm Where, (dQ/dt)r = Rate of release of PilolcarpineDp = Diffusivity of Pilocarpinehm = Thickness of membraneKm = Partition corefficient (Cr-Ct) = Difference in the Pilocarpine cone between reservoir in the core & tear fluid

If Cr>>Ct then the above equation can be simplified to:- (dQ/dt) =Dp.Km.Cs/hm

Where, Cs = Saturated Pilocarpine solution.

ADVANTAGES OF OCUSERTS:-Accurate and programmed dosingProvides better patient complianceLess frequency of dosingFewer ocular and systemic side effectsFree from preservatives

FACTORS AFFECTING INTRAOCULAR BIOAVAILABILITY :-

1. Inflow & Outflow of Lacrimal fluids.

2. Efficient naso-lacrimal drainage.

3. Interaction of drug with proteins of Lacrimal fluid.

4. Dilution with tears. 5. Limited and poor corneal permeability 6. Metabolism

RESCENT FORMULATION TRENDS IN OCDDS FOR THE ENHANCEMENT OF BIOAVAILABILITY :- 1. ADDITION OF VISCOSITY ENHANCERIncreases viscosity of the solution there by decreasing

solution drainage

Slows elimination rate from the precorneal area and enhances contact time.Generally hydrophilic polymers- ex. Methyl cellulose, polyvinyl alcohols, polyacrylic acids, sodium carboxy methyl cellulose, carbomer are used.A minimum viscosity of 20 cst is needed for optimum corneal absorption.

2. USE OF PENETRATION ENHANCER

Substances which increase the permeability characteristics of the cornea by modifying the integrity of corneal epithelium are known as penetration enhancers.

Modes of action:-Penetration enhancers act mainly on tight junctions, modify the integrity of the corneal epithelium & hence increase the permeability of the cell membrane.

Chelators :

e.g. EDTA, Salicylates

Surfactants :

e.g. palmiloyl carnitine , sodium caprate, Sodium dodecyl sulphate

Bile acids and salts :

e.g. Sodium deoxycholate, Sodium taurocholate, Sodium taurodeoxycholate, Taurocholic acid

Glycosides :

e.g. Saponins, Digitonon

Fatty acids :

e.g. Caprylic acid

Miscellaneous :

e.g. Azone, Cytochalasins

Preservatives :

e.g. Benzalkonium chloride

Glycosides:-

e.g. Saponin, Digitonin

3. PRODRUGS

Prodrugs enhance corneal drug permeability through

modification of the hydrophilicity or lipophilicity of the drug.

The method includes modification of chemical structure of the

drug molecule, thus making it selective, site specific and a safe

ocular drug delivery system.

Drugs with increased penetrability through prodrug formulations

are epinehrine, phenylephrine, timolol, pilocarpine

4. USE OF MUCOADHESIVES IN OCULAR DRUG DELIVERY SYSTEMS

Polymeric mucoadhesive vehicle: Retained in the eye due to non-covalent bonding with conjunctival mucine.

Mucine is capable of picking of 40-80 times of weight of water. Thus prolongs the residence time of drug in the conjuctival sac.

Mucoadhesives contain the dosage form which remains adhered to cornea until the polymer is degraded or mucus replaces itself.

Types-1. Naturally Occurring Mucoadhesives- Lectins, Fibronectins 2. Synthetic Mucoadhesives-PVA,Carbopol, carboxy methyl cellulose,

cross-linked polyacrylic acid

Drugs incarporated in to these are pilocarpine, lidocaine, benzocaine and prednisolone acetate.

MECHANISM OF MUCOADHESION

• The polymer undergoes swelling in water,

• Entanglement of the polymer chains with mucin on the epithelial surface.

• The un-ionized carboxylic acid residues on the polymer form hydrogen bonds with the mucin.

• The water-swellable yet water-insoluble systems are preferred

5. USE OF POLYMERS

Incorporation of polymers into an aqueous medium increases the viscosity there by improving the ocular contact time of drug solution .

An optimal viscosity of 12-15 cps has been suggested for ocular drug absorption.

Hydrophilic polymers- Ethyl acetate, Poly vinyl acetate, Poly acrylic acid

Hydrophobic polymers- Shellac, Glycerin monostearate, Nylon, Poly vinyl chloride

6. PHASE TRANSITION SYSTEM

Temperature dependent phase transition system e.g. Lutrol FC 127 and Poloxamer 407

Triggered transition system PH e.g. Cellulose acetate phthalate, Carbopol, Chitosan

Ion activated system gelrite - An ion activated in situ gelling polymer forms a clear gel in the presence of cation. e.g. Calcium or sodium ions present in the tears increase the corneal residence time & bioavailability of drugs.

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POLYMERS MECHANISM

Lutrol FC – 127 and Poloxamer 407

Viscosity increased when their temperature raised to eye temperature.

Cellulose acetate phthalate latex

Coagulates when its native pH 4.5 raised by tear fluid to pH 7.4

Gelrite Forms clear gel in the presence of cations

7. COLLAGEN SHIELDS:-Collagen is the structural protein of bones, tendons, ligaments, & skin and comprises more than 25% of the total body weight.

Collagen shields belong to soluble ophthalmic inserts manufactured from Procine scleral tissue.

Cross linked collagen shields might be useful in ocular drug delivery devices because they can allow drug concentrations to achieve higher levels in cornea & aqueous humor.

ADVANTAGES• Appropriate delivery system for both hydrophilic

and hydrophobic drugs with poor penetration properties

• Biological inertness, structural stability, good biocompatibility and low cost of production.

DISADVANTAGES

• Insertion technique is difficult & expulsion of shields may occur

• Not individually fit for each patient• Shields are not fully transparent & thus reduce

visual activity.

8. PSEUDOLATICES :-

Organic solution of polymers is dispersed in an aqueous phase to form O/W emulsion

Water is removed partially to an extent that residual water is removed sufficient enough to keep polymeric phase discrete & dispersed

On application leave an intact noninvasive continuous polymer film which reserves drugs

Drug released slowly over prolonged period of time , better ocular bioavailability patient compliance

9. PARTICULATE SYSEM :-(NANOPARTICLES & MICROSPHERES)

Nanoparticle- <1 micrometre

Microparticle- >1 micrometre

The maximum size limit for microparticles for ophthalmic administration is about 5-10 micrometer above which a scratching feeling in the eye can result upon ocular instillation.

That is why micro and nanoparticles are promising drug carriers for ophthalmic application.

The drugs are bound to small particles which are then dispensed in aqueous vehicles

Polybutylcyanoacrylate nanoparticles have been used for human being as a drug carrier

10. VESICULAR SYSTEM TYPES

1.- LIPOSOMES2.- NIOSOMES3.- DISCOSOMES4.- PHARMACOSOMES

LIPOSOMES:-Liposomes are biocompatible & biodegradable lipid vesicles made up of natural lipids and about 25–10 000 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.

Advantage:- Acurate dosing & improved bioavailability for lipophillic drugs.

NIOSOMES :-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.

Niosomes are nonionic surfactant vesicles that have potential applications in the delivery of hydrophobic or amphiphilic drugs.

NIOSOMES Vs LIPOSOMES

Non ionic surface active agent

PhospholipidHydrophilic drugs in

aqueous region encapsulatedLipophilic drugs located in the hydrophobic lamella

Niosomes are microscopic lamellar structures, which are formed on the admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media.Structurally, niosomes are similar to liposomes, in that they are also made up of a bilayer. However, the bilayer in the case of niosomes is made up of non-ionic surface active agents rather than phospholipids as seen in the case of liposomes.

DISCOMES:-

Soluble surface active agents when added in critical amount to vesicular dispersion leads to solubilization or breakdown of vesicles & translates them into mixed micellar systems E.g: Egg yolk phosphatidyl choline liposomes by the addition of non ionic surfactants of poly oxy ethylene cetyl ether till the lamellar and mixed lamellar coexist

Advantages: Minimal opacity imposes no hinderance to vision Increased patient complianceZero order release can be easily attained

PHARMACOSOMES:-

This term is used for pure drug vesicles formed by the amphiphilic drugs.

The amphiphilic prodrug is converted to pharmacosomes on dilution with water.

The vesicle formation takesplace not only just by association of phospholipids but also by amphiphilic molecular association

Since many drugs are also amphiphiles, they can form the vesicles

Advantages: Drug metabolism can be decreasedControled release profile can be achieved

11. The New ophthalmic delivery systems (NODS):-

The new ophthalmic delivery system (NODS) is a method of method of presenting drugs to the eye within a water soluble drug loaded film.

It provide for accurate, reproducible, dosing in an easily administered preservative free form.

Each NODS consists of a drug loaded film or (flag) attached to a handle film by means of thin membrane.

Shape and Area – 22 mm2 Thickness – 20 µm Total weight - 500 µg (of which 40% can be drug. )

CONTROLLED DELIVERY SYSTEMS :-1. Implants: 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 show no toxic signs.

Ex. Retisert® (non-biodegradable fluocinolone acetonide intravitreal implant; Bausch & Lomb) sterile implant consists of a tablet containing 0.59 mg fluocinolone acetonide.

Ozurdex® (biodegradable dexamethasone intravitreal implant; Allergan, Irvine, CA.) is composed of a biodegradable copolymer of lactic acid and glycolic acid with micronized dexamethasone. This implant is placed into the vitreous cavity using a single-use applicator.

2. Dendrimer:Dendrimers can successfully used for different routes of drug administration and have better water-solubility, bioavailability and biocompatibility.

2. Iontophoresis:

In Iontophoresis direct current drives ions into cells or tissues. For iontophoresis the ions of importance should be charged molecules of the drug.

Positively charged of drug are driven into the tissues at the anode and vice versa.

Ocular iontophoresis delivery is not only fast, painless and safe but it can also deliver high concentration of the drug to a specific site.

• 4. Microemulsion:

Microemulsion is dispersion of water and oil stabilized using surfactant and co- surfactant to reduce interfacial tension and usually characterized by small droplet size (100 nm), higher thermodynamic stability and clear appearance.

Selection of aqueous phase, organic phase and surfactant/co-surfactant systems are critical parameters which can affect stability of the system.

• 5. 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.

• 6. Microneedle:

Microneedle had shown prominent in vitro penetration into sclera and rapid dissolution of coating solution after insertion while in vivo drug level was found to be significantly higher than the level observed following topical drug administration like pilocarpine.

• 7. Mucoadhesive Polymers:

They are basically macromolecular hydrocolloids with plentiful hydrophilic functional groups, such as hydroxyl, carboxyl, amide and sulphate having capability for establishing electrostatic interactions.

A mucoadhesive drug formulation for the treatment of glaucoma was developed using a highly potent beta blocker drug, levobetaxolol (LB) hydrochloride and partially neutralized poly acrylic acid .

EVALUATION OF OCUSERTS% MOISTURE ABSORPTION :

It was carried out to check the physical stability or integrity at wet condition.

The prepared ocusert was accurately weighed and placed in a dessicator containing aluminium chloride with 79.5% moisture and it was kept for 3 days.

The ocusert was taken out and reweighed after 3 days.

% Moisture absorption = Final weight – Initial weight x 100

Initial weight

• % MOISTURE LOSS:

The prepared ocusert was initially weighed and kept in a dessicator containing fused anhydrous calcium chloride and it was kept for 3 days.

The ocusert was taken out and reweighed after 3 days.

% Moisture loss = Final weight – Initial weight x 100

Initial weight

• UNIFORMITY OF THICKNESS:

The thickness of the insert was determined using a Vernier caliper at five separate points of each insert.

For each formulation, five randomly selected inserts were tested for their thickness.

• UNIFORMITY OF WEIGHT:

From each batch, five inserts are taken out and weighed individually using digital balance (Asco, India). The mean weight of the insert is noted.

• IN-VITRO EVALUATION METHODS• BOTTLE METHOD:In this, dosage forms are placed in the bottle containing dissolution medium maintained at specified temperature and pH.The bottle is then shaken.A sample of medium is taken out at appropriate intervals and analyzed for the drug content. • DIFFUSION METHOD:Drug solution is placed in the donor compartment and buffer medium is placed in between donor and receptor compartment.Drug diffused in receptor compartment is measured at various time intervals.

• MODIFIED ROTATING BASKET METHOD:Dosage form is placed in a basket assembly connected to a stirrer.The assembly is lowered into a jacketed beaker containing buffer medium and temperature 37 degrees Centigrade.Samples are taken at appropriate time intervals and analyzed for drug content. • MODIFIED ROTATING PADDLE APPARATUS:Here, dosage form is placed into a diffusion cell which is placed in the flask of rotating paddle apparatus.The buffer medium is placed in the flask and paddle is rotated at 50 rpm.The entire unit is maintained at 37 degree C.Aliquots of sample are removed at appropriate time intervals and analyzed for drug content.

IN-VIVO STUDYThen the dosage form is removed carefully at regular time interval and are analyzed for drug content.

The drug remaining is subtracted from the initial drug content, which will give the amount of the drug absorbed in the eye of animal at particular time.

After one week of washed period, the experiment was repeated for two time as before.

Here, the dosage form is applied to one eye of animals and the other eye serves as control.

ACCELERATED STABILITY STUDIESThese are carried out to predict the breakdown that may occur over prolonged periods of storage at normal shelf condition.

Here, the dosage form is kept at elevated temperature or humidity or intensity of light, or oxygen.

Then after regular intervals of time sample is taken and analyzed for drug content.

From these results, graphical data treatment is plotted and shelf life and expiry date are determined.

DRUG BRAND NAME

FORM USE

Ozurdex Dexamethasone

Intravitreal implant

To treat swelling due to blockage of certain blood vessels

Lotemax Ioteprednol Eye drops To treat post operative inflammation

Omnipred , Pred Forte

Prednisolone acetate

Eye drops To treat inflammation of eyes, eyelids.Treatment of keratitis

Retisert Fluconazole Ophthalmic implant

Treat inflammation within eye due to infection & diseases

Atropine care

Atropine Ophthalmic solution

Mydriaticts, Treatment of certain inflammation conditions within the eye

Alrex Ioteprednol Eye drops Relief of temporary itching, redness, swelling & irritation of eye caused by seasonal allergies

Volaren Diclofenac Eye drops (NSAID)

Treating pain, redness, swelling & sensitivity to light after certain eye surgeries

REFERENCESBiopharmaceutics & Pharmacokinetics; Brahmankar & Jaiswal, 1st Edition, 368-369.Novel drug delivery systems: Y. W. Chein, 2nd Edition, 269-300.Controlled and Novel drug delivery; N. K. Jain, 1st Edition, 82-92.Advances in controlled and novel drug delivery system, N.K. Jain, 1st Edition, 218-223.Encyclopedia of controlled drug delivery system, Edith Mathionwitz, Vol.2, 1563-1576.Modern Pharmaceutics; Banker & Rhods, 3rd Edition, 489-541.

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