Tarun ocular drug delivery

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OCULAR DRUG DELIVERY PRESENTED BY- TARUN POKHARIYAL M.PHARM. (PHARMACEUTICS) JAIPUR NATIONAL UNIVERSITY (JAIPUR) 1

Transcript of Tarun ocular drug delivery

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OCULAR DRUG DELIVERY

PRESENTED BY- TARUN POKHARIYAL M.PHARM. (PHARMACEUTICS)JAIPUR NATIONAL UNIVERSITY (JAIPUR)

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CONTENTSo INTRODUCTIONo EYE:ANATOMY & PHYSIOLOGYo ABSORPTION OF DRUG IN EYEo PHARMACOKINETICo CONTROLLED OCULAR DRUG SYSTEMSo OCULAR DRUG DELIVERY DEVICESo OTHER DELIVERY DEVICESo RETROMETABOLIC DRUG DESIGNo EVALUATIONo ADVANCED DELIVERY SYSTEMo FUTURE TRENDSo CONCLUSIONo REFERENCES

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INTRODUCTION

Drug administration through eyes is just for effect in eyes

To reduce the systemic absorption of drug is primary goal

The normal volume of tears = 7 ul the blinking eye can accommodate a

volume of up to 30 ul without spillagethe drop volume = 50 ul

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ADVANTAGES-

1. Accurate dosing.2. Absence of preservative

3. Increase in shelf life due to absence of water.

4.Best of drug with slow dissolution eg.suspension

5.Flexibilty in drug choice7.Rapid action8. Self medication is easy 9.Decrease side effects to other organs

disadvantages1. Perceived by patient as foreign body.2. Movement around the eye.3. Occasional loss during sleep or while rubbing eyes.4. Interference with vision.5. Difficulty in placement & removal.6.Patient non compliance7. Blurred vision8. Irritation in eyes9.Not suitable for running people

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EYE :ANATOMY AND PHYSIOLOGY

1. Sclera,

2. Choroids,

•Outer-Epithelium(lipophilic),

•Middle-Stroma(hydrophilic),

•Inner-Endothelium(lipophilic).

3. Cornea,

4. Cilliary Body- Secretion of aq.

humor,

5. Lens,

6. Retina,

7. Conjuctiva,

8. Vitreous Compartment,

9. Lacrimal gland.

Diameter 23mm

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The sclera: The protective outer layer of the eye

The cornea: The front portion of the sclera. transparent and allows light to enter the eye.

Diameter-11.7mm and thickness -0.5-0.7mm The choroid the second layer. lies between the sclera and the

retina. contains the blood vessels & provide

nourishment to the outer layers of the retina.

The iris gives it color. consists of muscular tissue that

responds to surrounding light,

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The lens transparent, biconvex structure, function-refract and focus incoming light onto the retina.

The retina is innermost layer in the eye. converts images into electrical impulses that are sent along the optic nerve to the brain where the images are interpreted.

The macula located in the back of the eye, in the center of the retina. This area produces the sharpest vision.

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The inside of the eyeball is divided by the lens into two fluid-filled sections.

The larger section at the back of the eye is filled with a colorless gelatinous mass called the vitreous humor.

The smaller section in the front

contains a clear, water-like material called aqueous humor.

The conjunctiva is a mucous membrane that begins at the edge of the cornea and lines the inside surface of the eyelids and sclera,

serves to lubricate the eye.

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OPTHALMIC DISORDERS

COJUCNCTIVITIS- inflammation of conjuctiva

DRY EYE SYNDROME-inadequate wetting of ocular surface

GLAUCOMA-IRITIS-pain and inflammationROSACEABLEPHARITIS-inflammation of lid marginCHALAZIA-meibomian cysts of eylidKERATITIS

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ABSORPTION OF DRUG IN EYE

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Non-

Corneal Absorption

•Penetration across Sclera & Conjuctiva into Intra Ocular tissues

•Non-Productive: because penetrated drug is absorbed by general circulation

Corneal Absorption

•Outer Epithelium: rate limiting barrier, with pore size 60å,Only access to small ionic & lipohilic molecules

•Trans cellular transport: transport between corneal epithelium & stroma.

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OCULAR ABSORPTION

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Corneal Absorption

Depend upon physicochemical properties of drug

Only access to small ionic & lipophilic molecules

Outer Epithelium: rate limiting barrier

Trans cellular transport: transport between corneal epithelium & stroma

e.g. pilocarpine

Non-Corneal Absorption

Penetration across Sclera & Conjunctiva into Intra Ocular tissues

Non-Productive: because penetrated drug is absorbed by general circulation.

Minor pathway

Important for drug with low corneal permeability

e.g. inulin

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FATE OF OPHTHALMIC DRUG DELIVERY SYSTEMS

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DRUG ELIMINATION FROM LACRIMAL FLUID

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STRUCTURE OF THE TEAR FILM IN THE HUMAN EYE

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THE NASOLACHRYMAL DRAINAGE SYSTEM

Also responsibl

e for serious

side effects

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TRANSCORNEAL PENETRATION

EFFECTED MAINLY BY:-1.CORNEAL BARRIER2. PROPERTIES OF DRUG

SECTION THROUGH THE CORNEA.

Transcellular pathway

Paracellular pathway

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Schematic of corneal structure and its cellular organization of various transport-limiting

barriers

Contain very hydrophilicTissue, mol.size of 500 microm Can diffuse in stroma

Small molecules eg glycerolm.w.92 are able to penetrate

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Physiochemical properties of drug:-Hydrophilic drugs penetrate through

paracellular pathwayLipophilic drugs penetrate through

transcellular pathwayDrugs topically applied – passive

diffusion Transport of lysine – NA-K-ATPase

pump involved- carrier mediated transport.

Drug loaded nanoparticles- endocytic pathway.

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Lipophilicity SolubilityMolecular size & shapeChargeDegree of ionizationChemical equilibrium between ionized

and unionized in eye drop and in lacrimal fluid effect the penetration of ionizable drug.

Eg -pilocarpine (free base ) and timolol base penetrate better than its ionized form.

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NON –CORNEAL ABSORPTION

CONJUCTIVA ABSORPTION- for hydrophilic & mol. Size of 20000-40000 eg. insulin

SCLERA –through perivascular space through aq. Media of gel more permeable than

cornea mol.weight 229-1056 eg.

Sucrose,inulinRETINABLOOD RETINAL BARRIER

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CONJUNCTIVAL ABSORPTION

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BLOOD RETINAL BARRIER

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PHARMACOKINETICS OF O.D. ADMINISTRATION

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TEAR FLUID

PRECORNEAL

DRUG POOL

EPITHELIAL SAC

CORNEAL EPITHELIU

M

STROMA EPITHELIA

L

NASOLACRIMAL DRAINAGE

SYSTEMCONJUCTIVA

METABOLISM

AQUEOUS

HUMOR

ELIMINATION

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CONTROLLED DRUG DELIVERYREQUISITES OF CDDSa. To overcome the side effects of pulse dosingb. Provide sustained and controlled drug deliveryc. To increase ocular bioavailabilityd. To provide targeting within the ocular globee. To circumvent the protective barriersf. Patient compliance g. Improved therapeutic effect

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APPROACHES

TO PROLONG THE CONTACT TIME OF DRUG WITH CORNEAL SURFACE

ENHANCE CORNEAL PERMEABILITY

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WAYS TO GET THE AIM…..

POLYMERIC SOLUTION PHASE TRANSITION SYSTEMMUCOADHESIVE/ BIOADHESIVE

SYSTEMCOLLAGEN SHIELDSPSEUDOLATICESOCULAR PENETRATION ENHANCEROCULAR IONTOPHORESISOCULAR DD DEVICES

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POLYMERIC SOLUTION:- eg. Methyl cellulose, PVA,HPC,PVP.

Increase the corneal penetration.PHASE TRANSITION SYSTEMS:-liquid dosage

form eg. Lutrol FC-127

poloxamer 407,

gallen gum : forms in gel in presence of sod. ions

2.6 gm/L sodium ions ions in tears

cellulose acetate pthalate coagulates when pH increased 4.5 to 7.4

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USE OF MUCOADHESIVES IN OCULAR DRUG DELIVERY

Mucoadhesives adhered to cornea

Types-1. Naturally Occurring Mucoadhesives- Lectins,

Fibronectins 2. Synthetic Mucoadhesives-PVA,Carbopol,

carboxy methyl cellulose, cross-linked polyacrylic acid

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

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MUCOADHESIVE / BIOADHESIVE DOSAGE FORM:-

Polymer adhere to the mucin These may be polymeric solution or

microparticle suspension

Muco… polymers mainly macromolecular hydrocoloids with hydrophilic groups eg.carboxyl,hydroxyl,amide

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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

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Degree of mucoadhesive of polymerspolymer origin charge Solubility in Water Mucoadhesiv capacity

Poly acrylic acid Natural Anionic Insoluble Excellent

Carbomer Synthetic Anionic Insoluble +++

Hyaluronans Natural Anionic Soluble +++

Chitosan Natural Cationic Soluble good

Sodium CMC Natural anionic Soluble ++(+)

Poly (galacturronic)acid

Natural Anionic Insoluble ++

Sodium alginate Natural anionic Soluble ++(+)

Methyl cellulose Natural nonionic Soluble +

Pectin Natural anionic Soluble ++(+)

PVA Synthetic Nonionic Soluble +

PVP Synthetic Nonionic Soluble +

PEG Synthetic Nonionic Insoluble +(+)

HPMC Natural Nonionic Soluble +

Poloxamer Synthetic Nonionic Soluble +(+)

Xyloglucan Natural anionic Soluble +

Xanthan gum natural nonionic Insoluble poor 37

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Factors:- Dissolution of polymer Chain flexibility mol. Weight pH and ionic strength

COLLAGEN SHIELDS:-It is main constituent of food grade gelatinComprise 25% of total body protein in

mammelsDrug delivery by collagen shield……

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The corneal collagen shield A disposable, short-term therapeutic bandage lens for the

cornea. It conforms to the shape of the eye, protects the corneal

surface, and provides lubrication as it dissolves. The shields are derived from bovine collagen and are 14.5

mm in diameter. Sterilized by gamma irradiation.

Disadvantages

1. It is not optically clear.

2. The collagen shield causes some discomfort.

Clinical uses

3. Wound healing.

4. Treatment of dry eye.

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PSEUDOLATICES :-polymeric colloidal dispersion and film forming agent

OCULAR PENETRATION ENHANCER :-topical applied peptide and protiens.

Eg. Actin filament inhibitor surfactants bile salt chelators organic compounds

OCULAR IONTOPHORESIS:-

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NANOPARTICULATE DRUG DELIVERY

Size:10-1000nm

Types- 1.nanospheres , 2.nanocapsules

Drug is Dispersed, Encapsulated, or Adsorbed

Particulate systems in nanoparticulate drug deliery- 1,Topical system e.g. chloramphenicol (suspended), 2.local injectable system e.g. 5FU Polymer used are Biodegradable.

e.g. polyalkylacrylates 41

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Advantages of nanoparticles

Sustained drug release and prolonged therapeutic activity

Site-specific targeting Higher cellular permeability Protect the drug from chemical or enzymatic

hydrolysis Efficient in crossing membrane barriers -blood

retinal barrier Act as an inert carrier for ophthalmic drugs

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Preparation of Nanoparticles

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Solvent evaporation method

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OCULAR DRUG DELIVERY DEVICES

MATRIX TYPE DRUG DELIVERY SYSTEMHydrophilic

soft contact lenses

Soluble ocular insersScleral

buckling materials

CAPSULAR TYPE DRUG DELIVERY SYSTEM

Ocuserts

IMPLANTABLE DRUG

DELIVERY PUMPS

Osmotic minipumps

Implantable infusion systems

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HYDROPHILIC SOFT CONTACT LANSESBionite was developed in griffin lab.

Soflens was developed by Bausch &Lomb.

contact lanses made from hefilcon-ACopolymer(80% 2-hydroxy ethyl methacry-late and 20% N-vinyl-2-pyrollidone) 16 mm in diameter0.3 mm thick

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Classification of ocular inserts

Insoluble inserts• Diffusion

based(Ocusert®)

• Osmotic based• Soft(presoaked)

contact lenses

Bioerodible inserts e.g. Lacrisert®,

Minidisc.

Soluble inserts e.g. SODI, BioCor®-12,24,72.

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OCULAR INSERTS

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Desired criteria for ocular inserts

* Ease of handling and insertion* Lack of expulsion during wear* Reproducibility of release kinetics

(Zero-order drug delivery)* Applicability to variety of drugs* Non-interference with vision and

oxygen permeability.* Sterility.* Ease of manufacture

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A) Insoluble inserts-

e.g. Ocusert®: 20-40µg/hr for 7day Annular ring : Impregnated with Ti02 : For Visibility

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Diffusional Inserts :•Central reservoir of drug enclosed in Semi permeable or microporous membrane for diffusion of drug.

•Diffusion is controlled by Lacrimal Fluid penetrating through it.•Release follows : Zero Order Kinetics.

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SOLUBLE OCULAR INSERTS:-Eg. Poly vinyl alcohol inserts Soluble opthalmic drug insertPolypeptide devices

SODI –thin elastic oval plate Made from polymer and

Copolymer of polyacrylamide , ethylacrylate and vinylpyrollidone

MOA:-……

•Single SODI application : replaces 4-12 eye drops Instillation, or 3-6 application of Ointments.

•Once a day treatment of Glaucoma.

Advantages of SODI

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1.Lacrisert:• Sterile, Rod Shaped device.

• Composition: HPC.

• Weight:5mg,

• Dimension:Diameter:12.5mm, Length:3.5mm

• Use:-Dry eye treatment.

2.Minidisc: It is made up of counter disc with Convex front & Concave back surface in

contact with eye ball. 4-5mm in diameter. Composition : Silicon based polymer. Drug release upto170 hr.

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C) Biodegradable inserts

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LIPOSOMES

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• Vesicle composed of phospholipid bilayer enclosing aqueous compartment in alternate fashion.

• Biodegradable, Non-toxic in nature.• Types :1.MLV• 2.ULV-SUV(upto 100 nm)• LUV(more than 100 nm) • Polar drugs are incorporated in aqeous

compartment while lipophilic drugs are intercalated into the liposome membrane

• Phospholipids used- Phophotidylcholine, Phophotidic acid, Sphingomyline, Phosphotidyleserine,Cardiolipine

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ADVANTAGES •Drugs delivered intact to various body

tissues.•Liposomes can be used for both

hydrophilic and hydrophobic drug.•Possibility of targeting and decrease drug

toxicity.•The size, charge and other characteristics

can be altered according to drug and desired tissue.

DISADVANTAGES OF LIPOSOMES.•They need many modification for drug delivery

to special organs.•Cost .

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Preparation Of Liposomes

Reverse phase evaporation method54

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Degradation and Drug Release Of Liposomes

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1. Endocytosis

2. Fusion

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SCLAREL BUCKLING MATERIALS:-Eg. Gelatin film & solid silicon rubber

impregnated with antibiotic

OCUSERT AND RELATED DEVICES:-

A true controlled and continuous release and zero order kinetic fashion achieved by ocusert

First marketed by ALZA corporation pilocarpine ocusert improved the noncompliance problem

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Two types of ocuserts Ocusert pilo- 20 – 20 µg/h for 7 days Ocusert pilo- 40- 40 µg/h for 7 days

IMPLANTABLE SILICON RUBBER DEVICES:-

For hydrophobic drugs

BCNU(1,3-bis(2-chloroethyl)-1-nitrosourea)consist two sheets of silicon rubber

(0.13mm thick)

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OSMOTIC MINIPUMPGeneric osmotic minipump(ALZET) is a

useful implantable system.Pumping duration 2 weeks

IMPLANTABLE INFUSION SYSTEMInfusaid - device permit long term

infusion via refilling in animalsPumping force generated by an

expending fluid(Flurocarbon at liq. Gas equilibrium) at

body temp.

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Registeredname

Activesubstances

Implant size Marketingstatus

vitrasert® Ganciclovir Millimeter Clinical use

retisert® Flucinoloneacetonide

Tablet 3mmx 2mmx5mm

Clinical use

Medidur Flucinoloneacetonide

Cylindrical tube 3.5mm in length and0.37 mm in diameter

Phase 3

Posurdex Dexamethasone Microsized implant

Phase 3

Ozurdex® Dexamethasone intravitreal implant)0.7 mg

Clinical use

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OTHER DELIVERY SYSTEMS

Ocufit –currently developed. Made by silicone elastomer.

Diameter-1.9 mm & length is 25-30 mm

Lacrisert- made up of cellulose used to treat dry eye patients.

Minidisc ocular therapeutic system

New opthalmic delivery system

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RETROMETABOLIC DRUG DESIGN

CDS

CDS1 CDSn

D

Mi

SD

METABOLISM

M1

M2

Mn

METABOLISM

RETROMETABOLIC DESIGN

RETROMETABOLIC DRUG DESIGN

METABOLISM

I1

I2

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EVALUATION1. Gelling capacity2. Rheological properties3. In vitro drug release4. Texture analysis5. Isotonicity evaluation6. Drug polymer interaction study 7. Thermal analysis8. Antibacterial activity9. Occular irritancy test10.Accelereted stability study

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11. Thickness of ocular film12.Drug content uniformity13.Uniformity of weight14.% moisture content15. % moisture loss16. Sterility testing17.Growth promotion test

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ADVANCED DELIVERY SYSTEM1. Cell encapsulation2. Gene therepy3. Stem cell therepy4. Protein ad peptide therepy5. Sclaral plug therepy6. Si RNA therepy7. Oligonucleotide therepy8. Aptamer9. Ribozyme therepy

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FUTURE TRENDS

The sustained and controlled release technologies are being proposed and the possible benefits of using liposomes, nanoparticles and inserts will be at store in future.

Targeted drug delivery with modifications of conventional, advanced and novel ocular drug deliveries has potential as future drug delivery for eye.

It is possible to the give effective ocular drug delivery to any part of the eye.

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Current and future drugs in clinical trials for anterior DDSs. Active

ingredient Brand name Dosage form Release-

controlling excipient

Target Indication Developmental stage

Azithromycin AzaSite® Eye-drops Polycarbophil Bacterial conjunctivitis

Launched

Bromfenac (ISV-303)

------- Eye-drops Polycarbophil Post cataract surgery

P1/2

Timolol maleate Rysmon® TG Eye-drops Methylcellulose Glaucoma Launched

Betaxolol Betoptic S® Eye-drops Amberlite® IRP-69 Glaucoma Launched

Tobramycin/Dexamethasone

TobraDex® ST Eye-drops Xanthan gum Blepharitis Launched

Ketotifen -------- Soft contact lens ---------- Allergic conjunctivitis

P3

Latanoprost --------

Puctal plug

------Glaucoma P2

Bimatoprost --------

Puctal plug -------- Glaucoma P2

Dexamethasone phosphate (EGP-437)

EyeGate II® Iontophoresis ------- Dry eye Anterior uveitis

P3 P2

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Current and future drugs in clinical trials for posterior DDSs. Active

ingredient Brand name Dosage form Release-

controlling excipient

Target Indication Developmental stage

Ganciclovir Vitrasert® IVT, implant EVA/PVA CMV retinitis Launched

Fluocinolone acetonide

Retisert® IVT, implant Silicone/PVA Posterior uveitis Launched

Fluocinolone acetonide

Iluvien® IVT, implant Polyimide/PVA DME Wet AMD

P3 P2

Dexamethasone Ozurdex® IVT, implant poly(lactide-co-glycolide),

Posterior uveitis Launched

Triamcinolone acetonide

I-vation™ TA IVT, implant PMMA/EVA diabetic macular edema,

P2

Verteporfin Visudyne® IV, injection Liposome Wet AMD Launched

Difluprednate Durezol™ Eye-drops Emulsion DME Off-label

Triamcinolone acetonide

(IBI-20089)

------ IVT, injection Oil branch retinal vein occlusion,

P1

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CONCLUSION Very few advanced ocular drug delivery

systems have been commercialized.

The performance of these new products, however, is still far from being perfect.

More clinical studies are necessary to provide

further information and insights into these advanced ocular drug delivery systems.

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REFERENCES1. “ Targeted and controlled drug delivery system” by Vyas

S.P. and Khar K. R., published by CBS Publishers and distributors, first edition 2002

2. http://www.jgtps.com journal of global trend in pharmaceutical sciences Patel vishal & Y.K. Agrawal “current status and advanced approaches in ocular drug delivery system

3. Kumari A, Sharma PK and Garg VK: Ocular inserts — Advancement in therapy of eye diseases. Journal Advance Pharmaceutical Technology Research 2010; 3: 87-96.

4. Rathore K.S. review on “in – situ gelling ophthalmic drug delivery system” International journal of pharmacy and pharmaceutical sciences

5. V. Shankar , A.K. Chandrasekharan , S. durga. “ design and evaluation of diclofenac sodium ophthalmic inserts. Acta pharamaceutica sciencia 48: 5-10 (2006) .

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The eyes are the mirror of the soul… Take care of your eyes with gentleness.

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Tarun Pokhriyal
GOOD LUCK TO ALL FRIENDS