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