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Tarun ocular drug delivery

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  • 1. OCULAR DRUG DELIVERY PRESENTED BY- TARUN POKHARIYAL M.PHARM. (PHARMACEUTICS) JAIPUR NATIONAL UNIVERSITY (JAIPUR) 1
  • 2. 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 2
  • 3. 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 spillage the drop volume = 50 ul 3
  • 4. ADVANTAGES- disadvantages1. Accurate dosing. 1. Perceived by patient as2. Absence of preservative foreign body. 2. Movement around the3. Increase in shelf life due to eye.absence of water. 3. Occasional loss during sleep or while rubbing4.Best of drug with slow eyes.dissolution eg.suspension 4. Interference with vision.5.Flexibilty in drug choice 5. Difficulty in placement7.Rapid action & removal.8. Self medication is easy 6.Patient non compliance9.Decrease side effects to 7. Blurred visionother organs 8. Irritation in eyes 9.Not suitable for running people 4
  • 5. EYE :ANATOMY AND PHYSIOLOGY 1. Sclera, Diameter 23mm 2. Choroids, •Outer-Epithelium(lipophilic), 3. Cornea, •Middle-Stroma(hydrophilic), •Inner-Endothelium(lipophilic). 4. Cilliary Body- Secretion of aq. humor, 5. Lens, 6. Retina, 7. Conjuctiva, 8. Vitreous Compartment, 9. Lacrimal gland. 5
  • 6. The sclera: The protective outer layer of the eyeThe cornea: The front portion of the sclera. transparent and allows light to enter the eye.Diameter-11.7mm and thickness -0.5-0.7mmThe 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, 6
  • 7.  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. 7
  • 8. 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. 8
  • 9. OPTHALMIC DISORDERS COJUCNCTIVITIS- inflammation of conjuctiva DRY EYE SYNDROME-inadequate wetting of ocular surface GLAUCOMA- IRITIS-pain and inflammation ROSACEA BLEPHARITIS-inflammation of lid margin CHALAZIA-meibomian cysts of eylid KERATITIS 9
  • 10. ABSORPTION OF DRUG IN EYE 10
  • 11. • Penetration across Sclera & Conjuctiva into Intra Ocular tissues • Non-Productive: because penetrated drug isNon-Corneal absorbed by general circulationAbsorption • Outer Epithelium: rate limiting barrier, with pore size 60å,Only access to small ionic & lipohilic molecules Corneal • Trans cellular transport: transport between corneal epithelium & stroma.Absorption 11
  • 12. OCULAR ABSORPTIONCorneal Non-CornealAbsorption Absorption Depend upon physicochemical Penetration across Sclera & properties of drug Conjunctiva into Intra Ocular tissues Only access to small ionic & Non-Productive: because lipophilic molecules penetrated drug is absorbed by general circulation. Outer Epithelium: rate limiting barrier Minor pathway Trans cellular transport: transport between corneal Important for drug with epithelium & stroma low corneal permeability e.g. pilocarpine e.g. inulin 12
  • 13. FATE OF OPHTHALMIC DRUG DELIVERY SYSTEMS 13
  • 14. DRUG ELIMINATION FROM LACRIMAL FLUID 14
  • 15. STRUCTURE OF THE TEAR FILM IN THE HUMAN EYE 15
  • 16. Also responsible for serious side effectsTHE NASOLACHRYMAL DRAINAGE SYSTEM 16
  • 17. TRANSCORNEAL PENETRATION Transcellular pathwayEFFECTED MAINLY BY:-1.CORNEAL BARRIER Paracellular pathway2. PROPERTIES OF DRUG SECTION THROUGH THE CORNEA. 17
  • 18. Small molecules eg glycerol m.w.92 are able to penetrate Contain very hydrophilic Tissue, mol.size of 500 microm Can diffuse in stroma Schematic of corneal structure and its cellularorganization of various transport-limiting barriers 18
  • 19. Physiochemical properties of drug:- Hydrophilic drugs penetrate through paracellular pathway Lipophilic drugs penetrate through transcellular pathway Drugs topically applied – passive diffusion Transport of lysine – NA-K-ATPase pump involved- carrier mediated transport. Drug loaded nanoparticles- endocytic pathway. 19
  • 20.  Lipophilicity Solubility Molecular size & shape Charge Degree 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. 20
  • 21. 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,inulin RETINA BLOOD RETINAL BARRIER 21
  • 22. CONJUNCTIVAL ABSORPTION 22
  • 23. BLOOD RETINAL BARRIER 23
  • 24. PHARMACOKINETICS OF O.D. ADMINISTRATION 24
  • 25. TEARFLUID CORNEAL STROMAPRECORNEAL EPITHELIALDRUG POOL SAC EPITHELIUM EPITHELIALNASOLACRIMAL METABOLISM DRAINAGE SYSTEM CONJUCTIVA AQUEOUS HUMOR ELIMINATION 25
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  • 30. 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 complianceg. Improved therapeutic effect 30
  • 31. APPROACHESTO PROLONG THE CONTACT TIME OF DRUG WITHCORNEAL SURFACEENHANCE CORNEAL PERMEABILITY 31
  • 32. WAYS TO GET THE AIM….. POLYMERIC SOLUTION PHASE TRANSITION SYSTEM MUCOADHESIVE/ BIOADHESIVE SYSTEM COLLAGEN SHIELDS PSEUDOLATICES OCULAR PENETRATION ENHANCER OCULAR IONTOPHORESIS OCULAR DD DEVICES 32
  • 33. POLYMERIC SOLUTION:- eg. Methyl cellulose, PVA,HPC,PVP.Increase the corneal penetration.PHASE TRANSITION SYSTEMS:-liquid dosage form eg. Lutrol FC-127poloxamer 407,gallen gum : forms in gel in presence of sod. ions2.6 gm/L sodium ions ions in tearscellulose acetate pthalate coagulates when pH increased 4.5 to 7.4 33
  • 34. USE OF MUCOADHESIVES IN OCULAR DRUG DELIVERY Mucoadhesives adhered to cornea Types-1. Naturally Occurring Mucoadhesives- Lectins, Fibronectins2. Synthetic Mucoadhesives- PVA,Carbopol, carboxy methyl cellulose, cross- linked polyacrylic acid• Drugs incarporated in to this are pilocarpine, lidocaine, benzocaine and prednisolone acetate. 34
  • 35. MUCOADHESIVE / BIOADHESIVE DOSAGE FORM:-Polymer adhere to the mucinThese may be polymeric solution or microparticle suspensionMuco… polymers mainly macromolecular hydrocoloids with hydrophilic groups eg.carboxyl,hydroxyl,amide 35
  • 36. 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 36
  • 37. Degree of mucoadhesive of polymerspolymer origin charge Solubility in Water Mucoadhesiv capacityPoly acrylic acid Natural Anionic Insoluble ExcellentCarbomer Synthetic Anionic Insoluble +++Hyaluronans Natural Anionic Soluble +++Chitosan Natural Cationic Soluble goodSodium CMC Natural anionic Soluble ++(+)Poly (galacturronic) Natural Anionic Insoluble ++acidSodium 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
  • 38. Factors:- Dissolution of polymer Chain flexibility mol. Weight pH and ionic strengthCOLLAGEN SHIELDS:-It is main constituent of food grade gelatinComprise 25% of total body protein in mammelsDrug delivery by collagen shield…… 38
  • 39. 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.Disadvantages1. It is not optically clear.2. The collagen shield causes some discomfort.Clinical uses1. Wound healing.2. Treatment of dry eye. 39
  • 40. PSEUDOLATICES :-polymeric colloidal dispersion and film forming agentOCULAR PENETRATION ENHANCER :-topical applied peptide and protiens.Eg. Actin filament inhibitor surfactants bile salt chelators organic compoundsOCULAR IONTOPHORESIS:- 40
  • 41. 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
  • 42. 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 42
  • 43. Preparation of Nanoparticles Solvent evaporation method 43
  • 44. OCULAR DRUG DELIVERY DEVICES IMPLANTABLE CAPSULAR TYPE DRUG DRUG DELIVERY DELIVERY SYSTEM PUMPS Ocuserts Osmotic minipumps Implantable infusion systems 44
  • 45. 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 45
  • 46. OCULAR INSERTS Classification of ocular insertsInsoluble inserts Bioerodible inserts • Diffusion e.g. based(Ocusert®) Lacrisert®, Minidisc. • Osmotic based• Soft(presoaked) contact lenses Soluble inserts e.g. SODI, BioCor®-12,24,72. 46
  • 47. 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 47
  • 48. 48
  • 49. A) Insoluble inserts- 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.e.g. Ocusert®: 20-40µg/hr for 7day Annular ring : Impregnated with Ti02 : For Visibility 49
  • 50. SOLUBLE OCULAR INSERTS:-Eg. Poly vinyl alcohol insertsSoluble opthalmic drug insertPolypeptide devicesSODI –thin elastic oval plate Made from polymer andCopolymer of polyacrylamide , ethylacrylate and vinylpyrollidoneMOA:-……Advantages of SODI•Single SODI application : replaces 4-12 eye drops Instillation, or 3-6 application of Ointments.•Once a day treatment of Glaucoma. 50
  • 51. C) Biodegradable inserts1.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. 51
  • 52. LIPOSOMES• 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 52
  • 53. ADVANTAGES DISADVANTAGES OF• Drugs delivered intact to various LIPOSOMES body tissues. .• Liposomes can be used for both hydrophilic and hydrophobic drug. • They need many modification• Possibility of targeting and for drug delivery to special decrease drug toxicity. organs.• The size, charge and other • Cost . characteristics can be altered according to drug and desired tissue. 53
  • 54. Preparation Of LiposomesReverse phase evaporation method 54
  • 55. Degradation and Drug Release Of Liposomes1. Endocytosis 2. Fusion 55
  • 56. SCLAREL BUCKLING MATERIALS:-Eg. Gelatin film & solid silicon rubber impregnated with antibioticOCUSERT AND RELATED DEVICES:-A true controlled and continuous release and zero order kinetic fashion achieved by ocusertFirst marketed by ALZA corporation pilocarpine ocusert improved the noncompliance problem 56
  • 57. Two types of ocusertsOcusert pilo- 20 – 20 µg/h for 7 daysOcusert pilo- 40- 40 µg/h for 7 daysIMPLANTABLE SILICON RUBBER DEVICES:-For hydrophobic drugsBCNU(1,3-bis(2-chloroethyl)-1-nitrosourea)consist two sheets of silicon rubber (0.13mm thick) 57
  • 58. OSMOTIC MINIPUMPGeneric osmotic minipump(ALZET) is a useful implantable system.Pumping duration 2 weeksIMPLANTABLE 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. 58
  • 59. Registered Active Implant size Marketingname substances statusvitrasert® Ganciclovir Millimeter Clinical useretisert® Flucinolone Tablet 3mmx 2mmx Clinical use acetonide 5mmMedidur Flucinolone Cylindrical tube 3.5 Phase 3 acetonide mm in length and 0.37 mm in diameterPosurdex Dexamethasone Microsized implant Phase 3Ozurdex® Dexamethasone intravitreal implant) Clinical use 0.7 mg 59
  • 60. 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 60
  • 61. RETROMETABOLIC DRUG DESIGN METABOLISM CDSn CDS1 M1 METABOLISM D M2CDS Mn RETROMETABOLIC DESIGN I1 I2 METABOLISM Mi SD RETROMETABOLIC DRUG DESIGN 61
  • 62. EVALUATION1. Gelling capacity2. Rheological properties3. In vitro drug release4. Texture analysis5. Isotonicity evaluation6. Drug polymer interaction study7. Thermal analysis8. Antibacterial activity9. Occular irritancy test10. Accelereted stability study 62
  • 63. 11. Thickness of ocular film12.Drug content uniformity13.Uniformity of weight14.% moisture content15. % moisture loss16. Sterility testing17.Growth promotion test 63
  • 64. 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 64
  • 65. FUTURE TRENDSThe 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. 65
  • 66. Current and future drugs in clinical trials for anterior DDSs.Active ingredient Brand name Dosage form Release-controlling Target Indication Developmental stage excipientAzithromycin AzaSite® Eye-drops Polycarbophil Bacterial conjunctivitis LaunchedBromfenac ------- Eye-drops Polycarbophil Post cataract surgery P1/2(ISV-303)Timolol maleate Rysmon® TG Eye-drops Methylcellulose Glaucoma LaunchedBetaxolol Betoptic S® Eye-drops Amberlite® IRP-69 Glaucoma LaunchedTobramycin/Dexameth TobraDex® ST Eye-drops Xanthan gum Blepharitis LaunchedasoneKetotifen -------- Soft contact lens ---------- Allergic conjunctivitis P3Latanoprost Puctal plug P2 Glaucoma -------- ------Bimatoprost Puctal plug -------- Glaucoma P2 --------Dexamethasone EyeGate II® Iontophoresis ------- Dry eye P3phosphate Anterior uveitis P2(EGP-437) 66
  • 67. Current and future drugs in clinical trials for posterior DDSs.Active ingredient Brand name Dosage form Release-controlling Target Indication Developmental stage excipientGanciclovir Vitrasert® IVT, implant EVA/PVA CMV retinitis LaunchedFluocinolone Retisert® IVT, implant Silicone/PVA Posterior uveitis LaunchedacetonideFluocinolone Iluvien® IVT, implant Polyimide/PVA DME P3acetonide Wet AMD P2Dexamethasone Ozurdex® IVT, implant poly(lactide-co- Posterior uveitis Launched glycolide),Triamcinolone I-vation™ TA IVT, implant PMMA/EVA diabetic macular P2acetonide edema, Visudyne® IV, injection Liposome Wet AMD LaunchedVerteporfinDifluprednate Durezol™ Eye-drops Emulsion DME Off-labelTriamcinolone ------ IVT, injection Oil branch retinal vein P1acetonide occlusion,(IBI-20089) 67
  • 68. 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. 68
  • 69. REFERENCES1. “ Targeted and controlled drug delivery system” by Vyas S.P. and Khar K. R., published by CBS Publishers and distributors, first edition 20022. 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 system3. 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 sciences5. V. Shankar , A.K. Chandrasekharan , S. durga. “ design and evaluation of diclofenac sodium ophthalmic inserts. Acta pharamaceutica sciencia 48: 5-10 (2006) . 69
  • 70. The eyes are the mirror of thesoul… Take care of your eyeswith gentleness. 70

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