1. Drug delivery to the posterior segment of the eye for pharmacologic therapy Dr. Meenank. B M.S. Ophthalmology (Post-Graduate ) ASRAM medical college

2. Introduction Drug delivery into the posterior segment of the eye is complicated by the blood-ocular-barrier Prescribed drugs have to overcome these barriers to deliver therapeutic concentrations Thus, bio-degradable and non-biodegradable sustained release system for injection (or) transplantations into the vitreous as well as drug loaded nano-particles, microspheres, and liposomes emerged 3. Drug Delivery for Posterior Segment Eye 1. 2. 3. 4. 5. 6.Topical Systemic Sub-conjunctival Intravitreal Trans-scleral Iontophoretic 4. Over view 5. Topical Most successful in anterior segment eye diseases but, posterior segment of eye hinders many challenges Reflex tearing, blinking, drug metabolism, and drug binding corneal epithelium and endothelium along with conjunctival and, sclera. The long diffusion distance to reach the posterior chamber and the acellular nature of vitreous negative impact on pharmacokinetics and distribution of drug large mol. Wt. water solubility, highly charged, t Recent small mol. Wt. permeability, toxicity, slower degradation rate 6. Systemicoral BloodstreamRetinal pigment epitheliumRetinal blood vesselsVitreousIntravenousSystemicBlood retinal barrierPosterior chamber RPE show efflux pumps P-glycoprotein permeability of endogenous Multidrug restraint associated protein compounds into vitreous Thus, inc. quantities of drug to reach therapeutic conc. viz Inc. adverse effects Limitations Dec. in therapeutic effect and time due to dil. and degradation before reaching target Drug Drug interactions 7. Endophthalmitis fluoroquinolones klebsiella, pseudomanas Prodrugs lipophilic, better absorbed and converted by enzyme action Valganciclovir ganciclovir used in CMV retinitis Cyclodextrin cylindrical oligonucleotide, outer -hydrophilic, inner- lipophilic, better tolerated 8. Intravitreal More popular clinical settings Direct applications of drug into posterior segment eliminating barriers High doses can be reached to the target site without any alterations in the concentrations Effective treatment Limitations needs repeated injection can cause trauma, cataract, RD, haemorrhage, endophthalmitis 9. IntravitrealPneumatic Retinopexy Anti-bacterials (Endophthalmitis) Anti- viralsSF , CF, CF GPB-Vancomycin(1mg/0.1ml), cefazoline(2.25mg/0.1ml). GNB- Ceftazidine(2.25mg/0.1ml), Amikacin(0.4mg/0.08ml) Ganciclovir(2mg/0.05ml) Foscarnet(1.2mg/0.05ml)Anti- FungalsAmphotericine B(5g/0.1ml) Fluconazole(10g/0.1ml) Voriconazole(50 200g/0.1ml)SteroidsDexamethasone(400g/0.1ml, triamcinolone(4mg/0.1ml)Anti VEGF agentsRanibizumab-leucentis (0.5mg/0.05ml), Pegatanib- Macugen (0.3mg/0.1ml) 10. Indications Endophthalmitis CMV retinitis Unresponsive Post. Uveitis PDR AMD DME ME CRVO CNVM Contraindications Stroke Cardiac arrest Hypertension Complications Sterile Endophthalmitis (0.16% in 10,000) Retinal detachment (0.15% in 10,000) Lens trauma/ Ac. Cataract (0.07% in 10,000) Haemorrhage Angle closure IOP Wound leak Anaphylactic reaction Procedure 11. Trans-Scleral diffusion Newer method Less invasive Drug spreads through the ocular tissue to reach the neuroretina Includes 1. 2. 3. 4. 5.Sub- conjunctival Retrobulbar Pribulbar Sub- tenons Intra-scleral (newer) Limitations while crossing through many compound barriers bio-availability is drastically dec. thus, needs more dose 12. Barriers static, dynamic and, metabolic StaticDynamicMetabolicSclera: permeability decreases with inc. molecular radius hydrophilic nature. Permeability inc. with negatively charged solutesBlood and lymphatic flow: high flow causes faster elimination and min. penetrationCytochrome P450Choroid and Bruch: dec. permeability with inc. mol. Wt. and hydrophobic nature. permeability inc. negatively charged soluteBulk fluid flow: decreased penetrationLiposomal enzymesRPE: dec. permeability inc. mol. Radius Inc. permeability hydrophobic natureTransport proteins, drug efflux pump, ion transporter's 13. Sub conjunctival: Low doses for sustain release in ant. and post. Segment Hydrophilic drugs preferred penetrate sclera Sub- tenons: Injected as a depot into the sub-tenons space with a formulation Rataane angiostatic steroid anecortave for AMD Problem: reflex of drug 14. Iontophoretic Electro-dynamic process of drug delivery Charged molecules accelerates across the sclera onto the posterior chamber via direct electric current Non invasive Small packets of electric current is applied to enhance ionized drug penetration (Myles et al 05) Drug is carried with electrode carrying the same charge as the drug, with ground is placed on body Probe placed over pars-plans to bypass iris-lens barrier Eliminates most of the side effects due to needles 15. Factors effecting Amount of current used Drug concentration Treatment duration ph. Permeability Resistance of the tissue changes with repeated thx Alteration in the electric field changes drug permeability and peaks Advantage Non-invasive Non-infective Inc. t Ocuphor commercially available pegaptinib 16. Devises Coulomb-controlled Iontophoretic self calibration EyeGate II Delivery System water hydrolyses by current ion mobility con. Of drug to posterior chamber EyeGate II Delivery System 17. Ocular implants Bypass blood retinal barrier Concept: delivering drug below toxic level and at higher dose rate without any systemic side effects Sub-conjunctival implants for ant. Segment instilled thgh small incision Intravitreal and supra-choridal implants used for posterior segment Intra- scleral for ant and post segment inserted thgh 1 scleral thickness pocket and closed Devises : Non- biodegradable Biodegradable 18. Non-biodegradable implants Intravitreal Trans scleral IontophoreticBetter than tropical and sys. In giving high drug levels But, susceptible to rapid clearance (hrs.) frequent dosage Sustained release drug system - decrease frequency in application and complication and for cont. drug delivery Sustained release drug system Nano particles Micro particles Liposomes Implants 3 approved 2 non-biodegradable polymer 1 biodegradable polymer Made with pelleted drug core surrounded by non-reactive substance EVA, PVA 19. Ganciclovir 4.5mg of drugEthyl vinyl acetate- restrict surface diffusion of drug Poly vinyl coatpermeable to water1st non- biodegradable implant, Vitrasert Used for CMV retinitis in AIDS Site through pars plana into P.C. Drug delivery 1g/hr @ 6 months Advantage over I.V. and safe Complications: vit. Hx, rheg.RD, endophthalmitis, cataract, FB sensation, fibrovascular scar, conjunctival Hx, pellet separation 20. steroids Fluocinolone Acetonide (FA) Dexamethasone Cyclosporine Retisert (FA) for Ch. Non-infectious uveitis 0.59mg 0.6g /day @ 1 month (initial) 0.3 to 0.4 g/day @ 30 months FA 2.1mg 2g/day @ 1 month (initial) 1g/ day @ 3 yrs More than 50% improvement with in 1yr + no adjuvant thx in 80% of cases Complications: cataract and inc. IOP, VH,RD, maculopathy, ME, ptosis, diplopia, corneal ulcer, hypotony, perforation 21. FA in DR 57% in ME, and retinal thickness to 20% of control (Posurdex) FA in CRVO at 12 months VA 20/ 60 from base 20/ 126 central foveal thickness 622m to 199m Large mol. wt. compounds unsuccessfully incorporated into reservoir implants One exception: Encapsulation Cell Technology (ECT): cell based delivery system that can be used to deliver thx agent to eye in genetically modified semipermeable preventing immune entry and allowing drug diffusion freely 22. Triamcinolone Acetonide (TA) Triamcinolone Acetonide (TA) as a Rx for neovascular and oedematous proliferative of eye Useful as an anti- angiogenetic in neovascular and proliferative ischemic retinopathic eyes and exudative AMD TA = water insoluble, stays in vitreous for long Covered by poly vinyl coat (PVA) and ethyl vinyl coat (EVA) with t of 35 days with no new changes were seen under thx but existing changes could not be regressed 23. Beeley et al studied a S.R TA rod shaped 3.5mm - 4 weeks Coat- PMMC + nitinol Core matrix of drug + PBMC + PEVA STRIDE (Sustained Triamcinolone Release for Inhibition of DME ) I-Vation intravitreal non-biodegradable implant device , helical shape for sclera fixation delivering 1g/day and 3 g/day 24. Biodegradable implants To minimize the complications of surgical implants Biodegradable implants came into play Mostly used for acute onset of eye disease requiring loading and tapering doses Biodegradable implants rods, discs, pellets, plugs, and sheets Polymers available Poly lactic acid (PLA) Poly Glycolic acid (PGA) Poly lactic- co- glycolic acid (PLGA) Poly caprolactone Poly methylene malonate 25. Polymers used PLA and PLGA lactic slow degradation Glycolic faster degradation Following 1st order of kinetics rapid burst taper Advantage over non- biodegradable Replacement Flexibility of dosage Short duration weeks Long duration months/ yrs. Biodegradable implants can be used for in smaller incisions and multi drug dosages 26. In Rx PVR PGLA matrix of 5FU, TA (4 wks) and t- PA (2wks) Size 7 * 0.8 mm cylinder with 3 layers Multidrug Rx Dexamethasone for uveitis and DME by Ozurdex S.R dexamethasone is made of PLGA matrix Now its in phase III DME due to RVO Phase II significant improvement in V.A < 15 lines, retinal thickness, and florescent leak with minimal S.E - vitreous Hx and IOP Phase IIb suture less with 22 needle = no vit Hx / IOP Brimodine (BDNF & CNTF) similar to Ozurdex prevent apoptosis of RPE, and dry AMD 27. Novel drug delivery: micro particles and nanoparticles Sustained release drug system developed as an alt to implantation. Particulates using S.R with high target specificity in the form of Nanoparticles (1-10,000m) Micro particles (1- 10,000m) Nanospheres polymer-drug combination with polymer matrix Microcapsules particulate/ droplet enclosed in polymer membrane Sphere 2 weeks vitriomized eye Nanoparticles diffused rapidly ( ant , post. Segments ) Aliphatic polymers used PLA, PGA, PLGA, Poly caprolactone These are best for C.R, non-toxic, non-immunogenic, enzyme degraded 28. Capsulation sphere solvent evaporation process capsule emulsion diffusion process Drug hydrophobic oil-in-water emulsion in solvent prep. hydrophilic oil-in-oil emulsion for efficacy Intravitreal inj. With carrier sol for guidance 29. Polymeric microsphere used in targeting phagocytosis by RPE PLA + florescent dye PLA + florescent dye + rhodamine 6GX PLA + Rhodamine 6GX + Nile Red 4 months Steroids dexamethasone and budesonide in nano and micro particles for S.R Kompella et al sub conjunctival budesonide could inhibit VEGF expression in RPE cell line Gomez-Gaete et al TROJAN Dexamethasone PLGA nanoparticles suspension in spray drying form 30. Anti- virals encapsulated ganciclovir and acyclovir in polymeric micro and Nanospheres are used Owing to the ocular toxicity Duvvuri et al presented a empirical equation to describe the drug relation from ganciclovir load to PLGA sphere a thermo-remodeling polymer solution for transport and S.R of the drug This will maintain the drug level @ 0.8 g/day for 14 days inj t is 54 hrs Martinez- Sanchoz et al - Acyclovir (40mg -80mg) and Vit. A palmitate ( 10mg 80mg ) with S.R for 49 days Cortesi et at spray drying encapsulated acyclovir C.R. Others PVR Tamoxifen for autoimmune uveo-retinitis Gene therapy 31. Liposomes: Types of nano and micro particles of vesicles lipid system of 50m Allows encapsulation of dry molecules Proteins Nucleotides Plasmids Can be injected under liquid dosage with 27- 30 gauge Adv: less toxic ( topically, sub conjunctival ) Dis-adv: impaired vision