Intravitreal antibiotics new

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Intravitreal antibiotics new

  1. 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. 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. 3. • Barriers •
  4. 4. • Drug Delivery for Posterior Segment Eye 1. 2. 3. 4. 5. 6. Topical Systemic Sub-conjunctival Intravitreal Trans-scleral Iontophoretic
  5. 5. Over view
  6. 6. 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 conjunctiva 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, ↓t½ • Recent small mol. Wt. – ↑permeability, ↓toxicity, slower degradation rate
  7. 7. Systemic oral Bloodstream Retinal pigment epithelium Retinal blood vessels Vitreous Intravenous Systemic Blood retinal barrier Posterior 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
  8. 8. • 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
  9. 9. 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
  10. 10. Intravitreal Pneumatic Retinopexy Anti-bacterial’s (Endophthalmitis) Anti- viral’s SF₆ , C₃F₈, C₂F₆ 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- Fungal’s Amphotericine B(5µg/0.1ml) Fluconazole(10µg/0.1ml) Voriconazole(50 – 200µg/0.1ml) Steroids Dexamethasone, triamcinolone Anti VEGF agents Ranibizumab(0.5mg/0.05ml), Pegatanib Sodium(0.3mg/0.1ml)
  11. 11. • 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
  12. 12. 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
  13. 13. • Barriers – static, dynamic and, metabolic Static Dynamic Metabolic Sclera: permeability decreases with inc. molecular radius hydrophilic nature. Permeability inc. with negatively charged solutes Blood and lymphatic flow: high flow causes faster elimination and min. penetration Cytochrome P450 Choroid and Bruch: dec. permeability with inc. mol. Wt. and hydrophobic nature. permeability inc.– negatively charged solute Bulk fluid flow: decreased penetration Liposomal enzymes RPE: dec. permeability – inc. mol. Radius Inc. permeability hydrophobic nature Transport proteins, drug efflux pump, ion transporter's
  14. 14. • 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
  15. 15. 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
  16. 16. • 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. t½ • Ocuphor – commercially available pegaptinib
  17. 17. • 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
  18. 18. 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 1½ scleral thickness pocket and closed • Devises : Non- biodegradable Biodegradable
  19. 19. Non-biodegradable implants • Intravitreal • Trans scleral • Iontophoretic Better 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, no initial burst. • 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
  20. 20. Ganciclovir 4.5mg of drug Poly vinyl coatpermeable to water Ethyl vinyl acetate- restrict surface diffusion of drug Poly vinyl coat- • • • • • • 1st non- biodegradable implant Used for CMV retinitis in AIDS Site – through pars plana into P.C. Drug delivery – 1µg/hr @ 6 months Advantage over I.V. and safe Complications: vit. Hx, RD
  21. 21. steroids • • • • Fluocinolone Acetonide (FA) Dexamethasone Cyclosporine Retisert (FA) for Ch. Non-infectious uveitis 0.59mg – 0.6µg /day @ 1 month (initial) – 0.3 to 0.4 µg/day @ 30 months • FA 2.1mg – 2µg/day @ 1 month (initial) – 1µg/ day @ 3 yrs • More than 50% improvement with in 1yr + no adjuvant thx in 80% of cases • Complications: cataract and inc. IOP
  22. 22. • FA in DR – 57% in ↓ME, and retinal thickness to 20% of control • FA in CRVO – at 12 months VA 20/ 60 from base 20/ 126 central foveal thickness – 622µm to 199µm • 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 • CNTF-NT501 – ciliary neutrophilic factor protects retinal degeneration in animals ( completed phase I)
  23. 23. 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 t½ of 35 days with • no new changes were seen under thx but existing changes could not be regressed
  24. 24. • 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 1µg/day and 3 µg/day
  25. 25. 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
  26. 26. • 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
  27. 27. • 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, retinal thickness, and florescent leak with minimal S.E - vitreous Hx and IOP ↑ • Phase IIb – suture less with 22” needle = no vit Hx / IOP ↑
  28. 28. 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 (1-10,000µm) Micro particles (1- 10,000µm) 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
  29. 29. • 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
  30. 30. • 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
  31. 31. • 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 t½ 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
  32. 32. • Liposomes: • Types of nano and micro particles of vesicles lipid system of 50µm • 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

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