Drug delivery to the posterior
segment of the eye for
pharmacologic therapy
Dr. Meenank. B
M.S. Ophthalmology (Post-Gradua...
Introduction
• Drug delivery into the posterior segment of the eye is
complicated by the blood-ocular-barrier
• Prescribed...
• Drug Delivery for Posterior Segment Eye
1.
2.
3.
4.
5.
6.

Topical
Systemic
Sub-conjunctival
Intravitreal
Trans-scleral
...
Over view
Topical
• Most successful in anterior segment eye diseases but, posterior
segment of eye hinders many challenges
• Reflex ...
Systemic

oral
Bloodstream

Retinal
pigment
epithelium

Retinal
blood
vessels

Vitreous

Intravenous

Systemic

Blood reti...
• Endophthalmitis – fluoroquinolones – klebsiella, pseudomanas
• Prodrugs – lipophilic, better absorbed and converted by
e...
Intravitreal
• More popular clinical settings
• Direct applications of drug into posterior segment eliminating
barriers
• ...
Intravitreal

Pneumatic
Retinopexy
Anti-bacterial’s
(Endophthalmitis)
Anti- viral’s

SF₆ , C₃F₈, C₂F₆
GPB-Vancomycin(1mg/0...
• Indications –
• Endophthalmitis
• CMV retinitis
• Unresponsive Post.
Uveitis
• PDR
• AMD
• DME
• ME
• CRVO
• CNVM

• Con...
Trans-Scleral diffusion
• Newer method
• Less invasive
• Drug spreads through the ocular tissue to reach the neuroretina
•...
• Barriers – static, dynamic and, metabolic
Static

Dynamic

Metabolic

Sclera:
permeability decreases with inc.
molecular...
• Sub – conjunctival:
• Low doses for sustain release in ant. and post. Segment
• Hydrophilic drugs preferred – penetrate ...
Iontophoretic
• Electro-dynamic process of drug delivery
• Charged molecules accelerates across the sclera onto the
poster...
• Factors effecting –
•
•
•
•
•
•
•

Amount of current used
Drug concentration
Treatment duration
ph.
Permeability
Resista...
• Devises –
• Coulomb-controlled Iontophoretic – self calibration
• EyeGate II Delivery System – water hydrolyses by curre...
Ocular implants
• Bypass blood retinal barrier
• Concept: delivering drug below toxic level and at higher dose
rate withou...
Non-biodegradable implants
• Intravitreal
• Trans scleral
• Iontophoretic

Better than tropical and sys. In giving
high dr...
Ganciclovir

•
•
•
•
•
•

4.5mg of
drug

Ethyl vinyl
acetate- restrict
surface
diffusion of
drug
Poly vinyl coatpermeable ...
steroids
•
•
•
•

Fluocinolone Acetonide (FA)
Dexamethasone
Cyclosporine
Retisert (FA) for Ch. Non-infectious uveitis
0.59...
• FA in DR – 57% in ↓ME, and retinal thickness to 20% of
control (Posurdex)
• FA in CRVO – at 12 months VA 20/ 60 from bas...
Triamcinolone Acetonide (TA)
• Triamcinolone Acetonide (TA) – as a Rx for neovascular and
oedematous proliferative of eye
...
• Beeley et al – studied a S.R TA rod shaped 3.5mm - 4 weeks
Coat- PMMC + nitinol
Core – matrix of drug + PBMC + PEVA
• ST...
Biodegradable implants
• To minimize the complications of surgical implants
Biodegradable implants came into play
• Mostly...
• Polymers used – PLA and PLGA
• lactic – slow degradation
• Glycolic – faster degradation
• Following 1st order of kineti...
• 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
•
...
Novel drug delivery: micro particles
and nanoparticles
• Sustained release drug system developed as an alt to
implantation...
• Capsulation – sphere – solvent evaporation process
capsule – emulsion diffusion process
• Drug – hydrophobic – oil-in-wa...
• Polymeric microsphere used in targeting phagocytosis by RPE
PLA + florescent dye
PLA + florescent dye + rhodamine 6GX
PL...
• Anti- virals – encapsulated ganciclovir and acyclovir in
polymeric micro and Nanospheres are used
• Owing to the ocular ...
• Liposomes:
• Types of nano and micro particles of vesicles lipid system of 50µm
• Allows encapsulation of dry molecules
...
Drug delivery to the posterior segment of the eye for pharmacologic therapy
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Drug delivery to the posterior segment of the eye for pharmacologic therapy

  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. • Drug Delivery for Posterior Segment Eye 1. 2. 3. 4. 5. 6. Topical Systemic Sub-conjunctival Intravitreal Trans-scleral Iontophoretic
  4. 4. Over view
  5. 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, ↓t½ • Recent small mol. Wt. – ↑permeability, ↓toxicity, slower degradation rate
  6. 6. 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
  7. 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. 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. 9. 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(400µg/0.1ml, triamcinolone(4mg/0.1ml) Anti VEGF agents Ranibizumab-leucentis (0.5mg/0.05ml), Pegatanib- Macugen (0.3mg/0.1ml)
  10. 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. 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. 12. • 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
  13. 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. 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. 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. t½ • Ocuphor – commercially available pegaptinib
  16. 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. 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 1½ scleral thickness pocket and closed • Devises : Non- biodegradable Biodegradable
  18. 18. 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 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. 19. Ganciclovir • • • • • • 4.5mg of drug Ethyl vinyl acetate- restrict surface diffusion of drug Poly vinyl coatpermeable to water 1st non- biodegradable implant, Vitrasert 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, rheg.RD, endophthalmitis, cataract, FB sensation, fibrovascular scar, conjunctival Hx, pellet separation
  20. 20. 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, VH,RD, maculopathy, ME, ptosis, diplopia, corneal ulcer, hypotony, perforation
  21. 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 – 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
  22. 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 t½ of 35 days with • no new changes were seen under thx but existing changes could not be regressed
  23. 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 1µg/day and 3 µg/day
  24. 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. 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. 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. 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 (1-10,000µm) 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
  28. 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. 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. 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 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
  31. 31. • 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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