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
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
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. 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
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. • 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. • 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. 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. • Factors effecting –
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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. • 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. 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. 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 –
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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. Ganciclovir
4.5mg of drug
Poly vinyl coatpermeable to
water
Ethyl vinyl
acetate- restrict
surface diffusion
of drug
Poly vinyl coat-
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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. steroids
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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. • 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. 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. • 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. 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 –
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Poly lactic acid (PLA)
Poly Glycolic acid (PGA)
Poly lactic- co- glycolic acid (PLGA)
Poly caprolactone
Poly methylene malonate
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. • 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
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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. 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
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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. • 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.
31. • 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
32. • 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
33. • 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
