Drug delivery to the posterior segment of the eye for pharmacologic therapy

Dr. Meenank. BM.S. Ophthalmology (Post-Graduate )ASRAM medical college

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, micro-spheres, and liposomes emerged

• Barriers

•

• Drug Delivery for Posterior Segment Eye1. Topical2. Systemic3. Sub-conjunctival4. Intravitreal5. Trans-scleral6. Iontophoretic

Over view

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

Blood retinal barrier Posterior chamber

Retinal pigment

epithelium

Retinal blood

vessels

oral

Blood-stream

Intra-venous

Vitreous

Systemic

Systemic

• 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

• 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

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

Intravitreal Pneumatic Retinopexy

SF₆ , C₃F₈, C₂F₆

Anti-bacterial’s (Endophthalmitis)

GPB-Vancomycin(1mg/0/1ml), cefazoline(2.25mg/0.1ml). GNB- Ceftazidine(2.25mg/0.1ml), Amikacin(0.4mg/0.08ml)

Anti- viral’s 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)

• 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 Intravitreal Injection Technique.mp4

Trans-Scleral diffusion • Newer method• Less invasive • Drug spreads through the ocular tissue to reach the neuro-

retina • Includes –

1. Sub- conjunctival2. Retrobulbar3. Pribulbar4. Sub- tenons5. Intra-scleral (newer)

• Limitations – while crossing through many compound barriers bio-availability is drastically dec. thus, needs more dose

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

• Barriers – static, dynamic and, metabolic

• 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

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

• 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

• 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

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

Non-biodegradable implants• Intravitreal Better than tropical and sys. In giving • Trans scleral high drug levels But, susceptible to

rapid• Iontophoretic 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

• 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

Ganciclovir4.5mg of drug

Poly vinyl coat- permeable to

water

Ethyl vinyl acetate- restrict surface

diffusion of drug

Poly vinyl coat-

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

retisert implantation.mp4

• 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)

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

• Beeley et al – studied a S.R TA rod shaped 3.5mm - 4 weeksCoat- PMMC + nitinolCore – 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

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

• 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

• 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 ↑

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

• 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

• Polymeric microsphere used in targeting phagocytosis by RPEPLA + florescent dye PLA + florescent dye + rhodamine 6GXPLA + 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

• 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

• 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