OCULAR PHARMACOLOGY Moderator: Dr Mukunda

Speaker: Dr Rachana Menon

As we go….

Overview of ocular anatomy and physiology

Pharmacokinetics of ocular therapeutic agents

Ocular drug delivery system

Toxicology of ocular therapeutics

Extra ocular structures

• The orbital bone – Bony Socket, extra ocular muscles

• Lacrimal apparatus

• Conjunctiva – Thin, clear layer of skin

• The surface area of the conjunctiva (16-18 cm’) is larger

than that of the cornea (1 cm)

• Sclera

Lacrimal apparatus

CORNEA

CORNEAL REFLEX

Sclera

SCLERA

Dense, fibrous tissue that forms the outermost layer of the eye

Collagen fibers and proteoglycans Choroid, ciliary body, optic nerve, and iris.vascular choroid nourishes the outer retina by a capillary system in the

choriocapillaris

Aqueous humour• Clear colorless watery solution continuously circulated

from posterior chamber of the eye through out the anterior chamber

• Maintenance of IOP

• Ciliary body

2.5micro liters/min

VOLUME: 0.31 ml ( 0.25ml in AC/0.06 ml in PC)

Refractive index : 1.336

pH : 7.2 ( acidic)

Osmotic pressure: 20 mmHg

FORMATION• Diffusion -lipid soluble substances, are transported

through the lipid portions of the membrane of the tissues

between the capillaries and the posterior chamber

• Ultrafiltration -flow of water and water-soluble

substances, limited by size and charge, across

fenestrated ciliary capillary endothelia into the ciliary

stromaAccumulation of plasma ultra filtrate in the stroma, behind tight junctions of the non-pigmented epithelium, from which the posterior chamber aqueous humor is derived

Formation of Aqueous Humour

SITE : CILIARY BODY.

Blood-Retinal Blood-aqueous barrier

AQ1,AQ4

FLUID TRANSFER INTO AQUEOUS HUMOUR

Solutes and water are transported across the basolateral

membrane of NPE

Na+, K+ ATPase (70%) Na+ against electrochemical gradient

into aqueous, remaining (30%) transported passively or by

ultra filtration

Water released along osmotic gradient established by solute

transfer into aqueous through AQP1 and AQP4

final step in aqueous secretion

Carbonic anhydrase,- non-pigmented and pigmented ciliary

epithelia mediates the transport of bicarbonate across the ciliary

epithelium(HCO3-/Cl- exchangers as well as Cl- channels)

Chloride ion is the major anion transported across the epithelium

through Cl- channels

Ascorbic acid-(SVCT2)

Amino acids

DRAINAGE

• Consist of two pathways

– Trabecular / conventional outflow

– Uveoscleral / unconventional outflow

• PG increase uveoscleral flow to lower the IOP

Ciliary Process

Aq. In post Chamber

Anterior Chamber

Trabecular meshwork Ciliary body

Schlemms canal Suprachoroidal space

Collector channel Venous circulation cil. body, sclera and orbit

Episcleral veins

Trabecular Outflow90%

Uveoscleral Outflow10%

Biochemical composition

Pupil Contraction and Dilation

• Controlled by two muscles of the iris

– Sphincter muscle (pupil

constriction) – Innervated by the

parasympathetic nervous system

– Dilator muscle (relaxation) –

Innervated by the sympathetic

nervous system

• Sensory pathway for pupil constriction

Axons from retinal ganglion cells (input)

↓ Optic nerve → Optic chiasm → Optic

tract ↙ Edinger-Westphal ← Pretectal nucleus nucleus

EFFERENT PATHWAY

Autonomic Pharmacology of the Eye and Related Structures

  ANDRENERGIC RECEPTORS CHOLINERGIC RECEPTORS

TISSUE SUBTYPE RESPONSE SUBTYPE RESPONSE

Corneal epithelium β2 Unknown M3 UnknownCorneal

endothelium β2 Unknown Undefined Unknown

Iris radial muscle α1 Mydriasis    Iris sphincter

muscle     M3 MiosisTrabecular meshwork β2 Unknown    

Ciliary epithelium α2/β2

Aqueous production    

Ciliary muscle β2 Relaxation M3 Accomodation

Lacrimal gland α1 Secretion M2, M3 Secretion

Retinal pigment epithelium α1/β1

H2O transport/unknown    

Lens

Lens substance• Lens fibres

– Consist of primary and secondary fibers. They elongate and undergo differentiation with pyknocytosis and eventual loss of cell oraganelles and nucleus

– This is an important factor in the transparency of the lens

• Active transport of ions and low molecular weight

metabolite takes place between lens and aqueous humour

• Na-K-ATPase and a calmodulin - dependent Ca-

activated ATPase for the active transport of

electrolytes

• Fibre cells contain large concentrations of negatively

charged crystalline

• Positively charged cations enter the lens cell to maintain

electrical neutrality

• Amino acids – Energy dependent carrier mechanisms

• Lipids – high concentration of cholesterol and

sphingomyelin – membrane rigidity

• Glutathione - Major antioxidant in lens• Ascorbic acid • Inositol - Membrane rigidity• Taurine

The retinal pigment epithelium serves

vitamin A metabolism, phagocytosis of the rod outer segments,

and multiple transport processes

Pharmcokinetics of Ocular Therapeutics

Ocular Pharmacokinetics

Tear film and cul-de-sac,

Anterior chamber

The vitreous cavity

Retro or periocular space

Most topical ophthalmic drugs exhibit first order kinetics

OCULAR COMPARTMENTS

Factors Affecting Intraocular Bioavailability

Inflow & Outflow of Lacrimal fluids

Efficient naso-lacrimal drainage

Interaction of drug with proteins of Lacrimal fluid. Dilution with tears

Corneal barriers

Active ion transport at cornea

Size of the molecule, chemical structure, and steric configuration

Limited success in attaining therapeutic drug concentrations in the

posterior segment

LAG TIME

NASO MUCOSAL AQUEOUS HUMOUR

INTRA OCULAR STRUCTURES

MELANIN PIGMENT

PASSIVE DIFFUSION

Transporters

• The most commonly applicable influx transporters for

• Amino acid -to SLC1, SLC6, and SLC7 gene families-

glutamate transporters

• Peptide transporters-PEPT1, PEPT2

• Transporter-targeted prodrugs

Metabolism

• Enzymatic biotransformation – Esterases, oxidoreductases – Lysosomal enzymes– Peptidases– Glucuronide – Sulfate transferases, – Glutathione-conjugating enzymes

PRODRUG

Dipivefrin- epinephrine Latanoprost- PGF2

Elimination Depends on the drug's ability to penetrate across the

endothelial walls of the vessels

Clearance from the anterior chamber is faster for lipophilic

than for hydrophilic drugs

Clearance of lipophilic drugs - 20–30 micro l/min

Drug elimination takes place via uveal blood flow

Halflifes of drugs in the anterior chamber are typically an hour

The volumes of distribution are difficult to determine due to

the slow equilibration of drug in the ocular tissues

• `

OCULAR DELIVERY SYSTEMS

ConventionalConventional VesicularVesicular

Control releaseControl release ParticulateParticulate

SolutionsSuspensionEmulsionsOintmentInsertGels

SolutionsSuspensionEmulsionsOintmentInsertGels

ImplantsHydrogelsDendrimersIontoporesisCollagen ShieldContact LensesCyclodexrinMicroneedlesMicroemulsions

ImplantsHydrogelsDendrimersIontoporesisCollagen ShieldContact LensesCyclodexrinMicroneedlesMicroemulsions

LiposomesNiosomesDiscomesPharmacosomes

LiposomesNiosomesDiscomesPharmacosomes

MicroparticlesNanoparticlesMicroparticlesNanoparticles

AdvancedAdvanced

Scleral PlugsGene DeliverySi RNAStem Cell

Scleral PlugsGene DeliverySi RNAStem Cell

IDEAL CHARACTERISTICS OF OCDDS

Comfort

Ease of Handling

Reproducibility of release kinetics

Sterility

Stability

Ease of Manufacturing

EYE DROPS

Most common

• One drop = 40-70 µl

• Tear film - 7-10 µl. Tear turnover -15% per minute

• Topically administered solutions are washed away within just 15–30

sec after instillation• Poor bioavailability-difficult to achieve therapeutic drug

concentration into posterior segment ocular tissues following topical eye drops

• Ease of administration, compliance

• Measures to increase drop absorption:

- Wait 5-10 minutes between drops

- Compress lacrimal sac Keep lids closed for 5 minutes.

Solutions

Emulsion

Suspension

Ion exchange resin technology - betaxolol ionic

suspension (Betoptic S, 0.25%).

OINTMENTS AND GELS

• Prolongation of drug contact time with the external ocular

surface can be achieved using ophthalmic ointment

vehicle .

Drawback

• blurring of vision

• matting of eyelids

Prolonged retention in the

cul-de-sac

Longer drug action

No stinging on application

lack of preservatives,

Lesser likelihood of bacterial

contamination

Minimise morning lid

stickiness in cases of infective

conjunctivitis

Conventional delivery systemDosage Form Advantages Disadvantages

Solutions Convenience, Non invasiveRapid precorneal elimination,

non sustained action

Suspension-Viscocity enhancers

Patient compliance; best for drug with slow dissolution

Drug properties decide performance loss of both solutions and suspended

particles

Emulsion-Soyabean lecithin/Steryl amine

Prolonged release of drug from vehicle

Blurred vision, patient non compliance

OIL IN WATER - VEHICLE - Prednisolone 0.05% difluprednate,

Benzalkonium chlorideSodium taurocholate, saponins - Permeation enhancers

TobraDex

VESICULAR SYSTEM

•  Liposomes: Carrier system. Biocompatible and biodegradable lipid

vesicles-1965

• Made up of natural and synthetic lipids

• 10nm- 1 μm

• Intimate contact with the corneal and conjunctival surfaces which is

desirable for drugs that are poorly absorbed.

HIGH AGGREGATION

TENDENCY

Contd…

• The drugs with low partition coefficient

• Poor solubility

• Phosphatidylcholine ,cholesterol and

lipid-conjugated hydrophilic polymers as

the main ingredients.

• Increases the probability of ocular drug

absorption.

• LIMITATIONS

Chemical instability

Storage

Long term side effects-vitreal

condensation

Oxidative degradation of

phospholipids

Cost and purity of natural

phospholipids

ROSTAPORFINVERTEPORFIN

Niosomes

Niosomes are a novel drug delivery system, in which the

medication is encapsulated in a vesicle

Non-ionic surfactant such as Span – 60

Can entrap both hydrophobic and hydrophilic drugs

Do not require special handling techniques

• Sucrose ester surfactants • Polyoxyethylene alkyl ether surfactantsNimesulide, flurbiprofen, piroxicam,ketoconazole and bleomycin

BiodegrdableNon immunogenic

DISCOMES

Discomes - Giant niosomes (about 20 um size)

containing poly-24- oxy ethylene cholesteryl ether or

otherwise known as Solulan 24

Potential drug delivery carriers

Release drug in a sustained manner at the ocular site

Pharmacosomes – Amphiphilic lipid vesicular system drug bearing a free carboxyl group or active hydrogen atom can be esterified

Prodrug is converted to pharmacosomes on dilution with water - Aceclofenac phospholipid complex

The bilayer in the case of niosomes is made up of non-ionic surface active agents rather than phospholipids as seen in the case of liposomes Hydrophilic ends exposed on the outside and inside of the vesicle, while the hydrophobic chains face each other within the bilayer

Drug Formulation Result Year

GCV LiposomesIn vitro transcorneal permeation and in vivo ocular pharmokinectics was improved

2007

Ciprofloxacin Liposomal hydrogelFivefold higher transcorneal permeation than the liposomes alone

2010

LevofloxacinLiposomes attached to the contact lenses

Drug was released following first-order kinetics for more than 6 days and formulation had showed activity against S. aureus

2007

Herpes simplex virus antigens

Periocular vaccine

Treated rabbits showed anti-gB immune response and protected against reactivation of HSV infection

2006

AcetazolamideNeutral- and surface- charged liposomes

Positively charged liposomes reduced IOP and exhibited prolonged effect than negatively charged liposomes

2007

Implants Biodegradable polymers such as Poly Lactic Acid (PLA) effective to deliver

drugs in the vitreous cavity.

Site: Pars Plana -Invasive

CMV retinitis drug delivery to posterior ocular tissues, implants are placed intravitreally by

making incision through minor surgery

VITRASET- controlled-release intraocular implant of ganciclovir – FDA for the

treatment of AIDS associated cytomegalovirus retinitis

• OZURDEX (dexamethasone) biocompatible and biodegradable intravitreal

implant. Approved by FDA in June 2009 for macular edema

sustained drug release-6 monthslocal drug release to diseased ocular tissues in therapeutic levels, reduced side effects

Ocular iontophoresis

Contd.. Delivery of a high concentration of the drug to a specific site.

Non-invasive nature of delivery to both anterior and posterior

segment

Inert electrode, which electrolyzes water to produce the

hydroxide or hydronium ions required to propel charged drug

molecules

Able to overcome the potential side effects associated with

intraocular injections and implants

Sustained high ocular conc. minimal systemic absorption

Fast, painless, safe

Bacterial keratitis,Anterior uveitis( 28 days IOP controlled)

AMD

RANIBIZUMAB,PEGAPTANIB,ED-437(steroid)

DENDRIMER Nanoparticle (10-9) made up of a series of branches around

a central core

Ease of preparation and uptake by cells

Functionalization possibility to attach multiple surface groups

provides suitable alternative vehicle for ophthalmic drug delivery.

Entrap both hydrophilic and lipophilic drugs into their structure

can successfully used for different routes of drug administration

Functionalised terminal surfaced

Controlled and sustained release of drugs,Reduction in the

drug used

Easily made to remain within layers of skin and not

penetrate in systemic circulation

Bypassing the gastric medium

Increase in therapeutic efficacy, decrease in side effects

MECHANISM

Covalent bonding of drug to dendrimer

Releasing the drug due to changes in physical

environment such as pH, temperature

Dendrimer in ocular drug delivery- to enhance pilocarpine bioavailability

CYCLODEXTRINS• Penetration enhancers• Inrease aqueous solubility of lipophilic drugs• Increase bio-availability at the surface of biological

barriers• Decrease drug irritation in injectable and oral dosage

forms

Bispilocarpic acid – Pro-drug of pilocarpine which significantly increase the bioavailability of pilocarpine after topical administration to the cornea

PARTICULATESNANOPARTICLES/MICROPARTICLES Solid colloidal particles – Promising drug carriers for ophthalmic

application

The size -1-1000nm

USES: adjuvant in vaccines or drug carriers in which the active

ingredient is dissolved, entrapped, encapsulated, adsorbed or

chemically attached

Scratching feeling in the eye can result upon ocular instillation

Prepared using bio-adhesive polymers to provide sustained effect to

the entrapped drugs

Anti-inflammatory, Anti-allergic and

Beta-blocker drugs

Drug PolymerCarboplatin CH, SA

5-FU CH, SA

Sparfloxacin PLGA

BT Levofloxacin Sodium alginate PLGA

DS PLGA

Pilocarpine PLGA

Gatifloxacin/Prednisolone

Eudragit RS 100 and RL 100, coating with hyaluronic acid

Cloricromene (AD6) Eudragit

Brimonidine Eudragit RS 100

Tartrate Eudragit RL 100

Microemulsion

• Dispersions of two immiscible liquids, such as oil and

water, stabilized by an interfacial film of surfactant and

co-surfactant

• Co- surfactant to reduce interfacial tension

• Small droplet size (100 nm)

Contd…

• ADVANTAGE - Higher thermodynamic stability and

clear appearance

• Selection of aqueous phase, organic phase and

surfactant/co-surfactant systems are critical parameters

which can affect stability of the system

High drug solubilization, Long shelf-life Ease of manufacture

Microneedle

• Custom designed to penetrate only hundreds of microns

into sclera,. These needles help to deposit drug -

“Suprachoroidal Space” (SCS), coated with

pilocarpine,fluorescein

In vivo drug level significantly higher than the level

observed following topical drug administration - Evacizumab, Pilocarpine

AMD, Diabetic retinopathy Posterior uveitis

MINIMALLY INVASIVE

Mucoadhesive Polymers

Macromolecular hydrocolloids - Based on entanglement

of non-covalent bonds between polymers and mucous.

Hydrophilic functional groups, such as hydroxyl,

carboxyl, amide and sulphate having capability

forelectrostatic interactions

Treatment of glaucoma - Levobetaxolol (LB)

hydrochloride and PAA, CHITOSANImproves corneal contact

timeOPENS TIGHT JUNCTIONS

INSERTS CLASSIFICATION

NON ERODIBLE INSERTS Ocusert Contact lens

ERODIBLE INSERTS Lacriserts SODI Mindisc

NON ERODIBLE INSERTS OCUSERT

Flat, flexible, elliptical device placed in

the inferior cul-de-sac between the

sclera and the eyelid .STERILE .

Release Pilocarpine continuously at a

steady rate for 7 days.

1.Outer layer - ethylene vinyl acetate

copolymer layer.

2. Inner Core - Pilocarpine gelled with

alginate main polymer.

3. A retaining ring - impregnated with

titanium dioxide

TWO FORMS

Pilo – 20: 20 microgram/hour

Pilo – 40:40 micrograms/hour

Contd…

ADVANTAGES: Reduced local side effects and toxicity Around the clock control of IOP Improved compliance Prolong residence time of drug with a controlled

release manner Less affected by nasolacrimal damage

DISADVANTAGES: Retention in the eye for the full 7 days. Complexity and difficulty of usage is noticed particularly

in self administration. Tolerability in the eye is poor, due to rigidity, size or

shape Foreign body sensation and they are to be removed at

the end of the dosing period

CONTACT LENSES

• Circular shaped structures

• Drug incorporation depends on whether their structure is

hydrophilic or hydrophobic

• Drug release depends upon : Amount of drug Soaking time.

• Incorporate the drug either as a solution or suspension of

solid particles in the monomer mix -180hrs

CONTACT LENSES

ADVANTAGES

No preservation

To aid corneal wound healing

Size and shape

DISADVANTAGES

Handling and cleaning

Expensive

ERODIBLE INSERTS Absorb the aqueous tear fluid and gradually erode or

disintegrate.

The drug is slowly leached from the hydrophilic matrix.

They quickly lose their solid integrity and are squeezed

out of the eye with eye movement and blinking.

Do not have to be removed at the end of their use.

Three types

1. LACRISERTS

2. SODI

3. MINIDISC

Lacrisert• Sterile rod shaped device made up of hydroxyl propyl cellulose

without any preservative

Treatment of dry eye syndrome and keratitis sicca

MOA: imbibing water from the cornea and conjunctiva and form a

hydrophilic film which lubricates the cornea

Gets dissolved in 24hrs

It is inserted into the inferior fornix

SODI• Soluble ocular drug inserts

Small oval wafer Sterile thin film of oval shape

Weighs 15-16 mg

Inserted into the inferior cul-de-sac and get wets and

softens in 10-15 seconds

After 30-60 minutes, it turns into polymer solutions

and delivers the drug for about 24 hours

Use – GLAUCOMA ,TRACHOMA

Advantage – Single application

Pilocarpine, chloramphenicol

Minidisc• Countered disc

• Convex front and a concave back surface

• Diameter – 4 to 5 mm

• Composition: Silicone based polymer

• Can be hydrophilic or hydrophobic to permit extend

release of both water soluble and insoluble drugs

Intra Ocular Injections

INDICATIONS• Endophthalmitis• CMV retinitis• Unresponsive post uveitis• PDR• AMD • Diabetic macular edema• Macular edema• Recalcitrant macular edema• CRVO

Pharmacokinetics Drugs spread through vitreous at same rate as they will

through a free solution

3 major pathways of drug elimination

Aqueous Retinochoroidoscleral Lens

drainage membrane

(Hyrophilic (Lipohilic drugs)

Drugs)

• Drug decay rate is greater in diseased eye than in normal eye

Advantages

Poor ocular especially post segment penetrance of

systemically administered drugs attributed to

BLOOD AQUEOUS BARRIER

BLOOD RETINAL BARRIER

Higher efficacy of local treatment-desired dose at

target site

Reduced systemic toxicity

DisadvantagesLocal complications

Endophthalmitis

Vitreous haemorrhage

Retinal detachment

Retinal necrosis

Vascular shutdown

Local drug toxicity

Need of expertise

Presently used intra-vitreal drugs

Antibiotics – Anti-bacterials, anti-virals, anti-

fungals

Dexamethasone, triamcenolone, flucinolone

Anti VEGF-pegaptanib (macugen)

bevacizumab (avastin)

ranibizumab (lucentis)

Immuno suppressants - Cyclosporine

Recent Advances

siRNA therapy - directed against vascular endothelial growth factor (VEGF) or

VEGF receptor 1 (VEGFR1)

Oligonucleotide therapy blocking the synthesis of cellular proteins by

interfering with either the transcription of DNA to mRNA or the translation of

mRNA to proteins

Aptamer-oligonucleotide ligands that are used for high-affinity binding to

molecular targets .Adsorption and ramplification

Scleral Plug therapy -pars plana region of eye . Proliferative vitreoretinopathy,

cytomegalovirus retinitis

Ribosome therapy: Autosomal dominant rinitis pigmentosa

OCULAR TOXICITIES

Complications of topical administration

• Mechanical injury from the bottle e.g. corneal abrasion

• Pigmentation: epinephrine-adrenochrome

• Ocular damage: e.g. topical anesthetics, benzylkonium

• Hypersensitivity: e.g. atropine, neomycin, gentamicin

• Systemic effect: topical phenylephrine can increase BP

AMIDARONE• Keratopathy in almost 100% of patientsKeratopathy in almost 100% of patients

– Golden-brown verticillate whorl-like patternGolden-brown verticillate whorl-like pattern– AsymptomaticAsymptomatic

• Also causes corneal vortex keratopathy (corneal verticillata) which is whorl-shaped pigmented deposits in the corneal epithelium

Digitalis

• Causes chromatopsi (objects appear yellow) with overdose

Chloroquine

Hydroxychloroquine

• Cause vortex keratopathy (corneal verticillata) which is

usually asymptomatic but can present with glare and

photophobia

• Also cause bull’s eye maculopathy

CHORPROMAZINE• Corneal punctuate epithelial opacities, lens surface

opacities• Rarely symptomatic• Reversible with drug discontinuation

TOPIRAMATE• Causes acute angle-closure glaucoma

ETHAMBUTOL• Causes a dose-related optic neuropathy• Usually reversible but occasionally permanent visual

damage might occur

Isotretinoin - Impairment of dark adaptation

Chemotherapeutic agents Cisplatin- Optic neuritis

Cyclophosphamide-Blurred vision

5-FU – Puntal stenosis

Vincristine- Cranial palsy

Methotrexate- Periorbital odema

Doxorubicin-Conjuctivitis

Mitomycin C- Blurring of vision

Tamofixen-Posterio subcapsular catract

Corticosteroids

• Ocular side effects include:Ocular side effects include:

Cataract (posterior subcapsular)Cataract (posterior subcapsular)

Increased IOP (secondary open angle glaucoma)Increased IOP (secondary open angle glaucoma)

Immunosuppression leading to infectious Immunosuppression leading to infectious

complicationscomplications

Candida endophthalmitisCandida endophthalmitis Cytomegalovirus retinitisCytomegalovirus retinitis Ocular toxoplasmosisOcular toxoplasmosis Herpes simplex keratitisHerpes simplex keratitis Fungal keratitisFungal keratitis

Erectile DysfunctionAgents

Inhibiting PDE-5 (found in photoreceptors, mediates Inhibiting PDE-5 (found in photoreceptors, mediates

transduction) exceeding 50 mgtransduction) exceeding 50 mg

• Visual symptoms include bluish tinge or haze to vision, Visual symptoms include bluish tinge or haze to vision,

increased light sensitivity. Macular degenerationincreased light sensitivity. Macular degeneration

2005, FDA had received 43 reports of 2005, FDA had received 43 reports of NAION in men using these drugsNAION in men using these drugs

Statins

• Examples - pravastatin, lovastatin, simvastatin,

fluvastatin, atorvastatin, rosuvastatin

• Can cause cataract in high dosages specially if used

with erythromycin

OPTIC NEUROPATHY• Methanol

• Ethylene glycol (antifreeze)

• Chloramphenicol

• Isoniazid

• Lithium

• Streptomycin

• OCPs

• Quinine

• High-protein diet

• Carbon monoxide

• Lead

• Mercury

• Thallium (alopecia, skin

rash, severe vision loss)

• Malnutrition with vitamin B-1

deficiency

• Pernicious anemia (vitamin

B-12 malabsorption)

Herbal supplements

• Eye bright/Euphrasia

• Bilberry

• Gingko biloba

• St. John’s wort

• Canthexanthine – Crystalline-like retinopathy

• Licorice – Transient vision loss similar to migraine aura

Thank you