Dr Athmar Dhahir Habeeb - PowerPoint Presentation

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Dr Athmar Dhahir HabeebPhD in Industrial Pharmacy and pharmaceutical formulations

Barriers to ophthalmic drug delivery: The big challenge

Advanced drug delivery

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The aim of any final dosage form is to deliver the drug molecule in a therapeutic concentration to the site of action for an optimal period of time. Systemic drug distribution is often accompanied by side effects due to off-target effects Localised drug delivery to the site of action has the potential to minimise the amount of dose needed for efficacy. Systemic side effects can thus be minimised.

Certain modes of administration allow for localised treatment, e.g. pulmonary, transdermal, nasal, rectal, vaginal, buccal and ophthalmic routes

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Ophthalmic drug deliveryDrug delivery to the eye is one of the most important areas of modern ocular therapy and presents many opportunities and challenges. Local drug delivery to the eye can in some cases be accomplished, but there are major anatomical, biological and physicochemical barriers that can limit efficacy

An understanding of the barriers associated with ophthalmic drug delivery requires an understanding of the main parts of the eye and the function of each part.

The

eye consists of two compartments; the anterior segment (which is the front of the eye) and constitutes 1/3 of the globe while the other 2/3 of the globe is the posterior segment (which is the back of the eye).

The

eye is in direct contact with the environment and protected by the eyelids, tear film and the

cornea.

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The cornea is a transparent layer that covers the front of the eye (iris, which is the coloured part of the eye); it is highly innervated tissue with no blood supply. It depends on the aqueous humour for nourishment and removal of waste products. The front surface of the cornea is covered with a tear film. The cornea consists broadly of three tissue layers each separated by a membrane

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The cornea is a complex barrier for absorption of drugs into the eye. In addition to the cornea; tear turnover, nasolacrimal drainage and reflex blinking made topical administration of medicines using eye drop is only really appropriate to treat the periocular diseases.

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The cornea is connected to the sclera through the limbus region. The sclera is the white part of the eye that is tough in nature and is mainly comprised of collagen fibres. The sclera is covered by a mucous membrane called the conjunctiva (which covers the inside of the eyelid as well). The conjunctiva is a thin, transparent, mucous tissue that covers the front of the eye, except the cornea. It is enriched with blood and lymph vessels that help to nourish the ocular tissues. Its surface is covered by the mucus that helps to lubricate the eye ball during movement and impart wettability to the ocular

surfaces

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The uvea comprises the iris, ciliary body, and the choroid plexus. The iris is the coloured part of the eye. The anterior chamber is the space between the iris and the cornea while posterior chamber is the space between the iris and the lens (posterior to the iris and anterior to the lens); both are occupied by the aqueous humour .The aqueous humour is a transparent fluid that fills the anterior and posterior chambers .

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The main parts of the posterior segment are vitreous humour, retina, choroid and optic nerve. The

vitreous humour is a clear viscous gel that fills the posterior cavity of the eye. It is located between the lens and the retina.The retina

is a complex tissue that lies between the vitreous and

sclera.

The

choroid

is the vascularised tissue comprising the

blood-retinal-barrier

and separates the retina from the sclera.

The

blood-retinal barrier is considered the main key barrier for the absorption of drugs into the posterior segment after systemic

administration

Blood-ocular

barriers

The eye is protected from the xenobiotics in the blood stream by blood-ocular barriers. These

barriers have

two

parts:

Blood-aqueous

barrier

and

Blood-retina

barrier.

The

anterior

blood-eye

barrier

is composed of the endothelial cells in the uvea. This barrier prevents the

access

of plasma albumin into the aqueous

humor

and also limits the access of hydrophilic

drugs

from plasma into the aqueous

humor

.

The

posterior barrier

between blood stream and

eye

is comprised of retinal pigment epithelium (RPE) and the tight walls of retinal

capillaries.

Unlike

retinal capillaries the vasculature of the choroid has extensive blood flow

and

leaky walls.

Drugs

easily gain access to the choroidal extravascular space, but

thereafter

distribution into the retina is limited by the RPE and retinal endothelia.

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schematic illustration of the main parts of the anterior and posterior segments, barriers to ophthalmic drug delivery and routes of drug elimination from the vitreous.

The location of

ophthalmic barriers

(encircled in red) are; I) the cornea and tear film; II) blood-retinal barriers; III) blood-aqueous barriers.

Routes

of elimination from the vitreous (encircled in blue) are; 1) venous blood flow after diffusing across the iris surface; 2) aqueous humour outflow; 3) diffusion into the anterior chamber (1, 2 and 3 are referred to diffusion through the blood-aqueous barriers); 4) diffusion through the blood–retinal

barrier

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Anterior segment diseasesDry eye syndrome.Ocular allergic conjunctivitisPostoperative inflammationGlaucoma.Uveitis.

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Routes for anterior drug deliveryDrug delivery to the anterior segment following systemic administration is limited due to the blood–aqueous barrier,

Topical drug delivery to the eyeTopical drug delivery is the most convenient and efficacious method of ocular drug delivery

to the anterior segment.

The

advantages of this route are obvious

: it

allows the drug to selectively target

the anterior

chamber and it is

non-invasive

. However, on a practical note, only 1 – 7%

of the

instilled drug reaches the aqueous

humor

Although the corneal route is assumed to be the

principle route

of entry for topical drugs into the eye, studies

have conclusively

proved that the conjunctiva–scleral layer

also plays

a role in the drug absorption of large hydrophilic

molecules.

The permeability of the

conjunctiva to

large hydrophilic molecules is in fact twice that

of the

sclera and higher than the cornea

This

route is generally less productive

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Improving drug absorption by topical drug deliveryFollowing characteristics are required to optimize ocular drug delivery system:a. Good corneal penetration.b. Prolong contact time with corneal tissue.

c. Simplicity of instillation for the patient.d. Non irritative and comfortable form (viscous solution should not provoke lachrymal secretion

and reflex blinking)

e. Appropriate rheological properties and concentrations of the viscous system.

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Improving drug absorption by topical drug deliveryA) Reducing drug drainagePunctal

plug occlusion helps to reduce drug absorption by the large nasal mucosa and to decrease side

effects

.

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2- Increasing drug penetration through the epithelium (penetration enhancers such as benzalkonium chloride)

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3- Iontophoresis is a technique of introducing drugs into tissues noninvasively, by imposing electric currents across the cornea or sclera. Transcorneal iontophoresis has shown enhanced drug penetration into the aqueous

Iontophoresis is a new concept in ocular drug delivery system in which charged drug molecules

are used. Positive charge drug molecules were driven into the tissue at anode

and negative

charge drug molecule driven respectively at cathode. Ocular Iontophoresis is

safe, fast

and easy. It is also proficient to hold high concentration of drugs at targeted

tissue. Ocular

Iontophoresis delivery is not only fast, painless and safe but it can also deliver

high concentration

of the drug to a specific site

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B) Increasing retention time in the conjunctival cul-de-sacOphthalmic ointments are emulsions of aqueous drugs and ointment

bases (e.g., white petroleum). The major advantage is their tendency to serve as a drug depot in the conjunctival sac

, resulting in enhanced and sustained drug absorption.

The

disadvantages

include blurring of vision on

instillation, difficulty

in

applying the exact dose, and sensitivity of the base

to temperature.

Increasing viscosity of solutions

The viscosity of ophthalmic solutions can be increased

by methylcellulose

,

hydroxypropylmethycellulose

,

hydroxyethyl cellulose

and poly(vinyl alcohol) (PVA) among others.

They increase

the residence time of the drug and slow

clearance, resulting

in enhanced

absorption.

Patton and Robinson

Higher viscosity caused

ocular

surface irritation

, increased blinking and higher drainage. A more

viscous solution

also causes visual blurring and may block

the

puncti

and canaliculi.

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Mucoadhesive formulationsMucoadhesion refers to the process of attachment of the drug carrier system to the mucin coat covering the conjunctiva and cornea. Mucoadhesives

increase the residence time and, in addition, provide intimate contact between the drug and the absorbing tissue, which results in a high drug concentration in the local area and a high drug flux through

the absorbing

tissue.

The

most commonly used

mucoadhesives

are

macromolecular hydrocolloids that cannot

cross biological membranes

Hyaluronic acid is a

mucoadhesive

biological polymer

that also

has the advantages of having a high water binding

capacity, non-irritancy

, increased viscosity and

pseudoplastic

behaviour

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Gels and insertsIn situ gel-forming systems are formulations that undergo gellation on contact with the ocular system. They combine

the advantages of dispensing an aqueous solution with increased retention time of a high-viscosity formulation.

Ophthalmic inserts

are solid devices that are placed in

the conjunctival

cul-de-sac. These devices are designed to

release the

drug at a constant rate for a prolonged duration of

time whilst

minimising systemic absorption through the

nasal mucosa

and improving patient compliance

.

They are divided into biodegradable and non biodegradable inserts

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Non biodegradable:The pilocarpine Ocusert® (ALZA Corp.) was the first marketed device to achieve zero-order kinetics. The drug is contained in a reservoir enclosed by two release-controlling membranes made of ethylene vinyl acetate copolymer and surrounded by a ring to aid in the positioning and placement.Biodegradable:

Lacisert It is a sterile rod shaped device made up of hydroxyl propyl cellulose without any preservative is used for the treatment of dry eye syndromes

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Therapeutic contact lensesSoft contact lens-based DDSs have been investigated by several approaches: (1) Soak and absorption of drug solution (2) piggyback contact lens combined with a drug plate or drug solution (3) surface-modification to immobilize drugs on the surface of contact lenses (4) (incorporation of drugs in a colloidal structure dispersed in the lens (5) ion ligandcontaining

polymeric hydrogel and (6) molecularly imprinting of drugs.

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MicroparticlesLiposomes are biocompatible and biodegradable lipid vesicles They are having an intimate contact with the corneal and conjunctival surfaces which is desirable for drugs that are poorly absorbed, the drugs

with low partition coefficient, poor solubility or those with medium to high molecular weights and thus increases the probability of ocular drug absorption. The potential advantage achieved with

the liposome have been have been the control of the rate of encapsulated drug

and protection

of drug from metabolic enzymes present at tear corneal epithelium surface

.

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MicroparticlesNiosomes Niosomes are nonionic surfactant vesicles that have potential applications in the delivery of hydrophobic or amphiphilic drugs.

The major limitations of liposomes are chemical instability, oxidative degradation of phospholipids, cost and purity of natural phospholipids. To avoid this niosomes are developed as they are chemically stable as compared to

liposomes and

can entrap both hydrophobic and hydrophilic drugs. They are non toxic and do

not require

s

pecial handling

techniques.

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DendrimersDendrimers are successfully used for different routes of drug administration and have better water-solubility, bioavailability and biocompatibility. Dendrimers are a unique class of synthetic macromolecules that can be distinguished from classical linear polymers by their highly branched, monodispersed, circular, and symmetrical architecture

MicroemulsionNanosuspension

Prodrug

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Nanoparticles The polymeric nanoparticulate system comprises particles in the range of 1–1,000 nm in which the parent drug is adsorbed, entrapped, conjugated, or

encapsulated. The nanoparticulate system can be an alternative to address irritation and toxicity related issues of liposomes and dendrimers. Aqueous or nonaqueous

suspension of

drug-loaded nanoparticles can be administered

in the

cul-de-sac to achieve sustained drug delivery, which

can eliminate

frequent drug administration. Moreover, the

active drug

can be slowly released by diffusion, dissolution,

or mechanical

disintegration and/or erosion of the

polymer matrix.

Nanoemulsion

Nanoemulsion

offers several

advantages in

ocular drug delivery, such as high capacity to

dissolve both

hydrophilic and lipophilic drugs, stability,

improved bioavailability

, and good

spreadability

. In addition,

surfactants used

in formulating emulsions can also act as

penetration enhancers

, thereby improving drug

permeability across

the cornea.

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Subconjunctival drug delivery (injections and implants)The subconjunctival route is an attempt to minimise dosing frequency while maintaining a sustained drug delivery to the anterior and posterior segment over a prolonged duration of time. However, the morbidity of repeated subconjunctival injections, particularly in inflamed eyes, has reduced the

popularity of this route for anterior segment drug delivery.Placing injections subconjunctivally bypasses the lipid layers of the bulbar conjunctiva and places the drugs adjacent to the water-permeable sclera, increasing water-soluble drug penetration into the 

eye

. Local leakage also allows corneal penetration

Subconjunctival/

episcleral

implants have the

advantages of

direct delivery of medication into the eye,

fewer adverse

events than systemic delivery, and better

patient compliance

than topical eye drops. They are usually

inserted with

a small incision in the conjunctiva and placed in

direct contact

with the sclera

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AdvantagesMarkedly increased penetration of water soluble drugs.Short term high concentrations of drugs in cornea and anterior segment.Supplement to topical therapy.DisadvantagesLocal irritation, residues, necrosis and granuloma formation can occur at the site of injection.Once injected the drug(s) cannot be removed.Temporary pain at site of injection.Injection is quite difficult with potential of injury to eye.

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Surodex is a rod-shaped biodegradable poly(dl-lactide-co-glycolide) (PLGA) matrix implant (1.0 · 0.5mm) consisting of dexamethasone (60 mg) and PLGA with hydroxypropyl

methylcellulose, which provides sustained drug release at a constant rate over 7–10 days.26 The implant is inserted into the anterior chamber after cataract surgery to control postoperative

inflammation.

Glaucoma drainage devices

GDDs are implants used to create an alternative aqueous drainage pathway from the anterior chamber. A new drainage channel is formed by the tube to direct the aqueous flow into the subconjunctival space

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Ion-exchange resin The drug (acidic or basic in nature) is ionically bound to an ion-exchange resin to form an insoluble complex. Drug can only be released from the complex through exchange of the bound drug ions with physiological ions in body fluids. The actual resin is an insolubleBetaxolol hydrochloride (a cardioselective

betablocker) is available as an ion-resin suspension formulation (Betoptic-S®, Alcon, US). The positively charged drug is bound to a cation-exchange resin (Amberlite® IRP69). The matrix of Amberlite

IRP69 is styrene-

divinylbenzene

polymer and the functional portion is sodium polystyrene

sulphonate

.

Sulphonic

acid acts as a strong cation exchanger. The mobile, or exchangeable, cation is sodium; this can be exchanged for many cationic species. Upon ocular instillation of the suspension,

betaxolol

is displaced from the resin by the sodium ions in the tear film