ocular drug delivery

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OCULAR DRUG DELIVERY

Eye AnatomyEye Anatomy

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Drug fate in the eyeDrug fate in the eye

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Conventional drug DeliveryConventional drug Delivery

1. Eye drops

Spillage from eye

Overflow on eyelids

2. Eye ointments

Interference with vision

3. Ophthalmic gels

Less interference with vision

Matted eyelids

Problems with conventional dosage formsProblems with conventional dosage forms

Drainage & spillage of the instilled solution

Lacrimation & tear turnover

Tear evaporation

Drug metabolism

Nonproductive absorption

Limited corneal area & poor corneal permeability

Binding to lachrymal protein

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Conventional Ocular Delivery SystemConventional Ocular Delivery System

Miotics, mydriatics, cycloplegics, antibacterials, antiglaucoma drugs,

surgical adjuncts, diagnostics etc.

The adjuvants used for ophthalmic

adjustment of tonicity,

buffering & adjustment of pH,

stabilizing the active ingredients against decomposition,

increasing solubility,

imparting viscosity,

solvent

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IntroductionIntroduction

Objective of ocular NDDS is to maintain the drug in the biophase for an extended period of time.

The anatomy, physiology & biochemistry of the eye render this organ impervious to foreign substances.

It is challenge to the formulator to circumvent the protective barriers of the eye so that the drug reaches the biophase in sufficient concentration.

Physiological barriers to diffusion & productive absorption of topically applied drug exist in the precorneal & corneal spaces.

The precorneal constraints responsible for poor ocular bioavailability of conventional ophthalmic dosage forms are solution drainage, lacrimation, tear dilution, tear turnover & conjuctival absorption.

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Introduction………Introduction……… Drug solution drainage is the most significant factor in reducing the contact time of the drug with the cornea & consequently ocular bioavailability of topical dosage forms.

The instilled dose leaves the precorneal area within 2 minutes of instillation.

The ophthalmic dropper delivers 50-75 µL of the eye drops. If the patient does not blink, the eye can hold about 30 µL without spilling on the cheek. The natural tendency of the cul-de-sac to reduce its volume to 7-10 µL.

Most of the drug is rapidly lost through the nasolacrimal drainage immediately following dosing. The drainage allows the drug to be absorbed across the nasal mucosa into the systemic circulation.

The conjunctiva also possess relatively large surface area making the loss significant.

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Introduction…….Introduction……. Both conjunctival & nasal mucosa are the potential sites for systemic absorption of topically applied drug.

Tears dilute the drug remained in the cul-de-sac which reduces the transcorneal flux of the drug. The drug entity, pH, tonicity of the dosage form as well as formulation adjuvant stimulate tear production.

Topical application of the drug is further made inefficient by tear turnover.

Metabolism in the precorneal area also account for the further loss of the drug.

Due to all these factors typically less than 1% of the instilled drug reaches aqueous humor.

Further the hydrophobic nature of the corneal epithelium also contribute to the poor bioavailability.

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Introduction…….Introduction…….

The existing ocular drug delivery systems are thus fairly primitive & inefficient. Thus, the challenges to develop novel ocular drug delivery system are;

1. Improving ocular contact time

2. Enhancing site specificity

3. Enhancing corneal permeability

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Novel SystemsNovel Systems

I. Use of polymers

II. Mucoadhesives

III. Ophthalmic Inserts

IV. The NODS

V. Collagen shield drug delivery

VI. Nanoparticles

VII.Liposomes

VIII.Prodrugs

IX. Penetration Enhancers

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I. Role of Polymers in Ocular DeliveryI. Role of Polymers in Ocular Delivery

Incorporation of polymers into an aqueous vehicles increases the ocular contact time of drug.

The increased solution viscosity reduces the solution drainage.

Polymers used – PVA, PVP, MC, CMC & HPC

Increasing the solution viscosity of pilocarpine solution through the incorporation of MC reduced the solution drainage rate constant 10 times while 2 fold increase in its aqueous humor concentration found.

Natural polymers namely sodium hyaluronate & chondroitin sulfate are also used as viscosity builders.

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Role of Polymers in Ocular Delivery…Role of Polymers in Ocular Delivery…

In considering this approach of increasing solution viscosity to

enhance ocular drug absorption the lipophilicity of the drug should

be taken into account.

No statistically significant increase in aqueous humor

concentrations of drug whose PC exceeded 10 was observed on

increasing solution viscosity from 1-90cps.

Increasing solution viscosity has limited utility.

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II. MucoadhesivesII. Mucoadhesives External surfaces of the globe of the eye is coated with the thin film

of glycoprotein called as mucin.

Goblet cells on the conjunctiva secrets mucin & it forms the thin

layer over conjunctiva & cornea.

The mucin layer is capable of taking about 40-80 times its weight

of water due to substantial number of sugar groups present in

polypeptide backbone.

The mucin layer forms a part of precorneal tear film which

continuously bathes the corneal epithelium, conjunctiva epithelium

& cul-de-sac.

Natural & synthetic polymers that bind to the mucin non covalently

used for drug delivery.

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Mucoadhesives…..Mucoadhesives….. These bioadhesive polymers help in prolonging the release of the

drug from a dosage form by localizing it at a specific site where

mucus present.

They remain in contact with the precorneal tissues until mucin

turnover causes elimination of the polymer.

Good mucoadhesion in the eye is achieved with polymers

possessing the correct charge density, number of polar groups for

hydrogen bonding & balance of lipophilic to hydrophilic sections in

the polymer chain.

Hydrogen bonding play an important role in bioadhesion.

Electrostatic attraction also responsible for bioadhesion till some

extent.

e.g. CMC, carbopol, PMMA, PAA, polycarbophil, sodium alginate.

Viscosifying PolymersViscosifying Polymers

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III. Ophthalmic InsertsIII. Ophthalmic Inserts

Polymer based delivery devices for placement into cul-de-sac.

It offers an attractive approach to the problem of prolonging precorneal drug residence time.

It also offers the potential advantage of improving patient by reducing the dosing frequency

Desired criteria for a controlled release ocular insert are:

1. Comfort

2. Lack of explosion

3. Ease of handling & insertion

4. Non interference with vision & oxygen permeability

5. Reproducibility of release of kinetics

6. Sterility

7. Stability

8. Ease of manufacture

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Ophthalmic Inserts……Ophthalmic Inserts……Ophthalmic inserts are of 2 types:

1. Nonerodible Inserts

i. Ocusert

ii. Contact lens

iii. Ocufit

2. Erodible Inserts

i. The Lacrisert

ii. SODI

iii. Minidisc

Retention of these inserts are a function of size & shape.

Smaller devices are better retained than larger ones & rod shaped are better retained than oval ones.

Essential Requirements…Essential Requirements…

Physician acceptance;

User acceptance;

Ease of handling and insertion;

Patient comfort;

Lack of expulsion during wear;

Lack of toxicity;

Non-interference with vision and oxygen permeability

Reproducibility of release kinetics;

Applicability to a variety of drugs;

Sterility;

Stability;

Ease of manufacture;

Reasonable price;

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AdvantagesAdvantages

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Increased ocular residence, hence a prolonged drug activity and a

higher bioavailability with respect to standard vehicles;

Possibility of releasing drugs at a slow, constant rate;

Accurate dosing (contrary to eye drops that can be improperly

instilled by the patient and are partially lost after administration,

each insert can be made to contain a precise dose which is fully

retained at the administration site);

Reduction of systemic absorption (which occurs freely with eye

drops via the nasolacrimal duct and nasal mucosa);

Advantages…Advantages…

Better patient compliance, resulting from a reduced frequency of

administration and a lower incidence of visual and systemic side-

effects

Possibility of targeting internal ocular tissues through non-cornea1

(conjunctival, scleral) routes;

Increased shelf life with respect to aqueous solutions;

Exclusion of preservatives, thus reducing the risk of sensitivity

reactions; and

Possibility of incorporating various novel chemical/technological

approaches. Such as pro-drugs, mucoadhesives, permeation

enhancers, microparticulates, salts acting as buffers, etc. 23

DisadvantagesDisadvantages

A capital disadvantage of ophthalmic inserts resides in their

‘solidity’, i.e., in the fact that they are felt by the (often

oversensitive) patients as an extraneous body in the eye

This may constitute a formidable physical and psychological barrier

to user acceptance and compliance

Initial discomfort,

Their movement around the eye,

The occasional inadvertent loss during sleep or while rubbing

the eyes,

Their interference with vision and

A difficult placement (and removal, for insoluble types)

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Evaluation Of Ocular InsertsEvaluation Of Ocular Inserts

1. Thickness of film

2. Content uniformity

3. Uniformity of Weight

4. Percentage moisture absorption

5. Percentage moisture loss

6. In-vitro drug release

7. In-vivo drug release

8. Accelerated stability studies

9. Compatibility study

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NON-ERODIBLE INSERTSNON-ERODIBLE INSERTS

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1. Ocusert® 1. Ocusert® It is developed by Alza Corporation

First marketed in the U.S.A. in 1974

It is used in the treatment of chronic glaucoma.

It is available as Ocusert® Pilo 20 & Ocusert® Pilo 40

Sterile, Flat, flexible, elliptical device consisting of three layers

Membrane 1 & 4 – outer layers of EVA

Membrane 2 – retaining ring of EVA

impregnated with titanium dioxide

Membrane 3 – Pilocarpine reservoir

gelled with alginate

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Ocusert®…..Ocusert®….. All these four membranes put together

Retaining ring of EVA(Ethylene Vinyl Acetate) impregnated with Ti02 for

visibility purpose

It is preprogrammed to release pilocarpine at constant rate 20 or 40 µg/hr

around the clock for 7 days.

The higher release rate of Ocusert® Pilo 40 is achieved by making its rate

controlling membrane thinner & by the use of flux enhancer di 2-

ethylhexyl)phthalate

Precise controlled delivery of pilocarpine

Disadvantages – patient discomfort, risk of loss of insert from eye, removal

of system from the eye

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2. Contact Lens2. Contact Lens

Therapeutic soft lenses are often used to aid corneal wound in

patients with infection, corneal ulcers, characterized by marked

thinning of cornea.

The residence time of drugs using presoaked lenses is not

significantly prolonged.

Most of the drug released in first 30 minutes from presoaked contact

lens.

The use of preservative benzalkonium chloride leads to toxic effects.

The supply of oxygen to the eye tissues & the build up of harmful

metabolite such as CO2 complications also arises during use of

presoaked contact lens.

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Contact Lens…..Contact Lens…..

Thus, an alternative approach is to incorporate the drug either as

solution or suspension of solid particles in the monomer matrix.

The polymerization is then carried out to fabricate the contact lens

With this approach the release of the drug is significantly prolonged

to many hours compared to presoaked lenses as well the problem of

concentration of preservative is eliminated, since the drug is added

without any preservative

Disadvantages are problem of discomfort & difficulty in handling and

insertion particularly in case of presoaked lenses

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3. Ocufit SR®3. Ocufit SR®

It is a sustained release, rod-shaped device made of

silicone

elastomer

Patented in 1992 by Escalon Ophthalmics Inc.

It was designed to fit the shape and size of the

human

conjunctival fornix

It is 1.9 mm in diameter and 25-30mm in length,

The insoluble Ocufit® reportedly combines two

important features, long retention and sustained

drug release. When placed in the upper fornix of

volunteers, placebo devices were retained for 2

weeks or more in 70% of the cases

The insoluble Ocufit® reportedly combines two

important features, long retention and sustained

drug release.

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ERODIBLE INSERTSERODIBLE INSERTS

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4. Lacrisert®4. Lacrisert®

It is a sterile, translucent rod shaped device made of HPC

without any preservative is used for treatment of dry eye

syndrome

The device is introduced by Merck, Sharp & Dohme

It weighs 5mg & measures 12.7mm in diameter with a length

of 3.5mm

It is useful in treatment of patients with keratitis sicca whose

symptoms are difficult to treat with artificial tear alone

It is inserted into the inferior fornix where it imbibes

the water from the conjunctiva & cornea, forms a

hydrophilic film which stabilizes the tear film &

hydrates, lubricates cornea.

Day long relief from dry eye syndrome is reported

from a single insert placed in the eye early in the

morning.

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5. The SODI®5. The SODI®

Soluble Ophthalmic Drug Insert (SODI) is a small oval wafer developed

by Soviet scientists

The unit is made from acrylamide, N-vinylpyrrolidone & ethylacrylate

(ratio 0.25 : 0.25 : 0.5)

It weighs 15-16mg which is placed in the inferior cul-de-sac where

wetted by the tear film, it softens in 10-15 seconds & assumes the

curved configuration of the globe

The film turns into a viscous polymer mass, thereafter in 30-60 minutes

it becomes polymer solution

A single SODI application constitutes once a day therapy for the

treatment of glaucoma

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6. OTS or Minidisc6. OTS or Minidisc

It consists of a contoured disc with a convex front & a

concave back surface in the contact with the eye ball.

It is like a miniature contact lens with a diameter of 4-5mm.

The major component of OTS is a silicone based prepolymer-

α-ω-bis(4-methacyloxy)-butylpolydimethylsiloxane (M2DX).

The OTS can be hydrophilic or hydrophobic to permit the

release of both water soluble & insoluble drugs.

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IV. The NODSIV. The NODS

The new ophthalmic delivery system (NODS) is a method of

presenting drugs to the eye within a water soluble drug

loaded film

It provides for accurate, reproducible dosing in an easily

administered preservative free form

The drug is incorporated into a water soluble PVA film

Each NODS consists of a drug loaded film or flag attached to

a handle film by means of thin membrane

On contact with the tear film in the lower conjunctival sac the

membrane quickly dissolves releasing the flag into the tear

film

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IV. The NODS….IV. The NODS….

The flag hydrates & disperses allowing diffusion & absorption

of the drug

The handle is provided with a paper backing for strength

Both soluble drugs such as pilocarpine & insoluble drugs such

as tropicamide can be formulated into the NODS

The delivery of insoluble drug in NODS has shown improved

bioavailability compared with a standard solution

The NODSThe NODS

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V. Corneal Collagen ShieldsV. Corneal Collagen Shields

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V. Corneal Collagen ShieldsV. Corneal Collagen Shields

Collagen:

Collagen is a structural protein that can be safely applied to eye

tissues

Collagen is the structural protein of bones, tendons, ligaments and

skin and comprises more than 25% of the total body protein in

mammals

Collagen is a naturally occurring protein that is totally safe for use on

and in the body

collagen is an essential element for healing wounds anywhere in the

body, including the eye

The creation of collagen shields has provided a means to

promote wound healing & to deliver the drugs

It seemed that naturally occurring enzymes in the tear film

caused the collagen contact lens to dissolve over a period of

time

Collagen is extracted & moulded into contact lens

configuration

The shields are sterilized by gamma radiation then

dehydrated

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V. Corneal Collagen Shields…V. Corneal Collagen Shields…

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Drugs can be incorporated in the collagen matrix during

manufacture. As the shield dissolves the drug is released gradually

in the tear film, maintaining high concentrations on the corneal

surface & increasing drug permeation through the cornea & into the

aqueous humor

Potential use for the collagen shields is that of ocular surface

protection

In nearly all types of eye surgery, the surface coat (the sclera or the

cornea) must be incised to allow access to the interior part of the

eye

Healing of incision is of crucial importance to the success of the

surgery

The wound must be adequately protected from the external

environment as well as from the blinking action of the eyelids


In addition to patching therapy, ophthalmologists have used special

soft contact lenses (called "bandage" contact lenses) to provide

protection to the surface of the eye

Therapeutic corneal bandages. One of these (Bio-Car, Bausch and

Lomb, Clearwater, FL) is made of porcine scleral collagen, while

others (Medilens, Chiron Ophthalmics, Irvine, California, and

ProShield, Alcon Surgical, Fort Worth, Texas) are prepared from

bovine corium tissue

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These bandage contact lenses are expensive and have been

associated with some complications, particularly when they are used

over a long period of time

As the collagen shield contains a naturally occurring protein, it would

appear to be an ideal alternative to bandage contact lenses for

protecting the eye

This area of research is in its infancy and is being conducted

primarily at the UIC Eye Center

Preliminary results have shown that the collagen shield can indeed

provide an adequate protective environment to allow healing of

surgical and traumatic wounds to the eye 46


It should be pointed out that collagen shields are mostly

used as a bandage lens, and their use as drug delivery

systems is still experimental

The future for collagen shields is highly promising

The characteristics of providing ocular lubrication,

protection, and drug delivery and the potential for

better and faster wound healing may eventually

make these shields a standard part of ophthalmic

practice 47


The use of nanotechnology-based drug delivery systems (1-100nm)

like nanosuspensions, solid lipid nanoparticles has led to the solution

of various solubility-related problems of poorly soluble drugs, like

dexamethasone, budenoside, gancyclovir

Depending on their particle charge, surface properties and

relative hydrophobicity, nanoparticles can be designed to be

successfully used in overcoming retinal barriers.

In addition to these points, encapsulation of drugs in nanoparticles,

can also provide protection for the drug and hence prolong exposure

of the drug by controlled release

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VI. NanoparticlesVI. Nanoparticles

Nanotechnology-based drug delivery is also very efficient in crossing

membrane barriers, such as the blood retinal barrier in the eye

The drug delivery systems based on nanotechnology may prove to

be the best drug delivery tools for some chronic ocular diseases, in

which frequent drug administration is necessary, for example in

ophthalmic diseases like chronic cytomegalovirus retinitis

In recent studies of nanoparticles, the most commonly used

polymers are various poly(alkylcyanoacrylates), poly-e-caprolactone

and polylactic-co-glycolic acid, all of which are biodegradable

polymers that undergo hydrolysis in tears

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VI. Nanoparticles…VI. Nanoparticles…

Nanoparticles made up of mucoadhesive polymers is one of

the site targeting approach used

Nanoparticles for ophthalmic drug delivery are produced by

emulsion polymerization

In this process a poorly soluble monomer is dissolved in the

continuous phase which can be aqueous or organic

Polymerization can be started by chemical initiation or by

irradiation with gamma rays or UV visible light

The drugs may be added, before, during or after the

polymerization 50

VI. Nanoparticles…VI. Nanoparticles…

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VII. LiposomesVII. Liposomes

Liposomes are concentric vesicles composed of lipid

membrane enclosing an aqueous volume

They deliver both hydrophilic & hydrophobic drugs

Ocular delivery via liposomes is significant for lipophilic drugs

to a greater extent than hydrophilic drugs

Liposomes suspended in 1%HPMC & 0.45%w/v of PVA were

retained on the corneal surface for a significantly longer

period than suspended in buffer

The effectiveness of liposomes in ocular drug delivery depends on a

number of factors, including

Drug encapsulation efficiency,

Size,

Charge of liposomes,

Distribution of a drug within liposomes,

Stability of liposomes in the conjunctival sac and ocular

tissues,

Their retention in the conjunctival sac, and

The affinity liposomes exhibit towards the corneal surface

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VII. Liposomes…VII. Liposomes…

It is considered that solid particles intended for ophthalmic use

should not exceed 5–10 micron diameter

Positively charged liposomes seem to be preferentially captured at

the negatively charged corneal surface as compared with neutral or

negatively charged liposomes

These liposomes bind intimately on the corneal surface leading to an

increase of residence time, therefore, leading to an increase in the

corneal absorption time

The degree of liposome–cell interaction can be improved by

increasing the degree of positive surface charge using stearylamine

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Liposomes a potentially useful system for ocular delivery they are not

very popular because of their short shelf life, limited drug capacity,

and problems in sterilization

Further developments to render the vesicular systems more effective:

Use of mucoadhesive polymers

Use of either the viscosity increasing agent with vesicles and/or the use

of penetration enhancers along with the vesicles in the formulation.

Viscosity imparting agents prolongs the corneal contact time whereas

penetration enhancers increase the rate and amount of drug transport

Collagen corneal shields impregnated with liposomes

Entrapmentof drug-cyclodextrin complex within vesicles

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Particulate SystemsParticulate Systems

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VIII. ProdrugsVIII. Prodrugs

Prodrugs are pharmacologically inactive derivatives of drug

molecules that require a chemical or enzymatic transformation in

order to release the active drug within the body

Prodrugs have also been called reversible or bioreversible derivatives

and latentiated drugs

Prodrugs are simple chemical derivatives which are one or two

chemical or enzymatic steps away from the parent drug

It is a useful technique in improving corneal permeability of drugs

The concept of double prodrug i.e. prodrug of

prodrug is also gaining importance.

E.g. (dibenzyl)bispilocarpates, a new class of

pilocarpine double prodrug with adequate amount

of aqueous solubility, improved delivery

characteristics & stability

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VIII. ProdrugsVIII. Prodrugs

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Drugs Prodrugs Therapeutic use

Epinephrine Dipivalyl epinephrine Treatment of glaucoma

Phenylephrine Phenylephrine oxazolidine

alpha-adrenergic agent

Prostaglandins PGF methyl and PGF isopropyl esters

Treatment of glaucoma

Timolol alkyl, cycloalkyl, aryl esters and carbamate ester

Beta-Antagonists (beta blockers)

Pilocarpine Pilocarpic acid mono- and diesters, quaternary salts of pilocarpine

Treatment of glaucoma

Steroids acetate ester, phosphate ester

Anti-inflammatory agent

Acyclovir N-substituted (aminomethyl)benzoate ester

Antiviral agent

Pilocarpine ProdrugsPilocarpine Prodrugs

Pilocarpine is a direct-acting cholinergic agonist used for the control of

the elevated IOP associated with glaucoma.

Pilocarpine shows a low ocular bioavailability (l-3% of instilled dose) due

to poor absorption into the cornea, coupled with a short duration of

action.

Consequently, concentrated pilocarpine eyedrops must be administered

3-4 times daily resulting in undesirable side-effects and poor patient

compliance.

The absorption of pilocarpine is mainly limited by its low lipophilicity (log

Papp = - 0.15) and its short duration of action is due to rapid

elimination.

Thus lipophilic prodrugs of pilocarpine providing controlled release and

improved ocular delivery have been developed. 60

A series of pilocarpit acid monoesters and

diesters as prodrugs of pilocarpine

Pilocarpic acid monoesters undergo spontaneous

lactonization to pilocarpine in aqueous solution

Monoesters were more lipophilic than

pilocarpine and increased the ocular

bioavailability of pilocarpine

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Several monoesters also prolonged the duration of action 1.5 times

compared to pilocarpine. The poor aqueous stability of the monoesters

limited their practical use

The half-lives of monoesters in aqueous solution (pH 7.4) varied from

0.5 h to 18 h at 37°C. Although monoesters are more stable in acidic

solutions, the preparation of ready-to-use eye drops with an acceptable

shelf-life was not possible

The stability problem of pilocarpic acid monoesters was overcome by

using the double prodrug concept

Pilocarpine double prodrugs, pilocarpic acid diesters, were prepared by

esterifying the alcoholic hydroxyl group of pilocarpic acid monoester

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IX. Penetration EnhancersIX. Penetration Enhancers This is an alternative approach to improve the bioavailability of ocular drugs

by incorporation of penetration enhancers

The preservative agents used in most formulations serve as potential

penetration enhancers. E.g. 0.01% benzalkonium chloride, chlorhexidine

gluconate

Endothelial degeneration is occurred from the prolonged administration of

benzalkonium chloride

The potential benefits are negated by toxic effects

Endothelial degeneration occur from topical administration of BAK

Another approach is ion pair formation which results in altered drug species

with respect to ionic size, diffusivity & partitioning behavior

Duration of action of the ODDSDuration of action of the ODDS

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Ocular DDSOcular DDS

I. Use of polymers

II. Mucoadhesives

III. Ophthalmic Inserts

IV. The NODS

V. Collagen shield drug delivery

VI. Nanoparticles

VII.Liposomes

VIII.Prodrugs

IX. Penetration Enhancers

Ocular iontophoresisIntraocular solutions

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Ocular IontophoresisOcular Iontophoresis

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IntroductionIntroduction

It was first investigated by in 1908 by the German

Investigator Wirtz

Iontophoresis is the use of a direct electrical current to

drive topically applied ionized substances into or through

a tissue.

It is a non-invasive technique

Iontophoresis is based on the physical principle that ions with

the same charge repel (electrorepulsion) and ions with

opposite charge attract (electroosmosis).

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Iontophoresis usually employs low voltage (10 V or less) to supply

a continuous direct current of 0.5 mA/cm2 or less.

Iontophoretic transport results from the passage of a current from

electrodes into an electrolyte solution and thus into the skin or body

Thus, positive ions (cations) are attracted to the negative electrode

(or cathode) and repelled by the positive electrode (or anode).

Conversely, negative ions (anions) are attracted to the positive

electrode and repelled by the negative electrode.

When iontophoresis is used therapeutically, the ions of importance

are charged molecules of the drug or other bioactive

substances. 68

The drug is applied with an electrode carrying the same charge of

the drug, & the ground electrode, which is of opposite charge, is

placed elsewhere on the body to complete circuit.

The drug serves as a conductor of the current through the tissues.

The ionized substances are driven into the tissues by

electrorepulsion at either the anode (if they carry a positive charge)

or the cathode (if they carry a negative charge).

The ionized substances are driven into the tissues by

electrorepulsion at either the anode (if they carry a positive charge)

or the cathode (if they carry a negative charge).

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These basic operational guidelines have enabled

iontophoresis to be used to enhance drug delivery

in a wide variety of conditions.

Iontophoresis was extensively investigated for

delivering ophthalmic drugs, including

antibacterial, antifungal, antiviral, steroids

antimetabolites & genes

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Routes….Routes….

The drugs can be delivered either by transscleral or

transcorneal iontophoresis.

Transscleral iontophoresis presents more advantages

when compared to transcorneal delivery, owing to

scleral larger surface area, enhanced delivery of the

drugs to the posterior segment and least possibilities of

systemic absorption.

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1st LAW1st LAW

Laws of physics and chemistry will help to delineate the

important parameters in iontophoretic transport.

Those parameters are the amount of drug transported, the

current rate, and the amount of time that current is applied.

The first law is Ohm’s law:

V = IR

where V is the electromotive force in volts,

I is the current in milliamperes (mA), and

R is the resistance in ohms

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At constant voltage, any change in resistance

results in a change in the current.

With iontophoresis, resistance decreases during the

procedure.

The result is that the current (mA) increases and

must be reduced to maintain a constant current

over time.

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2nd LAW2nd LAW

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A second law important for iontophoresis is Coulomb’s law:

Q = IT

where Q is the quantity of electricity,

I is the current in mA, and

T is the time in minutes.

Thus, Q, which is the total current dosage, can be expressed as mA-

minutes.

Precise conditions for specific iontophoretic applications can be

expressed as a minimum, maximum, or a range of mA-minutes

3rd LAW3rd LAW

Finally, a third important physical principle is Faraday’s law:

where D is the drug delivered in gram-equivalents,

I is the current in mA,

T is the time in minutes,

IZI is the valence of the drug, and

F is Faraday’s constant

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Faraday’s constant is the electrical charge carried

by 1 gram equivalent of a substance.

The importance of this proportional relationship is

that if more current is applied (either by increasing

the current rate or increasing the time of

application of a constant low current), more of the

drug enters the tissue.

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Factors influencing iontophoretic penetration Factors influencing iontophoretic penetration

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Physiochemical properties of the compound

(molecular size, charge, concentration)

The solution factor (type of the buffer, pH, presence

of other compounds)

The electrical and technical factors (different types

of current, electrodes, treatment length, current density)

Biological or physiological variations (site, humidity,

regional blood flow)

Factors influencing iontophoretic penetration Factors influencing iontophoretic penetration

AdvantagesAdvantages

High intraocular and especially posterior pole drug tissue

concentration in a controlled and safe fashion, while minimizing the

systemic drug exposure

It causes minimum discomfort to patients and is not entirely

harmless for ocular tissues

The ease of administration and the potential possibility to apply for

example transscleral CCI (Coulomb-controlled iontophoresis) on a

repetitive basis make this treatment modality of special interest in

chronic and long-term intraocular diseases

This non-invasive drug delivery system minimizes the risk of trauma

due to drug delivery ways such as intravitreal or peribulbar

injections, possible risk of infection and inflammation and

hemorrhages.

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DisadvantagesDisadvantages

Cannot deliver drug by iontophoresis if drug causes

irritation

There is a limit to the amount of medication

that can be delivered usually 5 to 10mg/hr.

Some drugs cause long lasting pigmentation after

iontophoretic application.

Iontophoresis is restricted to drugs that can be

formulated in ionized form.

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Iontophoresis DeviceIontophoresis Device

Iontophoretic devices vary in complexity,

The basic design is a unit with

A power source (either a battery or an on-line unit with a

voltage regulator),

A milliampere meter to measure the current,

A rheostat to control the amount of current flowing through the

system, and

Two electrodes Platinum is the material of choice for the

electrodes, since it releases almost no ions, undergoes

degradation at a slow rate, and is nontoxic.

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Iontophoresis Device (Eye Gate®) Iontophoresis Device (Eye Gate®)

The Eyegate® advantages-

Non-invasive delivery to

anterior and posterior

chambers of the eye

Programmable dose control

Potential for increased patient

safety

Delivery time just 1-4 minutes

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Ocular iontophoresis in the RabbitOcular iontophoresis in the Rabbit

A variety of iontophoretic apparatuses exist for use in ocular

iontophoresis.

They mainly consist of either an eyecup or an applicator

probe.

Figure shows a diagram of ocular iontophoresis of a positively

charged drug in a rabbit.

The eyecup, with an internal diameter of 1 cm, is placed

over the cornea and filled with the drug solution.

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A metal electrode that is connected to a direct

current power supply is submerged in the solution

in the eyecup without making contact with the

surface of the eye.

The ground electrode, connected to the other

terminal of the power supply, is attached to the ear

of the rabbit via wet (0.9% NaCl) gauze to ensure a

good connection. 87

With the hand-held applicator probe, the metal (platinum)

electrode extends into the eyecup that is filled with the drug

solution.

The eyecup is placed against the eye and is held in place

throughout the entire iontophoresis procedure.

Iontophoresis requires a complete electrical circuit with direct

current passing from the anode to the cathode and from the

cathode back to the anode.

The two electrodes are placed as anatomically close to each

other as possible on the body, which is an excellent conductor

of electricity, to complete the circuit. 88

89

90

The drug is placed in a cylindrical eye cup with a central

diameter of 9–12 mm; the inner circumference of the eye cup

fits within the corneoscleral limbus.

The current is controlled by a rheostat on the direct current

transformer.

In general, the current should not exceed 2.0 mA and the time

be no longer than 10 min.

In the case illustrated here, the drug molecules (cations) have

a positive charge.

91

Therefore, the platinum electrode connected to the

anode (the positively charged pole) is placed in contact

with the solution.

The other electrode (cathode) is connected to the ear or

front leg of the rabbit to complete the circuit.

The positively charged anode drives the positively

charged drug molecules from the solution into the eye at

a greater rate than would be observed with simple

diffusion. 92

RequirementsRequirements

The drug solution or preparation to be iontophoresed should

be devoid or have a minimum of extraneous ions.

Drugs with one or more pKa values either below pH 6 or

above pH 8 are generally excellent candidates for

iontophoresis into the eye because these drugs will be in the

ionized form at the physiological pH of the eye.

The salt form of a drug is also preferred for iontophoresis

since the dissociated salt is highly soluble.

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ApplicationsApplications

Glaucoma

Ocular Anesthesia

Ocular Inflammation

Ocular Infection

Antiviral Agent for Treatment of Cytomegalovirus

Retinitis

Herpes Simplex Virus Infection

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The commercial devicesThe commercial devicesCompany Model

IOMED, Inc Phoresor II Auto- PM900

Life-Tech, Inc. Iontophor-II - 6111 PM/DX

General Medical Company The Drionic unit

Wescor, Inc. Macroduct model 3700

Fischer Co., Inc Fischer Galvanic Unit, Model MD-

1a

Dagan Corporation Dagan 6400 Advanced model

MedTherm Corporation Electro-Medicator Model A1

Parkell Desensitron II model number

ID643DGC

Eye Gate Pharma Eye Gate II 96

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Questions……Questions……

Give different advantages of ocular drug delivery systems over conventional

ophthalmic formulations. (2)

Give a detail in Lacrisert and the SODI.(3)

Explain in detail with examples the role of polymers in ocular drug delivery systems.(2)

Discuss various polymers used in ocular drug delivery systems.(3)

Write a note on Lacrisert.(4)

What are ophthalmic inserts? Discuss in detail erodible inserts.(4)

Write a note on Lacrisert.(3)

Write a need for ocular mucoadhesive preparations.

Discuss the various polymers used in ocular delivery systems(4)

What are ocular inserts? Discuss in detail non-erodible ocular inserts.(7)

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“Sight is the sense which is more valuable than all the

rest”So, take care of eyes!!!

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Documents

ocular drug delivery