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1. Eye drops

 Spillage from eye

 Overflow on eyelids

!. Eye ointments

 Ônterference with vision

. Ophthalmic gels

mess interference with vision

 Matted eyelids

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¦ 



 
  

 ÷rainage & spillage of the instilled solution

 macrimation & tear turnover

 Tear evaporation

 ÷rug metabolism

 Nonproductive absorption

 mimited corneal area & poor corneal permeability

 Binding to lachrymal protein

0
?

 
 ÷


 

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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Ô 


Objective of ocular N÷÷S 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.

Ôt 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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Ô 


÷rug 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 µm of the eye drops. Ôf the patient
does not blink, the eye can hold about 30 µm without spilling on the cheek.
The natural tendency of the cul-de-sac to reduce its volume to 7-10 µm.

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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Ô 


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.

÷ue 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.

|
Ô 


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

1. Ômproving ocular contact time

2. Enhancing site specificity

3. Enhancing corneal permeability


 

Ô. Use of polymers

ÔÔ. Mucoadhesives

ÔÔÔ. Ophthalmic Ônserts

Ô . The NODS

. Collagen shield drug delivery

Ô. Nanoparticles

ÔÔ.Liposomes

ÔÔÔ.Prodrugs

Ô
. Penetration Enhancers

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Ô
 ¦ 


 ÷



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

The increased solution viscosity reduces the solution drainage.

Polymers used ² PVA, PVP, MC, CMC & HPC

Ôncreasing 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.



 ¦ 


 ÷



Ôn 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.

Ôncreasing solution viscosity has limited utility.

]
ÔÔ




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.
V





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.

0






 ¦ 


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

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

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

÷esired criteria for a controlled release ocular insert are:

1. Comfort

2. mack 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 are of 2 types:

1. Nonerodible Inserts

i. Ocusert

ii. Contact lens

iii. Ocufit

2. Erodible Inserts

i. The macrisert

ii. SO÷Ô

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.

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

 






Physician acceptance;
User acceptance;
Ease of handling and insertion;
Patient comfort;
mack of expulsion during wear;
mack 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;

!|



 Ôncreased 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);




 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;

 Ôncreased 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.
!!
÷



 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
 Ônitial 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)

!


 
 Ô


1. Thickness of film

2. Content uniformity

3. Uniformity of Weight

4. Percentage moisture absorption

5. Percentage moisture loss

6. Ôn-vitro drug release

7. Ôn-vivo drug release

8. Accelerated stability studies

9. Compatibility study
!]
 ÷Ô
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Ôt is developed by Alza Corporation

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

Ôt is used in the treatment of chronic glaucoma.

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

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

Membrane 1 & 4 ² outer layers of EVA

Membrane ! ² retaining ring of EVA

impregnated with titanium dioxide

Membrane  ² Pilocarpine reservoir

gelled with alginate

!0



All these four membranes put together

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

Ôt 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

÷isadvantages ² patient discomfort, risk of loss of insert from eye, removal of

system from the eye

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!?

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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?

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

÷isadvantages are problem of discomfort & difficulty in handling and

insertion particularly in case of presoaked lenses

!£


 
Ôt is a sustained release, rod-shaped device made of silicone

elastomer

Patented in 1992 by Escalon Ophthalmics Ônc.

Ôt was designed to fit the shape and size of the human

conjunctival fornix

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

|
The insoluble OcufitX 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 OcufitX reportedly combines two

important features, long retention and sustained drug
release.


÷Ô
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]



Ôt 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 & ÷ohme

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

3.5mm

Ôt is useful in treatment of patients with keratitis sicca whose

symptoms are difficult to treat with artificial tear alone


Ôt 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.

÷ay long relief from dry eye syndrome is reported from

a single insert placed in the eye early in the morning.

]
V
÷Ô
Soluble Ophthalmic ÷rug Ônsert (SO÷Ô) 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)

Ôt 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 SO÷Ô application constitutes once a day therapy for the treatment of
glaucoma
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0 



Ôt consists of a contoured disc with a convex front & a concave back
surface in the contact with the eye ball.

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

The major component of OTS is a silicone based prepolymer-ǂÑǚ-

bis(4-methacyloxy)-butylpolydimethylsiloxane (M2÷ ).

The OTS can be hydrophilic or hydrophobic to permit the release of

both water soluble & insoluble drugs.

0
Ô
÷
The new ophthalmic delivery system (NO÷S) is a method of
presenting drugs to the eye within a water soluble drug loaded film

Ôt provides for accurate, reproducible dosing in an easily

administered preservative free form

The drug is incorporated into a water soluble PVA film

Each NO÷S 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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Ô
÷

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 NO÷S

The delivery of insoluble drug in NO÷S has shown improved

bioavailability compared with a standard solution

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÷

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? 
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? 
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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

Ôt 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

]!
? 
 ? 




 ÷rugs 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

 Ôn 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

]
? 
 ? 




 Ôn 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 momb,

Clearwater, Fm) is made of porcine scleral collagen, while others (Medilens,
Chiron Ophthalmics, Ôrvine, California, and ProShield, Alcon Surgical,
Fort Worth, Texas) are prepared from bovine corium tissue

]]
? 
 ? 




 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 UÔC 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
]V
? 
 ? 




 Ôt 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

]0
Ô 



 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

 ÷epending on their particle charge, surface properties and relative

hydrophobicity, nanoparticles can be designed to be successfully used in
overcoming retinal barriers.

 Ôn 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

]G
Ô 



 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

 Ôn 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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Ô 



Nanoparticles made up of mucoadhesive polymers is one of the site

targeting approach used

Nanoparticles for ophthalmic drug delivery are produced by

emulsion polymerization

Ôn 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

]£
V|
ÔÔ



miposomes 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

miposomes 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

ÔÔ



 The effectiveness of liposomes in ocular drug delivery depends on a number

of factors, including

 ÷rug encapsulation efficiency,

 Size,

 Charge of liposomes,

 ÷istribution 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

V!
ÔÔ



 Ôt is considered that solid particles intended for ophthalmic use should not
exceed 5²10 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 liposome²cell interaction can be improved by increasing the

degree of positive surface charge using stearylamine

V
ÔÔ



 miposomes 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

V]
¦ 


 


VV
ÔÔÔ¦ 

 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

 Ôt is a useful technique in improving corneal permeability of drugs

V0
ÔÔÔ¦ 


 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

VG
Drugs Prodrugs Therapeutic use

Epinephrine ÷ipivalyl epinephrine Treatment of glaucoma

Phenylephrine Phenylephrine alpha-adrenergic agent

oxazolidine
Prostaglandins PGF methyl and PGF Treatment of glaucoma
isopropyl esters
Timolol alkyl, cycloalkyl, aryl Beta-Antagonists (beta
esters and carbamate blockers)
ester
Pilocarpine Pilocarpic acid mono- Treatment of glaucoma
and diesters, quaternary
salts of pilocarpine

Steroids acetate ester, phosphate Anti-inflammatory agent

ester

Acyclovir N-substituted Antiviral agent

(aminomethyl)benzoate
ester
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¦
 

¦ 


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

elevated ÔOP 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.

V£
¦
 

¦ 


 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

0|
¦
 

¦ 


 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

Ô¦

 


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

0!
÷

 
 
÷÷

0

 ÷÷

Ô. Use of polymers
 Ocular iontophoresis
ÔÔ. Mucoadhesives
 Ôntraocular solutions
ÔÔÔ. Ophthalmic Ônserts

Ô . The NODS

. Collagen shield drug

delivery

Ô. Nanoparticles

ÔÔ.Liposomes

ÔÔÔ.Prodrugs

Ô
. Penetration Enhancers

0]
0V
Ô 



 Ôt was first investigated by in 1908 by the German Investigator

Wirtz

 Ôontophoresis is the use of a direct electrical current to drive

topically applied ionized substances into or through a tissue.

 Ôt is a non-invasive technique

 Ôontophoresis is based on the physical principle that ions with the

same charge repel (electrorepulsion) and ions with opposite charge
attract (electroosmosis).

00
 Ôontophoresis usually employs low voltage (10 V or less) to supply a
continuous direct current of 0.5 mA/cm2 or less.

 Ôontophoretic 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.

0G
 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).

0u
 These basic operational guidelines have enabled
iontophoresis to be used to enhance drug delivery in a
wide variety of conditions.

 Ôontophoresis was extensively investigated for

delivering ophthalmic drugs, including antibacterial,
antifungal, antiviral, steroids antimetabolites & genes

0£




 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.

G|
G

G!

 

 maws 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 = ÔR

where V is the electromotive force in volts,

Ô is the current in milliamperes (mA), and

R is the resistance in ohms

G
 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.

G]
! 

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

Q = ÔT

where Q is the quantity of electricity,

Ô 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

GV
  

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

where ÷ is the drug delivered in gram-equivalents,

Ô is the current in mA,

T is the time in minutes,

Ô
Ô is the valence of the drug, and

F is Faraday·s constant
G0
 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.

GG
- 






 

 


Gu
- 






 

 


 ¦hysiochemical properties of the compound (molecular

size, charge, concentration)

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

other compounds)

 ëhe electrical and technical factors (different types of

current, electrodes, treatment length, current density)

 iological or physiological variations (site, humidity,

regional blood flow)



 High intraocular and especially posterior pole drug tissue concentration in

a controlled and safe fashion, while minimizing the systemic drug exposure

 Ôt 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 CCÔ (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.
u|
÷



 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.

 Ôontophoresis is restricted to drugs that can be formulated in

ionized form.

Ô

 ÷



 Ôontophoretic 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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The Eyegate® advantages-

 Non-invasive delivery to anterior

and posterior chambers of the
eye

 Programmable dose control

 Potential for increased patient

safety

 ÷elivery time just 1-4 minutes

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 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.

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 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.

 Ôontophoresis 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.
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 The drug is placed in a cylindrical eye cup with a central diameter
of 9²12 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.

 Ôn general, the current should not exceed 2.0 mA and the time be no
longer than 10 min.

 Ôn the case illustrated here, the drug molecules (cations) have a

positive charge.

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 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.








 The drug solution or preparation to be iontophoresed should be

devoid or have a minimum of extraneous ions.

 ÷rugs 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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 Glaucoma

 Ocular Anesthesia

 Ocular Ônflammation

 Ocular Ônfection

 Antiviral Agent for Treatment of Cytomegalovirus Retinitis

 Herpes Simplex Virus Ônfection

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Company Model
ÔOME÷, Ônc Phoresor ÔÔ Auto- PM900

mife-Tech, Ônc. Ôontophor-ÔÔ - 6111 PM/÷

General Medical Company The ÷rionic unit

Wescor, Ônc. Macroduct model 3700

Fischer Co., Ônc Fischer Galvanic Unit, Model M÷-1a

÷agan Corporation ÷agan 6400 Advanced model

MedTherm Corporation Electro-Medicator Model A1

Parkell ÷esensitron ÔÔ model number

Ô÷643÷GC

Eye Gate Pharma Eye Gate ÔÔ

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 Give different advantages of ocular drug delivery systems over conventional ophthalmic
formulations. (2)

 Give a detail in macrisert and the SO÷Ô.(3)

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

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

 Write a note on macrisert.(4)

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

 Write a note on macrisert.(3)

 Write a need for ocular mucoadhesive preparations.

 ÷iscuss the various polymers used in ocular delivery systems(4)

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

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