ocular drug delivery system by karam-c

Karamshi R. Chaudhari M. Pharm. 1 (Pharmaceutics)

1

Prepared by:- Karamshi R. Chaudhari M. Pharm.-I (Pharmaceutics)

Department of Pharmaceutical Sciences, Saurashtra University,

Rajkot.

Guided by:- Mahesh R. Dabhi Asst. Prof. Pharmaceutics


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CONTENTS

I. INTRODUCTION

II. ANATOMY OF THE EYE

III. MECHANISMS AND BARRIARS FOR OCULAR DRUG

ABSORPTION

IV. CONVENTIONAL OCULAR FORMULATIONS

V. RECENT OCULAR DRUG DELIVERY FORMULATIONS

1. OCULAR PENETRATION ENHANCERS

2. MUCOADHESIVE DOSAGE FORMS

3. COLLAGEN SHIELDS

4. DENDRIMERS

4. 1. General Chemical Structure

4. 2. Physical Properties

4. 3. Applications In Ocular Drug Delivery

5. IN SITU-FORMING HYDROGELS

5. 1. Introduction

5. 2. Temperature Induced Gelation

5. 3. Ph Induced Gelation

5. 4. Osmotically Induced Gelation

5. 5. Performance Of ‘In-Situ’ Gelling Hydrogels

6. MICRO AND NANO PARTICLES

6. 1. Methods Of Preparation Of Nanoparticles

6. 2. Polymers Used In The Preparation Of Nanoparticles

7. IONTOPHORESIS

7. 1. Introduction

7. 2. Design Of Iontophoresis Devices

7. 3. Approaches Of Iontophoretic Delivery

VI. REFERENCES


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I. INTRODUCTION

Ocular administration of the drug is primarily related with the treatment of ophthalmic

diseases, not for gaining systemic action.

Ophthalmic drug delivery is one of the most interesting and challenging endeavours

facing the pharmaceutical scientist. The anatomy, physiology, and biochemistry of the eye

render this organ highly impervious to foreign substances. A significant challenge to the

formulator is to circumvent the protective barriers of the eye without causing permanent

tissue damage. Development of newer, more sensitive diagnostic techniques and novel

therapeutic agents continue to provide ocular delivery systems with high therapeutic efficacy.

The goal of pharmacotherapeutics is to treat a disease in a consistent and predictable

fashion. An assumption is made that a correlation exists between the concentration of a drug

at its intended site of action and the resulting pharmacological effect. The specific aim of

designing a therapeutic system is to achieve an optimal concentration of a drug at the active

site for the appropriate duration. Ocular disposition and elimination of a therapeutic agent is

dependent upon its physicochemical properties as well as the relevant ocular anatomy and

physiology. A successful design of a drug delivery system, therefore, requires an integrated

knowledge of the drug molecule and the constraints offered by the ocular route of

administration.

Major classes of the drugs that are administered through ocular route are Miotics,

Mydriatics/Cycloplegics, Anti-inflammatories, Anti-infectives, Surgical adjuvants,

Diagnostics etc.

Historically, the bulk of the research has been aimed at delivery to the anterior

segment tissues, but whenever an ophthalmic drug is applied topically to the anterior segment

of the eye, only a small amount (5%) actually penetrates the cornea and reaches the internal

anterior tissue of the eyes. Rapid and efficient drainage by the nasolacrimal apparatus,

noncorneal absorption, and the relative impermeability of the cornea to both hydrophilic and

hydrophobic molecules, all account for such poor ocular bioavailability. The various

approaches that have been attempted to increase the bioavailability and the duration of the

therapeutic action of ocular drugs can be divided into two categories. The first one is based

on the use of sustained drug delivery systems, which provide the controlled and continuous

delivery of ophthalmic drugs, such as implants, inserts, and colloids. The second involves

maximizing corneal drug absorption and minimizing precorneal drug loss through viscosity

and penetration enhancers, prodrugs, and colloids.

Drug delivery to the posterior eye, where 40% of main ocular diseases are located, is

another great challenge in ophthalmology. Only recently has research been directed at

delivery to the tissues of the posterior globe.


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II. ANATOMY OF THE EYE

Structure of eye ball:-

Three layers

1. Outer layer: Clear transparent

cornea anteriorly & white

opaque sclera posteriorly.

Conjunctiva is present

anteriorly above sclera.

2. Middle later: Iris anteriorly, the choroids posteriorly & cilliary body connecting them

both.

3. Inner Layer: Retina which is an extension of central nervous system (optic nerve)

Fluid system:-

1. Aqueous humor

2. Vitreous humor.

The structure of cornea consists of epithelium-stroma-epithelium which is like fat-water-

fat, so penetration of drug depends on the oil/water partition co-efficient.


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III. MECHANISMS AND BARRIARS FOR OCULAR DRUG ABSORPTION

Topical delivery into the cul-de-sac is, by far, the most common route of ocular drug

delivery. Adsorption from this site may be corneal or noncorneal. The so called noncorneal

route of absorption involves penetration across the sclera and conjunctiva into the intraocular

tissues. This mechanism of absorption is usually nonproductive, as drug penetrating the

surface of the eye beyond the corneal-scleral limbus is taken up by the local capillary beds

and removed to the general circulation2. This noncorneal absorption in general precludes

entry into the aqueous humor.

Recent studies, suggest that the noncorneal route of absorption may be significant for

poorly cornea-permeable drugs; however, corneal absorption represents the major mechanism

of absorption for most therapeutic entities. The anatomical structures of the cornea exert

unique differential solubility requirements for drug candidates. In terms of transcorneal flux

of drugs, the cornea can be viewed as a trilaminate structure consisting of three major

diffusional barriers: epithelium, stroma, and endothelium. The epithelium and endothelium

contain on the order of 100-fold the amount of lipid material per unit mass of the stroma3.

Depending on the physiochemical properties of the drug entity, the diffusional resistance

offered by these tissues varies greatly4, 5

. The outermost layer, the epithelium, represents the

rate-limiting barrier for trans-corneal diffusion of most hydrophilic drugs. The epithelium is

composed of five to seven cell layers. The basement cells are columnar in nature, allowing

for minimal paracellular transport. Corneal surface epithelial intracellular pore size has been

estimated to be about 60 A˚ 6. Small ionic and hydrophilic molecules appear to gain access to

the anterior chamber through these pores7; however, for most drugs, paracellular transport is

precluded by the interjectional complexes.

Sandwiched between the corneal epithelium and endothelium is the stroma (substantia

propia). The stroma constitutes 85–90% of the total corneal mass and is composed of mainly

of hydrated collagen8. The stroma exerts a diffusional barrier to highly lipophilic drugs owing

to its hydrophilic nature. There are no tight junction complexes in the stroma, and

paracellular transport through this tissue is possible.

The endothelium is lipoidal in nature; however, it does not offer a significant barrier

to the transcorneal diffusion of most drugs. Endothelial permeability depends solely on

molecular weight and not on the charge of hydrophilic nature of the compound9, 10

.

Transcellular transport across the corneal epithelium and stroma is the major mechanism of

ocular absorption of topically applied ophthalmic pharmaceuticals.


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Fig. illustration of ocular drug penetration barriers


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IV. CONVENTIONAL OCULAR FORMULATIONS

Dosage

form

Advantages Disadvantages

Solutions •Convenience •Loss of drug by drainage

•Nonsustained action

Suspensions •Patient compliance

•Best for drugs with slow

dissolution

•Drug properties decide

performance

Emulsions •Prolonged release of drug

from vehicle

•Patient non compliance

•Blurred vision

•Possible oil entrapment

Ointment •Flexibility in drug choice

•Improved drug stability

•Increased tissue contact time

•Inhibition of dilution by tears

•Resistance to nasolacrimal

drainage.

•Sticking of eyelids

•Poor patient compliance

•Blurred vision

•No true sustained effect

•Drug choice limited by

partition coefficient

Gels •Comfortable

•Less blurred vision than

ointment

•No rate control on diffusion

•Matted eyelids after use

Erodible

inserts

•Sophisticated and effective

delivery system

•Flexibility in drug type and

dissolution rate

•Need only be introduced into

eye and not removed

•Patient discomfort

•Requires patient insertion

•Movement of system around

eye can cause abrasion

Non-

erodible

inserts

•Controlled rate of release

•Prolonged delivery

•Flexibility for type of drug

selected

•Patient discomfort

•Irritation to eye

•Patient placement and

removal

•Tissue fibrosis.


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V. RECENT OCULAR DRUG DELIVERY FORMULATIONS

Two Major Approaches:

1. To prolong the contact time of drug with corneal surface.

2. To enhance corneal permeability either by mild structural alteration of corneal

epithelium or by modification of chemical structure of the drug molecules.

Formulations:

1. Ocular Penetration Enhancers

2. Mucoadhesive dosage form

3. Collagen Shields

4. Dendrimers

5. In Situ-Forming Hydrogels

6. Micro And Nano Particles

7. Iontophoresis


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1. OCULAR PENETRATION ENHANCERS

After topical instillation of an eye drop, the drug is subject to a number of very efficient

elimination mechanisms such as drainage, binding to proteins, normal tear turnover, induced

tear production, and non-productive absorption via the conjunctiva.

Typically, drug absorption is virtually

complete in 90 seconds due to the rapid

removal of drug from the precorneal area

and also the cornea is poorly permeable to

both hydrophilic and hydrophobic

compounds. As a result, only approximately

10% or less of the topically applied dose

can be absorbed into the anterior segment

of the eye11

.

One approach to improve ocular

bioavailability is penetration enhancement.

Ideally, penetration enhancers should have

the following characteristics12

:

1. The absorbing-enhancing action

should be immediate and

unidirectional, and the duration

should be specific and predictable.

2. There is immediate recovery of the

tissue after removing the absorption

enhancers.

3. There is no systemic and local effect

associated with the enhancers.

4. The enhancers should be physically

and chemically compatible with a

wide range of drugs and excipients.

Basically, penetration enhancers work by

one or more of the following mechanisms13

:

1. Altering membrane structure and enhancing transcellular transport by extracting

membrane components and/or increasing fluidity.

2. Enhancing paracellular transport: Chelating calcium ions leads to opening of tight

junctions; Inducing high osmotic pressure that transiently opens tight junctions;

Introducing agents to disrupt the structure of tight junctions.

3. Altering mucus structure and rheology so that this diffusion barrier is weakened.

4. Modifying the physical properties of the drug-enhancer entity. 5. Inhibiting enzyme activity.

Examples14

Surfactants

Spans 20, 40 and 85,

Tweens 20, 40 and 81,

Aptet 100, G 1045,

Brji 35 and 58,

Myrj 52 and 53

Bile Acids

Deoxycholic acid

Taurocholic acid

Taurodeoxycholic acid

Urodeoxycholic acid

Taurorsodeoxycholic acid

Fatty acids Capric acid

Preservatives

Benzalkonium chloride

Chlorhexidine digluconate

Benzyl alcohol

Chlorbutanol

2-Phenylethanol

Propyl paraben

Chelating Agents EDTA

Others

a-cyclodextrin

Azone

Hexamethylene

Lauramide

Hexamethylene

Octanamide

Decylmethylsulfoxide

Saponin


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2. MUCOADHESIVE DOSAGE FORMS

Mucoadhesive dosage forms can provide a localized delivery of medicinal agents to a

specific site in the body. The ability of mucoadhesive dosage forms to provide an intimate

contact of the delivery system with the absorbing corneal layer would undoubtedly improve

ocular bioavailability. The intimate contact may result in high drug concentration in the local

area and hence high drug flux through the absorbing tissue. The intimate contact may also

increase the local permeability of high molecular weight drugs such as peptides and proteins.

The major constituents of mucus are water (95%) and high molecular weight glucoproteins

capable of forming slimy, viscoelastic gels15

.

The principal functions of the mucus layer are lubrication and protection of the underlying

epithelial cells from dehydration and other challenges. The mechanism of mucoadhesion is

simply a physical entanglement. The polymer undergoes swelling in water, which permits

entanglement of the polymer chains with mucin on the epithelial surface of the tissue16

. The

un-ionized carboxylic acid residues on the polymer form hydrogen bonds with the mucin

molecule.

Some examples of Mucoadhesive polymers are Carboxymethylcellulose, Carbopol,

hydroxypropylcellulose, Poly(methyl methacrylate), Polyacrylamide, Poly(acrylic acid),

Gelatin, Sodium alginate, Dextran, etc.

Number of factors can affect the performance of mucoadhesives such as polymer’s adhesion

property, swelling characterisation, hydration time, molecular weight, degree of cross linking,

pH, mucin turn over, extent of drug incorporation, etc.

Drug can be incorporated in Mucoadhesive polymer by various approaches such:

1. Coated on micro capsule,

2. Laminated,

3. Entrapment within the polymer, etc.


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3. COLLAGEN SHIELDS

Bloomfield et al. were the

first to suggest that collagen

might provide a suitable

carrier for sustained ocular

drug delivery. Collagen

inserts -a potential new

vehicle for the sustained

administration of drugs to

the cornea.

Clinical studies

demonstrated that the

collagen shield is easy to use

in the ophthalmologist’s

office, prevents delay in

beginning therapy, and

maintains therapeutic

concentrations of drug in the eye without the need for frequent topical instillation of drops17

.

The safety of collagen for human use is evidenced by its diverse uses and biomedical

applications. In medicine, collagen has been used in cardiovascular surgery, plastic surgery,

orthopedics, urology, neurosurgery, and ophthalmology. The major medical application of

collagen is catgut suture In the manufacture of corneal collagen shields, the ability to control

the amount of cross-linking in the collagen subunits by exposure to ultraviolet (UV) light is

an important physicochemical property, because the amount of cross-linking is related to the

dissolution time of the shield on the cornea18, 19

.

The collagen shield is designed to be a disposable, short-term therapeutic bandage lens for

the cornea. It conforms to the shape of the eye, protects the corneal surface, and provides

lubrication as it dissolves. Although collagen shields produce some discomfort and interfere

with vision, corneal collagen shields could become a commonly employed technological

improvement in ophthalmic drug delivery20

.


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4. DENDRIMERS

Dendrimers, synthetic spherical macromolecules named after their characteristic ‘‘tree-like’’

or dendritic branching around a central core, are a new class of polymers. The branching

structure makes them a useful vector capable of efficient drug and gene delivery. Their

nanoscopic architecture could provide a solution to current ocular drug delivery problems21

.

Tomalia et al.22

developed the first dendrimer, named the StarburstTM polyamidoamine

(PAMAM) dendrimer because of its dendritic branches and controlled starburst growth. This

macromolecule is built on an ammonia core with extending branches of alternating methyl

acrylate and ethylene diamine molecules23

. The cascade is continued by adding methyl

acrylate moieties onto the reactive ends of the ethylene diamine molecules and then ethylene

diamine moieties onto the methyl acrylate. Each addition creates another branched layer,

referred to as a generation. Each generation causes an exponential increase in the surface

reactive sites that may have functional implications24

. The critical molecular design

parameters of size, shape, surface chemistry, flexibility, and topology can be carefully

regulated to create the complex molecule. In addition, the dendrimer possesses a remarkably

cell like construction consisting of a low-density core and modifiable internal and external

surfaces, making it a perfect container or scaffolding for drugs, DNA, and protein.

Dendrimers show great promise for a variety of uses such as drug and gene delivery systems,

imaging agents, diagnostic kits, tumour therapy, industrial catalysts, and sensors.

4.1. General Chemical Structure

Dendrimers are composed of concentric, geometrically progressive layers created through


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radial amplification from a single, central initiator core molecule containing either three or

four reactive sites such as ammonia or ethylene diamine. Like the nucleus of the biotic cell,

the core contains the basic information of the dendrimer; it defines the final size, shape,

multiplicity, and functionality of the entire structure. Starting from the centre, each layer

stores information, which is transferred to the next outer layer or generation via covalent

connections, determining that layer’s physical properties23

.

4.2. Physical Properties

The physical properties of dendrimers depend on the chemical structure/steric properties of

internal and external functional groups. The shape may range from an almost perfect sphere

to an ellipsoid to a cylinder-like structure composed of intricately branched ‘‘fans’’ extending

out of an elongated base25

. Changes in the core molecule and/or the number of reactive sites

present on the core can also influence the shape. Newer dendrimers use phosphorus- or

silicone-containing molecules, hydrocarbons, lysine, or thiols as the internal cores23, 24

. The

dendrimer can also be adjusted based on the selection of reactants. Usually size is dependant

on the number of generations assembled, but it can also be influenced by the length of the

monomers used and the angles between the monomers24

. The average mass of a dendrimer

varies from about 500 to 1500 Daltons, with the diameter of a spherical dendrimer varying

from about 10 A ˚ (first generation) to a maximum of about 130 A Dendrimers are relatively

stable, covalent macromolecules. They exist independently from each other and from their

external environment. As the dendrimer grows, steric congestion eventually prevents further

growth. At this point, the dendrimer converts from an open structure to a tight spheroid with

open cavities and a dense surface26

. A specific dendrimer’s stability depends on the reactivity

of the functional groups located on its surface, which can be modified to achieve the

necessary level of stability.

4.3. Applications in ocular drug delivery

Hudde et al.27

reported the efficiency of gene transfer to the corneal endothelium using

PAMAM dendrimers in an ex vivo model. The dendrimer was complexed with a plasmid

containing a reporter gene, β-galactosidase, in a ratio of 18 : 1 and incubated with a quarter of

a full-thickness rabbit cornea. The expression of β-galactosidase was assessed after 3 days: 6–

10% of the endothelial cells were stained blue 24

.

Dendrimer therapy could also correct hereditary diseases such as lattice corneal dystrophy by

introducing the normal gene (i.e., transforming growth factor, β-induced gene) into the

endothelial cells so a functioning protein could be expressed.

Diseases of the retina include retinitis pigmentosa and macular degeneration; both result in

blindness due to the death of retinal cells. Drugs applied to the cornea usually do not reach

the back of the eye. Therefore, direct injection of the drugs into the vitreous is required to

target the retina. While this method provides adequate drug levels, it is not without significant

risk of retinal detachment, endophthalmitis, vitreal hemorrhage, and/or cellular toxicity28, 29,

30. The use of dendrimers to deliver drugs and gene therapy to this area of the eye has great

potential.


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5. IN SITU-FORMING HYDROGELS

5.1. Introduction

In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the

ocular cul-desac to form visco-elastic gel and this provides a response to environmental

changes. In the past few years, an impressive number of novel temperature, pH, and ion

induced in situ-forming systems have been reported for sustain ophthalmic drug delivery.

Each system has its own advantages and drawbacks. The choice of a particular hydrogel

depends on its intrinsic properties and envisaged therapeutic use. This review includes

various temperature, pH, and ion induced in situ-forming polymeric systems used to achieve

prolonged contact time of drugs with the cornea and increase their bioavailability31

.

The most common way to improve drug retention on the corneal surface is undoubtedly by

using polymers to increase solution viscosity. Hydrogels are polymers endowed with an

ability to swell in water or aqueous solvents and induce a liquid–gel transition. Currently, two

groups of hydrogels are distinguished, namely preformed and in situ forming gels. Preformed

hydrogels can be defined as simple viscous solutions which do not undergo any modifications

after administration. In situ forming gels are formulations, applied as solutions, sols, or

suspensions, that undergo gelation after instillation due to physic-chemical, changes inherent

to the eye32

.

In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the

ocular cul-de-sac to form viscoelastic gel and this provides a response to environmental

changes33

.

Three methods have been employed to cause phase transition on the surface: change in

temperature34

, pH35

, and electrolyte composition36

.

5.2. Temperature Induced Gelation

These hydrogels are liquid at room temperature (20–25 °C) and undergo gelation when in

contact with body fluids (35– 37 °C), due to an increase in temperature37

. For example

Poloxamers, cellulose derivatives, and xyloglucan.

5.2.1. Poloxamer

PEO-PPO-PEO (Poloxamer).

The Poloxamer series covers a range of liquids, pastes, and solids They are formed by central

hydrophobic part (polyoxypropylene) surrounded by hydrophilic part (ethylene oxide).

Depending on the ratio and the distribution along the chain of the hydrophobic and

hydrophilic subunits, several molecular weights are available, leading to different gelation


15

properties. Concentrated aqueous solutions of Poloxamer form thermoreversible gels. it has

suggested that intramolecular hydrogen bonds might promote gelation38

. Poloxamers have

been widely investigated as ocular drug delivery systems. The enhanced activity of

pilocarpine in Poloxamer 407 gels when compared with a simple solution has been

reported34

.

At room temperature (< 25 °C), the solution behaves as a mobile viscous liquid, which is

transformed into a semisolid transparent gel at body temperature (37 °C). At room

temperature (b25 °C), the solution behaves as a mobile viscous liquid, which is transformed

into a semisolid transparent gel at body temperature (37 °C). Preliminary toxicity data

indicate that this copolymer is well tolerated. Poloxamer formulation generally increased

drug residence time at application sites, resulting in improved bioavailability and efficacy39

.

Potential drawbacks of Poloxamer gels include their weak mechanical strength, rapid erosion

(i.e. dissolution from the surface), and the nonbiodegradability of PEO-PPO-PEO, which

prevents the use of high molecular weight polymers that cannot be eliminated by renal

excretion.

5.2.2. Cellulose derivatives

Most natural polymer aqueous solutions form a gel phase when their temperature is lowered.

Classic examples of natural polymers exhibiting a sol–gel transition include gelatin and

carrageenan.

At elevated temperatures, these polymers adopt a random coil conformation in solution. Upon

cooling, a continuous network is formed by partial helix formation40

.

Some cellulose derivatives are an exception to this gelation mechanism. At low

concentrations (1–10 wt.%), their aqueous solutions are liquid at low temperature, but gel

upon heating. Methylcellulose (Fig. a) and hydroxypropyl methylcellulose (HPMC) (Fig. b)

are typical examples of such polymers.


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Methylcellulose solutions transform into opaque gels between 40 and 50 °C, whereas HPMC

shows phase transition between 75 and 90 °C. These phase transition temperatures can be

lowered by chemical or physical modifications. For example, NaCl decreases the transition

temperature of methylcellulose solutions to 32–34 °C. Similarly, by reducing the

hydroxypropyl molar substitution of HPMC, its transition temperature can be lowered to

about 40 °C.

Gelation of methylcellulose or HPMC solutions is primarily caused by the hydrophobic

interaction between molecules containing methoxy substitution. At low temperatures, the

macromolecules are hydrated, and there is little polymer– polymer interaction other than

simple entanglement. As the temperature is raised, the polymers gradually lose their water of

hydration, which is reflected by a decline in relative viscosity. Eventually, when sufficient

but not complete dehydration of the polymer occurs, polymer–polymer associations take

place, and the system approaches an infinite network structure, as reflected experimentally by

a sharp rise in relative viscosity. This sol–gel transformation has been exploited to design in

situ gelling systems. These systems exhibited low viscosity at 23 °C and formed soft gels at

37 °C 41

.

5.3. pH Induced Gelation

5.3.1. Pseudolatexes

Pseudolatexes can be described as artificial latexes prepared by the dispersion of a pre-

existing polymer in an aqueous medium. In situ gelling pseudolatexes for ophthalmic use can

be described as aqueous colloidal dispersions of polymer, which become viscous gels after

instillation in the conjunctival cul-desac due to modification of the pH. Pseudolatexes are

obtained by dispersion of an organic solution of a preformed polymer in an aqueous medium,

leading to an O/W emulsion. Solvents from the internal phase are then evaporated to obtain a

fluid dispersion of polymeric particles with a size generally smaller than 1 μm. Two principal

methods are commonly used to prepare ophthalmic pseudolatexes, the solvent evaporation

process and the salting out process. Both methods allow the production of a lyophilized and

easily redispersible powder.

Some Prerequisites necessary for an optimal formulation of ophthalmic pseudo latex are

listed below:

Solubility of the polymer selected in organic solvents as well as insolubility in water.

Existence on the macromolecule of ionizable groups, which can react with the

electrolytes of the lachrymal fluid.

Use of a high molecular weight polymer.

Rapid coagulation process after instillation to avoid precorneal drainage of the

instilled formulation before the phenomenon of gelation appears.

Compatibility of the different components of the colloidal dispersion with precorneal

tissues32

.


17

5.3.2. Cellulose acetate phthalate latex (CAP-latex).

The choice of this polymer was determined by the compatibility of the polymer with the

active compound, the ability of the CAP latex to be a free-running solution at pH 4.2 and a

gel at 7.2, and finally, the latex stability at relatively low pH which is a prerequisite to

ensuring the stability of pilocarpine.

Cellulose acetate phthalate latex

The efficacy of a preparation based on pseudolatex has been evaluated by measuring

pharmacological responses and precorneal residence time by γ scintigraphy. A sensation of

discomfort seems to be unavoidable after the coagulation of the solution in the cul-de-sac as

is the case for any semisolid preparation32

.

5.3.3. Carbomer

Cross-linked poly (acrylic acid) of high molecular weight, commercially available as

Carbopol®, is widely used in ophthalmology to enhance precorneal retention to the eye32

.

Carbopol® 934 is a synthetic polymer composed of 62% of carboxyl groups with a high

molecular weight (approximately 3×106) formed by repeating units of acrylic acid, cross-


18

linked with either allylsucrose or allylethers of pentaerythritol42

. Carbopol offers the

advantage of exhibiting excellent mucoadhesive properties when compared with other

polymers. Carbopol is a polyacrylic acid (PAA) polymer, which shows a sol to gel transition

in aqueous solution as the pH is raised above its pKa of about 5.5 43

.

5.4. Osmotically Induced Gelation

In this method, gelling of the solution instilled is triggered by change in the ionic strength44

.

5.4.1. Gelrite

Gellan gum (Gelrite) is a linear, anionic heteropolysaccharide secreted by the microbe

Sphingomonas elodea. The polymer backbone consists of glucose, glucuronic acid, and

rhamnose in the molar ratio 2:1:1 45

. Gelrite® (deacetylated gellan gum) is one of the most

interesting in situ gelling polymers that has been tested since it seems to perform very well in

humans. Gelrite has been granted regulatory approval as pharmaceutical excipient and is

marketed by Merck in a controlled-release glaucoma formulation called Blocarden® Depot

(Timoptic®). Formulations with the Gelrite can be administered to ocular mucosa as a

lowviscosity solution. On contact with cations in tear fluid the formulation will form a clear

gel46

. This is caused by cross linking of the negatively charged polysaccharide helices by

monovalent and divalent cations (Na+, K+, Ca+ ). In an ion free aqueous medium, Gelrite

forms double helices at room temperature. This solution has a viscosity close to that of water

and the helices are only weakly associated with each other. When gel-promoting cations are

present, some of the helices associate into cation-mediated aggregates, which cross-link the

polymer.

5.4.2. Alginates

Alginate with a high guluronic acid content will improve the gelling properties and reduce the

total polymer to be introduced into the eye. The alginate forms 3-dimensional ionotropic

hydrogel matrices, generally by the preferential interaction of calcium ions with the G

moieties resulting in the formation of inhomogeneous gel. Calcium-crosslinked alginate gels

have shown good mechanical properties even when prepared from relatively low solution

concentrations of the polymer, 0.5% w/v, and they can physically entrap a whole array of

molecules, and sustain their release.

5.5. Performance of ‘In-Situ’ Gelling Hydrogels

In fact, an enhanced viscosity induces an increase in ocular contact time by reducing the

drainage rate and, as a consequence, improves the overall bioavailability of an instilled

solution47

. below a certain viscosity, there is no real improvement of bioavailability, and

upon this limit there is no further increase of the residence contact time and blinking becomes

painful48

.


19

It is important to point out that data on rabbits do not always match the results in humans. In

fact, one of the main differences is the rabbit blinking rate, which is as low as 4–5 blinks per

hour, compared with 15–16/min in humans49

. Also it is interesting to note that cation

concentration in tears is lower in rabbits, which, along with their lower basal tear turnover,

can result in a markedly different gellation of, for example, gellan gum from that found in

humans.

Systemic absorption can be minimized by reducing the instilled volume50

, controlling drug

release51

, pro-drug derivatization52

and adding vasoconstrictive agents53

. The occlusion of the

puncta54

by applying prolonged pressure or enhancing the formulation's viscosity can also be

an alternative.


20

6. MICRO AND NANO PARTICLES

Micro and nanotechnology

involving drug-loaded polymer

particles has been proposed as

an ophthalmic drug delivery

technique that may enhance

dosage form acceptability while

providing sustained release in

the ocular milieu. Particulate

drug delivery consists of

microparticles, nanoparticles,

microspheres, nanospheres,

microcapsules, and

nanocapsules55

.

They consist of macromolecular

materials and can be used

therapeutically by themselves,

e.g., as adjuvant in vaccines, or

as drug carriers, in which the

active principle (drug or

biologically active material) is dissolved, entrapped, encapsulated, and/or to which active

principle is absorbed, adsorbed, or attached.

Polymers used for the preparation of microparticulates may be erodible, biodegradable,

nonerodible, or ion exchange resins56

. Nanoparticles made of nonbiodegradable polymers are

neither digested by enzymes nor degraded in vivo through a chemical pathway57

. The risk of

chronic toxicity due to the intracellular overloading of nondegradable polymers would be a

limitation of their systemic administration to human beings, making these materials more

suitable for removable inserts or implants.

Erodible systems have an inherent advantage over other systems in that the self-eroding

process of the hydrolysable polymer obviates the need for their removal or retrieval after the

drug is delivered. Upon the administration of particle suspension in the eyes, particles reside

at the delivery site and the drug is released from the polymer matrix through diffusion,

erosion, ion exchange, or combinations thereof58

.

Nanoparticles, when formulated properly, provide controlled drug release and prolonged

therapeutic effect. To achieve these characteristics, particles must be retained in the cul-de-

sac after topical administration, and the entrapped drug must be released from the particles at

an appropriate rate. The utility of nanoparticles as an ocular drug delivery system may

depend on (a) optimizing lipophilic-hydrophilic properties of the polymer-drug system, (b)

optimizing rates of biodegradation in the precorneal pocket, and (c) increasing retention

efficiency in the precorneal pocket. It is highly desirable to formulate the particles with


21

bioadhesive materials in order to enhance the retention time of the particles in the ocular cul-

de-sac. Without bioadhesion, nanoparticles could be eliminated as quickly as aqueous

solutions from the precorneal site. Bioadhesive systems can be either polymeric solutions59

or

particulate systems60

. With several pilot studies using natural bioadhesive polymers

demonstrating promising improvements in ocular bioavailability, synthetic biodegradable and

bioadhesive polyalkylcyanoacrylate systems were developed, and these may prove to be the

most promising particulate ocular drug delivery systems of the future.

Polyalkylcyanoacrylates gained popularity because of their apparent lack of toxicity, proven

by decades of safe and successful use in surgery61

, which from a toxicological point of view

is a very favourable characteristic for a preferred pharmaceutical drug delivery system.

6.1. Methods of Preparation of Nanoparticles

6.1.1. Polymerization in a Continuous Aqueous Phase

In this process monomers are dissolved in the aqueous phase and within emulsifier micelles.

Additional monomers may be present as monomer droplets stabilized by emulsifier

molecules. Initiation of polymerization takes place in the aqueous phase when the dissolved

monomer molecules are hit by a starter molecule or by high-energy radiation62, 63

.

Polymerization and chain growth is maintained by further monomer molecules, which

originate from the aqueous phase, the emulsifier micelles, or the monomer droplets. The

monomer droplets and the emulsifier micelles therefore act mainly as reservoirs for the

monomers or for the emulsifier, which later stabilize the polymer particles after phase

separation and prevent coagulation. Also, to prevent excessively rapid polymerization and

promote the formation of nanoparticles, emulsion polymerization is carried out at an acidic

pH (pH is 1–2)64

. The drugs may be added before, during, or after polymerization and

formation of particles.

6.1.2. Interfacial Polymerization

Interfacial polymerization of the polyalkylcyanoacrylate polymers allows the formation of

nanocapsules with a shell-like wall65

. This carrier type can encapsulate drugs with lipophilic

character, and the rate of encapsulation is generally related to the solubility of the drug in the

oily compartment65

. The technique involves dissolving the polyalkylcyanoacrylate (PACA)

monomers and lipophilic drug in an ethanolic solution or oil and slowly injecting this mixture

into a well-stirred solution of 0.5% poloxamer 338 in water at pH 6 (may contain nonionic

surfactant)66

. At the oil/water interface, nanoparticles with a shell-like wall are formed

spontaneously by hydroxyl ion–induced polymerization, and the polymeric colloidal

suspension occurs immediately.

6.1.3. Polymerization by Denaturation or Desolvation of Natural Proteins


22

Macromolecules such as albumin or gelatin can form nanoparticles through the desolvation

and denaturation processes. Desolvation of macromolecules in aqueous solution can be

induced by changes in pH, charge, or the addition of desolvating agents such as ethanol66

.

The desolvation process induces the swollen molecules to coil tightly. At this point, the

tightly coiled macromolecules can be fixed and hardened by crosslinking with glutaraldehyde

to form nanoparticles rather than nanocapsules. Nanoparticles are then purified by gel

filtration. The denaturation process involves preparing an emulsion from an aqueous phase

containing the drug, magnetite particles, and the macromolecule and cottonseed oil67, 68

.

Polymerization is carried out by heat denaturation at temperatures above 120 C or by

chemical crosslinking. Nanoparticles are precipitated out and washed with ether (or in the

case of gelatin, acetone) and stored in the dry form.

6.1.4. Solvent Evaporation Method

Gurny et al.69

were the first to use this process for the production of polylactic acid

nanoparticles containing testosterone. In this method, the polymer of interest is dissolved in

an organic solvent, suspended in a suitable water or oil medium, after which the solvent is

extracted from the droplets. The particles obtained after solvent evaporation are recovered by

filtration, centrifugation, or lyophilization. In general, the diameter of the particles depends

on the size of the microdroplets that are formed in the emulsion before evaporation of the

solvent. Chiang et al. used the solvent evaporation technique with an oil-in-oil emulsion to

prepare polylactide-co-glycolide microspheres of 5-fluorouracil for ocular delivery70

.

Microspheres containing cyclosporin A have been prepared with a mixture of 50 : 50

polylactic and polyglycolic acid polymers using the solvent evaporation process. The

polymer and drug mixture was dissolved in a mixture of chloroform and acetone, emulsified

in an aqueous solution of polyvinyl alcohol, and stirred for 24 hours to evaporate the organic

solvent and yield the microparticle dispersion71

.

6.1.5. Ionic Gelation Technique

De Campos et al. developed chitosan nanoparticles using the ionic gelation technique72

.

Nanoparticles were obtained upon the addition of sodium tripolyphosphate aqueous solution

to an aqueous polymer solution of chitosan under magnetic stirring at room temperature. The

formation of nanoparticles was a result of the interaction between the negative groups of the

tripolyphosphate and the positively charged amino groups of chitosan. In this technique, drug

in an acetonitrile-water mixture can be incorporated either into chitosan solution or the

tripolyphosphate solution.

6.1.6. Nano-precipitation

Fessi et al. 73

developed nanoparticles using this method. In this technique a polymer and a

specified quantity of drug is dissolved in acetonitrile. The organic phase is then added

dropwise to the aqueous phase and stirred magnetically at room temperature until complete

evaporation of the organic phase takes place. Drug-free nanoparticles may be prepared using

the same procedure by simply omitting the drug.


23

6.1.7. Spray-Drying

In this technique74

, microparticles are prepared by dissolving the polymer of interest in an

organic solvent. The drug is added to this solution and spray-dried using a spray-dryer. The

process parameters and spray nozzle size are set up as required. The spray-dried product is

collected by a cyclone separator.

6.2. Polymers used in the Preparation of Nanoparticles

A successful nanoparticulate system may be one that has a high loading capacity, thus

reducing the quantity of carrier required for administration. The drug can be either adsorbed

onto the surface of performed particles or incorporated into the nanospheres during the

polymerization process. Concerning the loading capacity of nanoparticles, it has been found

that both the nature and quantities of the monomer used influences the absorption capacity of

the carrier. Generally, the longer the chain length, the higher is the affinity of the drug to the

polymer.

Several types of polymeric nanoparticles are used in ophthalmic drug Delivery

Polymethylmethacrylate (PMMA), acrylic copolymer Nanoparticles, polystyrene, polyvinyl

pyridine, Cellulose acetate phthalate, PACA, poly-e-caprolactone (PECL) nanocapsules, etc.


24

7. IONTOPHORESIS

7.1. Introduction

Iontophoresis is the use of a direct electrical current to drive topically applied ionized

substances into or through a tissue75

. Iontophoresis is based on the physical principle that ions

with the same charge repel (electro-repulsion) and ions with opposite charge attract (electro-

osmosis).

Iontophoresis usually employs low voltage (10V or less) to supply a continuous direct current

of 0.5mA/cm2 or less. These basic operational guidelines have enabled iontophoresis to be

used to enhance drug delivery in a wide variety of conditions. Iontophoresis causes increased

transport of ionized substances into or through a tissue by application of an external electric

current.

When iontophoresis is used therapeutically, the ions of importance are charged molecules of

the drug or other bioactive substances. The ionized substances are driven into the tissues by

electro-repulsion at either the anode (if they carry a positive charge) or the cathode (if they

carry a negative charge) 76

.

7.2. Design of Iontophoresis Devices

Iontophoretic devices vary in complexity, but 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.

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 about 1 cm,

is placed over the cornea and

filled with the drug solution. 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. 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


25

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.

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 eye77

. The salt form of a drug is also preferred

for iontophoresis since the dissociated salt is highly soluble. The drug is driven into the

ocular tissue with an electrode carrying the same charge as the drug while the ground

electrode, which is of the opposite charge, is placed elsewhere on the body (usually the ear)

to complete the circuit. The drug or bioactive substance serves as a conductor of the current

through the ocular tissue. The transported drugs or bioactive substance either remains in the

tissue until they are altered / metabolized or are carried away by the blood vascular network.

7.3. Approaches of Iontophoretic Delivery

Iontophoresis of the various classes of drugs (antibiotics, antivirals, antifungal,

antimetabolite, adrenergic, steroid, anaesthetic, and dyes) can be delivered by two

approaches78

.

7.3.1. Trans-corneal iontophoresis

That delivers a high concentration of drug to the anterior segment of the eye such as cornea,

aqueous humour, ciliary body, and lens.

7.3.2. Trans-scleral iontophoresis

That can produce significantly high and sustained drug concentration in the vitreous humour

and retina.


26

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