1

Prepared by:Karamshi R. Chaudhari

M. Pharm.-I
(Pharmaceutics)

Guided by:Mahesh R. Dabhi

Asst. Prof.
Pharmaceutics

Department of Pharmaceutical Sciences,

Saurashtra University,

Rajkot.

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

2
CONTENTS
9.

INTRODUCTION

35.

ANATOMY OF THE EYE

61.

MECHANISMS AND BARRIARS FOR OCULAR DRUG

ABSORPTION

IV.CONVENTIONAL OCULAR FORMULATIONS

22.

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
Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

3
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.

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

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

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

5
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
2

and removed to the general circulation . 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
3

contain on the order of 100-fold the amount of lipid material per unit mass of the stroma .
Depending on the physiochemical properties of the drug entity, the diffusional resistance
4, 5

offered by these tissues varies greatly . 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
6

estimated to be about 60 A . Small ionic and hydrophilic molecules appear to gain access to
7

the anterior chamber through these pores ; 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 8590% of the total corneal mass and is composed of mainly
8
of hydrated collagen . 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
9, 10
molecular weight and not on the charge of hydrophilic nature of the compound
.
Transcellular transport across the corneal epithelium and stroma is the major mechanism of
ocular absorption of topically applied ophthalmic pharmaceuticals.

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

Fig. illustration of ocular drug penetration barriers

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

7
IV. CONVENTIONAL OCULAR FORMULATIONS

Dosage
form

Advantages

Convenienc
Solutions e

Suspensi
ons
Patient compliance
Best for drugs with
slow
dissolution
Emulsion Prolonged release of
s
drug
from vehicle

Disadvantages

Loss of drug by drainage

Nonsustained
action
decid
Drug properties
e
performance

Patient non
compliance
Blurred vision
Possible oil
entrapment
Ointment Flexibility in drug choice Sticking of eyelids
Improved drug stability Poor patient compliance
Increased tissue contact
time
Blurred vision
Inhibition of dilution by
tears
No true sustained effect
Resistance
Drug choice limited
to
nasolacrimal by
drainage.
partition coefficient
Comfortabl
No rate control on
Gels
e
diffusion
Less blurred vision
than
Matted eyelids after use
ointment
Sophisticat
and
Erodible ed
effective Patient discomfort
delivery
Requires patient
inserts
system
insertion
Flexibility in drug type
Movement of system
and
around
dissolution
eye can cause
rate
abrasion

Need only be introduced

into
eye and not removed
Nonerodible
inserts

Controlled rate of
release
Prolonged delivery
Flexibility for type of
drug
selected

Patient discomfort
Irritation to eye
Patien
placemen
t
t
remov
al
Tissue fibrosis.

and

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

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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

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

9
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
11
eye .
One approach to improve ocular bioavailability is
penetration enhancement. Ideally, penetration
enhancers
should
have
the
following
12

characteristics :
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
13
of the following mechanisms :

Examples

14

Spans 20, 40 and 85,

Tweens 20, 40 and 81,
Surfactants
Aptet 100, G 1045,
Brji 35 and 58,
Myrj 52 and 53
Deoxycholic acid
Taurocholic acid
Bile Acids
Taurodeoxycholic acid
Urodeoxycholic acid
Taurorsodeoxycholic acid
Fatty acids
Capric acid
Benzalkonium chloride
Chlorhexidine digluconate
Preservatives
Benzyl alcohol
Chlorbutanol
2-Phenylethanol
Propyl paraben
Chelating Agents EDTA
a-cyclodextrin
Azone
Hexamethylene
Lauramide
Others
Hexamethylene
Octanamide
Decylmethylsulfoxide
Saponin
junctions;
1. Altering membrane structure
Inducing
and enhancing transcellular
high
transport
by
extracting
osmotic
membrane components and/or
pressure
increasing fluidity.
that
2. Enhancing
paracellular
transiently
transport: Chelating calcium
opens tight 3.
ions leads to opening of tight

junctions;
Introducing
agents
to
disrupt the
structure of4.
tight
junctions.
5.
Altering

mucus
structure
and
rheology so that this
diffusion
barrier
is
weakened.
Modifying the physical
properties of the drugenhancer entity.
Inhibiting enzyme activity.

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

10
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
15

capable of forming slimy, viscoelastic gels .

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
16

entanglement of the polymer chains with mucin on the epithelial surface of the tissue . 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 polymers 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.

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

11
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
ophthalmologists
office, prevents delay in
beginning
therapy,
and
maintains
therapeutic
17

concentrations of drug in the eye without the need for frequent topical instillation of drops .
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 cornea

18, 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
20

improvement in ophthalmic drug delivery .

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

12
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
21

nanoscopic architecture could provide a solution to current ocular drug delivery problems .
22

Tomalia et al. 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
23

acrylate and ethylene diamine molecules . 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
24

reactive sites that may have functional implications . 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

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

13
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
23

connections, determining that layers physical properties .

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
25

out of an elongated base . 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
23, 24

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

. 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
24

monomers used and the angles between the monomers . 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
26

open cavities and a dense surface . A specific dendrimers 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
27

Hudde et al. 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, -galactosidase, in a ratio of 18 : 1 and incubated with a quarter of
a full-thickness rabbit cornea. The expression of -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, -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 toxicity

28, 29,

30

. The use of dendrimers to deliver drugs and gene therapy to this area of the eye has great
potential.
Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

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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
31

prolonged contact time of drugs with the cornea and increase their bioavailability .
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 liquidgel 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
32
to the eye .
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
33
changes .
Three methods have been employed to cause phase transition on the surface: change in
34
35
36
temperature , pH , and electrolyte composition .
5.2. Temperature Induced Gelation
These hydrogels are liquid at room temperature (2025 C) and undergo gelation when in
37
contact with body fluids (35 37 C), due to an increase in temperature . 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
Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

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properties. Concentrated aqueous solutions of Poloxamer form thermoreversible gels. it has
38
suggested that intramolecular hydrogen bonds might promote gelation . 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
34
reported .
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
39

drug residence time at application sites, resulting in improved bioavailability and efficacy .
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 solgel transition include gelatin and
carrageenan.
At elevated temperatures, these polymers adopt a random coil conformation in solution. Upon
40
cooling, a continuous network is formed by partial helix formation .
Some cellulose derivatives are an exception to this gelation mechanism. At low
concentrations (110 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.

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

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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 3234 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, polymerpolymer associations take place,
and the system approaches an infinite network structure, as reflected experimentally by a
sharp rise in relative viscosity. This solgel transformation has been exploited to design in
situ gelling systems. These systems exhibited low viscosity at 23 C and formed soft gels at
41
37 C .

5.3. pH Induced Gelation

5.3.1. Pseudolatexes
Pseudolatexes can be described as artificial latexes prepared by the dispersion of a preexisting 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 m. 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:
1
2

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.
3
Use of a high molecular weight polymer.
4
Rapid coagulation process after instillation to avoid precorneal drainage of the
instilled formulation before the phenomenon of gelation appears.
5
Compatibility of the different components of the colloidal dispersion with
32
precorneal tissues .
Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

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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 scintigraphy. A sensation of
discomfort seems to be unavoidable after the coagulation of the solution in the cul-de-sac as
32

is the case for any semisolid preparation .

5.3.3. Carbomer
Cross-linked poly (acrylic acid) of high molecular weight, commercially available as
32
Carbopol, is widely used in ophthalmology to enhance precorneal retention to the eye .

Carbopol 934 is a synthetic polymer composed of 62% of carboxyl groups with a high
molecular weight (approximately 3106) formed by repeating units of acrylic acid, cross-

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Pharm. 1 (Pharmaceutics)

M.

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42

linked with either allylsucrose or allylethers of pentaerythritol . 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
43
in aqueous solution as the pH is raised above its pKa of about 5.5 .

5.4. Osmotically Induced Gelation

44

In this method, gelling of the solution instilled is triggered by change in the ionic strength .
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
45

rhamnose in the molar ratio 2:1:1 . 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
46

gel . 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
47
solution . 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
48
painful .
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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 45 blinks per
49

hour, compared with 1516/min in humans . 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.
50

Systemic absorption can be minimized by reducing the instilled volume , controlling drug
51
52
53
release , pro-drug derivatization and adding vasoconstrictive agents . The occlusion of
54
the puncta by applying prolonged pressure or enhancing the formulation's viscosity can also
be an alternative.

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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
55

nanocapsules .
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,
56
nonerodible, or ion exchange resins . Nanoparticles made of nonbiodegradable polymers are
57
neither digested by enzymes nor degraded in vivo through a chemical pathway . 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,
58

erosion, ion exchange, or combinations thereof .

Nanoparticles, when formulated properly, provide controlled drug release and prolonged
therapeutic effect. To achieve these characteristics, particles must be retained in the cul-desac 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
Karamshi R. Chaudhari
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21
bioadhesive materials in order to enhance the retention time of the particles in the ocular culde-sac. Without bioadhesion, nanoparticles could be eliminated as quickly as aqueous
59
solutions from the precorneal site. Bioadhesive systems can be either polymeric solutions
60

or particulate systems . 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
61
by decades of safe and successful use in surgery , 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
62, 63

monomer molecules are hit by a starter molecule or by high-energy radiation

.
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
64

pH (pH is 12) . 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
65
nanocapsules with a shell-like wall . 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
65
oily compartment . 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
66
surfactant) . At the oil/water interface, nanoparticles with a shell-like wall are formed
spontaneously by hydroxyl ioninduced polymerization, and the polymeric colloidal
suspension occurs immediately.
6.1.3. Polymerization by Denaturation or Desolvation of Natural Proteins
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22
Macromolecules such as albumin or gelatin can form nanoparticles through the desolvation
and denaturation processes. Desolvation of macromolecules in aqueous solution can be
66

induced by changes in pH, charge, or the addition of desolvating agents such as ethanol .
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
67, 68

containing the drug, magnetite particles, and the macromolecule and cottonseed oil
.
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
69

Gurny et al. 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
70

prepare polylactide-co-glycolide microspheres of 5-fluorouracil for ocular delivery .

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
71
solvent and yield the microparticle dispersion .
6.1.5. Ionic Gelation Technique
72

De Campos et al. developed chitosan nanoparticles using the ionic gelation technique .
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
73

Fessi et al. 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.
Karamshi R. Chaudhari
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23
6.1.7. Spray-Drying
74

In this technique , 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.

Karamshi R. Chaudhari
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24
7. IONTOPHORESIS
7.1. Introduction
Iontophoresis is the use of a direct electrical current to drive topically applied ionized
75
substances into or through a tissue . 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
2
of 0.5mA/cm 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
Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

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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 pK a values either below pH 6 or above pH 8 are
generally excellent candidates for iontophoresis into the eye because these drugs will be in
77

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. 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
78
approaches .
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.

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26
VI. REFERENCES
1.

Urtti, A. (2006) Challenges and obstacles of ocular pharmacokinetics and drug

delivery. Adv. Drug Deliv. Rev. 58, 11311135.

2.

D. M. Maurice. The eye. In: H. Davsoned, ed. Vegetative Physiology and

Biochemistry. New York: Academic Press, 1969.

3.

D. G. Cogan and E. D. Hirch. Cornea: Permeability to weak electrolytes. Arch.

Ophthalmol. 32:276, 1944.
V. E. Kinsey. Physiology of the eye. In; F. Adler, H., eds. St. Louis: Mosby, 1965.

4.
5.

H. S. Huang, R. D. Schoenwald, and J. L. Lach. Corneal penetration behavior of betablocking agents II: Assessment of barrier contributions. J. Pharm. Sci. 72:12721279,
1983.

6.

V. H. L. Lee. Mechanisms and facilitation of corneal drug penetration, J Controlled

Rel, 11:79 (1990).

7.

S. D. Klyce and C. E. Crosson. Transport processes across the rabbit corneal

epithelium: a review. Curr. Eye Res. 4:323331, 1985.

8.

A. K. Mitra. Ophthalmic drug delivery. In: P. Tyle, ed. Drug Delivery Devices. New
York: Marcel Dekker, 1988.

9.

A. M. Tonjum. Permeability of rabbit corneal epithelium to horseradish peroxidase

after the influence of benzalkonium chloride. Acta Ophthalmol. (Copenh.) 53:335
473, 1975.

10.

S. Mishima. Clinical pharmacokinetics of the eye. Proctor lecture. Invest.

Ophthalmol. Vis. Sci. 21:504541, 1981.

11.

Thomas Wai- Yip Lee and Joseph R. Robinson, Ocular Penetration Enhancers, School
of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A.

12.

Junginger, H. E., and Verhoef, J. C. Macromolecules as safe penetration enhancers for

hydrophilic drugsa fiction? Pharmaceut. Sci. Technol. Today 1:370376, 1998.

13.

Robinson, J. R., and Yang, X. Absorption enhancers. In: Encyclopedia of

Pharmaceutical Technology, Vol. 18 (Swarbrick J. and Boylan J. C. (eds.), Marcel
Dekker, New York, 1999, pp. 127.

14.

Sasaki, H., Yamamura, K., Mukai, Nishida, K., Nakamura, J., Nakashima, M., and
Ichikawa, M. Enhancement of ocular drug penetration, Crit. Rev. Drug Carrier Syst.
16:85146, 1999.

15.

Thomas P. Johnston, Clapton S. Dias, and Ashim K. Mitra, Mucoadhesive polymers in

Ophthalmic Drug DeliveryUniversity of MissouriKansas City, Kansas City,
Missouri, U.S.A.

16.

Mikos, A. G., and Peppas, N. A. (1986). Systems for controlled release of drug. V.
Bioadhesive systems, S.T.P. Pharm., 2:705.

17.

Shiro Higaki, Marvin E. Myles, Jeannette M. Loutsch, and James M. Hill, Corneal
Collagen Shields for Ocular Drug Delivery, LSU Eye and Vision Center of
Excellence, Louisiana State University Health Science Center, New Orleans,
Louisiana, U.S.A.

18.

Chvapil, M., Kronenthal, R. L., and van Winkle, Jr., W. (1973). Medical and surgical
applications of collagen, Int. Rev. connect. Tissue Res., 6:1.

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

27
19.

Kuwano, M., Horibe, Y., and Kawashima, Y. (1997). Effect of collagen crosslinking in
collagen corneal shields on ocular drug delivery, J. Ocul. Pharmacol. Ther., 13:31 40.

20.

Dorigo, M. T., De Natale, R., and Miglioli, P. A. (1995). Collagen shields delivery of
netilmicin: a study of ocular pharmacokinetics, Chemotherapy, 41:1.

21.

Jeannette M. Loutsch, Desiree Ong, and James M. Hill LSU Eye and Vision Center of
Excellence, Louisiana State University Health Science Center, New Orleans,
Louisiana, U.S.A.

22.

Tomalia, D. A., Baker, H., Dewald, J., Hall, M., Kallos, G., Roeck, J., Ryder, J., and
Smith, P. (1985). A new class of polymers: Starburst-dendritic macromolecules.
Polym. J., 17:117132.

23.

Tomalia, D. A., Naylor, A. M., and Goddard, W. A. I. (1990). Starburst dendrimers:

molecular-level control of size, shape, surface chemistry, topology, and flexibility
from atoms to macroscopic matter. Angew. Chem. Int. Ed. Engl., 29:138175.
Tomalia, D. A. (1995). Dendrimer molecules. Sci. Am., 5:42.

24.
25.

Tomalia, D. A., and Esfand, R. (1997). Dendrons, dendrimers, and dendrigrafts.

Chem. Ind., 6:416420.

26.

Frechet, J. M. J. (1994). Functional polymers and dendrimers: Reactivity, molecular

architecture, and interfacial energy. Science, 263:17101715.

27.

Hudde, T., Rayner, S. A., Comer, R. M., Weber, M., Isaacs, J. D., Waldmann, H.,
Larkin, D. F. P., and George, A. J. T. (1999). Activated polyamidoamine dendrimers, a
non-viral vector for gene transfer to the corneal endothelium. Gene Ther. 6:939.

28.

Henry, K., Cantrill, H., Fletcher, C., Chinnock, B. J., and Balfour, H. H. Jr. (1987).
Use of intravitreal ganciclovir (dihydroxy propoxymethyl guanine) for
cytomegalovirus retinitis in a patient with AIDS. Am. J. Ophthalmol., 103:17.

29.

Schwartz, D. M. (1996). New therapies for cytomegalovirus retinitis. Int. Ophthalmol.

Clin., 36:1.

30.

Harris, M. L., and Mathalone, M. B. (1989). Intravitreal ganciclovir in CMV retinitis:

Case report. Br. J. Ophthalmol., 73:382.

31.

Basavaraj K. Nanjawade, F.V. Manvi, A.S. Manjappa, In situ-forming hydrogels for

sustained ophthalmic drug delivery, Journal of Controlled Release 122 (2007) 119
134.

32.

O. Felt,V.Baeyens,M. Zignani, P.Buri, R.Gurny,Mucosal drug delivery ocular

Encyclopedia of controlled drug delivery, vol. 2, University of Geneva, Geneva,
Switzerland, 1999, pp. 605622.

33.

Z. Mazor, U. Ticho, U. Rehany, L. Rose, Piloplex, a new long-acting pilocarpine

polymer salt. B: comparative study of the visual effects of pilocarpine and Piloplex
eye drops, Br. J. Ophthalmol. 63 (1979) 5861.

34.

S.C. Miller, M.D. Donovan, Effect of poloxamer 407 gel on the miotic activity of
pilocarpine nitrate in rabbits, Int. J. Pharm. 12 (1982) 147152.

35.

R. Gurny, T. Boye, H. Ibrahim, Ocular therapy with nanoparticulate systems for

controlled drug delivery, J. Control. Release 2 (1985) 353361.
Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

28
36.

R. Moorhouse, G.T. Colegrove, P.A. Sandford, J.K. Baird, K.S. Kang, PS-60: a new
gel-forming polysaccharide, in: D.A. Brant (Ed.), Solution Properties of
Polysaccharides. ACS Symposium series, Washington-DC, 1981, pp. 111124.

37.

A.S. Hoffman, A. Afrassiabi, L.C. Dong, Thermally reversible hydrogels: II. Delivery
and selective removal of substances from aqueous solutions, J. Control. Release 4
(1986) 213222.

38.

S.C. Miller, B.R. Drabic, Rheological properties of poloxamer vehicles, Int. J. Pharm.
18 (1984) 269276.

39.

A.H. El-Kamel, In vitro and in vivo evaluation of Pluronic F127-based ocular

delivery system for timolol maleate, Int. J. Pharm. 241 (2002) 4755.

40.

W.F. Harrington, P.H. Von Hippel, The structure of collagen and gelatin, Adv. Protein
Chem. 16 (1961) 1138.

41.

E.R. Gariepy, J.C. Leroux, In situ-forming hydrogelsreview of temperaturesensitive systems, Eur. J. Pharm. Biopharm. 58 (2004) 409426.

42.

J.W. McGinity, M.R. Harris, K. Patel, S.S. Davis, Carbomer. Handbook of

Pharmaceutical Excipients. American Pharmaceutical Association. Washington-DC,
USA. The Pharmaceutical Society of Great Britain, England, (1986), pp. 4142.

43.

N.M. Davies, S.J. Farr, J. Hadgraft, I.W. Kellaway, Evaluation of mucoadhesive

polymers in ocular drug delivery. I. Viscous solutions, Pharm. Res. 8 (8) (1991) 1039
1043.

44.

S. Bhaskaran, P.K. Lakshmi, C.G. Harish, Topical ocular drug delivery a review,
Ind. J. Pharm. Sci. 67 (4) (2005) 404408.

45.

P.E. Jansson, B. Lindberg, Structural studies of gellan gum, an extracellular

polysaccharide elaborated by Pseuomonas elodea, Carbohydr. Res. 124 (1983) 135
139.

46.

A. Rozier, C. Mazuel, J. Grove, B. Plazonnet, Gelrite: a novel ionactivated in situ

gelling polymer for ophthalmic vehicles. Effect on bioavailability of timolol, Int. J.
Pharm. 57 (1989) 163168.

47.

S.S. Chrai, J.R. Robinson, Ocular evaluation of methylcellulose vehicle in albino

rabbits, J. Pharm. Sci. 63 (1974) 12181223.

48.

T.F. Patton, J.R. Robinson, Ocular evaluation of polyvinyl alcohol vehicle in rabbits,
J. Pharm. Sci. 64 (8) (1975) 13121316.

49.

J.L. Greaves, O. Olejnik, C.G. Wilson, Polymers and the precorneal tear film, STP
Pharm. Sci. 2 (1992) 1333.

50.

A. Urtti, L. Salminen, Minimizing systemic absorption of topically administered

ophthalmic drugs, Surv. Ophthalmol. 37 (1993) 435456.

51.

A. Urtti, J.D. Pipkin, G. Rork, T. Sendo, U. Finnc, A.J. Repta, Controlled drug
delivery devices for experimental ocular studies with timolol. Ocular and systemic
absorption in rabbits, Int. J. Pharm. 61 (1990) 241249.

52.

J. Grove, M. Durr, M.-P. Quint, B. Plazonnet, The effect of vehicle viscosity on the
ocular bioavailability of L-653.328, Int. J. Pharm. 66 (1990) 2328.

53.

J.C. Folk, V. Kumar, W.A. Barcellos, R.D. Schoenwald, D.S. Chien, Aqueous vs
viscous phenylephrine II. Mydriatic effects, Arch. Ophthalmol. 104 (1986) 1192
1193.
Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.

29
54.

S.-C. Chang, V.H.L. Lee, Nasal and conjunctival contributions to the systemic
absorption of topical timolol in the pigmented rabbit: implications in the design of
strategies to maximize the ratio of ocular to systemic absorption, J. Ocular Pharmacol.
3 (1987) 159169.

55.

Murali K. Kothuri, Swathi Pinnamaneni,_ Nandita G. Das, and Sudip K. Das,

microparticles and nano particles in ocular drug delivery, Idaho State University,
Pocatello, Idaho, U.S.A.

56.

Schulman, J. A., and Peyman, G. A. (1993). Intracameral, intravitreal, and retinal drug
delivery. In: A. K. Mitra (ed.), Ophthalmic Drug Delivery Systems. Marcel Dekker,
New York, pp. 383425.

57.

Kreuter, J., Tauber, U., and Illi, V. (1979). Distribution and elimination of poly
methyl-2-14-(methacrylate) nanoparticle radioactivity after injection in rat and mice.
J. Pharm. Sci., 68:1443.

58.

Lee, V. H. K., Wood, R. W., Kreuter, J., Harima, T., and Robinson, J. R. (1986).
Ocular drug delivery of progesterone using nanoparticles. J. Microen., 3:213.

59.

Gurny, R., Ibrahim, H., Aebi, A., Buri, P., Wilson, C. G., and Washington, N. (1987).
Design and evaluation of controlled release systems for the eye. J. Cont. Rel., 6:367.

60.

Hui, H. W., and Robinson, J. R. (1985). Ocular delivery of progesterone using a

bioadhesive polymer. Int. J. Pharm., 26:203.

61.

Collins, J. A., James, P. M., Levitski, S. A., Brendenburg, C. E., Anderson, R. W.,
Leonard, F., and Hardway, R. M. (1969). Clinical use in severe combat 460 Kothuri et
al. Copyright 2003 Marcel Dekker, Inc. casualties. Cyanoacrylate adhesive as
topical homeostatic aids. Surgery, 65:260.

62.

Kreuter, J. (1983). Evaluation of nanoparticles as drug delivery systems. I.

Preparation methods. Pharm. Acta. Helv., 58:196.

63.

Kreuter, J. (1992). Nanoparticles-Preparation and applications. In: Microcapsules and

Nanocapsules in Medicine and Pharmacy, M. Don Brow (ed.). CRC Press Inc., Boca
Raton, pp. 126143.

64.

Mezei, M., and Meisner, D. (1993). Liposomes and nanoparticles as ocular drug
delivery systems. In: Biopharmaceutics of Ocular Drug Delivery. CRC Press, Inc.,
Boca Raton, pp. 91101.

65.

Al Khouri Fallouh, N., Roblot-Treupel, L., Fess, H., Devissaguet, J. P. H., and
Puissieux, F. (1986). Development of a new process for the manufacture of
polyisobutylcyanoacrylate nanoparticles. Int. J. Pharm., 28:125.

66.

Marty, J. J., Oppenheim, R. C., and Speiser, P. (1978). Nanoparticles a new colloidal
drug delivery systems. Pharm. Acta. Helv., 53:17.

67.

Scheffel, U., Rhodes, B. A., Natarajan, T. K., Jr., and Wagner, H. N. (1972). Albumin
microspheres for the study of reticuloendothelial system. J. Nucl. Med., 13:498.

68.

Widder, K., Fluoret, G., and Senyei, A. (1979). Magnetic microspheres: Synthesis of a
novel parenteral drug carrier. J. Pharm. Sci., 68:79.

69.

Gurny, R., Peppas, N. A., Harrington, D. D., and Banker, G. S. (1981). Development
of biodegradable and injectable lattices for the controlled release of potent drugs.
Drug Dev. Ind. Pharm., 7:1.
Karamshi R. Chaudhari
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M.

30
70.

Chiang, C. H., Tung, S. M., Lu, D. W., and Yeh, M. K. (2001). In vitro and in vivo
evaluation of an ocular delivery system of 5-fluorouracil microspheres. J. Ocul.
Pharmacol. Ther., 17:545.

71.

Harper, C. A. 3rd, Khoobehi, B., Peyman, G. A., Gebhardt, B. M., and Dunlap, W. A.
(199394). Bioavailability of microsphere-entrapped cyclosporine A in the cornea and
aqueous of rabbits. Int. Ophthalmol., 17:337.

72.

De Campos, A. M., Sa nchez, A., and Alonso, M. J. (2001). Chitosan nanoparticles: a

new vehicle for the improvement of the delivery of drugs to the ocular surface.
Application to cyclosporin A. Int. J. Pharm., 224:159.

73.

Fessi, H., Puisieux, F., Devissaguet, J. P., Ammoury, N., and Benita, S. (1989).
Nanocapsule formation by interfacial polymer deposition following solvent
displacement. Int. J. Pharm., 55:R1.

74.

OHara, P., and Hickey, A. J. (2000). Respirable PLGA microspheres containing

rifampicin for the treatment of tuberculosis: manufacture and characterization. Pharm.
Res., 17:955.
Sing, P., and Maibach, H. I. (1994). Iontophoresis in drug delivery: Basic principles
and applications. Crit. Rev. Therp. Drug Carrier Systems, 11:161213.
Guy, R. H., Kalia, Y. N., Delgado-Charro, M. B., Merino, V., Lopez, A., and Marro,
D. (2000). Iontophoresis: electrorepulsion and electroosmosis. J. Control Release,
64:129132.
Sarraf, D., and Lee, D. A. (1994). The role of iontophoresis in ocular drug delivery. J.
Ocular Pharm., 10:6981.
Pillai, O., Nair, V., Poduri, R., and Panchagnula, R. (1999). Transdermal
iontophoresis. Part II: Peptide and protein delivery. Methods Find. Exp. Clin.
Pharmacol., 21:229240.

75.
76.
77.
78.

Karamshi R. Chaudhari
Pharm. 1 (Pharmaceutics)

M.