Transcript Lecture 10. Manufacturing of eye preparations

Manufacturing of eye
preparations.
One of the major problems encountered with topical
administration is the rapid precorneal loss caused by
nasolacrimal drainage and high tear fl uid turnover, which
leads to drug concentrations of typically less than 10% of
the applied drug.
Approaches to improve the ocular bioavailability have been
attempted in two directions: to increase the corneal
permeability by using penetrations enhancers or prodrugs
and to prolong the contact time with the ocular surface by
using viscosity - enhancing or in situ gelling polymers
Conventional dosage forms such as solutions, suspensions,
and ointments account for almost 90% of the currently
accessible ophthalmic formulations on the market. They
offer some advantages such as their ease of administration
by the patient, ease of preparation, and the low production
costs. However, there are also signifi cant disadvantages
associated with the use of conventional solutions in
particular, including the very short contact time with the
ocular surface and the fast nasolacrimal drainage, both
leading to a poor bioavailability of the drug.
Various ophthalmic delivery systems have been investigated
to increase the corneal permeability and prolong the contact
time with the ocular surface. However, conventional eye
drops prepared and administered as aqueous solutions
remain the most commonly used dosage form in ocular
disease management.
Solutions
The reasons behind choosing solutions over other dosage
forms are their favorable cost advantage, the simplicity of
formulation development and production, and the high
acceptance by patients. However, there are also a few
drawbacks, such as rapid and extensive precorneal loss,
high absorption via the conjunctiva and the nasolacrimal
duct leading to systemic side effects, as well as the
increased installation frequency resulting in low patient
compliance.
Some of these problems have been encountered by addition
of viscosity - enhancing agents such as cellulose derivates,
which are believed to increase the viscosity of the
preparation and consequently reduce the drainage rate. The
use of viscosity enhancers will be discussed later in this
section.
Suspensions
Suspensions of the micronized drug ( < 10 μ m) in a suitable
aqueous vehicle are formulated, where the active compound
is water insoluble. This is the case for most of the steroids.
It is assumed that the drug particles remain in the
conjunctival sac, thus promoting a sustained release effect.
There have been many studies trying to prove this
assumption, but none of them has revealed a pronounced
prolonged release profi le.
According to Davies, topical ophthalmic suspensions have a
number of limitations compared to solutions. They need to
be adequately shaken before use to ensure correct dosing, a
process which can result in poor patient compliance. In
addition, they need to be sterilized, which may cause
physical instability of the formulation.
Furthermore, the amount of drug required to achieve only a
moderate increase in bioavailability is very high, rendering
suspensions expensive in terms of their production costs.
The drug particle size plays the most important role in the
formulation process of suspensions. Particles greater than
10 μ m cause patient discomfort. As they are perceived as
foreign substances, they cause refl ex tearing in order to
eliminate the particles from the ocular surface. A study by
Schoenwald and Stewart showed the infl uence of the
particle size of dexamethasone on its bioavailability.a
The in vivo dissolution rate decreased with increasing
particle size to the point when particles were removed from
the conjunctival sac before the dissolution was complete.
As a result, achieving a near - solution state with small
particles that are easy to resuspend and show minimal
sedimentation remains the goal when formulation of a
suspension is unavoidable.
Ointments
Ointments generally consist of a dissolved or dispersed drug
in an appropriate vehicle base. They are the most commonly
used semisolid preparations as they are well tolerated and
fairly safe and increase the ocular bioavailability of the
drug. The instilled ointment breaks up into small oily
droplets that remain in the cul - de - sac as a drug depot.
The drug eventually gets to the ointment – tear interface due
to the shearing action of the eyelids.
Sieg and Robinson compared the bioavailability of fl
uorometholone in a solution, a suspension, and an ointment.
They found that the peak concentration (cmax ) of the drug
in the aqueous humor of rabbits was comparable with all
three formulations, whereas the time to peak concentration (
tmax ) occurred much later with the ointment, leading to a
signifi cantly greater total bioavailability of the drug.
Overall, ophthalmic ointments offer the following
advantages: reduced dilution of the medication via the tear
fi lm, resistance to nasolacrimal drainage, and an increased
precorneal contact time. However, oily viscous preparations
for ophthalmic use (such as ointments) can cause blurred
vision and matting of the eyelids and may also be associated
with discomfort by the patient as well as occasional ocular
mucosal irritation. Ointments are therefore generally used in
combination with eye drops, which can be administered
during the day, while the ointment is applied at night, when
clear vision is not required.
Polymeric systems used for ocular drug delivery can be
divided into three groups: viscosity - enhancing polymers,
which simply increase the formulation viscosity, resulting
in
decreased
lacrimal
drainage
and
enhanced
bioavailability; mucoadhesive polymers, which interact
with the ocular mucin, therefore increasing the contact time
with the ocular tissues; and in situ gelling polymers, which
undergo sol - to – gel phase transition upon exposure to the
physiological conditions present in the eye.
Viscosity -Enhancing Polymers
In order to reduce the lacrimal clearance (drainage) of
ophthalmic solutions, various polymers have been added to
increase the viscosity of conventional eye drops, prolong
precorneal contact time, and subsequently improve ocular
bioavailability of the drug. Among the range of hydrophilic
polymers investigated in the area of ocular drug delivery are
polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP),
cellulose derivates such as methylcellulose (MC), and
polyacrylic acids (carbopols).
Chrai and Robinson evaluated the use of an MC solution of
pilocarpine in albino rabbits and found a decrease in the
drainage rate with increasing viscosity.
Patton and Robinson investigated the relationship between
the viscosity and the contact time or drainage rate and
demonstrated an optimum viscosity of 12 – 15 cps for an
MC solution in rabbits. The infl uence of different polymers
on the activity of pilocarpine in rabbits and human was
reported by Saettone et al.
The ocular shear rate ranges from 0.03 s − 1 during
interblinking periods to 4250 – 28,500 s − 1 during
blinking. It has a great infl uence on the rheological
properties of viscous ocular dosage forms and consequently
the bioavailability of the incorporated drug. Newtonian
systems do not show any real improvement of
bioavailability below a certain viscosity and blinking
becomes painful, followed by refl ex tearing, if the viscosity
is too high. While the viscosity of Newtonian systems is
independent from the shear rate, non - Newtonian
pseudoplastic or so – called shear - thinning systems exhibit
a decrease in viscosity with increasing shear rates.
Mucoadhesive Polymers
Bioadhesion refers to the attachment of a drug molecule or a
delivery system to a specifi c biological tissue by means of
interfacial forces. If the surface of the tissue is covered by a
mucin fi lm, as is the case for the external globe, it is more
commonly referred to as mucoadhesion.
In order to be an effective mucoadhesive excipient,
polymers must show one or more of the following features:
strong hydrogen binding group, strong anionic charge, high
molecular weight, suffi cient chain fl exibility, surface
energy properties favoring spreading onto the mucus, and
near - zero contact angle to allow maximum contact with
the mucin coat.
The most commonly used bioadhesives are macromolecular
hydrocolloids with numerous hydrophilic functional groups
capable of forming hydrogen bonds (such as carboxyl,
hydroxyl, amide, and sulfate groups). Hui and Robinson
were the fi rst to demonstrate the usefulness of bioadhesive
polymers in improving the ocular bioavailability of
progesterone. Saettone et al. evaluated a series of
bioadhesive dosage forms for ocular delivery of pilocarpine
and tropicamide and found hyaluronic acid to be the most
promising mucoadhesive polymer.
Lehr et al. suggested that cationic polymers, which are able
to interact with the negative sialic acid residues of the
mucin, would probably show better mucoadhesive
properties than anionic or neutral polymers. They
investigated the polycationic polymer chitosan and
demonstrated that the mucoadhesive performance of
chitosan was signifi cantly higher in neutral or slightly
alkaline pH as it is present in the tear fl uid.a
However, according to Park and Robinson, polyanions are
better than polycations in terms of binding and potential
toxicity. In general, both anionic and cationic charged
polymers demonstrate better mucoadhesive properties than
nonionic polymer, such as cellulose derivates or PVA.a
The mechanism of mucoadhesion involves a series of
different steps. First, the mucoadhesive formulation needs
to establish an intimate contact with the corneal surface.
Prerequisites are either good wetting or swelling of the
mucoadhesive polymer as well as suffi cient spreading
across the cornea.
The second stage involves the penetration of the
mucoadhesive polymer chains into the crevices of the tissue
surface and also the entanglement with the mucous chains.
On a molecular level, mucoadhesion is a results of van - der
- Waals forces, electrostatic attractions, hydrogen bonding,
and hydrophobic interactions.
Mucoadhesive polymers increase the contact time of a
formulation with the tear fi lm and simulate the continuous
delivery of tears due to a high water – restraining capacity.
As such, they allow a decrease in the instillation frequency
compared to common eye drops and are therefore useful as
artifi cial tear products.
In Situ Gelling Systems
In situ gelling systems are viscous polymer - based liquids
that exhibit sol - to - gel phase transition on the ocular
surface due to change in a specifi c physicochemical
parameter (ionic strength, temperature, pH, or solvent
exchange). They are highly advantageous over preformed
gels as they can easily be instilled in liquid form but are
capable of prolonging the residence time of the formulation
on the surface of the eye due to gelling.
The principal advantage of in situ gelling systems is the
easy, accurate, and reproducible administration of a dose
compared to the application of preformed gels.
The concept of forming gels in situ (e.g., in the cul - de - sac
of the eye) was fi rst suggested in the early 1980s, and ever
since then various triggers of in situ gelling have been
further investigated.
Polymers that may undergo sol - to - gel transition triggered
by a change in pH are cellulose acetate phthalate (CAP) and
cross - linked polyacrylic acid derivates such as carbopols,
methacrylates and polycarbophils. CAP latex is a free running solution at pH 4.4 which undergoes sol - to - gel
transition when the pH is raised to that of the tear fl uid.
This is due to neutralization of the acid groups contained in
the polymer chains, which leads to a massive swelling of
the particles. The use of pH – sensitive latex nanoparticles
has been described by Gurny et al. Carbopols have apparent
p Ka values in the range of 4 – 5 resulting in rapid gelation
due to rise in pH after ocular administration.
Gellan gum is an anionic polysaccharide which undergoes
phase transition under the infl uence of an increased ionic
strength. In fact, the gel strength increases proportionally
with the amount of mono - or divalent cations present in the
tear fl uid.
As a consequence, the usual refl ex tearing, which leads to a
dilution of common viscous solutions, further enhances the
viscosity of gellan gum formulations due to the increased
amount of tear fl uid and thus higher cation concentration.
Shedden et al compared the plasma concentrations of
timolol following multiple applications of Timoptic - XE
and a timolol maleate solution. They found that a once daily application of the in situ gelling formulation was suffi
cient to reduce the intraocular pressure to levels comparable
to a twice - daily application of the solution, leading to
better patient compliance as well as a reduction in systemic
side effects.
Poloxamers or pluronics are block copolymers consisting of
poly(oxyethylene) and poly(oxypropylene) units. They
rapidly undergo thermal gelation when the temperature is
raised to that of the ocaular surface (32 ° C), while they
remain liquid at refrigerator temperature. Poloxamers
exhibit surface active properties, but even if used in high
concentrations (usually between 20 and 30%), Pluronic
F127 was found no more damaging to the cornea than a
physiological saline solution.
In order to reduce the total polymer concentration and
achieve better gelling properties, several poloxamer
combinations have been tested. Wei et al used a mixture of
Pluronic F127 and F68 resulting in a more suitable phase
transition temperature with a free - fl owing liquid under 25
° C.
Combining thermal - with pH - dependent gelation, Kumar
et al. developed a combination of methylcellulose 15% and
carbopol 0.3%.
This composition exhibited a sol - to - gel transition
between 25 and 37 ° C with a pH increase from 4 to 7.4. A
possible mechanism for the thermal effect could be the
decrease in the degree of the methylcellulose hydration,
while the polyacrylic acid can transform into a gel upon an
increase in pH due to the buffering properties of the tear fl
uid.
Colloidal carriers have been investigated as drug delivery
systems for the past 30 years in order to achieve specifi c
drug targeting, facilitate the bioavailability of drugs through
biological membranes, and protect the drug against
enzymatic degradation.
Their use in topical administration and especially in ocular
delivery however has only been studied for the last two
decades.
Colloidal carriers are small particulate systems ranging in
size from 100 to 400 nm.
As they are usually suspended in an aqueous solution, they
can easily be administered as eye drops, thus avoiding the
potential discomfort resulting from bigger particles present
in ocular suspensions or from viscous or sticky
preparations.
Most efforts in ophthalmic drug delivery have been made
with the aim of increasing the corneal penetration of the
drug. Calvo et al. have shown that colloidal particles are
preferably taken up by the corneal epithelium via
endocytosis. It has also been stated by Lallemand and co workers , that the cornea acts as a drug reservoir, slowly
releasing the active compound present in the colloidal
delivery system to the surrounding ocular tissues.
Nanoparticles
Nanoparticles have been among the most widely studied
particulate delivery systems over the past three decades.
They are defi ned as submicrometer - sized polymeric
colloidal particles ranging from 10 to 1000 nm in which the
drug can be dissolved, entrapped, encapsulated, or
adsorbed.
Depending on the preparation process, nanospheres or
nanocapsules can be obtained. Nanospheres have a
matrixlike structure where the drug can either be fi rmly
adsorbed at the surface of the particle or be
dispersed/dissolved in the matrix. Nanocapsules, on the
other hand, consist of a polymer shell and a core, where the
drug can either be dissolved in the inner core or be adsorbed
onto the surface.a
The fi rst nanoparticulate delivery system studied was
Piloplex, consisting of pilocarpine ionically bound to
poly(methyl)methacrylate – acrylic acid copolymer
nanoparticles. Klein et al. found that a twice - daily
application of Piloplex in glaucoma patients was just
as effective as three to six instillations of conventional
pilocarpine eye drops. However, the formulation was
never accepted for commercialization due to various
formulation - related problems, including the
nonbiodegradability, local toxicity, and diffi culty of
preparing a sterile formulation.
Another early attempt to formulate a nanoparticulate system
for the delivery of pilocarpine was made by Gurny. This
formulation was based on pilocarpine dispersed in a
hydrogen CAP pseudolatex formulation. Gurny and co workers compared the formed nanoparticles to a 0.125%
solution of hyaluronic acid some years after their fi rst
investigation and found that the viscous hyaluronic acid
system showed a signifi cantly longer retention time in front
of the eye than the pseudolatex formulation.
The most commonly used biodegradable polymers in
the preparation of nanoparticulate systems for ocular
drug delivery are poly - alkylcyanoacrylates, poly - ε caprolactone, and polylactic - co - glycolic acid
copolymers. Marchal - Heussler et al. compared the
three particulate delivery systems using antiglaucoma
drugs including betaxolol and cartechol. Results
showed that poly - ε - caprolactone (nanospheres and
nanocapsules) exhibited the highest pharmacological
activity when loaded with betaxolol.
It seemed that the higher ocular activity was related to the
hydrophobic nature of the carrier and that the mechanism of
action seemed to be directly linked to the agglomeration of
the particles in the conjunctival sac. In general,
nanocapsules displayed a much better effect than
nanospheres probably due to the fact that the active
compound was in its un - ionized form in the oily core and
could diffuse faster into the cornea. Diffusion of the drug
from the oily core of the nanocapsule to the corneal
epithelium seems to be more effective than diffusion from
the internal, more hydrophilic matrix of the nanospheres.
In order to achieve a sustained drug release and a prolonged
therapeutic activity, nanoparticles must be retained in the
cul - de - sac and the entrapped drug must be released from
the particles at a certain rate. If the release is too fast, there
is no sustained release effect. If it is too slow, the
concentration of the drug in the tears might be too low to
achieve penetration into the ocular tissues. The major
limiting issues for the development of nanoparticles include
the control of particle size and drug release rate as well as
the formulation stability.
So far, there is only one microparticulate ocular delivery
system on the market. Betoptic S is obtained by binding of
betaxolol to ion exchange resin particles. Betoptic S 0.25%
was found to be bioequivalent to the Betoptic 0.5% solution
in lowering the intraocular pressure.
Liposomes
Liposomes were fi rst reported by Bangham in the 1960s
and have been investigated as drug delivery systems for
various routes ever since then. They offer some promising
features for ophthalmic drug delivery as they can be
administered as eye drops but will localize and maintain the
pharmacological activity of the drug at its site of action.
Due to the nature of the lipids used, conventional liposomes
are completely biodegradable, biocompatible, and relatively
nontoxic.
A liposome or so - called vesicle consists of one or more
concentric spheres of lipid bilayers separated by water
compartments with a diameter ranging from 80 nm to 100 μ
m. Owing to their amphiphilic nature, liposomes can
accommodate both lipohilic (in the lipid bilayer) and
hydrophilic (encapsulated in the central aqueous
compartment) drugs.
According to their size, liposomes are classifi ed as either
small unilamellar vesicles (SUVs) (10 – 100 nm) or large
unilamellar vesicles (LUVs) (100 – 300 nm). If more than
one bilayer is present, they are referred to as multilamellar
vesicles (MLVs). Depending on their lipid composition,
they can have a positive, negative, or neutral surface charge.
Liposomes are potentially valuable as ocular drug delivery
systems due to their simplicity of preparation and versatility
in physical characteristics. However, their use is limited by
instability (due to hydrolysis of the phospholipids), limited
drug - loading capacity, technical diffi culties in obtaining
sterile preparations, and blurred vision due to their size and
opacity.
In addition, liposomes are subject to the same rapid
precorneal clearance as conventional ocular solutions,
especially the ones with a negative or no surface charge.
Positively charged liposomes, on the other hand, were
reported to exhibit a prolonged precorneal retention due to
electrostatic interactions with the negative sialic acid
residues of the mucin layer .
There have been several attempts to use liposomes in
combination with other newer formulation approaches,
such as incorporating them into mucoadhesive gels or
coating
them
with
mucoadhesive
polymers.
Mucoadhesive polymers inves- tigated in this regard
were poly(acrylic acid) (PAA), hyaluronic acid (HA),
chitosan, and poloxamer.
Durrani and co - workers reported on the infl uence of a
carbopol coating on the corneal retention of pilocarpine loaded liposomes, and demonstrated a biphasic response
with an initial low intensity followed by a sustained
reaction.
Bochot et al. developed a novel delivery system for
oligonucleotides by incorporating them into liposomes and
then dispersing them into a thermosensitive gel composed
of poloxamer 407. They compared the in vitro release of the
model oligonucleotides pdT16 from simple poloxamer gels
(20 and 27% poloxamer) with the ones where pdT16 was
encapsulated into liposomes and then dispersed within the
gels.
They found that the release of the oligonucleotides from the
gels was controlled by the poloxamer dissolution, whereas
the dispersion of liposomes within 27% poloxamer gel was
shown to slow down the diffusion of pdT16 out of the gel.
Niosomes
In order to circumvent some of the limitations encountered
with liposomes, such as their chemical instability, the cost
and purity of the natural phospholipids, and oxidative
degradation of the phospholipids, niosomes have been
developed. Niosomes are nonionic surfactant vesicles which
exhibit the same bilayered structures as liposomes. Their
advantages over liposomes include improved chemical
stability and low production costs. Moreover, niosomes are
biocompatible, biodegradable, and nonimmunogenic.
They were also shown to increase the ocular bioavailability
of hydrophilic drugs signifi cantly more than liposomes.
This is due to the fact that the surfactants in the niosomes
act as penetrations enhancers and remove the mucous layer
from the ocular surface.
A modifi ed version of niosomes are the so - called
discomes, which vary from the conventional niosomes in
size and shape. The larger size of the vesicles (12 – 60 μ m)
prevents their drainage into the nasolacrimal drainage
system. Furthermore, their disclike shape provides them
with a better fi t in the cul - de - sac of the eye.
Vyas et al. demonstrated that discomes entrapped higher
amounts of timolol maleate than niosomes and that both
niosomes and discomes signifi cantly increased the
bioavailability of timolol maleate when compared to a
conventional timolol maleate solution.
Microemulsions
Microemulsions (MEs) are colloidal dispersions composed
of an oil phase, an aqueous phase, and one or more
surfactants.
They
are
optically
isotropic
and
thermodynamically stable and appear as transparent liquids
as the droplet size of the dispersed phase is less than 150
nm. One of their main advantages is their ability to increase
the solubilization of lipophilic and hydrophilic drugs
accompanied by a decrease in systemic absorption.
Moreover, MEs are transparent systems thus enable
monitoring of phase separation and/or precipitation. In
addition, MEs possess low surface tension and therefore
exhibit good wetting and spreading properties.
While the presence of surfactants is advantageous due to an
increase in cellular membrane permeability, which
facilitates drug absorption and bioavailability, caution needs
to be taken in relation to the amount of surfactant
incorporated, as high concentrations can lead to ocular
toxicity.
In general, nonionic surfactants are preferred over ionic
ones, which are generally too toxic to be used in ophthalmic
formulations. Surfactants most frequently utilized for the
preparation of MEs are poloxamers, polysorbates, and
polyethylene glycol derivatives.
Similar to all other colloidal delivery systems discussed
above it was hypothesized by numerous research teams that
a positive charge (provided by cationic surfactants ) would
increase the ocular residence time of the formulation due to
electrostatic interactions with the negatively charged mucin
residues. However, toxicological studies contradicted this
assumption regarding the ocular effects, and so far there has
been no publication demonstrating a distinct benefi cial
effect of charged surfactants incorporated into MEs.
Microemulsions can be classifi ed into three different types
depending on their microstructure: oil - in - water (o/w
ME), water - in - oil (w/o ME), and bicontinuous ME.
They have been investigated by physical chemists since the
1940s but have only gained attention as potential ocular
drug delivery carriers within the last two decades.
Gasco and co - workers investigated the potential
application of o/w lecithin
MEs for ocular administration of timolol, in which the drug
was present as an ion pair with octanoate. The ocular
bioavailability of the timolol ion pair incorporated into the
ME was compared to that of an ion pair solution as well as a
simple timolol solution. Areas under the curve for the ME
and the ion pair solution respectively were 3.5 and 4.2 times
higher than that of the simple timolol solution. A prolonged
absorption was achieved using the ME with detectable
amounts of the drug still present 120 min after instillation.
Various lecithin - based MEs were also characterized by
Hasse and Keipert.
The formulations were tested in terms of their
physicochemical parameters (pH, refractive index,
osmolality, viscosity, and surface tension) and physiological
compatibility (HET - CAM and Draize test). In addition, in
vitro and in vivo evaluations were performed. The tested
MEs showed favorable physicochemical parameters and no
ocular irritation as well as a prolonged pilocarpine release in
vitro and in vivo.
Muchtar and co - workers prepared MEs with
poloxamer 188 and soybean lecithin to deliver
indometacin to the ocular tissues. They found a
threefold increased indomethacin concentration in the
cornea and aqueous humor 1 h post - instillation.
Beilin et al. demonstrated a prolonged ocular retention of a
submicrometer emulsion (SME) in the conjunctival sac
using a fl uorescent marker (0.01% calcein) as well as the
miotic response of New Zealand Albino rabbits to
pilocarpine. They found that the fl uorescence intensity of
calcein in SME was signifi cantly higher than that of a
calcein solution at all time points.
Moreover, the pilocarpine SME exhibited a longer duration
of miosis than the simple pilocarpine solution. It should be
mentioned that SMEs are true emulsions, being different
from MEs. They do not form spontaneously and are
kinetically rather than thermodynamically stable. They
generally require high - shear homogenization to form and
are more susceptible to phase inversion.
Furthermore, they are neither transparent nor translucent but
rather turbid due their larger droplet size compared to MEs.
While the two terms are used interchangeably in the the
scientifi c literature, they actually refer to two distinct
categories of dispersed systems and should be differentiated
from each other.
The w/o MEs composed of water, Crodamol EO, Crill
1, and Crillet 4 were investigated as potential ocular
delivery systems by Alany et al. It was hypothesized
that w/o MEs undergo phase transition into lamellar
liquid crystals (LCs) upon aqueous dilution by the
tears, prolonging the precorneal retention time due to
an increase in the formulation ’ s viscosity.
HET - CAM studies revealed no ocular irritancy by the
excipients used. Ocular drainage was evaluated via γ scintigraphy and demonstrated a signifi cantly higher
precorneal retention of the tested microemulsions compared
to an aqueous solution.
The use of MEs in ocular delivery is very attractive due to
all the advantages offered by these formulations. They are
thermodynamically stable and transparent, possess low
viscosity, and thus are easy to instill, formulate, and
sterilize (via fi ltration).
Moreover, they offer the possibility of reservoir and/or
localizer effects. All these factors, in addition to the ones
previously mentioned, render MEs promising ocular
delivery systems.
Many other ocular delivery approaches have been
investigated over the past decades, including the use of
prodrugs, penetration enhancers, cyclodextrins, as well as
different types of ocular inserts. In addition, iontophoresis,
which is an active drug delivery approach utilizing
electrical current of only 1 – 2 mA to transport ionized
drugs across the cornea, offers an effective, noninvasive
method for ocular delivery.
Another more recent approach is the use of dendrimers in
ocular therapy. Dendrimers are synthetic spherical
molecules named after their characteristic treelike
branching around a central core with a size ranging from 2
to 10 nm in diameter. So far, PAMAM (polyamidoamine)
has been the most commonly studied dendrimer system for
ocular use.
Prodrugs
Prodrugs are pharmacologically inactive derivates of drug
molecules that require a chemical or enzymatic
transformation into their active parent drug. To be effective,
an ocular prodrug should show an appropriate lipophilicity
to facilitate corneal absorption, posses suffi cient aqueous
solubility and stability to be formulated as an eye drop, and
demonstrate the ability to be converted to the active parent
drug at a rate that meets therapeutic needs.
When considering ophthalmic drug molecules as prodrug
candidates, the following factors need to be considered: the
pathway and mechanism of ocular drug penetration, the
functional groups of the drug candidate amenable to
prodrug derivatization, and the enzymes present in the
ocular tissues, which are necessary for prodrug activation.
The majority of ophthalmic prodrugs developed so far are
chemically classifi ed as ester. They are derived from the
esterifi cation of the hydroxyl or carboxylic acid groups
present in the parent molecule. Of all enzymes participating
in the activation of prodrugs, esterases, which are present in
all anterior segment tissues except the tear fi lm, have
received the most attention.
However, the concept of prodrugs was not fully exploited
until the introduction of dipivefrin (epinephrine prodrug) in
the late 1970s. Kaback and co - workers found that a 0.1%
dipivalyl epinephrine solution lowered the intraocular
pressure as effective as a 2% epinephrine solution, while
signifi cantly lowering the systemic side effects.
Wei et al. compared the ocular penetration, distribution, and
metabolism of epinephrine and dipivalyl epinephrine and
found the partition coeffi cient of the later to be 100 – 600
times higher than that of epinephrine, therefore leading to a
10 - times faster absorption into the rabbit eye.
Dipivefrin was the only commercially available
ophthalmic prodrug at that time. However, numerous
prodrug derivates have been designed to improve the
effi cacy of ophthalmic drugs ever since.
Jarvinen and co - workers synthesized unique O, O′ (xylylene)bispilocarpic acid esters containing two pilocarpic
acid monoesters linked with one moiety. The found that
prodrug showed a two - to seven - fold higher corneal
permeability than pilocarpine itself despite the high
molecular weight.
Tirucherai et al. formulated an acyl ester prodrug of
ganciclovir. The increased permeability was associated with
a linear increased susceptibility of the ganciclovir esters to
the esterases present in the cornea.
So far, aims that have been achieved by using prodrugs
include the modifi cation of the drug ’ s duration of action,
reduction of the systemic absorption, and reduction of
ocular and systemic side effects. Although prodrugs are
commonly used to treat diseases of the anterior segment,
there have also been attempts to treat conditions associated
with the posterior segment of the eye.a
Penetration Enhancers
The transport process across the corneal tissue is the rate limiting step in ocular drug absorption. Increasing the
permeability of the corneal epithelium by penetration
enhancers is likely to enhance the drug transport across the
corneal tissues and therefore improve ocular bioavailability
of the drug.
Penetration enhancers act by increasing the permeability of
the corneal cell membrane and/or loosening the tight
junctions between the epithelial cells, which primarily
restrict the entry of molecules via the paracellular pathway.
Classes of penetration enhancers include surfactants, bile
salts, calcium chelators, preservatives, fatty acids, and some
glycosides such a saponin.
Surfactants are perceived to enhance drug absorption by
disturbing the integrity of the plasma membranes. When
present at low concentrations, surfactants are incorporated
into the lipid bilayer, leading to polar defects in the
membrane, which change the membrane ’ s physical
properties.
When the lipid bilayer is saturated, micelles start to form,
enclosing phospholipids from the membranes, hence
leading to membrane solubilization. Saettone et al. found an
increased corneal permeability for atenolol, timolol, and
betaxolol by including 0.05% Brij 35, Brij 78, and Brij 98
into their formulations.
Bile salts are amphiphilic molecules that are surface active
and self - associate to form micelles in aqueous solution.
They increase corneal permeability by changing the
rheological properties of the bilayer. A number of bile salts
such as deoxycholate, taurodeoxycholate, and glycocholate
have been tested so far, and it was suggested, that a
difference in their physicochemical properties (solubilizing
activity, lipophilicity, Ca 2+ sequestration capacity) is
probably related to their performance as permeability enhancing agents.
Large numbers of penetration enhancers have been
investigated to date. However, the unique structure of the
corneal/conjunctival tissues requires caution. When
selecting penetration enhancers for ocular delivery, their
capacity to affect the integrity of the epithelial surfaces
needs to be considered. Studies have shown that penetration
enhancers themselves can penetrate ocular tissues, which
could lead to potential toxicity.
EDTA concentrations in the iris – ciliary body, for example,
were found to be high enough to alter the permeability of
the blood vessels in the uveal tract, therefore indirectly
accelerating the drug ’ s removal from the aqueous humor.
Similarly, benzalkonium chloride (BAC), a cationic
surfactant which shows the highest penetration - enhancing
effect among the currently used preservatives, was found to
accumulate in the cornea for several days.
Cyclodextrins
Cyclodextrins were introduced into the area of ocular drug
delivery in the early 1990s. They are a group of
homologous cyclic oligosaccharides with a hydrophilic
outer surface and a lipophilic cavity in the center. Their
initial aim was to increase the solubility of lipophilic drugs
by forming inclusion complexes.
Cyclodextrin complexation generally results in improved
wettability, dissolution, solubility, and stability in solution
as well as reduced side effects.
It is assumed that cyclodextrins are too large and
hydrophilic to penetrate biological membranes. However,
they act as penetration enhancers by assuring a high drug
concentration at the corneal surface, from where the drug
then partitions into the ocular tissues.
Even though cyclodextrins drug complexes seem to
decrease ocular toxicity of irritant drugs, cyclodextrins
themselves may exhibit ocular toxicity and should therefore
be screened by performing corneal sensitivity studies.
Among all cyclodextrin derivates investigated, hydroxy propyl - β - cyclodextrin showed the most favorable
properties in terms of toxicity.
Nijhawan and Agarwal investigated inclusion complexes of
ciprofl oxacin hydrochloride and hydroxy - propyl - β cyclodextrin and found that the complexes exhibited better
stability, biological activity, and ocular tolerance than the
uncomplexed drug in solution.
Aktas et al. showed an increased permeation of pilocarpine
nitrate complexed with hydroxy - propyl - β - cyclodextrin
using isolated rabbit cornea. They found a signifi cant
reduction in the pupil diameter compared to a simple
aqueous solution of the same active compound.
Cyclodextrins improve chemical stability, increase the drug
’ s bioavailability, and decrease local irritation. However,
the improvement of ocular bioavailability seems to be
limited by the very slow dissociation of the complexes in
the precorneal tear fl uid.
Several studies have shown that combinations of
cyclodextrins drug complexes and viscosity enhancers can
signifi cantly improved ocular absorption and should
therefore be further investigated.
Ocular Inserts
Solid ocular dosage forms such as fi lms, erodible and
nonerodible inserts, rods, and shields have been developed
to overcome the typical pulse - entry - type drug release
associated with conventional ocular dosage forms. This
pulse entry is characterized by a transient overdose, a
relatively short period of appropriate dosing, followed by a
prolonged period of underdosing.
Ocular inserts were developed in order to overcome these
disadvantages by providing a more controlled, sustained,
and continuous drug delivery by maintaining an effective
drug concentration in the target tissues and yet minimizing
the number of applications.
Ocular inserts probably represent one of the oldest
ophthalmic formulation approaches. In 1948 the British
Pharmacopoeia described an atropine - in – gelatin wafer
and ever since then numerous systems have been developed
applying various polymers and different release principals.
However, the diffi culty of insertion by the patient, foreign body sensation, and inadvertent loss of inserts from the eye
make these systems less popular, especially among the
elderly. Furthermore, the high cost involved in manufacture
prevented the insert market from taking off.
Two products, Alza Ocusert and Merck Lacrisert, have been
marketed, although Ocusert is no longer available. Ocusert
is a membrane - controlled reservoir system for the
treatment of glaucoma. It contains pilocarpine and alginic
acid in the core reservoir, sandwiched between two
transparent, lipophilic ethylenevinyl acetate (EVA) rate controlling membranes, which allow the drug to diffuse
from the reservoir at a precisely determined rate for a period
of seven days.
This system is nonbiodegradable and must therefore be
removed after use. Lacrisert, on the other hand, is a soluble
minirod of hydroxypropylmethyl cellulose without any
active ingredient.
The system is placed in the conjunctival sac, where it softens
within an hour and completely dissolves within 14 – 18 h.
Lacrisert stabilizes and thickens the precorneal tear fi lm
and prolongs the tear fi lm break - up time, which is usually
accelerated in patients with dry - eye syndrome
(keratoconjunctivitis sicca).
A number of ocular inserts using different techniques,
namely soluble, erodible, nonerodible, and hydrogel inserts
with polymers such as cellulose derivates, acrylates, and
poly(ethylene oxide), have been investigated over the last
few decades.
An example of a degradable matrix system is the
pilocarpine - containing inserts formulated by Saettone et al.
Pilocarpine nitrate and polyacrylic acid were incorporated
into a matrix containing polyvinyl alcohol and two types of
hydroxypropyl methylcellulose. It was shown that all inserts
signifi cantly increased the pharmacological effect (miotic
response) compared to a solution of pilocarpine nitrate.
Sasaki et al. prepared nondegradable disc - type ophthalmic
inserts of β - blockers using different polymers. They found
that inserts made from poly(hydroxypropyl methacrylate)
were able to control the release of tilisolol hydrochloride.
Numerous studies have also been performed on soluble
collagen shields. Collagen shields are fabricated from
porcine scleral tissue, which has a similar collagen
composition to that of the human cornea. Drug loading is
typically achieved by soaking the collagen shield in the
drug solution prior to application. Designed to slowly
dissolve within 12, 24, or 72 h, collagen shields have
attracted much interest as potential sustained ocular drug
delivery systems over the last years.
Although conventional eye drops still represent about 90%
of all marketed ophthalmic dosage forms, there have been
signifi cant efforts towards the development of new drug
delivery systems.
Only a few of these new ophthalmic drug delivery systems
have been commercialized over the past decades, but
research in the different areas of ocular drug delivery has
provided important impetus and dynamism, with the
promise of some new and exciting developments in the fi
eld.
An ideal ophthalmic delivery system should be able to
achieve an effective drug concentration at the target site for
an extended period of time while minimizing systemic side
effects. In addition, the system should be comfortable and
easy to use, as the patient ’ s acceptance will continue to
play an important role in the design of future ocular
formulations.
All delivery technologies mentioned in this chapter hold
unlimited potential for clinical ophthalmology. However,
each of them still bears its own drawbacks. To circumvent
these, newer trends are directed toward combinations of the
different drug delivery approaches. Examples for this
include the incorporation of particulates into in situ gelling
systems or coating of nanoparticles with mucoadhesive
polymers.
These combinations will open new directions for the
improvement of ocular bioavailability, but they will also
increase the complexity of the formulations, thus increasing
the diffi culties in understanding the mechanism of action of
the drug delivery systems.
Many interesting delivery approaches have been
investigated during the past decades in order to optimize
ocular bioavailability, but much remains to be learned
before the perfect ocular drug delivery system can be
developed.