Plh S 1350-9462(97)00002-5

Ophthalmic Drug Delivery Systems Recent Advances

Chryst~:le Le Bourlais I, Liliane Acar 1, Hosein Zia 2, Pierre A. Sado 1,
Thomas Needham 2 and Roger Leverg¢
tLaboratoire de Pharmacie Galbnique, Biopharmacie et Pharmaeie Clinique, Faeult~ de Pharmacie,
Universitk de Rennes, 35043, Rennes, France and 2Department of Applied Pharmaceutical Sciences,
College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA

CONTENTS

Abstract .............................................................................. 34
1. I n t r o d u c t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
1.1. C o n v e n t i o n a l D o s a g e F o r m s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
1.2. P h y s i o l o g i c a l C o n s i d e r a t i o n s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
1.3. P h a r m a c o k i n e t i c C o n s i d e r a t i o n s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
1.4. Interest in N e w D r u g D e l i v e r y Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2. P o l y m e r i c G e l s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.1. B i o a d h e s i v e H y d r o g e l s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.1.1. D e f i n i t i o n ~ e s c r i p t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.1.2. T h e r a p e u t i c a p p r o a c h in o p h t h a l m o l o g y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2,1.2.1. O c u l a r t o l e r a n c e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.2. In Situ A c t i v a t e d G e l - f o r m i n g Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
2.2.1. D e f i n i t i o n ~ d e s c r i p t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
2.2.2. T h e r a p e u t i c a p p r o a c h in o p h t h a l m o l o g y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3. C o l l o i d a l Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.1. L i p o s o m e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.1.1. D e f i n i t i o n ~ d e s c r i p t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.1.2. T h e r a p e u t i c a p p r o a c h in o p h t h a l m o l o g y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.2. N a n o p a r t i c l e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.2.1. D e f i n i t i o n - - d e s c r i p t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.2.2. T h e r a p e u t i c a p p r o a c h in o p h t h a l m o l o g y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4. O t h e r D r u g Deliivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.1. C y c l o d e x t r i n s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4,1.1. D e f i n i t i o n - - d e s c r i p t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.1.2. T h e r a p e u t i c a p p r o a c h in o p h t h a l m o l o g y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.2. C o l l a g e n Shields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.2.1. D e f i n i t i o n - - d e s c r i p t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.2.2. T h e r a p e u t i c a p p r o a c h in o p h t h a l m o l o g y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5. C o n c l u s i o n s - - F u t u r e D i r e c t i o n s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.1. N e w Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Progress in Retinal and Eye Research Vol. 17, No. 1, pp. 33-58, 1998
O 1997 Elsevier Science Ltd. All rights reserved
Printed in Great Britain
1350-9462/98 $17.00 + 13.00
34 C. Le Bourlais et al.
Abstract--Eye-drops are the conventional dosage forms that account for 90% of currently accessible ophthalmic
formulations. Despite the excellent acceptance by patients, one of the major problems encountered is rapid precorneal drug
loss. To improve ocular drug bioavailability, there is a significant effort directed towards new drug delivery systems
for ophthalmic administration.
This chapter will focus on three representative areas of ophthalmic drug delivery systems: polymeric gels, colloidal
systems, cyclodextrins and collagen shields.
Hydrogels generally offer a moderate improvement of ocular drug bioavailability with the disadvantage of blurring of
vision. In situ activated gel-forming systems are preferred as they can be delivered in drop form with sustained release
properties. Colloidal systems including liposomes and nanoparticles have the convenience of a drop, which is able to
maintain drug activity at its site of action and is suitable for poorly water-soluble drugs. Among the new therapeutic
approaches in ophthalmology, cyclodextrins represent an alternative approach to increase the solubility of the drug in
solution and to increase corneal permeability. Finally, collagen shields have been developed as a new continuous-delivery
system for drugs that provide high and sustained levels of drugs to the cornea, despite a problem of tolerance.
It seems that new tendency of research in ophthalmic drug delivery systems is directed towards a combination of
several drug delivery technologies. There is a tendency to develop systems which not only prolong the contact time of the
vehicle at the ocular surface, but which at the same time slow down the elimination of the drug. Combination of drug
delivery systems could open a new directive for improving results and the therapeutic response of non-efficacioussystems.
© 1997 Elsevier Science Ltd.

1. I N T R O D U C T I O N 1.2. Physiological Considerations

1.1. Conventional Dosage Forms The extent of absorption of an ophthalmic drug

Medication is applied to the surface of the
eye for two purposes: to treat the outside of
the eye for such infections as conjunctivitis,
blepharitis, keratitis sicca, or to provide intra-
ocular treatment through the cornea for diseases
such as glaucoma or uveitis. Most ocular diseases
are treated with topical application of solutions
administered as eye-drops. These conventional
dosage forms account for nearly 90% of the
currently accessible marketed formulations. Eye-
drops used for soluble drug, require frequent
instillations of highly concentrated solutions. The
practical reasons for selecting solutions are the
generally favorable cost advantage, the greater
simplicity of formulation development and pro-
duction and the good acceptance by patients
despite a little blurring (Fitzgerald and Wilson,
1994).
One of the major problems encountered with
the topical delivery of ophthalmic drugs is the
rapid and extensive precorneal loss caused by
drainage and high tear fluid turnover. After
instillation of an eyedrop, typically less than 5%
of the applied drug penetrates the cornea and
reaches intraocular tissues, while a major fraction
of the instilled dose is often absorbed systemically
via the conjunctiva and nasolacrimal duct (Lang,
1995).
is severely limited by physiological contraints.
A m o n g the factors that limit ocular absorption
is the relatively impermeable corneal barrier. The
cornea consists of three membranes, the epi-
thelium, the endothelium and inner stroma which
are the main absorptive barriers. The epithelium
facing the tears with lipophilic cellular layers, acts
as a barrier to ion transport. The tight junctions of
the corneal epithelium serve as a selective barrier
for small molecules and they prevent the diffusion
of macromolecules via the paraceUular route.
The stroma beneath the epithelium is a highly
hydrophilic layer making up 90% of the cornea.
The corneal endothelium is responsible for
maintaining normal corneal hydration.
Clearly then, the more lipophilic the drugs are,
the more resistance they will find crossing the
stroma. The more hydrophilic a drug, the more
resistant the epithelium, whereas the stroma and
endothelium are limited in their resistance.
The conjunctiva is a thin, vascularized mucus
membrane that lines the inner surface of the eyelids
and covers the anterior part of the sclera up to the
cornea. Owing to the relative leakiness of the
membrane, rich blood flow and large surface area,
conjunctival uptake of a topically applied drug
from tear fluid is typically an order of magnitude
greater than corneal uptake (Ahmed and Patton,
1985).
 Ophthalmic Drug Delivery Systems
Topically applied drugs reach the bloodstream
mainly via absorption across the mucosa in
the nasal cavity which is contiguous with the
conjunctival sac (Chang and Lee, 1987). Conse-
quently, delivery systems that prolong the resi-
dence time of the applied dose in the conjunctival
sac would be expected to reduce systemic drug
absorption.
Physico-chemical drug properties, such as
lipophilicity (Schoenwald and Huang, 1983),
solubility, molecular size and shape (Grass and
Robinson, 1988; Liaw and Robinson, 1992; Huang
et al., 1989), charge (Rojanasakul et al., 1992;
Liaw et al., 1992) and degree of ionization (Sieg
and Robinson, 1977; Maren and Jankowska, 1985;
Brechu and Maren, 1993) affect the route and rate
of permeation in cornea.
Some authors consider the optimum solubility
for corneal absorption is found in drugs with an
octanol/buffer distribution coefficient in the range
of 100-1000, i.e. more lipophilic than hydrophilic
(Schoenwald and Ward, 1978; Schoenwald and
Huang, 1983). Moreover, unionized species usually
penetrate the lipid membranes more easily than the
ionized form.
Covering the cortjunctiva and corneal surfaces
of the eye is the mucin coat. This mucus layer
secreted by the goblet cells of the conjunctiva
is multifunctional in its role; it hydrates,
cleanses, lubricates and serves as a defense against
pathogens. Ocular mucoadhesion relies on the
interaction of a polymer.
1.3. Pharmacokinetic Considerations
Since the 1980s an increase in the understanding
of the pharmacokinetics of the eye has developed
from a number of strategic clinical papers, and led
to a regeneration of interest in the various formu-
lations and in the nmrket implications. Important
reviews have been published by Shell (1982),
Mishima (1981); Schoenwald (1990) and Lee and
Robinson (1979).
One of the main disadvantages in assessing new
delivery systems is that it is virtually impossible to
carry out in vivo studies on an intact human, partly
because it is difficult to sample fluids and tissues
35
without causing severe distress and damaging the
tissue itself.
After topical administration of an ophthalmic
drug solution, the drug is firstly mixed with the
lacrimal fluid. The contact time of drug with
ocular tissues is relatively short (1-2 min) because
of the permanent production of lacrymal fluid
(0.5-2.2/~l/min). Then, approximately half of the
drug flows through the upper canaliculus and
the other half, through the lower canaliculus into
the lacrimal sac, which opens into the nasolacrimal
duct. Drainage of lacrymal fluid during blinking
(every 12 s) towards the nasolacrimal duct induces
a rapid elimination of conventional dosage
forms (Ahmed and Patton, 1985, 1987). The drug
is absorbed into the retina-choroid via an
extracorneal, or sclero-conjunctival route; the iris
and ciliary body are presumably supplied via both
the transcorneal and the extracorneal pathways.
Drugs penetrate across the corneal epithelium
via the transcellular or paracellular pathway.
Lipophilic drugs prefer the transcellular route,
while hydrophilic drugs penetrate primarily
through the paracellular pathway, which involves
passive or altered diffusion through intercellular
spaces. The transcorneal penetration appears to be
hindered by the binding of the drug to the corneal
tissues. The cornea may act as a drug reservoir,
slowly releasing the drug into the aqueous humour,
where levels decrease very slowly (Romanelli et al.,
1994).
Then, drugs are distributed from the aqueous
humour to the intraocular tissues, i.e. iris-ciliary
body, lens, vitreous and choroid-retina and
eliminated mainly via aqueous humour turnover
and venous blood flow in the anterior uvea. It is
suggested that ocular penetration via the sclero-
conjunctival route is more rapid (for a hydrophilic
drug) than via the transcorneal route (Romanelli
et al., 1994).
Both transconjunctival absorption and trans-
nasal absorption after drainage via the naso-
lacrimal duct are generally undesirable, not only
because of the loss of active ingredient into the
systemic circulation, but also because of possible
side-effects, for instance the effects on the heart
when beta-blockers are administered for the
treatment of wide-angle glaucoma (Meseguer
et al., 1994).
,4
36 C. Le Bourlais et al.
1.4. Interest in New Drug Delivery Systems
Although eye-drops represent 90% of all
ophthalmic dosage forms, there is a significant
effort directed towards new drug delivery systems
for ophthalmic administration.
To overcome the disadvantages of eye-drops,
various ophthalmic drug delivery systems, such as
hydrogels, micro-and nanoparticles, liposomes and
collagen shields have been investigated.
Drug delivery, as it pertains to the eye, is a
generic term which is defined broadly as represent-
ing an approach to controlling and ultimately
optimizing delivery of the drug to its target tissue
in the eye.
An optimum ocular drug delivery system would
be one which can be delivered in eye-drop form
with no creation of blurred vision or irritancy and
which would need no more than one to two
instillations each day (Van Ooteghem, 1995).
The benefits to the patient are simplicity a
diminished frequency of administration, lower
toxicity, and side-effects.
The emergence of new and innovative means for
improving therapeutic efficacy suggests that a
greater choice of dosage forms will be provided to
physicians and patients in the next decade. Most of
the formulation efforts aim at maximizing ocular
drug absorption through prolongation of the drug
residence time in the cornea and conjunctival sac,
as well as to slow drug release from the delivery
system and minimize precorneal drug loss.
Control can be minimal, such as retarding
drainage by the use of viscolysing agents added to
aqueous solutions, or extensive, as exeplified by
the diffusion-controlled, nonerodible polymeric
insert. Inserts are selected for their particularly
long duration of action and the low bioavailability
of the drug, the good control of the rate of
administration and because they are not blurring.
However, one of the disadvantages of inserts is
the lack of patient acceptance owing to difficult
administration.
Despite this, some blurring gels are selected
for their relatively long duration of action, their
simple administration, reduced frequency of
administeration and for their intermediate cost.
Colloidal systems have the advantage of
easy administration and efficacy over their long
residence time. Some clinical studies are necessary
to provide more information concerning these new
drug delivery systems.
This review will focus on three avenues of
development that promise a major impact on
future ocular drug therapeutics: polymeric gels
including bioadhesive hydrogels and in situ
activated gel-forming systems; colloidal systems
including liposomes and nanoparticles; and finally
cyclodextrins and collagen shields as a new
therapeutic approach in ophthalmology.
2. POLYMERIC GELS
Polymeric gels are classified into two distinct
groups: preformed and in situ forming gels, both of
which improve bioavailability and decrease the
side-effects induced by the systemic absorption
of topically applied ophthalmic drugs.
2.1. Bioadhesive Hydrogels
The efficacy of ophthalmic semi-solid hydrogels
is mostly based on an increase of ocular residence
time, via enhanced viscosity and mucoadhesive
properties.
Bioadhesive polymers have generated consider-
able interest in recent years as a way to subtantially
improve the performance of controlled delivery
systems. The reasons for this interest are that these
polymers can improve drug delivery through
optimum contact with the absorbing surface in
order to prolong residence time and reduce dosing
frequency.
Bioadhesion is not a new concept, given that
cells attach to each other with great strength.
Bioadhesive polymers are capable of forming
strong non-covalent bonds with the mucin coating
biological membranes and remain in place as long
as the mucin is present.
2.1.1. Definition--description
Bioadhesive polymers are usually macro-
molecular hydrocolloids with numerous hydro-
philic functional groups (Robinson and Mlynek,
 Ophthalmic Drug Delivery Systems
1995). Hyaluronic acid (HA) is a high molecular
weight biological polymer consisting of linear
polysaccharides present in the extracellular matrix.
In the eye, HA is present in the vitreous body and
in low concentrations in the aqueous humour
(Liesang, 1990). HA has been shown to be a potent
mucoadhesive polymer (Saettone et al., 1989).
Some investigations with the use of exogenous HA
had led to the characterization of this compound
as a topical pseudoplastic polymer that guarantees
a better protection of the cornea (Marriott and
Gregory, 1990; Liesang, 1990).
Most of the bioadhesives performed for
drug delivery systems are composed of
synthetic mucoadhesives, including water-soluble
polymers that are linear chains, and water-
insoluble polymers that are swellable networks
joined by cross-linking agents. Typically, these
polymers have high molecular weight molecules
(5000-10000 Da) which cannot cross biological
membranes and include cellulosic components like
sodium carboxyrnethylcellulose (CMC), or poly-
anion bioadhesives like polyacrylic acid (PAA).
The viscosity of a polymer solution is a measure
of its resistance to flow, which is a complex
function of its molecular weight, its concentration,
as well as temperature and shear stress. According
to the type of flow, fluids can be classified into
two categories: newtonian and non-newtonian,
depending upon whether or not the viscosity
changes with the shear rate.
With newtonian systems whose viscosity
is independent of the shear rate, 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 painful with increasingly viscous
gels (Van Ooteghem, 1995; Ludwig and Van
Ooteghem, 1992; Schoenwald and Ward, 1978).
On the other hand, non-newtonian formulations
that display pseudoplastic properties can acquire
a viscosity decrease with increasing shear rate,
creating blinking and ocular movement. Shear
rates associated with normal blinking are quite
important and range from 0 at rest to 10000 s-'
during blinking. Pseudoplasticity is thus interesting
because it offers significantly less resistance
to blinking and shows much greater acceptance
than viscous newtonian formulations (Greaves
37
et al., 1992; Van Ooteghem, 1995). Moreover, it is
widely accepted that such non-newtonian vehicles
as HA, and polyacrylic acids are more effective
than newtonian formulations containing polyvinyl
alcohol or cellulose in a similar viscosity range.
Furthermore, viscosity and rheological behavior
are not the only factors to be considered. Muco-
adhesive and wetting properties are also critical
parameters to take into consideration (Dittgen
et al., 1992), during ophthalmic formulation. Park
and Robinson (1987), Ponchel et al. (1987), Slovin
and Robinson (1993) and Duchfine et al. (1988)
showed an interest in the bioadhesive properties of
polyacrylic acid hydrogels and their ability to
interpenetrate the mucin at the surface of the eye.
According to Robinson (1989), the best bio-
adhesive polymers are polyanions such as poly-
acrylic acids i.e. carbopol 934P, polycarbophil and
carboxymethylcellulose.
Of the polyacrylic acids, several of the carbopols
are appropriate for use in the pharmaceutical
industry. For example, carbopol 934P is lightly
cross-linked and has a molecular weight of
approximately 3 000 000 Da and is readily soluble
in aqueous solutions.
Polycarbophil is an anionic bioadhesive water-
insoluble cross-linked polyacrylic acid polymer
which swells and incorporates large quantities of
water at neutral pH. This mucoadhesive system
was subsequently explored in detail by Park and
Robinson (1985), Middleton et al. (1990) and
Middleton and Robinson (1991).
2.1.2. Therapeutic approach in ophthalmology
The mucoadhesive polymeric gels are potentially
able to prolong significantly drug contact time with
the cornea owing to their increased viscosity and
optimal miscibility with tear fluid. They have also
been studied for their ocular and percutaneous
tolerability.
Of the numerous commercial formulations,
hydrogels are widely accepted as tear substi-
tutes, because of their prolonged residence time
on the eye surface. For example, celluloses
(Lacril), polyvinyl alcohol (Liquifilm), polyacrylic
acid (Lacrigel, Lubrithal, Gel-Larm), and hyal-
uronic acid (Hy-Drop) are frequently used in
38 C. Le Bourlais et al.
formulations for the treatment of keratoconjunc-
tivitis sicca (Zignani et al., 1995). The utilization of
hydrogels in drug delivery systems is becoming
more important as some products are now
commercialized.
Products based on HA are widely used in
intraocular surgery and are mostly used during
cataract surgery to maintain the shape of the
anterior chamber at high concentrations of more
than 1% (Healon, Pharmacia, Viscoat, Genzyme
Corp., Amvisc, Med Chem Products). However,
the considerable technological demands to produce
a non-inflammatory compound at a designated
molecular weight are responsible for the high cost
of hyaluronate sodium (HS) solution.
Hyaluronic acid is also a component of topical
formulations. Its physicochemical properties allow
the stabilization of the lacrymal film by increasing
the tear break-up time in dry eye patients. Thus,
this biological polymer is the most physiological
compatible vehicle used as a tear substitute.
Snibson et al. (1990) observed in keratoconjunc-
tivitis sicca (KCS) patients that the residence times
for the 0.2 and 0.3% sodium hyaluronate (SH)
solutions were significantly longer (12-24min)
than those for buffered saline solution (1-2 min).
SH has also been administered experimentally
to humans by Ludwig and Van Ooteghem (1992)
with the tracer, fluorescein, to show an increased
precorneal residence time with a 0.25% HA
solution. Gurny et al. (1990) showed that SH
allowed maintenance of 50% of the activity up to
20 min after administration.
According to Durrani et al. (1995), the mole-
cular weight of the hyaluronic acid polymer
influences directly the ability of retention potential
at the ocular surface. In their study, they showed
that 0.2% SH formulations, with high molecular
weight (2.2 × 106) induced a retention time
significantly longer compared with lower mole-
cular weights (134 000 and 620 000).
Llaroche et al. (1991) showed real therapeutic
progress in the treatment of dry eye syndrome
with polyacrylic acid tear substitute (Gel-Larmes).
The study comparing Gel-Larmes with eye-drops
of chondroitin sulphate, evidenced an efficacy in
the treatment of dry eye syndrome.
The lubricant PAA gel, Lubrithal, was retained
significantly longer in patients with dry eyes
(93 min) compared with another lubricant gel
containing polyvinyl alcohol, Liquifilm (41 min)
(al Mansouri et aL, 1994).
According to the results reported in Table 1,
there is a high variability depending on the studies
and depending on the methodology. Drug concen-
trations or drug activity were measured in the
aqueous humour, in tears or in the cornea,
increasing the difficulty of comparing the different
studies. Moreover, in vivo studies showed a high
interindividual variability in the results owing to

Table 1. Evaluation of Polymeric Gels Instilled into the Eye by Measuring the Remaining Activity or Ocular
Concentration after a Given Time
Polymeric gel Remaining activity/ocular
tested Drug/tracer Time concentration Reference
HA ~gTc 36 min 35% Snibson et al., 1990
HA "qn 11 min 50% Durrani et al., 1995
HA fluorescein 20 min 50% Gurny et al., 1990
PAA pilocarpine I h 23% Davies et al., 1991
PAA tropicamide 2h MRT Saettone et al., 1982
CMC timolol 45 min MRT Kyyr6nen and Urtti, 1990
CMC timolol 30 min 64 #g/g (cornea) J/irvinen et al., 1992
PAA timolol 1h 25/~g/g Thermes et al., 1992a
PVA 26/~g/g (cornea)
PAA betaxolol 20 min 2 #g/g (cornea) Weinreb and Jani, 1992
CMC acetazolamide 6h - 2 0 % lOP reduction Tous and E1 Nasser, 1992
HA gentamicin 20 min 300 #g/ml (tears) Bernatchez et al., 1993
Polycarbophil gentamicin 1h 4/~g/g (cornea) Lehr et al., 1994
PAA flurbiprofen 24 h - 1 0 0 % IOP reduction Mengi and Deshpande, 1992
HA methyl-prednisolone 8h 10-80 #g/ml (tears) Kyyr6nen et al., 1992
Polycarbophil fluoro-metholone 190 min MRT (aqueous humour) Middleton et al., 1990
HA, hyaluronic acid; PAA, polyacrylic acid; CMC, carboxymethylcellulose; MRT, mean residence time.
 Ophthalmic Drug Delivery Systems
the difficulty in assessing the drug residence time
in the eye.
The potential bioadhesive properties of these
gels were compared with drugs of various solubility
such as pilocarpine, antihypertensive agents, anti-
biotics, and topical steroids.
Several studies showed the superiority of
polyacrylic acid hydrogels over other non-
newtonian polymeric systems such as polyvinyl
alcohol (PVA). r)avies et al. (1991) demonstrated
that the precorneal retention of the PAA solution
was significantly greater (23% of residual activity)
than that of the PVA solution (13% of residual
activity) on the miotic response intensity of
pilocarpine, l h after administration. Comparable
experiments haw,~ been carried out by Saettone
et al. with pilocarpine in the rabbit eye (Saettone
et al., 1982, 1986).
The antihypertensive fl-blocker, timolol was
evaluated in several studies after ophthalmic
administration. The ocular concentration of
timolol was improved 3- to 9-fold in the presence
of the vehicle, sodium carboxymethylcellulose,
compared with non viscous eye-drops (Kyyr6nen
and Urtti, 1990). The improved ocular penetration
was probably due to the longer corneal contact.
Moreover, a decreased rate of systemic absorption
was attributed to the slower spreading of the
solution on the nasal mucosa.
When comparing the effects of two strongly
bioadhesive polymers, carboxymethylcellulose and
PAA, on the systemic absorption of ophthalmic
timolol in rabbit,,;, J/irvinen et al. (1992) observed
that equiviscous solutions of both polymers
decreased the systemic absorption of timolol
equally, by decreasing both the Cmaxand AUC of
timolol in plasma (50%). Moreover, in this study,
it was suggested that the partitioning of timolol
from the corneal epithelium to the stroma was slow
compared with the drainage of the formulation
from the ocular surface. The authors observed a
very slow diffusion from corneal epithelium to the
stroma.
Thermes et al. (1992a) have evaluated the ocular
bioavailability of a 0.5% timolol solution in
rabbits compared with 0.5% timolol in isoviscous
solutions of the newtonian polymer, PVA and
the non-newtonian polymer, PAA. The results
indicated that the bioadhesive and non-newtonian
39
PAA polymer p r o d u c e d lower ocular concen-
trations, and the concentration vs time profiles
were flatter. This could be consistent with the
slower release of timolol from PAA and the longer
retention of the vehicle in the conjunctival sac by
mucoadhesion.
In a more recent study, Mayer and Von der Ohe
(1996) showed the same efficacy in lowering intra-
ocular pressure of a novel 0.1% timolol in PAA
hydrogel in healthy volunteers compared with the
commercially available aqueous timolol solution
with a 5-fold higher concentration, 0.5%.
Weinreb and Jani (1992) evaluated the ocular
bioavailability of another fl-adrenoreceptor antag-
onist, betaxolol, formulated with polyacrylic acid
in comparison with a 0.5% solution of betaxolol
in rabbits. The results suggested that the PAA
formulation provided a more constant release of
betaxolol than the solution.
Acetazolamide formulated in CMC (carboxy-
methylcellulose) was compared with the saline
solution of the drug in patients with unilateral
open-angle glaucoma. The duration of action was
longer than 8 and less than 24 h, however, the
results were not spectacular and were significant
only when using high drug concentrations (Tous
and E1 Nasser, 1992).
The antibiotic, gentamicin, was formulated
with 0.25% hyaluronic acid to increase precorneal
drug residence time in volunteers (Bernatchez
et al., 1993). The results were not spectacular,
but suggested that HA increased gentamicin
bioavailability on the ocular surface, resulting in
higher concentrations for at least 10 min after
instillation.
Gentamicin was also investigated by Lehr et al.
(1994) using polycarbophil to improve the ocular
delivery of topically applied hydrophilic drug in
rabbits. The polymeric formulation increased the
uptake of gentamicin by the bulbar conjunctiva
twice, as compared with an aqueous control
formulation.
Another antibiotic, fucidic acid, formulated with
PAA is now commercialized as viscous eye-drops,
Fucithalmic. This new commercial dosage form
has been shown to give a long-lasting antibiotic
efficiency in 340 patients with acute conjunctivitis,
and was preferred to chloramphenicol eye-drops
(Horven, 1993).
40 C. Le Bourlais et al.
The use of the same polymer, polyacrylic gel
with flurbiprofen (anti-inflammatory) showed that
bioadhesion played an important role in increased
drug release (Mengi and Deshpande, 1992).
In the study of Benedetti et al. (1990), hydro-
cortisone was incorporated into microspheres of
HA esters. This particular drug delivery system
allowed an in vitro release of the drug 10 min after
being in contact with water so that the drug could
diffuse through the gel-like structure of the
hydrated polymer. In the study of Kyyr6nen et al.
(1992), the in vivo release of methylprednisolone
vehicled in hyaluronic acid high viscous gels was
9-12-times lower (8 h) compared with a control
suspension (30 min). There were no initial peaks
with the hyaluronate ester formulation, as ob-
served for the control. The prolonged residence
time seemed due to the high viscous gel forming a
film on the cornea.
Middteton et al. (1990) and Middleton and
Robinson (1991) formulated a polycarbophil
bioadhesive vehicle, with in situ gelling properties.
They found that they could administer ocular
fluorometholone as a drop that would gel in the
precorneal area. Administration to a few human
volunteers showed the product was comfortable
and retained at least half of the administered drug
for longer than 1 h.
In an e x vivo study using bovine cornea, Le
Bourlais et al. (1997) have tested PAA polymeric
gels in aqueous/non-aqueous solvents incorporat-
ing the immunosuppressive agent, cyclosporin.
The new polymeric gel showed a significantly
improved drug corneal penetration with a percent
absorption of 6.1% compared with 2.5% for the
oily reference vehicle. However, the histological
observations showed some modifications on the
cornea (opacity, reduction of thickness and
keratinized epithelium cells), which were probably
due to the toxicity of non-aqueous solvents
(propyleneglycot300 and glycerol) that were present
in high proportion in the formulation. To explain
the results, the authors have postulated that
polymeric chains of PAA gel containing only
10% water probably interpenetrated very strongly
within the mucin covering the cornea. Thus, the
interaction of the gel with the cornea was
significant in providing high corneal absorption
and modification of the tissue.
Ayers et al. (1996) demonstrated the potential
for polyacrylic acid to be a controlled release drug
delivery vehicle for ribozyme, an oligonucleotide
potentially able to prevent HIV proliferation.
The formulation promoted ribozyme-based thera-
peutics, to gain entry into a disease tissue and
cell. Ribozyme formulated with polyacrylic acid
showed 5-10-fold more ribozyme in the eye as
compared with the control (1% absorption). As
previously mentioned by several authors, charac-
terization of tracer partitioning showed that it was
localized in the corneal epithelium and the
ribozyme levels persisted in the ocular tissue for 3 h
after administration.
2.1.2.1. Ocular tolerance
Due to resistance to eyelid motion, highly
viscous solutions are often associated with dis-
comfort and result in blurred vision. Actually,
blurred vision is one of the most frequent
complaints reported by patients using highly
viscous vehicles. However, the lacrimation and
blinking reflex are usually present after instillation
of hydrogels, and thus these products are more
acceptable (Dudinski et al., 1983; Allen et al.,
1984; Gurny et al., 1987; Chang et al., 1988;
Ludwig and Van Ooteghem, 1988, 1992). Para-
doxically, the deposits around the eyelids, the
splashing, and especially the crusting and sticking
of eyelids are considered unpleasant, as well as
cosmetically unacceptable. Corneal change (haze/
opacity) has been noticed with polyacrylic acid,
contained in Pilopine HS Ophthalmic Gel after
8 weeks of administration (Allen et al., 1984).
More recently, Nagasubramanian et al. (1994)
by measuring corneal thickness in 34 patients
undergoing treatment for glaucoma with 4%
pilocarpine gel, observed that their were no adverse
corneal effects of pilocarpine gel therapy, and it
appeared safe for long-term use.
Administration of an accurate dose in the eye is
one of the difficulties encountered with gellified
systems owing to the variation of the amount
of drug delivered during topical administration
(Gurtler, 1995).
In conclusion, those studies have provided
further evidence for the role of mucoadhesive
 Ophthalmic Drug Delivery Systems
polymers in ocular drug delivery. However, while
offering some advantages, the increased vehicle
viscosity approach to enhancing ocular bio-
availability shows well-defined limitations. In most
cases, substantial viscosity increases only lead
to modest bioavailability enhancement. Blurring
of vision and irritation seem to be the major
disadvantages with eye-drops and, as a conse-
quence, patients generally prefer to use eye-drops
even though more frequent administration is
required.
2.2. In Situ Activated Gel-forming Systems
A more desirable dosage form would be one that
can be delivered in a drop form, creates little to no
problem for vision, and needs to be dosed no more
frequently than once or twice daily.
2.2.1. Definition--description
Several types of polymers have been utilized to
this end. In situ activated gel-forming systems can
be described as viscous liquids that upon exposure
to physiological conditions will shift to a gel phase.
The principal advantage of this formulation is the
possibility of administering accurate and repro-
ducible quantities, in constrast to already gelled
formulations and moreover promoting precorneal
retention. This new concept of producing a gel in
situ was suggested for the first time in the early
1980s.
Three methods have been employed to cause
phase transition on the eye surface: change in
viscosity can be triggered by a change in
temperature (Miller and Donovan, 1982), pH
(Gurny, 1981; Gurny et al., 1985, 1987), or
electrolyte composition (Rozier et al., 1989).
Sustained drug delivery can be achieved by use
of a polymer that changes from sol to gel at
the temperature of the eye. The poloxamers are
polyols with thermal gelling properties whose
solution viscosity increases when temperature is
raised to the eye temperature (33-34°C) from a
critical temperature (16°C) (Miller and Donovan,
1982; Vadnere et al., 1984). Actually, in con-
centrations above 120% w/w (usually 20-30%)
41
poloxamers exhibit the phenomenon of reverse
thermal gelation, remaining as solutions at
refregirator temperature and gelling upon warming
to ambient temperature.
Cellulose acetophtalate (CAP) is a polymer
with potentially useful properties for sustained
drug delivery to the eye, since latex is a free-
running solution at a pH of 4.4 which undergoes
coagulation when the pH is raised by the tear
fluid to pH 7.4. The use of pH-sensitive latex
nanoparticles has been described by Gurny (1981)
and Gurny et al. (1985, 1993). The latex
formulation tested has a total content of polymer
of 30% w/v and an average particle size of
250 nm.
In situ activated gel-forming system has also
been used with gellan gum, an anionic extracellular
polysaccharide secreted by Pseudomonas elodea.
Gellan gum (Gelrite) formulated in aqueous
solution, forms clear gels in the presence of the
mono or divalent cations typically found in the tear
fluids. The polymeric concentration is much lower
compared with previously described systems
(Moorhouse et al., 1981).
More recently, in an attempt to reduce polymer
content, Kumar and Himmelstein (1995) and
Kumar et al. (1995) developed a combination of
polymers, methylcellulose, or hydroxypropyl-
methylcellulose (HPMC) and carbopol. The
former polymers exhibited thermal gellation and
the latter pH dependent gellation. The final
formulation formed an easy flowing formulation
which reversibly gelled in a sol gel transition
between 25 and 37°C, as well as with a pH increase
from 4 to 7.4. A possible mechanism of the thermal
effect could be a decrease of degree of hydration of
methylcellutose, concomitantly with a confor-
mational change of the polymer structure with the
increase in temperature. The acidic solution of
polyacrylic acid can transform into a gel upon an
increase in the pH by the buffering action of tear
fluid.
2.2.2. Therapeutic approach in ophthalmology
Miller and Donovan (1982) examined a
temperature-sensitive solution of poloxamer used
to deliver the meiotic agent pilocarpine. They
obtained a significant increase of the meiosis with
42 C. Le Bourlais et al.
a formulation using Pluronic F127 as compared
with the aqueous solution of the drug.
The poloxamers are reported to be well tolerated
and non-toxic even though large amounts
(20-30%) of polymer are required to obtain a
suitable gel (Gilbert et al., 1986; Koller and Buri,
1987). Showing mucomimetic properties as well as
optical clarity, they could be successfully used as
tear substitutes (Koller and Buri, 1987).
The use of pH-sensitive latex nanoparticles has
been described by Gurny et al. (1985). After
instillation of pilocarpine incorporated in the
pH-sensitive CAP latex nanoparticles, the resulting
meiosis was significantly prolonged as compared
with the aqueous solution in the rabbit. The
formulation containing 2% of the drug had an
almost constant pharmacological response with the
meiosis continuing for up to 5 h.
Vyas et al. (1992) performed pseudolatex-based
ocular formulations of pilocarpine prepared using
different combinations of Eudragit and polyvinyl
pyrrolidone. Prolonged therapeutic efficacy of
the drug was observed in vivo, with a prolonged
half-life of 30 min versus 7.3 min after adminis-
tration of the aqueous solution.
Gurny et al. (1987) compared formulations such
as a pH-sensitive dispersion, a temperature setting
gel and HA containing pilocarpine on the miotic
response. It was demonstrated that HA containing
ocular formulations provided the highest miotic
response in man, whereas the results were less
significant using the in situ activated gel-forming
systems. The in situ activated gel-forming systems
were washed off the corneal surface very rapidly as
miotic activity could be followed for only 10 min
after administration.
Gellan gum was studied in humans by Maurice
and Srinivas (1992), who introduced fluorescein as
a tracer in a Gelrite formulation and in isotonic
buffer solutions. The gel afforded a 2-fold increase
in the penetration of fluorescein as compared with
the solution.
In their study, Rozier et al. (1989) found an
improvement in the ocular absorption of timolol in
the albino rabbit when administered in Gelrite,
when compared with an equiviscous solution of
hydroxyethylcellulose. Corneal concentrations of
drug from both formulations were detectable for
2 h with a significantly higher corneal content of
timolol at all time points after administration
of Gelrite formulation. According to the authors,
solutions of gellan gum were very well tolerated by
the eye.
Favorable results were obtained in terms of peak
and duration of activity in 45 patients with high
intraocular pressure following topical instillation
of timolol maleate in Gelrite rather than in buffer
(Vogel et al., 1990).
Greaves et al. (1990) compared the rate of
clearance of radiolabelled Gelrite with hydroxy-
ethylcellulose (HEC) solution and isotonic saline.
Despite high variability, the gellan gum formu-
lation with a mean half-life of 18 min offered
significant higher retention as compared with the
HEC solution (1.5 min) or saline (0.4 min). In
a gamma scintigraphic evaluation of Gelrite,
Meseguer et al. (1994), showed that 94% of the
activity remained in the eye 1 min after adminis-
tration of Gelrite, compared with only 22% with
the buffered solution, and 60% with the HEC
solution.
Gunning et al. (1993) used Gelrite to study the
ocular hypotensive activities of a potent topical
carbonic anhydrase inhibitor, in 73 patients.
The peak effect occurred from 2 to 6 h after
administration, showing a prolonged contact time
with the formulation. Patient convenience was
satisfactory, and the short-term side-effects were
mild.
In a recent study comparing 0.5% timolol
gellan gum and 0.5% aqueous timolol in 42
healthy vonlunteers, Dickstein and Aarsland
(1996) showed that the advantage of timolol gellan
gum was its reduced systemic absorption resulting
in significantly less reduction in both resting and
peak heart rate.
Sanzgiri et al. (1993)compared various systems
of methylprednisolone (MP): ester of Gelrite
eye-drops, gellan-MP film and gellan film with
dispersed MP. The authors showed that the gellan
eye-drops provided significant precorneal MP
levels over a period of 6 h. They suggested that
gellan eye-drops provided better performance
because they afforded the advantage of faster
gellation over a higher surface area, whereas results
obtained with the gellan-MP film seem to indicate
that the gellation at the surface of the film occured
very slowly and the rate of release was not
 Ophthalmic Drug Delivery Systems
controlled. The eye-drops provided the conven-
ience and ease of administration into the eye of
rabbits but were seen to form an opaque gel-like
material immediately after administration into the
eye, presumably due to a geUan-cation interaction
in the buffer. However, it did not seem to cause
undue irritation.
Kumar and Hiimmelstein (1995) combined
thermo and pH-sensitive properties of both poly-
acrylic acid and hydroxypropylmethycellulose
(HPMC) to be used as an in situ gelling ophthalmic
drug delivery system. This HPMC-PAA combi-
nation showed slow in vitro release of incorporated
timolol maleate.
The in situ gelling systems seem promising
because, as with non-viscous eye-drops accurate
and precise administration is possible and they
provide good sustained release properties. Gelrite
has been the most widely studied and seems to be
preferred as compared with the pH-sensitive or
temperature setting systems.
3. COLLOIDAL SYSTEMS
A liquid retentive drug delivery system, can
be represented by a colloidal system containing
drug in carrier. Colloidal carriers (liposomes,
nanoparticles) have been widely studied for the
past 20 years with the objective of increasing the
specificity of action of drugs towards a specific
target, to facilitate the bioavailability of drugs
through biological membranes, or to protect
a drug against enzyme inactivation. Their use in
topical administration and especially ocular
administration has been studied for only 10 years.
3.1. Liposomes
3.1.1. Definition--description
One of the more recent applications is employing
liposomes as drug delivery systems in ophthal-
mology. Liposomes offer a promising avenue to
fulfill the need for an ophthalmic drug delivery
system that has the convenience of a drop, but will
localize and maintain drug activity at its site of
action.
43
Liposomes are microscopic vesicles composed
of membrane-like lipid bilayers surrounding
aqueous compartments. They are composed
of lipids similar to those present in biological
membranes, therefore they are expected to be
biocompatible and biodegradable. If the liposomes
are formed in the presence of a drug, the drug,
depending on its solubility characteristics, will be
incorporated into either the aqueous compartment
or the lipid layer. Thus, liposomes can accommo-
date both hydrophilic and lipophilic compounds,
so that it is possible to apply water-insoluble
drugs in a liquid dosage form (Shell, 1985; Meisner
and Mezei, 1995). Because of the nature of the
components used for their preparation, liposomes
are considered as biocompatible and bioerodible
vesicles.
According to their size, liposomes are known
as either small unilamellar vesicles (SUV)
(10-100 nm) or large unilamellar vesicles (LUV)
(100-3000 nm). If more bilayers are present they
are referred to as multilamellar vesicles (MLV).
Depending on the composition, liposomes can
have a positive, negative, or neutral surface
charge.
The simplicity of preparation despite the lack
of long-term stability in the aqueous form, and
the versatility in physical characteristics confer a
unique and useful property to liposomes for use as
an ocular drug delivery system.
3.1.2. Therapeutic approach in ophthalmology
The development of liposomes for ocular drug
delivery has not received as much attention as
other routes of administration, and as such there
is still no liposomal ophthalmic drug product
on the market. However, this colloidal system has
been widely studied as a means to improve and
facilitate corneal drug transport.
Some investigators have experimented with
liposomes for topical instillation and for intra-
vitreal and subconjunctival injection and showed
an enhanced absorption of liposome-encapsulated
drugs.
The behaviour of liposomes as an ocular
drug delivery system has been observed to be,
in part, due to surface charge. Positively charged
44 C. Le Bourlais et al.
liposomes seemed to be preferentially captured at
the negatively charged corneal surface as compared
with neutral or negatively charged liposomes. The
binding affinity of liposomes to the cornea suggests
that the interaction is probably electrostatic in
nature (Schaeffer and Krohn, 1982; Mezei and
Gulasekharam, 1982; Singh and Mezei, 1983; Lee
et al., 1985; Lee, 1993).
Schaeffer and Krohn (1982) investigated the
effect of liposomes on the in vitro corneal
penetration of penicillin G. The most effective
composition, i.e. positively charged SUVs, pro-
duced a 4-fold increase in transcorneal flux of
penicillin. Fitzgerald et al. (1987) confirmed the
superiority of positively charged liposomes to
increase corneal absorption with mean high life
of 3.8 min with S U V + , which was significantly
higher than 1 min and 1.1 min for S U V -
and SUV neutral, respectively. It was interesting
to note that in their study a mean half-life of
2.1 min was obtained for nanoparticles of poly-
butylcyanoacrylate.
According to Meisner and Mezei (1995) and
Shek and Barber (1987), liposomes with a positive
surface charge provide more stable adsorption
because the corneal epithelium is thinly coated
with negatively charged mucin. However, it is
important to note that the stearylamine used to
prepare positive liposomes has been reported to be
toxic to cells and appears to be irritating to the eye
(Taniguchi et al., 1988).
Szulc et al. (1988) showed that the liposomal
encapsulation of the hydrophilic drug, pilocarpine,
enhanced its pharmacological effect in rabbits
when using positively charged vesicles.
In the investigations of Singh and Mezei using
triamcinolone (Singh and Mezei, 1983) and
dihydrostreptomycin (Singh and Mezei, 1984)
as model compounds, the results suggested that
liposome encapsulation altered ocular drug dispo-
sition depending on the type of liposomes and the
physicochemical properties of the encapsulated
drug. The association between the drug molecules
and the lipid vesicles was found to be a major
factor influencing drug disposition; and liposomal
drug delivery is probably more favorable for
lipophilic, rather than hydrophilic drugs.
Milani et al. (1993) showed in a rat model that
encapsulation of an immunosuppressive and a
lipophilic drug, cyclosporin, into liposomes could
represent an interesting formulation in ophthal-
mology by improving the survival rate of corneal
grafts in comparison with an oily vehicle.
Pleyer et al. (1994) also investigated the ability
of liposomes to deliver cyclosporine to the eye.
The drug was applied topically in olive oil drops
(control), in a liposome-encapsulated form, and in
a collagen shield which was soaked in the liposome
preparation. Both test formulations showed higher
concentrations in the cornea, as compared with
the control. This study clearly demonstrated the
superiority of liposomes over the oily vehicle, and
the possibility of using liposomes in a combined
delivery system with collagen shields to further
increase its slow release property.
The potential of using adhesive liposomes as a
means of facilitating the transport of drugs
through the cornea and enhancing bioavailability
has also been studied. The results of Durrani et al.
(1992) and Davies et al. (1992) showed that coating
liposomes with bioadhesive polymer (carbopol
1342) increased corneal retention. Durrani et al.
(1992) showed that carbopol-coated liposomes
produced a larger area under the meiotic intensity
curve (AUC) and a longer duration of action of
pilocarpine that could be followed for 3 h, as
compared with uncoated vesicles (2 h). They also
demonstrated the biphasic response characterized
by a lower initial intensity but a longer duration
of action when using coated liposomes. Davies
et al. (1992) showed in the corneal clearance
profiles of tropicamide that 50% of the initial
mydriatic response remained associated with
the corneal region for carbopol-coated liposomes,
vs 18% for uncoated vesicles. The coating of
liposomes with carbopol reduced the initial
rapid drainage phase, resulting in an increase of
instilled activity remaining associated with the
cornea. Analysis of the AUC, however, indicated
that the enhanced corneal retention of polymer-
coated liposomes was of short duration, and no
statistically significant increase in corneal retention
was afforded by polymer coating when compared
at 30 min after instillation.
The administration of liposome suspensions by
the subconjunctival and intravitreal route has been
investigated by several groups of researchers.
The main goals of this research were to provide
 Ophthalmic Drug Delivery Systems
more effective therapy through direct targeting to
the site of action and to prolong activity by
providing extended levels of drug at the targeted
site. Barza et al. (1984) found significant differ-
ences in clearance and distribution of gentamicin in
the conjunctiva with the liposomal form up to 24 h
postinjection. Experiments by Alghadyan et al.
(1988) with cyclosporin, however, did not display
any significant advantage over the free drug.
Liposomes can be intravitreally injected to avoid
repeated injections; of compounds rapidly cleared
from the triggered site. Liposome-encapsulated
amphotericin B, when injected intravitreally
produced less toxicity than the commercial
amphotericin B solution (Liu et al., 1989). Peyman
and co-workers have evaluated several liposomal
compounds including gentamicin (Fishman et al.,
1986), clindamycin (Fiscella et al., 1987) and an
antiviral agent such as ganciclovir (Peyman et al.,
1987). Although retardation of drug clearance
varied, all compounds benefited from liposomal
encapsulation. Liposome-encapsulated ganciclovir
was also investigated by Le Bourlais et al. (1996).
In our study we found that after a single injection
of the liposomal drug in rabbits, therapeutic levels
of ganciclovir were still detected 30 days following
injection. Our results were in agreement with the
results obtained by Peyman et al. (1987) and
Diaz-Llopis et al. (1992).
3.2. Nanoparticles
3.2.1. Definition--description
Nanoparticles are one of the most studied
colloidal systems over the past two decades
with the object of improving targeting of drug to
organs and increasing drug bioavailability across
biological membranes.
Nanoparticles are polymeric colloidal particles
ranging in size from 10 to 1000 nm (1/~m). They
consist of macromolecular materials in which the
drug is dissolved, entrapped, encapsulated, and/or
to which the drug is adsorbed or attached (Kreuter,
1990).
They can be classified into two groups: nano-
spheres and nanocapsules. Nanospheres are small
solid matricial spheres constituting of dense solid
45
polymeric network, developing over a large specific
area (Rollot et al., 1986). Drugs can either be
incorporated in the matrix of the nanospheres
or adsorbed onto the surface of the colloidal
carrier. Nanocapsules are small capsules formed of
a central cavity (oily droplet) surrounded by a
polymeric membrane.
Various polymers can be used to fabricate
nanoparticles such as polyacrylamide, poly-
methylmethacrylate (Kreuter and Speiser, 1976;
Rolland et al., 1986), polylactic-co-glycolic acid
and E-caprolactone (Fessi et al., 1989).
3.2.2. Therapeutic approach in ophthalmology
Nanoparticles have been revealed to be efficient
as ocular drug delivery systems by prolonging the
duration of the action of drugs.
The first studies concerned Piloplex systems
constisting of pilocarpine-loaded nanospheres
using a poly(methylmethacrylate-acrylic acid)
copolymer (Ticho et al., 1979). In clinical trials,
Piloplex lowered the intra-ocular pressure. Those
systems based on non-biodegradable polymers
were not investigated further. However, numerous
studies have investigated nanospheres, such
as alkylcyanoacrylate nanocapsules obtained by
polymerization of a monomer (Table 2).
Andermann et al. (1982) investigated the efficacy
of the antihypertensive drug delivery system,
Glauplex, a commercialized polymeric emulsion
containing pilocarpine.
Wood et al. (1985) showed that after adminis-
tration to rabbits of poly(alkylcyanoacrylate)
(PACA) nanospheres labeled with [14]-C, degra-
dation of the nanoparticles in tears occurred at a
relatively rapid rate for the first hour with
approximately 19% degradation. It was interesting
to note that only 0.1% of the initial amount was
found in the cornea and the conjunctiva, however,
this concentration was relatively constant for 6 h
after instillation. This result suggested that
nanospheres were able to adhere to the corneal and
conjunctival surfaces.
Further work has been conducted by
Harmia et al. (1986), testing polybutylcyano-
acrylate nanospheres containing pilocarpine. Two
formulations were tested: the first containing
46 C. Le Bourlais et al.

Table 2. Evaluation o f Nanoparticles Instilled into the E y e by M e a s u r i n g the R e m a i n i n g A c t i v i t y or Ocular Concentration

after a Given Time
Remaining activity/ocular
Formulation tested Drug/tracer Time concentration Reference
NS (PACA) '4C 6 h 1 #g/g (cornea) Wood et al., 1985
NS (PBCA) pilocarpine 30 min 6.5 pg/ml (aq h) Diepold et al., 1989
6 h - 3 0 % reduction in lOP
NS (PBCA) amikacin 3 h 32 pg/g (cornea) Losa et al., 1991
1.5 gg/ml (aq h)
NS (PBCA) betaxolol 6 h - 2 0 % reduction in IOP Marchal-Heussler et al., 1990
NC (PECL) betaxolol 6 h - 2 7 % reduction in lOP Marchal-Heussler et al., 1992
NS betaxolol 6h PBCA: - 2 0 % Marchal-Heussler et al., 1993
(PBCA/PECL/PLAGA) PECL: - 25%
PLAGA: - 15%
reduction in lOP
NS/NC (PECL) carteolol 6h NS: - 17% Marchal-Heussler et al., 1993
NC: - 2 5 %
reduction in IOP
NC (PBCA/PECL) metipranolol 6h - 1 0 % reduction in IOP Losa et al., 1993
NC (PIBCA) cyclosporin 6h 10 pg/g (cornea) Calvo et al., 1996b
NS/NC (PECL) indomethacin 6h NS: 85 pg/cm 2 Calvo et al., 1996a
NC: 85 #g/cm2(cornea)
NC (PECL) indium oxinate 1h 30%/g (cornea) Maincent, 1995
PBCA, poly-isobutylcyanoacrylate; PECL, poly-E-caprolactone; PLAGA, polylactic-co glycolic acid; NS, nanosphere; NC,
nanocapsule.

pilocarpine inside the matrix of the particle, the
other one with pilocarpine adsorbed onto the
surface area of the particle. The miotic response
intensity was the same for both formulations.
However, the formulation containing the drug on
the surface of the particle maintained the effect for
longer. The result, which was not significant with
pilocarpine included inside the nanospheres, was
correlated to a slow and incomplete degradation
of the polymer in tears, as mentioned above.
The same conclusions were made by Diepold
et al. (1989) with pilocarpine nitrate loaded onto
nanospheres.
These results have been confirmed in a study of
polybutylcyanocarylate nanospheres (Li et al.,
1986). The lipophilic nature of the drug (progester-
one) resulted in an encapsulation rate around
100% in the carrier, but the strong affinity of the
drug for the polymer and the slow degradation of
the polymer did not provide a sufficient release of
the drug. Thus, it seems that the major problem
with the use of alkylcyanoacrylate nanospheres is
very slow drug release out of the matrix, compared
with the residence time of the particle in the
precorneal area.
The same experiment was performed by
incorporating a hydrophilic antibiotic, amikacin
sulfate into nanospheres of poly-isobutylcyano-
acrylate (Losa et al., 1991). The increase of the
amikacin concentration in the aqueous humour
and cornea was statistically significant for nano-
spheres with respect to the control solution.
However, the matrix system used with hydrophilic
drugs was limited, owing to a slow drug desorption
from the polymeric nanospheres. These results
agree with the conclusion of Marchal-Heussler
et al. (1990) which demonstrated that surface
charge and the binding type of the drug onto
nanospheres were the most important factors in
improving the therapeutic response of betaxolol.
In further studies, the same authors compared
the efficiency of nanoparticles as a function of the
type of polymer constituting the drug delivery
system. Marchal-Heussler et al. (1992, 1993) tested
poly-e-caprolactone, polylactic-co-glycolic acid
copolymers and poly-isobutylcyanoacrylate. The
decrease in intraocular pressure of antiglaucoma-
tous drugs such as betaxolol and carteolol were
more pronounced with the colloidal carriers
using poly-e-caprolactone (nanospheres or nano-
capsules). It seems that the more hydrophobic the
carrier, the higher the ocular activity of the
drug. The mechanism of action seemed to be
directly linked to the agglomeration of the poly-e-
 Ophthalmic Drug Delivery Systems
caprolactone nanoparticles in the conjunctival sac.
Furthermore, for poly-e-caprolactone the nano-
capsules displayed a better effect than nanospheres,
probably because the entrapped drug was in the
unionized form in the oily core of the carrier and
could diffuse at a greater rate into the cornea.
Diffusion of the drug from the oily phase to the
corneal epithelium seems to be more effective than
diffusion from the internal matrix of the nano-
spheres.
This new dosage form produced an enhanced
therapeutic effect with much a lower drug
concentration, thus minimizing systemic effects.
This was confirmed by Losa et al. ( 1991, 1992,
1993) with the ophthalmic administration of
metipranolol incorporated into either poly-e-
caprolactone or polybutylcyanoacrylate nano-
capsules.
According to most authors, one of the reasons
for the efficency of nanocapsules was their
bioadhesive properties, which result in prolonged
residence time and an increased biological response
(Wood et al., 1985; Kreuter, 1990; Zimmer and
Kreuter, 1995; Das et al., 1995).
Zimmer et al. (1991) studied the transport
pathway of poly-isobutylcyanoacrylate nano-
spheres through the rabbit cornea and conjunctiva
by using fluorescent laser dyes. The results
showed a fluorescence signal inside the cells and
within corneal cells. A transcellular pathway was
observed. However, penetration was observed
only into the fir,;t two cell layers with no full
penetration occurring. They concluded that the
penetration of nanoparticles into eye tissue
was limited to the precorneal area. The penetration
into the cells showed an uptake of fluorescent
dye in the form of granules and vesicles only
after binding to the nanoparticles, whereas the
dye in the form of a solution did not penetrate
into these cells. An uptake mechanism for small
particles by phagocytosis was therefore most
likely.
Calvo et al. (1996b) studied the efficacy of
cyclosporin in nanocapsules encapsulated on the
corneal concentration of the drug as compared
with an oily solution of cyclosporin A. The
nanocapsules induced corneal levels five times
higher than those of the control group for up to 3
days.
47
Le Bourlais et al. (1997) showed in an e x vivo
study that nanocapsules of poly-isobutylcyano-
acrylate enhanced bovine corneal absorption of
cyclosporin (5.8%) compared with an oily vehicle
as a control (2.5%). Moreover, we showed that
there was limited penetration of the drug into the
cornea with a partitioning essentially localized at
the superficial layers of the epithelium, and no
complete penetration. Our results were in agrement
with the results obtained in the literature
(DiazLlopis and Menezo, 1989; Minguez et al.,
1992; Wiederholdt et al., 1986). However, the
nanocapsule suspension seemed to induce some
keratinized epithelium cells after 24 h contact time
with the tissue.
Alonso et al. (1995) showed that nanocapsules,
nanospheres of poly-e-caprolactone and nano-
emulsions provided corneal absorption of two
lipophilic drugs (cyclosporin and indometacin).
They showed that corneal absorption of cyclo-
sporine was five times superior with nanocapsules
of poly-~-caprolactone as compared with the oily
solution.
Calvo et al. (1996a) compared the corneal
penetration through isolated corneas of encapsu-
lated indomethacin from nanoparticles and
nanocapsules of PECL and from submicron
emulsions. For the three formulations investigated
the increased penetration was more than 3-fold
that of the commercial eye-drops during the 6 h
of the study. The authors concluded that the
main factor responsible for the favorable corneal
transport of indomethacin was the colloidal nature
of these carriers, rather than their inner structure
or composition.
Most authors agreed that nanoparticles did not
seem to be responsible for toxicity or irritation on
the cornea. However, some authors (Marchal-
Heussler et al., 1992, 1993; Calvo et al., 1994;
Zimmer et al., 1991) observed that nanoparticles
consisting of PACA, damaged the corneal epi-
thelium by disrupting the cell membranes.
However, their observations of PELC nanocap-
sules did not mention any toxicity to the corneal
epithelium cells.
In conclusion, the results of the different studies
show the potential of colloidal systems as ocular
drug delivery systems for either hydrophobic or
hydrophilic drugs which are liquid dosage forms
48 C. Le Bourlais et al.
that do not interfere with vision, such as semi-solid
formulations.
4. OTHER DRUG DELIVERY SYSTEMS
4.1. Cyclodextrins
4.1.1. Definition--description
The pharmaceutical use of cyclodextrins (CD) is
confined mainly to the complexation of problem-
atic drugs (poorly soluble, unstable, irritating,
difficult to formulate substances). CD complexa-
tion generally results in improved wettability,
dissolution, solubility, improved stability in sol-
utions and reduced side-effects (Szejtli, 1994).
Cyclodextrins (CDs) are a group of homologous
cyclic oligosaccharides with a hydrophilic outer
surface consisting of six, seven or eight glucose
units, namely ~-, fl- or 7-cyclodextrin, respectively.
Although soluble in water, CDs have a lipophilic
cavity in the center. They form inclusion complexes
with many lipophilic drugs by taking up a
drug molecule, or part of it, within the lumen,
resulting in an increase in solubility (Kristinsson
et al., 1996). The first cyclodextrins studied were
shown to be responsible for hemolytic activity and
nephrotoxicity, which have a relatively low
aqueous solubility and have limited the widespread
use of these cyclodextrins, particularly for ocular
and parenteral administration (Usayapant et al.,
1991). Among cyclodextrin derivatives, hydroxy-
propyl-fl-cyclodextrin was shown to be the most
favorable in the hemolysis study on human
erythrocytes.
4.1.2. Therapeutic approach in ophthalmology
The development of an ophthalmic drug delivery
system based on cyclodextrins is relatively recent,
occurring in the early 1990s.
Cyclodextrins were introduced in ocular drug
formulations initially with the aim of increasing the
solubility of lipophilic drugs in solution. The
authors also observed a decreased toxicity of
the drug-cyclodextrin complex compared with
the usual drug formulation or the prodrug
solution (i.e. pilocarpine prodrug). Finally, most
authors showed increased corneal permeability,
and increased bioavailability of the drug despite
the assumption that the complexes did not
penetrate across biological membranes. However,
cyclodextrin derivatives possess their own toxicity
and these observations vary depending on the
studies.
Kanai et al. (1989) tested different combinations
of ~-CD and a lipophilic immunosuppressive
agent, cyclosporin. They found that the complex
of cyclosporin-~-CD resulted in lower corneal
toxicity and penetrated into the cornea 5-10 times
more than did the drug in a lipophilic vehicle.
Cheeks et al. (1992) confirmed these results in their
study on the corneal penetration of cyclosporin.
Sasamoto et al. (1991), when testing the
same cyclosporin-~-cyclodextrin complex to in-
crease drug solubility, recommended topical
~-cyclodextrin-cyclosporin as treating anterior
uveitis in rats with the same efficacy as topical
fluorometholone solution.
Results with other CD derivatives of fl-cyclo-
dextrin, such as hydroxypropyl-fl-cyclodextrin
(HP-fl-CD), have revealed favorable toxicological
properties after ocular administration. The ocular
administration of fl-cyclodextrins at concen-
trations up to 12.5% was well-tolerated by the
rabbit corneal epithelium (Freedman et al., 1993;
Jansen et al., 1990; Reer et al., 1994). Since
irritation is related to the drug concentration in
ocular surface tissues, it is not surprising that local
irritation is sometimes encountered. Drug delivery
technology should offer the potential for minimiz-
ation of irritation. Recently, some cyclodextrin
adjuvants in eye-drops were shown to reduce the
ocular irritation seen with pilocarpine prodrugs.
Suhonen et al. (1995) administered a pilocarpine
prodrug solution to rabbits diluted in 5-15%
HP-fl-CD solutions to decrease the ocular toxicity
attributed to the prodrug. The authors showed
that ocular irritation was at the same level as
commercial pilocarpine eye-drops. However, the
pilocarpine prodrug was better tolerated in cyclo-
dextrin solution than in saline. Moreover, the
formulation tested showed decreased peak and
prolonged duration of meiosis compared with
pilocarpine solution. It is generally assumed that
cyclodextrins and drug-cyclodextrin complexes
 Ophthalmic Drug Delivery Systems
do not penetrate, biological membranes. The
decreased peak of meiosis was explained by a
significant decrease in the fraction of the free drug
in the CD solution.
JS.rvinen et al. (1994) studied the complex-
ation of pilocarpine prodrug with various fl-
cyclodextrin derivatives. They showed that sul-
phobutyl ether fl-cyclodextrin, (SBE4-fl-CD)
increased the aqueous stability of pilocarpine at
pH 7.0. However, their results could not confirm
the increase in ocular bioavailability of pilo-
carpine in rabbits, as shown by Freedman
et al. (1993), who concluded that the underlying
mechanism of action by which fl-CD increased
the apparent ocular absorption of pilocarpine was
unknown.
More recently, J~irvinen et al. (1995) showed
that SBE-fl-CD solution eliminated the eye
irritation due to t]he prodrug, and also improved
ocular absorption by increasing the viscosity of the
solution with poly(vinyl alcohol) (PVA).
In a similar study, Jarho et al. (1996) confirmed
that the complexation of pilocarpine prodrug with
SBE7-fl-CD improved tolerance for the prodrug.
Furthermore, ocular absorption was also improved
by increasing the viscosity of the complex solution
with PVA.
Complexation of a poorly water soluble drug
such as dexamethasone with HPCD was investi-
gated by Usayapant et al. (1991) to formulate an
ophthalmic solution of dexamethasone. Ocular
bioavailability was improved with the complex
solution compared with the drug suspension.
However, a difficulty encountered with drug-
cyclodextrin complexes was the insignificant
dissociation of the administered complex within
the residence time in the precorneal fluid to release
a free drug into the tear film and at the corneal
surface. The precorneal fluid volume was found to
be too low to cause any significant dissociation of
the administered complex.
In a recent study, Kristinsson et al. (1996)
coadministered HP-fl-CD and dexamethasone.
They confirmed the results obtained by Usayapant
et al. Moreover, the authors showed that since
the solubility of the drug was substantially
increased with cyclodextrins, higher concentrations
of drug may be administered, further increasing the
corneal penetration of dexamethasone.
49
Reer et al. (1994) confirmed the increased
corneal permeability of a solution of the NSAID,
diclofenac, containing HP-fl-CD, as compared
with the commercial solution of Voltaren.
Cyclodextrins seem to be beneficial for poorly
water-soluble drugs by improving ocular
bioavailability and avoiding the use of ointment
and oily vehicles. However, they do not seem to
afford a real improvement for hydrophilic drugs
except for eliminating ocular irritation when the
drug is responsible for this damage. The improve-
ment of ocular bioavailability seems to be limited
by the very slow dissociation of the drug-CD
complex in the lacrymal fluid. The combination of
cyclodextrins with viscous polymers, for example,
seems to have the potential to provide efficient
drug delivery systems.
4.2. Collagen Shields
A starting point in the selection of a retentive
system is to consider erodible and non-erodible
inserts which have proven to have a long duration
of release and to be able to modify drug
bioavailability when compared with their solution
dosage form counterparts. However, therapeuti-
cally successful as inserts may be, they are not well
tolerated by patients, and considering their high
cost per dose (Robinson and Mlynek, 1995) are not
perceived as desirable next-generation topical
ocular drug delivery systems.
Ocusert ~: (Alza Corporation) is an insoluble
ophthalmic insert classified in the group of
diffusional systems. It consists of a central
reservoir of drug (e.g. pilocarpine) enclosed
between two semipermeable membranes which
allow the drug to diffuse from the reservoir at a
precisely determined rate for a period of 7 days.
Prolonged reduction in intraocular pressure was
achieved with a single Ocusert ~" in patients with
hypertensive open-angle glaucoma. Because of the
insolubility of the Ocusert ~ device, it must be
removed after use (Gurtler, 1995). The inserts were
well tolerated but after prolonged wear tended
to swell and partially fragment. Finally, it is
recommended that they not be worn for more than
12 h, despite the potential for prolonged release of
several days (Dimitriu et al., 1988).
50 C. Le Bourlais et al.
A collagen shield is a soluble insert which offers
the advantage of being entirely soluble so that
it does not need to be removed from its site of
application, thus limiting the interventions to
insertion only.
4.2.1. Definition--description
Collagen shields belong to the soluble
ophthalmic inserts which are based on natural
polymers and which include the oldest component
of ophthalmic inserts described in the literature:
collagen. As a first attempt at use, collagen has
been used to fabricate erodible inserts for
placement in the fornix for long-term delivery
of pilocarpine into the eye (Bloomfield et al.,
1978).
Collagen shields are fabricated from porcine
scleral tissue, which bear a collagen composition
similar to that of the human cornea. The shields
are hydrated before they are placed on the eye,
having been stored in a dehydrated state.
Typically, the drug is loaded into the collagen
shield simply by soaking it in the drug solution
for a period of time prior to application. Once
in the eye, shields are hydrated by tear fluids,
and then soften and form a clear, pliable, thin
film approximately 0.1 mm in thickness, with a
diameter of 14.5 mm and a base curve of 9 mm
that conforms to the corneal surface. Designed to
slowly dissolve within 12, 24, or 72 h, the shield has
stimulated much interest as a potential sustained
ocular drug delivery system (Lee, 1990).
4.2.2. Therapeutic approach in ophthalmology
A number of studies have demonstrated the
efficacy of the corneal collagen shield as a drug
delivery system. The collagen shield has been
used as a corneal bandage and as a drug delivery
device. This drug delivery device has been used
to deliver antibiotics, antifungals, steroids and
immunosuppressives. When a collagen shield is
hydrated in a solution containing a water-soluble
drug, the collagen matrix may act as a reservoir,
increasing the contact time between the drug and
the cornea.
Vasantha et al. (1988) utilized collagen film as
a new biodegradable carrier for a long-acting
delivery system for pilocarpine. The release studies
indicated that after an initial bolus release, pilo-
carpine was released at a constant rate following
zero-order kinetics. The release rate of pitocarpine
could be regulated from 5 to 15 days depending on
modification of the collagen carrier.
The collagen shields of gentamicin were studied
in rabbit eyes for absorption into the aqueous
humour and corneal penetration. Drug levels
measured in the cornea and aqueous humour were
significantly higher than after frequent adminis-
tration of drops or often contact lens application
in the cornea (Unterman et al., 1988).
Collagen shields pre-soaked in tobramycin
were used to treat a Pseudomonas aeruginosa-
infected cornea excoriation. This therapeutic
system was more effective in concentrating the
antibiotic in the aqueous humour than drops
(Sawusch et al., 1988). In another study, the
same researchers compared topical tobramycin in
the presence of collagen shields and soft contact
lenses (O'Brien et al., 1988). They showed that
collagen shields allowed a significant increase in
drug penetration into the anterior chamber after
60 min.
The antifungal agent, amphotericin B, was
studied in collagen shields formulations which
were able to maintain ocular drug levels in the
anterior segment of rabbit eye, as well as
frequent-drop delivery with the potential benefit
of added convenience and compliance (Schwartz
et al., 1990).
Lee et al. (1992) tested various combinations
of drugs in the same collagen shield. They
revealed some difficulties with the mixture and
showed severe corneal toxicity associated with
aggregate formation in a mixture of gentamicin
and methylprednisolone; drugs commonly used
to treat ocular disease. This system was not
recommended for a multidrug delivery system.
In the study by Sawusch et al. (1989), methyl-
prednisolone was formulated with a collagen
shield. It was shown that ocular penetration of the
drug was enhanced by the delivery system at 30 an
120 min in rabbits.
The work of Mahlberg et al. (1991) showed that
collagen shields of cyclosporin were effective
 Ophthalmic Drug Delivery Systems
against corneal graft rejection in rabbits as
they allowed a slow release of the drug and an
increase of corneal absorption when compared
with olive oil. "]?he results were confirmed in
separate studies by Reidy et al. (1990) and Chen
et al. (1990).
Despite findings that suggest the superiority of
shields in drug delivery, there are a number of
difficulties related to the design and use of collagen
shields. Hydrated shields are difficult to handle
and cannot be inserted by patients themselves.
Collagen shields are designed to be inserted in a
physician's office, often produce some discomfort,
and interfere with vision. Shields are not
individually fit for each patient, as are soft contact
lenses, and therefore, comfort may be problematic
and expulsion of the shield may occur (Kaufman
et al., 1994).
Kaufman et al. (1994) have developed a new
drug delivery system, collasomes. They combined
collagen pieces or particles and a viscous vehicle
that could be instilled beneath the eyelid, thereby
simplifying application and reducing the blurring
of vision. Collasomes hydrated in a solution of
sodium fluorescein and suspended in a methyl-
cellulose vehicle were used as a model for delivery
of water-soluble drugs. The results produced
fluorescein concentrations 17-42 times higher
in the cornea and 6-8 times higher in the
aqueous humor as compared with the fluorescein-
containing vehicle alone. The collasomes were well
tolerated, and because the collagen particles are
suspended in carrier vehicles, they could be
instilled safely and effectively by patients in much
the same fashion as drops or ointments.
For patients with conditions requiring chronic
rather than acute therapy, the advantages of
collagen shields in providing high and sustained
levels of drugs and/or lubricants to the cornea are
outweighed by the difficulty of inserting the shield
and the problem of blurred vision.
In conclusion, we can say that in the majority of
instances, there is a moderate to marked improve-
ment in the extent of drug ocular absorption. Thus,
collagen shields seem to be an appropriate delivery
system for both hydrophilic and hydrophobic
drugs with poor penetration properties; and would
afford a new continuous-delivery system for these
drugs. Collagen film, because of its biological
51
inertness, structural stability, good biocompatibil-
ity and low cost of production, proved to be a
promising carrier for ophthalmic drug delivery
systems. However, clinical trials are still required
to establish the long-term efficacy and safety of
these devices.
5. CONCLUSIONS--FUTURE DIRECTIONS
Currently, very few new ophthalmic drug
delivery systems have been commercialized. How-
ever, research on new drug delivery systems seems
to have provided an important dynamism as never
before, with the promise of some new and exciting
directions.
The most widely developed drug delivery system
is represented by the polymeric hydrogels. Hydro-
gels generally offer a moderate improvement of
ocular drug bioavailability despite their favorable
bioadhesive properties. One of the disadvantages
is that hydrogel may result in blurred vision as
well as foreign body sensation to patients. In situ
activated gel-forming systems seem to be preferred
as they can be administered in drop form and
create significantly less problems with vision.
Moreover, they provide good sustained release
properties. Development of colloidal systems
including liposomes and nanoparticles is much less
developed for ocular drug delivery. However, they
provide the convenience of a drop, maintain drug
activity at the site of action and are suitable for
poorly water-soluble drugs. One of the difficulties
is a slower release of the drug from colloidal
carriers than is necessary for optimal corneal
absorption. More clinical studies are necessary to
provide further information and insights into this
new ophthalmic drug delivery system. Among the
new therapeutic approachs in ophthalmology,
cyclodextrins have been introduced as a means of
increasing the solubility of poorly water-soluble
drugs, which may provide increased corneal
permeability and thus represents an alternative
for ophthalmic drug delivery systems. Finally,
collagen shields have been developed as a new
continuous-delivery system for drugs which pro-
vides high and sustained levels of drugs to the
cornea, but with the difficulties of insertion of the
device and blurred vision.
52 C. Le Bourlais et al.
5.1. New Perspectives
Other recently described bioadhesive poly-
saccharides, such as xanthane and carrageenan
derivatives, seem to show interesting sustained
release properties and adequate ocular compatibil-
ity. (Thermes et al., 1992b). In a recent study,
Verschueren et al. (1996) used the polysaccharide,
carrageenan, to produce an in situ gelling system
for ophthalmic use. They observed that the
carrageenans were very similar to gellan gum and
seem to be well accepted.
The tendency today in ophthalmic research is
to develop systems which not only prolong the
contact time of the vehicle with the ocular surface,
but which would at the same time reduce
elimination of the drug. This approach is based on
the supposition that the drug is retained in the
vehicle by bonds which are sufficiently labile not
to remain trapped beyond the residence time of
the vehicle in the precorneal region.
Hoffman et al. (1995) developed a new
bioadhesive polymer composed of polyacrylic acid
copolymerized with Pluronic. The conjugation of
this thermally induced, phase-separating graft
polymer on the backbone of a bioadhesive poly-
mer yielded a bioadhesive vehicle with a pro-
longed residence time plus a prolonged drug
release period in contact with mucosal surfaces
such as the eye. According to Robinson and
Mlynek (1995), new polymeric gels with a biphasic
activity are necessary to acomplish both ocular
drug retention and prolonged release of drug from
the vehicle.
A new delivery system for ophthalmic drugs
involving both a polymeric network and ion
exchange resin particles as carriers was developed
to bind and release betaxolol (Jani et al., 1994).
Drug resin particles (Amberlite) were incorporated
into a structured vehicle, containing Carbopol
934P, to enhance the physical stability and ease
of resuspendability of the product. The resulting
0.25% betoptic S ophthalmic suspension product,
marketed in the US since February 1990, has
an increased bioavailability, equivalent to Betoptic
0.5% sterile ophthalmic solution at half the
concentration of the drug; and pharmaceutically,
is a suspension which settles slowly, providing
uniform dosage and increased ocular comfort.
In recent studies, some authors have been
tempted to combine the properties of colloidal
carriers and polymeric systems. The addition of the
bioadhesive polymer (polyacrylic acid) as a coating
for nanoparticles has been shown to prolong
residence time, which induces a prolongation of the
meiotic response of pilocarpine in the rabbit,
as compared with uncoated nanoparticles or to
a hydrogel of polyacrylic acid itself (Zimmer
et al., 1994, 1995). It was proposed that the
combination of particles with bioadhesive polymer
reinforced nanosphere adhesion to the precorneal/
conjunctival mucin layer and hence led to a
prolongation of the residence time of the drug in
the eye.
Albertsson et al. (1996) developed a novel
microsphere-gel formulation aimed at extending
precorneal residence times for ocular drugs.
Poly(adipic anhydride) was used for microencapsu-
lation of timolol maleate. The incorporation of the
microspheres into a gel resulted in extended release
of timolol maleate, which was controlled by the
surface erosion of the polymer.
Le Bourlais et al. (1997) developed a nanocap-
sule gel which combined the adhesion properties of
the polyacrylic acid polymer with encapsulated
cyclosporin into nanocapsules. This new drug
delivery system demonstrated the highest corneal
absorption rate, when compared with a polymeric
gel, nanocapsules, or an oily vehicle as the control.
Moreover, this formulation presented a level of
safety for ocular administration. The results
obtained with this new promising drug delivery
system should be confirmed in an in vivo study.
Combination of delivery systems may open a
new direction to improving therapeutic activity.
However, these combinations increase the com-
plexity of the formulations, as well a, increasing the
difficulties in understanding the mechanism of
action of the drug delivery systems.
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