Advanced Drug Delivery Reviews 60 (2008) 1663–1673

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Polyoxyethylated nonionic surfactants and their applications in topical ocular

drug delivery
Jim Jiao ⁎
Pfizer Global Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA

a r t i c l e i n f o a b s t r a c t

Article history: Topical dosing of ophthalmic drugs to the eye is a widely accepted route of administration because of convenience,
Received 6 August 2008 ease of use, and non-invasiveness. However, it has been well recognized that topical ocular delivery endures a low
Accepted 5 September 2008 bioavailability due to the anatomical and physiological constraints of the eye which limit drug absorption from the
Available online 20 September 2008
pre-corneal surface. Nonionic surfactants as versatile functional agents in topical ocular drug delivery systems are
uniquely suited to meet the challenges through their potential ability to increase bioavailability by increasing drug
Keywords:
Polyoxyethylated nonionic surfactant
solubility, prolonging pre-corneal retention, and enhancing permeability. This review attempts to place in
Surface active agent perspective the importance of polyoxyethylated nonionic surfactants in the design and development of topical
Micelle ocular drug delivery systems by assessing their compatibility with common ophthalmic inactive ingredients, their
Solubility impact on product stability, and their roles in facilitating ocular drugs to reach the target sites.
Ocular topical drug delivery © 2008 Elsevier B.V. All rights reserved.
Permeability

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1663
2. Properties of polyoxythylated nonionic surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1665
2.1. Surface and thermodynamic properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1665
2.2. Micellization process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1665
2.3. Dynamics of micellar equilibrium of nonionic surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1666
2.4. Micelle core polarity and solubilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1666
3. Applications in topical ocular formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1666
3.1. Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1666
3.2. Considerations for formulation design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1667
3.2.1. Effect on preservatives effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1667
3.2.2. Effect on product oxidative stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1668
3.2.3. Effect on drug adsorption, drop weight, and flow behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1668
4. Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1669
4.1. Ocular absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1669
4.2. Permeability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1669
4.3. Effect on drug pharmacokinetic profiles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1670
5. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1670
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671

1. Introduction tion of high throughput techniques for screening new compounds for
pharmacological activity. The high throughput has produced a large
In the past decade nonionic surfactants have found increasing number of new therapeutic candidates with poor aqueous solubility
applications in pharmaceutical preparations due to the implementa- [1]. These poorly water soluble candidates, categorized as class II or IV
compounds according to the biopharmaceutical classification scheme
(BCS) [2], impose a significant challenge for scientists in drug
⁎ Tel.: +1 860 441 3136; fax: +1 860 441 0467 development to provide effective delivery systems. Several approaches
E-mail address: jim.jiao@pfizer.com. utilizing nonionic surfactants to increase the bioavailability of the BCS

0169-409X/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2008.09.002
1664 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673

II/IV compounds and thereby the efficacy of the drugs have increas-
ingly been taken such as lipid based delivery systems, drug-polymer
amorphous dispersions, and particle size reduction [3].
Poor aqueous solubility of compounds affects pharmaceutical
product development in nearly all therapeutic areas including
ophthalmology. Despite the accessibility of the front of the eye,
efficient delivery of drug to treat various ocular disorders is a
challenge to the formulation scientist in addition to the often low
drug solubility. The majority of ophthalmic medications are formu-
lated as eye drops delivered topically to the eye. Due to anatomical
constraints, the volume that can be administered is limited to
approximately 30 μL. This, together with the efficient clearance
system that exists in the front of the eye, makes it difficult to maintain
an effective pre-ocular drug concentration for a desired length of time
[4]. The bioavailability of eye drops is typically less than 5% in spite of
frequent instillations.
Various formulation strategies have been used to increase aqueous
solubility of active pharmaceutical ingredients and pre-ocular retention
of eye drops. The most successful of these has been the inclusion of
polymeric surface active agents, particularly those able to undergo a
transition from a solution to a gel under the conditions of the pre-ocular
area and those that can interact with the mucous layer on the eye
surface. Different dosage forms including micellar systems, emulsions,
liposomes, and nanosized suspensions which generally require the
presence of surface active agents have also been reported to be useful to
overcome insufficient drug solubility and increase efficiency of drug
delivery, especially when the target site is intro-ocular.
Nonionic surfactants are the major type of surface active agents
used in ophthalmic delivery systems since their advantages with
respect to compatibility, stability, and toxicity are quite significant
compared to the cationic, anionic, or amphoteric counterparts [5,6].
They are generally less toxic, less hemolytic, and less irritating to the
ocular surface, and tend to maintain near physiological pH values
when in solution. The nonionic molecules are comprised of both polar
and non-polar segments, possessing a broad range of interfacial
activity and versatile functions as wetting agents, emulsifiers,
solubilizers, ocular permeability enhancers, and in some cases P-
glycoprotein inhibitors.
Polyoxyethylated nonionic surfactants are of great importance and
find widespread applications in ophthalmics among the nonionics.
Well known examples are Polysorbates, Tyloxapol, and Poloxamers.
Applications of other polyoxyethylated surfactants such as Cremophor
EL, Brij, and alpha-Tocopherol TPGS have also been reported in the
literature. These surfactants are often referred as polymeric ethers
since they all contain a common hydrophilic moiety of the molecules,
polyethylene oxide or polyethylene glycol, which has a repeated
(CH2CH2O)n ether structure with n generally in a range of 10 to
100 units (Table 1).
The purpose of this review is to summarize the surface and
thermodynamic properties of polyoxyethylated nonionic surfactants,
evaluate the recent advancement of these surface active agents in
ophthalmic topical drug delivery, and analyze advantages and
potential pitfalls of using them as ocular formulation ingredients to
address solubility, compatibility, and bioavailability issues. The effects
of these surfactants on biopharmaceutics of the ocular drugs are
assessed and information on their safety to the eye tissues over
chronic exposure is provided. Understanding of usefulness and
appropriate functions of these surfactants in topical ocular dosage

Table 1
Commonly used polyoxyethylated nonionic surfactants for topical ocular drug delivery

Surfactant Chemical structure MW g/mol HLB value CMCa (wt.%) Precedence in

marketed product
Polysorbate 80 1310 15.0 0.0013% or 10 μM Refresh endura
Restasis
Blephamide
Viva ultra tears

w + x + y + z = 20
Cremophor EL 2560 12–14 0.02% n/a

x + y + z = 35
Brij 35 CH3(CH2)11O(CH2CH2O)23H 1198 16.9 0.011% or 92 μM n/a
Alpha-Tocopherol TPGS 1513 13.0 0.02% n/a

Poloxamer 188 HO–(C2H4O)a–(C3H6O)b–(C2H4O)a–H 8400 (7680–9510) 29 0.1% Neosporin

a = ca. 80, b = ca. 27
Tyloxapol 4500 12.5 0.0081% or 18 μM Alrex
Azopt
Lotemax
Nevanac
TobraDx
Zylet

Polyoxyl stearate 40 1968 15.3 0.015% n/a

a
Ref [7].
 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673 1665

forms will aid in effective and efficient ophthalmic drug product
development.
2. Properties of polyoxythylated nonionic surfactants
2.1. Surface and thermodynamic properties
Polyoxyethylated nonionic surfactants are amphiphiles, that is,
they have a dual nature with part of the molecule exhibiting
hydrophilicity and the other lipophilicity. Unlike the ionics, the
exact region of the nonionic molecule comprising the hydrophilic
polar head or the lipophilic alkyl tail may not be readily elucidated
from the molecular structure. A generally accepted view is that the
polyoxyethylene chain serves as the hydrophilic region while the
remainder of the molecule or a portion of it serves as the lipophilic
one. Many parameters can affect the physicochemical and thermo-
dynamic properties of the surface active agents making up this type of
surfactant. The two main determinants are the distribution of
polyoxyethylene chains within the molecule and the structure of the
hydrophobic segment which typically consists of alkylphenols,
alkylalcohols, or fatty acids [8].
The aqueous solubility of the polyethoxylated nonionic surfactant
depends both on the alkyl chain length and the number of ethylene
oxide units in the molecule. Surfactants with an average alkyl chain
length of 12 carbon atoms and containing more than 5 ethylene oxide
units are usually soluble in water at room temperature [9]. Polysorbate
80, commercially also known as Tween 80, a trademark of Croda
International that is derived from polyethoxylated sorbitan and oleic
acid, and Cremophor EL, a registered trademark of BASF that is
prepared by reacting ethylene oxide with hydroxyl groups of the
castor oil triglyceride, contain 20 and 35 ethylene oxide units,
respectively, and hence are water soluble. According to the HLB
system designed for categorizing the nonionic surfactants [10,11], the
higher the percentage weight of polyethylene oxide in the molecule,
the higher HLB value a surfactant holds and the more soluble in
aqueous solution it is as a consequence.
The surface or interfacial tension that polyethoxylated nonionic
surfactants produce at the concentration they form aggregates is
usually higher compared to that of ionics, making the nonionics less
destructive on cell membranes and thus less irritating and toxic. In
addition, the nonionics are usually more bulky in size, less polar, and
less preferentially adsorbed at the surface, therefore, having a
tendency to associate together at a much lower concentration to
reduce the surface free energy.
2.2. Micellization process
outer layer of the micelles to interface with the aqueous bulk phase. In
the case of polyethylene oxide and polypropylene oxide triblock
copolymers, i.e. Poloxamers, it is the polypropylene oxide that
dehydrates in solution and becomes the hydrophobic domain of the
micelle when the surfactant molecules aggregate to form assembly at
or above the CMC [12]. The CMC value (mol/L) of polyoxyethylated
nonionic surfactants in general is about two orders of magnitude
lower than the corresponding anionics with the same alkyl chain
length (Fig. 1). The assembly of these surfactants into micelles can be
largely explained by the relative interactions between the hydrophilic
and hydrophobic segments with one another and the surrounding
medium [13].
The relation between the CMC and the polyoxyalkylene chain
length as well as the number of carbon atoms in the hydrophobic
segment can be described by the following generalized equation [14]:
ln ½CMC ¼ −nWCH2 =kT−mWPO&EO =kT þ const
where n is the number of carbon atoms in the hydrophobic moiety,
WCH2 is the van der Waals energy of interaction per CH2 group in
adjacent hydrocarbon chains due to the micelle formation, WPO&EO is
the van der Waals energy of interaction per propylene oxide or
ethylene oxide unit similar to WCH2, k is the Boltzmann constant, and T
is the Kelvin temperature. In general, the CMC of the polyoxyethylated
nonionic surfactants increases as polyoxyalkylene chain length is
increased.
Formation of micelles at a concentration below the CMC has been
observed [15]. The premicellar structures are not stable and can
undergo a quick disintegration when temperature is increased,
evidenced by the polarity change of micelles at different tempera-
tures. In the premicellar and early micellar stages, thermal stability of
aggregates varied significantly with the structure and size of both the
hydrophobic and hydrophilic moieties of the surfactant molecules.
The assemblies formed by surfactants with short polyoxyethylene
chains and highly branched aliphatic segments are mostly unstable.
In nonionic surfactants, the CMC is largely affected by the extent of
the hydration of polyoxyethylene chains of the surfactant molecules,
which is temperature dependent. The CMC and size of micelles
typically increase as temperature is increased (or bell-shaped over a
wide temperature range) due to dehydration of polyoxyethylene
chains. The loss of hydrates at elevated temperatures often is so
extensive that the formation of micelle aggregates or precipitates
large enough to scatter visible light can occur [9].
The effect of change in pH on the CMC of the polyoxyethylated
nonionic surfactants has been investigated using surface tension and
light-scattering methods. It is shown that a linear relationship exists
between the free energy of micellization and pH. Such linear

Like other types of surface active agents, the polyoxyethylated

nonionic surfactants form micellar structures at or above a concen-
tration threshold known as the critical micelle concentration (CMC) in
solution. Below the CMC, the number of individual surfactant
molecules adsorbing at the air–water interface increases with
increasing concentration of surfactants. At the CMC both the bulk
solution and the interface are saturated, and any additional surfactant
unimers will associate together to form micelles, driven entropically
via the expulsion of ordered water molecules into the bulk aqueous
phase. The standard change in free energy for the micellization
process is expressed by ΔG = RT ln(CMC), where R represents the gas
constant and T is the temperature of the system.
During the micellization process, the hydrophobic blocks of a
surfactant molecule associate to form the core region, whereas the
hydrophilic segments position between the core and the external
aqueous medium. Hence the hydrophobic core is stabilized by the
hydrophilic shell, which serves as an interface (corona) between the
bulk aqueous phase and the hydrophobic domain. The polyoxyethy- Fig. 1. Variation of the surface tension and CMC with types of surfactants (using average
lene chain of the molecule is the primary segment comprising the values of representative ionic, sodium lauryl sulfate, and nonionic, polysorbate 80).
1666 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673
relationship is attributed to the different water structures around
individual surfactant molecules as well as micelles. It has been
demonstrated that the water structure is more open, flexible, and thus
less ordered in acidic solutions, resulting in a higher configurational
micellization entropy compared to that in alkaline solutions [16].
2.3. Dynamics of micellar equilibrium of nonionic surfactants
Micelles are in dynamic equilibrium, constantly disintegrating and
reforming. There are two mechanisms that have been proposed to
describe the micellar equilibrium process: a fast relaxation where
individual surfactant molecules are constantly being exchanged
between the micelles and the surrounding bulk phase, and a slow
relaxation in which the micelles themselves are continuously
disintegrating and reassembling. The relaxation process is character-
ized by the slow relaxation time that is directly related to the micellar
stability. The observed slow micelle relaxation time is typically in the
range from microseconds to seconds. It is shown that the slow
relaxation times are much longer for nonionic surfactants than for
ionic ones, presumably because of the absence of ionic repulsion
between the head groups in the nonionics [17].
Some polyoxyethylated nonionic surfactants exhibit unusually
long relaxation time. Synperonic A7, a C12–C15 alkylalcohol poly-
ethylene oxide (n = 7) ether, takes more than 2 min to complete a cycle
of its relaxation process and is often referred as a frozen micelle
compared to those exhibiting a millisecond time scale. The consider-
ably long micellar relaxation was attributed to the broad molecular
weight distribution and the presence of impurities [18]. It is known
that Synperonic A7 contains a significant amount of long-chain
alcohols which apparently contribute to the stability of the micelles.
The surfactants Synperonic A7, Brij 35, and Synperonic A50 all have
comparable alkyl chain lengths but increasing degree of ethoxylation.
It is clear that increasing the number of ethylene oxide units decreases
the relaxation time. Such trend was also observed for other types of
polyoxyethylated nonionic surfactants [19].
Octylphenol ethoxylates, known as Triton, have also been
extensively studied for micellar kinetics due to specific UV absorbance
characteristics associated with the aromatic structure in that
molecule. Various techniques such as temperature-jump, pressure-
jump, and stopped-flow were used to characterize the micellar
kinetics. A linear relationship between the micellar relaxation time
and surfactant concentration has been established [20]. Results reveal
that the relaxation time decreases as the surfactant concentration is
increased, indicating that the formation or disintegration rate of
micelles under the equilibrium condition for octylphenol ethoxylates
becomes faster at higher surfactant concentrations.
Different drugs behave differently when they are solubilized in a
surfactant system. Some drugs get inactivated, whereas others show
higher activity. The properties such as solubility, diffusion coefficient,
and lipid-water partition coefficient of drugs in the presence of
micelles may differ significantly from individual components, i.e., the
properties of the free drugs [21]. Due to a slower relaxation process
nonionic surfactants generally produce more pronounced impact than
ionic surfactants on the properties of species, such as drugs,
incorporated in the micelles. The change in the properties of drugs
caused by nonionic micelles has many implications to topical ocular
drug delivery, which has been the subject of numerous investigations.
2.4. Micelle core polarity and solubilization
The micelle cores of surfactants in aqueous solutions are relatively
non-polar compared to the bulk medium, which preferentially
solubilize poorly water soluble compounds partitioned into the
micelles. In view of amphiphilic nature and structural features of
micelle-forming surfactant molecules, it is not illogical to believe that
there should be a continuous change in hydrophilicity or hydro-
Table 2
Micelle core polarity of some polyethoxylated nonionic surfactants
Surfactant Micelle core polarity (Pyrene peak ratio I1/I3) Ref
Cremophor EL 1.05 [22]
Polysorbate 80 1.13 [22]
Poloxamer 1.21 [22]
Tyloxapol 1.35 [23]
Triton X-100 1.40 [23]
phobicity of the micellar assembly with continuous change in the
distance from the micellar surface to the interior of the micelle. This
behavior of micelles is expected to remain unchanged with a change
in the shape or size of a micelle, because the change in micellar shape
and size does not bring a significant change in the micellar surfactant
molecular arrangement. The notion of continuous increase in
hydrophobicity with increasing distance from exterior to interior or
core of a micelle is supported by the micellar core polarity.
Generally the lower the core polarity the higher the effectiveness
of the micelle solubilization is on a molar basis. Table 2 shows the rank
order of several common polyoxyethylated nonionic surfactants with
respect to micellar core polarity, determined using Pyrene fluorescent
spectrum (Pyrene peak I1/I3 ratio that is sensitive to micro-region
polarity changes). The results suggest that Cremophor EL and
Polysorbate 80 micelle cores provide a relatively more favorable
environment to poor water soluble compounds in aqueous solution
compared to the other nonionic surfactants, indicating that they are
more effective in solubilizing water insoluble compounds.
3. Applications in topical ocular formulations
3.1. Applications
Polyoxyethylated nonionic surfactants have been widely used in
the topical delivery of ophthalmic drugs for the treatment of various
ocular disorders such as dry eye, inflammation, allergy, ocular
hypertension, glaucoma, etc. The dosage forms in which these
surfactants are applicable to are micellar solution, emulsion [24],
microemulsion [25], suspension [26], noisome [27], and liposome
[28,29]. The functional roles these surfactants play in the ophthalmic
preparations range from wetting, emulsification, solubilization, and
permeability enhancement (Table 3). An application as active
lubricant in the marketed corneal lubricating eye drops is also
precedented [36].
Zimmer et al. [37] evaluated a micellar polysorbate 80 eye drop for
hydrocortisone delivery to healthy and inflamed eyes. The formulation
was tested by measuring the in-vitro transport of radiolabelled
hydrocortisone through porcine cornea and then under in-vivo
conditions in healthy and inflamed eyes of rabbits. The application of
the micellar formulation led to higher hydrocortisone tissue concentra-
tions than a non-micelle based formulation used as reference.
Carmignani et al. [35] reported an improved tropicamide eye drop
formulation compared to the marketed tropicamide eye drops that is
formulated at pH 4.4–5.0. The pH of the tropicamide product on the
market is in the acidic region to obtain a sufficient solubility of the drug
for the required doses to be delivered. However, the acidic vehicle used
commercially is irritating and induces copious lacrimation, resulting in a
low bioavailability. Three nonionic surfactants, namely Tyloxapol,
Cremophor EL, and Poloxamer 108, were evaluated as solubilizer to
increase the solubility of tropicamide. It was observed that the micelle-
based formulations with these surfactants showed a small but
statistically significant improvement (increased bioavailability) in the
test animals when compared with the commercial solution eye drops.
Kuwano et al. [33] studied a cyclosporine eye drop containing polyoxyl
40 stearate, a mono- or di-stearate polyoxyethylene ester. The distribu-
tion of cyclosporine in rabbit cornea, conjunctiva, lacrimal gland was
 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673 1667

Table 3
Some applications of polyoxyethylated nonionic surfactants in topical ocular dosage forms

Surfactant Active agent Formulation Test model Observation Ref

Brij 35, 78, and 98 Atenolol Timolol Betaxolol Micellar solution Rabbits The corneal permeability was increased significantly [30]
Poloxamer 407 Indomethacin (IND) Micellar solution Rabbits Improved bioavailability and faster onset time compared [31]
to the marketed IND product
Poloxamer Gene 0.08 mg/mL plasmid and Albino rabbits and mice Gene expression detected in the treated eyes [26]
0.3% poloxamer solution around iris, sclera, conjunctiva, and lateral rectus muscle of
rabbit eyes and also in the intraocular tissues of mice
Poloxamer (Pluronic F127) Pilocarpine Micellar solution Rabbits Enhanced miotic response to a single instillation of Pilocarpine [32]
eye drops compared to an aqueous solution of the drug
Polyoxyl stearate CsA Micellar solution Rabbits Corneal CsA level is 60 fold higher for 0.1% CsA in polyoxyl 40 [33]
stearate micelles compared to 0.1% CsA caster oil solution
Polysorbate 80 Difluprednate o/w emulsion Rabbits Higher concentration of Difluprednate in aqueous humor [34]
compared to that delivered with a suspension formulation
Tyloxapol, Cremophor EL, Tropicamide Micellar solution Rabbits Micellar solutions improved bioavailability of a commercial [35]
and Poloxamer 108 Tropicamide eye drop to a small but statistically significant
extent

determined after topical administration. It was observed that the against microbial spoilage depends on the free (unbound) preserva-
micellar formulation was superior to a control (non-micellar formula- tive concentration in the aqueous solution. The nonionic surfactants
tion) with respect to the extent of drug penetration across corneal have a strong degree of interactions with the preservatives used in the
membrane and ocular tissue exposure. ocular products such that the concentration of free preservative in the
product can be depleted below a biological effective level [43].
3.2. Considerations for formulation design Since only the free preservative molecules are effective they must not
be bound to other components of the formulation. For multi-use
In the development of eye drops a careful evaluation and preserved ocular drug preparations containing nonionic surfactants the
characterization of the nonionic surfactants used in the preparations key to synergism between the surfactants and preservatives is to
should be carried out in order to fully understand the effects of these formulate the preservative system so that the concentration of the
surfactants on the properties of the formulations. The interactions surfactant is below the CMC [44,45]. When a situation arises which
between nonionic surfactants and other formulation ingredients may requires a concentration above the CMC, an ingredient capable of
rise, which can potentially affect the shelf-life, manufacturability, and supporting the antimicrobial activity of preservatives such as EDTA may
performance of a product. Some of these interactions involving need to be incorporated in the dosage form to boost the preservative
polyoxyethylated nonionic surfactants are discussed in the section effectiveness [46]. EDTA is a widely used chelating agent and has an
below. effect on the cell wall of the various organisms. EDTA itself is insufficient
to cause cell death, but is significantly pronounced to cause some
3.2.1. Effect on preservatives effectiveness structural changes in the cell wall, particularly of Pseudomonas
The ocular diseases such as glaucoma require chronic medical aeruginosa, to facilitate the entry of the preservative [47].
treatment. For cost-effective and patient safety, the topical ocular Kurup et al. [48] evaluated antibacterial activities of three
medications often contain preservatives to prevent potential micro- preservatives, methyl p-hydroxybenzoate, phenoxyethanol, and
bial contamination to the dispensed medication with repeated patient chlorocresol, in the presence of varying concentrations of polysorbate
use over a period of weeks or months. One of the most effective and 80. Below the CMC the bactericidal activities of these preservatives
commonly used ocular preservatives for the prevention of microbial increased as the concentration of polysorbate 80 was increased. A
contamination is benzalkonium chloride with which nearly 80% of the linear relationship was found to exist between the concentration of
currently marketed topical eye care products are preserved [38].
Benzalkonium chloride, alkyl dimethyl benzyl ammonium chlor-
ide, is a mixture of alkylbenzyl dimethylammonium chlorides of
various alkyl chain lengths (n-C8H17 to n-C16H33). It is effective against
bacteria as well as some viruses and fungi. The greatest biocidal
activity is associated with the C12–C14 alkyl derivatives. Benzalkonium
is also a cationic surfactant and kills organisms by disrupting
intermolecular interactions, causing dissociation of cellular mem-
brane bilayers and subsequent leakage of cellular contents. The
antimicrobial effectiveness of benzalkonium chloride, however, is
reduced in the presence of a polyoxyethylated nonionic surfactant and
completely inactivated (Fig. 2) when the concentration of the nonionic
surfactant exceeds a certain level above the CMC [39]. The reduction
or loss of antimicrobial activity of benzalkonium results from its
interactions with the surface active agents by either partitioning into
micelles or formation of preservative-surfactant co-micelles, hinder-
ing the ability of benzalkonium to disrupt microbial cell membranes
[40–42].
The reduction of the antimicrobial activities of other commonly
used ocular preservatives (such as chlorobutanol, chlorohexidine
gluconate, methylparaben, and propylparaben) in the presence of Fig. 2. A narrow concentration band of nonionic surfactant may exist, which satisfies
nonionic surfactants has also been reported [40]. The studies show both drug solubilization and preservative effectiveness requirement (use Benzalkonium
that the preservation of solubilized and emulsified disperse systems Chloride and Tween 80 as an example).
1668 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673
each of the preservatives required to reduce the microbial population
to the level specified in the pharmacopeia and the polysorbate 80
concentration. The enhanced antimicrobial activity of the preserva-
tives below the polysorbate 80 CMC was attributed to the reduction in
the surface tension of the medium due to the presence of the
surfactant. Low surface tension promotes the adsorption and uptake of
the preservatives by bacterial cells.
Kazmi et al. [49] reported the use of a three-chambered dialysis
cell to estimate the distribution of preservatives between the oil phase
and the aqueous phase of an emulsion stabilized by a polyoxyethy-
lated nonionic surfactant. The method was used to differentiate
between preservative that was bound or solubilized by the surfactant,
and preservative that was free in the aqueous phase. The distribution
data were plotted on a three-dimensional graph from which a total
concentration of preservative needed to provide a given free
concentration in the aqueous phase could be determined.
The interactions between ocular preservatives and nonionic
surfactants can be characterized using mathematical modeling of
competitive binding theory. Kazmi et al. [50,51] examined the
interactions of a number of commonly used preservatives (benzoic
acid, p-hydroxybenzoic acid, methylparaben, propylparaben, and
chloroxylenol) with a polyoxyethylated nonionic surfactant Cetoma-
crogol (polyethylene glycol cetyl ether or Brij 58). They concluded
after comparison of various methods that the Scatchard equation is
the most satisfactory model for describing or expressing the
interaction. Binding parameters determined from a Scatchard plot in
the concentration range of free preservative appropriate for anti-
microbial activity can be used to calculate the total concentration of
the preservative required in the surfactant system.
3.2.2. Effect on product oxidative stability
It has been well documented that polyoxyethylated nonionic
surfactants including polyethylene glycols, polyethylene oxides,
polysorbates, polyoxyethylene alkyl ethers, and other ethylene
oxide-based surfactants generally have some residual level of
peroxides present as supplied. [52,53]. Peroxides, either hydro or
organic types, can act to initiate radical chain processes and oxidize
susceptible drugs via direct reaction with the drugs, resulting in
significant damage to the active pharmaceutical ingredients, espe-
cially in situations with high excipient-to-drug ratios [54].
Polyoxyethylated nonionic surfactants are also subject to auto-
xidation that leads to formation of peroxides on storage. The
autoxidation starts with metal- and/or light-induced decomposition
of alkyl polyoxyethylene chain, propagates with oxygen consumption,
and terminates with collision among radicals. Results of the
autoxidation include not only the formation of peroxides on
polyoxyethylene chains but also changes in physicochemical proper-
ties of the surfactants such as a reduction in the cloud point, pH, and
surface tension due to the formation of breakdown products [55,56].
The oxidative damaging effect of peroxides on drug molecules has
been extensively reported. These include oxidation of benzocaine
hydrochloride [57], penicillins [58], and aminophylline [59] by
peroxides generated from polyoxyethylated nonionic surfactants.
Knepp et al. [60] demonstrated that alkyl hydroperoxides in
polysorbate 80 induced oxidation, dimerization, and subsequent
aggregation of recombinant human ciliary neurotrophic factor
(rhCNTF) in solution and the rate of reaction was similar to that
induced by hydrogen peroxide at the same concentration. Herman et
al. [61] were able to correlate the level of peroxides in polysorbate 80
and the degree of oxidation of recombinant human granulocyte
colony-stimulating factor (rhG-CSF) during storage. Miki et al. [62]
reported that there was a linkage between the oxidation of
hydroperoxidase and residual peroxides from Triton X-100, a nonionic
surfactant consisting of polyoxyethylated alkylphenol.
The initial residual level of peroxides from polyoxyethylated
nonionics plays a critical role in determining the extent of the
peroxide-induced oxidative drug degradation. The initial peroxides
present in the surfactants are produced during the ethoxylation and
subsequent bleaching steps of the manufacturing process. Many
manufacturers bleach their polyoxyethylated products to make them
colorless for a better appearance. Often the compounds that are
sensitive to oxidative degradation are less stable in the colorless
surfactants. To address this issue some suppliers have eliminated the
bleaching step (such as 4HP or super refined grade Polysorbate 80
from Croda International).
Controlling the source of oxygen, therefore controlling the level of
residual peroxides in surfactants through blocking the propagation
process of the autoxidation, is also important in protecting oxidation-
sensitive compounds/products. Some manufacturers have used this
strategy to limit the peroxide formation during storage and shipment
by packaging surfactants under nitrogen. Johnson et al. [63] showed
that removal of oxygen in the headspace of ampoules prevented
oxidation of Fenprostalene by peroxides generated in polyethylene
glycol 400 on storage. Ha et al. [64] reported that peroxide-induced
oxidation of recombinant human interleukin-2 mutein could be
effectively prevented/inhibited by reducing the contact of the protein
formulation with oxygen or air.
Use of antioxidants for minimizing the peroxidative degradation
pathway has also been reported. Butylated hydroxytoluene (BHT) is
commonly used by vendors as additive in the polyoxyethylated
nonionic surfactants to prevent the oxidative degradation. Several
antioxidants, including cysteine, glutathione, and methionine, have
also been shown to prevent oxidation of proteins caused by alkyl
peroxides in polysorbate 80 and hydrogen peroxide in solution [60].
However, antioxidant itself can be a concern for some pharmaceutical
formulations. Under some storage or packaging conditions, the BHT
forms strongly colored by-products or volatilizes, resulting in reduced
levels in the dosage form and correspondingly greater instability.
Vitamin E TPGS, a polyoxyethylated nonionic surfactant, is a water
soluble form of vitamin E and prepared by esterifying d-alpha-
tocopheryl acid succinate with polyethylene glycol 1000. Vitamin E is
a known antioxidant and vital for nerve and muscle cell functions.
Vitamin E inhibits the enzyme lipoxygenase, which is responsible for
the formation of leukotrienes that cause inflammation. This can be
useful in the treatment of asthma and other inflammatory conditions
such as arthritis. At higher doses, vitamin E has been shown to exhibit
antithrombolytic activity by increasing the production of prostaglan-
dins. Vitamin E TPGS, a derivative of Vitamin E, has shown utility as
antioxidant to against damage caused by peroxides and free radicals
introduced or formed during product preparation/storage. Vitamin E
TPGS also works synergistically with other antioxidants such as
vitamin C and β-carotene, to quench potentially harmful oxidation-
inducing substances [65–68].
3.2.3. Effect on drug adsorption, drop weight, and flow behavior
Eye drops containing prostaglandin derivatives may be prone to
adsorption onto various surfaces, causing drug loss during product
manufacture and storage. Adsorption of prostaglandin to resin
container and other surfaces can be reduced by adding nonionic
surfactants to eye drops [69]. Most of nonionic surfactants in solution
exhibit pseudoplastic flow and in some cases are capable of forming
gel under the physiological condition. Nonionic surfactants added to
topical ocular preparations may cause changes in dynamic surface
tension, viscosity, or other rheological behavior to a certain degree. It
has been shown that the lower the dynamic surface tension of the
solution, the lower the weight of drops delivered, which needs to be
taken into consideration during the product development [70].
The change in viscosity or other rheological properties including
yield stress, storage/loss modulus, and thixotropy as a result of
addition of nonionic surfactants to eye drops may not significantly
affect the drop volume/weight within the normal concentration range
of surfactants used [71]. However, the ramifications of nonionic
 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673
surfactants on rheological and diffusional behavior of enhanced-
viscosity eye care products containing carbopol, methylcellulose, and
other viscosity agents are likely to not be trivial [72,73].
4. Biopharmaceutics
4.1. Ocular absorption
Drugs are commonly applied to the eye for a localized action on the
surface or in the interior of the eye [4]. A major problem in ocular
therapeutics is the attainment of an optimal drug concentration at the
site of action. Poor bioavailability of drugs from ocular dosage form is
mainly due to the pre-corneal loss caused by tear dynamics, systemic
absorption, transient residence time in ocular surface, binding by the
lacrimal proteins, limited corneal area, and the relative imperme-
ability of the corneal epithelial membrane [74]. Due to these
physiological and anatomical constraints, only a small fraction of the
administered drug is ocularly absorbed, even with a frequent dosing
[75].
Under the normal conditions (average tear volume and turnover
rate) the contact time of the drug with the ocular absorbing surfaces
(cornea and sclera) is typically less than 2 min. For a micelle system,
upon topical administration free drug is absorbed into the eye and
instantly new free drug is released from micelles according to a shift in
the equilibrium between free drug and drug in micelle (Fig. 3). This is
true when the micellar relaxation time is short and/or the process of
drug partitioning in and out of micelles is fast. Thus, the ocular drug
absorption rates from a micelle and a solution system are comparable
if the effects of surfactants on the physical properties of the delivery
systems and the integrity of ocular epithelium are negligible.
Some polyoxyethylated nonionic surfactants used in drug delivery
applications can affect physical properties of drug products such as
viscosity, film spreading, and film strength. The pre-corneal residence
of an ophthalmic solution can be increased by the inclusion of such
surfactants to increase ocular absorption. Poloxamer, a triblock
copolymer consisting of a central hydrophobic block of polyoxypro-
pylene flanked by two hydrophilic blocks of polyoxyethylene, is
known to have a thermo-gelling behavior and has been used for the
development of a thermosetting ophthalmic drug delivery system in
order to increase ocular residence time [76]. The fluid nature of the
formulation allows ease of administration while the in situ self gelling
property facilitates increased pre-ocular retention [77]. It has been
suggested that this type of surfactant provides mucoadhesive
characteristics to ocular dosage forms [78,79] and is more effective
in increasing drug residence time than other approaches including
those with charged lipids to enhance interactions with mucins.
Fig. 3. Schematic of topical ocular drug absorption from a micellar delivery system after
instillation.
1669
4.2. Permeability
Surfactants have been suggested to increase drug permeability
through the cell membranes or via transcellular pathway. Ocular
epithelial cells are surrounded by an outer cell membrane composed
of a phospholipid bilayer with the proteins embedded in the lipid
membrane. When present at low concentrations, the surfactants are
incorporated into the lipid bilayer, forming polar defects which change
the physical properties of the cell membranes. When the lipid bilayer is
saturated, mixed micelles begin to form, resulting in the removal of
phospholipids from the cell membranes and hence leading to
membrane solubilization. It has therefore been suggested that a dose-
dependent increase in the permeability of the cell membrane is
responsible for the surfactant-induced increase in the permeability
across different epithelia [80,81].
Marsh and Maurice [82] studied the effect of nonionic surfactants
of various HLB values on corneal permeability and toxicity in humans.
The surfactants with HLB values between 16 and 17, which correspond
to Polysorbate 20 and Brij 35, were found to be most effective in
increasing corneal permeability. At 1% solution, these surfactants were
reported to increase fluorescein penetration fivefold without observed
ocular irritation. Saettone et al. [30] evaluated the corneal perme-
ability of atenolol, timolol, levobunolol, and betaxolol, the topical β-
adrenergic receptor antagonists for the treatment of glaucoma, in the
presence of various polyoxyethylene alkyl ethers (Brij 35, 78, and 98,
respectively). The permeability of the β-blockers across rabbit cornea
was increased when dosed with the nonionic surfactants. The
increased transcorneal permeation was more significant for the
hydrophilic drugs (atenolol and timolol) than for the more lipophilic
ones (levobunolol and betaxolol), possibly due to the inherent
preferential permeation of less hydrophobic compounds by corneal
stroma. The study showed that the polyoxyethylated nonionic
surfactants were safe as penetration promoters. Their apparent safety
at the tested concentrations was confirmed by their inability to
increase the corneal hydration level beyond the normal value, and by
their lack of irritant effect in-vivo, as evidenced by a Draize test.
P-glycoprotein, a transporter regulating the infiltration of various
substrates across the cell membrane, is known to play an important role
in limiting drug absorption, owning to its ubiquitous expression in most
tissues as well as its ability to efflux a wide spectrum of compounds. P-gp
is extensively distributed in normal cells such as those lining the
intestine, liver cells, renal proximal tubular cells, and capillary
endothelial cells comprising the blood-brain barrier. P-gp has also
been identified in various ocular tissues such as conjunctival epithelial
cells, iris and ciliary muscle cells, retinal capillary endothelial cells,
retinal pigmented epithelial cells, and ciliary non-pigmented epithelial
cells. More recently, P-gp has been identified in the human and rabbit
corneas [83], the main route by which intraocular drug absorption takes
place. When the drug target site is the cornea or the anterior/posterior
chamber, drug must be absorbed from the pre-ocular region into the eye.
The majority of polyoxyethylated nonionic surfactants are P-gp
efflux pump inhibitors that can reduce tissue P-gp expression and
increase drug absorption, resulting in a higher bioavailability. There-
fore, the use of the nonionic surfactant systems as a means of
delivering poorly absorbed drugs has been recognized as a strategy to
overcome P-gp efflux activity and improve drug efficacy. Reported
applications include anticancer drugs such as doxorubicin and
daurorubicin [84], steroids such as hydrocortisone and dexametha-
sone [85], HIV protease inhibitors such as ritonavir [86] and saquinavir
[87], cardiovascular drugs such as digoxin and quinidine [88], and
ophthalmic beta-blockers such as timolol [30] and acebutolol [89].
The mechanism of P-gp inhibition by polyoxyethylated nonionic
surfactants has not yet been completely understood, but appears to be
surfactant and/or transporter dependent [90]. Competitive inhibition of
substrate binding, alteration of membrane fluidity, and shutdown of
efflux pump ATPase are among the several possible mechanisms that
1670 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673
have been proposed. Both Polysorbate 80 and Cremophor EL were
reported to increase apical-to-basolateral permeability and at the same
time decrease basolateral-to-apical permeability of many P-gp sub-
strates. Polysorbate 80 mainly inhibits the intestinal peptide transporter,
whereas Cremophor EL primarily affects the monocarboxylic acid
transporter, the two different forms of membrane transporters [91].
The inhibitory effects of these two surfactants on P-gp efflux may be
related to their ability of modulating cell membrane fluidity. However,
the changes in membrane fluidity may not be a generalized mechanism
to reduce the transporter activity for all the nonionic surfactants.
Vitamin E TPGS has been reported as a potent and effective oral
absorption enhancer among the nonionic surfactants [92–95]. The
enhancing effect was demonstrated to carry out in a manner
consistent with a surfactant-induced inhibition of P-glycoprotein
mediated efflux. However, the exact inhibition mechanism remains
unclear for TPGS. The alteration of membrane fluidity induced by TPGS
was only observed at the surfactant concentration 100 times higher
than those needed to achieve a full efflux deactivation [90], indicating
that the mechanism TPGS inhibits transporter activity and therefore
enhances permeability is likely different than that observed for
Polysorbate 80 and Cremophor EL [91]. It was proposed that blocking
ATPase action, consequently depleting the P-gp efflux pump energy
source, is a possible factor contributing to the inhibitory ability of
TPGS [92]. A study on the TPGS function of P-gp inhibition with
different polyethylene oxide chain length in TPGS molecule revealed
that the current commercial product (TPGS 1000) exhibits greater
activity compared to its analogues [96] (Table 4).
4.3. Effect on drug pharmacokinetic profiles
Topical anti-glaucoma and intraocular pressure-lowing drugs must
penetrate across the tissues of the eye (i.e. cornea, sclera, and partially
conjunctiva) to reach their therapeutic targets. Often, these tissues
present the rate-limiting step for effective delivery. Furthermore rapid
tears turnover, lachrymal drainage, and low volume of ocular fluids
make the drugs much less available on the ocular surface for the
penetration. As a consequence, the bioavailability of an eye drop is
typically low and frequent instillations are often required to maintain
therapeutic drug concentrations at target sites [98].
After topical administration the majority of the instilled dose is
rapidly removed away from the eye through systemic absorption by
various routes of conjunctiva, nasal mucosa, lacrimal drainage system,
pharynx, gastrointestinal tract, skin at the cheek and lips [80,99–101].
The drugs absorbed systemically are ‘non-productive’ and will not get
into the anterior segment of the eye where the sites of action are often
located. The rate of non-productive absorption of eye drops ranges
from 65% for dipivalylepinephrine to 74% for flurbiprofen and 80% for
timolol [102]. The surfactants applied to the eye as inactive
component of ophthalmic drops will be absorbed along with drugs
through the non-productive routes and enter the systemic circulation.
For polyoxyethylated nonionic surfactants, upon entering the
systemic circulation micelles will eventually fall apart through
biodegradation or through simple dilution into surfactant unimers.
The tissue distribution of these surfactants is relatively low due to a
Table 4
Relative efflux inhibition effectiveness of some polyoxyethylated nonionic surfactants
[97]
P-gp Inhibitor (CMC %)
TPGS (0.02)
Cremophor EL (0.02)
Polysorbate 80 (0.0013)
Pluronic F85 (0.03)
Tyloxapol (0.008)
PEG 300
moderate to high hydrophilicity and/or possible strong binding with
plasma proteins. The dissociated individual surfactant molecules are
below the renal molecular weight threshold (40–50 kDa) and will be
mainly eliminated by renal excretion with only a small portion
removed by the biliary secretion [22].
Wang and Stern [103] studied the disposition and pharmacoki-
netics in rodents of Poloxamer 108, a polyoxypropylene-polyoxyethy-
lene block copolymer with an average molecular weight of 4.75 kDa.
They observed that approximately 94% of the 14C-labeled Poloxamer
108 was excreted in the urine and only small residues were detected in
the kidney, liver, small intestine, and carcass 20 h after administration.
The plasma disappearance kinetics was found to be independent of
the doses studied. The biofate of Poloxamer 188 in rats, rabbits, dogs
and humans was also investigated [104]. The plasma concentration of
this surfactant increased linearly with increasing dose in all species
tested. Renal clearance accounted for 90% of total plasma clearance in
humans.
Cremophor EL levels in plasma were reported to follow bi-
exponential decay kinetics [105]. The distribution volume of Cremo-
phor EL is less than the volume of the plasma and the extracellular
compartment, indicating that the tissue distribution of Cremophor EL
is insignificant. The elimination half-life of Cremophor EL is relatively
long and a sustained presence of substantial levels at 24 h after
administration was observed. Cremophor micelles are able to persist
for several hours after dilution below the CMC [106]. The clearance
path of nonionic surfactants through the kidneys or by other means of
excretion opens the potential for micelles that are stable in plasma and
that, by either preventing the drug from rapid renal clearance or
protection from metabolic enzymes, are able to alter the blood
disposition and pharmacokinetics of biologically active compounds
[22]. This may affect the toxicity profiles of the ophthalmic drugs
applied topically as eye drops.
Cremophor EL has been shown to reduce the systemic clearance of
multiple drugs, including doxorubicin and paclitaxel in humans. A
nonlinear pharmacokinetics exists for Taxol, paclitaxel in a pharma-
ceutical vehicle containing Cremophor EL [107]. Since blood concen-
trations of Cremophor EL that are above the CMC can be achieved in
humans [108], it has therefore been argued specifically for paclitaxel
that intact Cremophor EL micelles in the blood are responsible for
altering paclitaxel pharmacokinetics.
There is no data yet to show that all polyoxyethylated nonionic
surfactants can affect the blood disposition and clearance of active
compounds. The majority of clinical investigations have shown little
alteration in the pharmacokinetic profiles of paclitaxel and other
therapeutic agents when administered with Polysorbate 80. It was
demonstrated that Polysorbate 80 was quickly degraded in the presence
of plasma esterases, accompanied by a quantitative release of oleic acid
from the molecule. It is argued that the gentle impact of Polysorbate 80
on pharmacokinetic behaviors of drugs is a result of the rapid plasma
esterase-sensitive breakdown of the surfactant, making Polysorbate 80 a
much more favorable component for formulation and solubilization of
poorly water soluble agents than Cremophor EL [108,109].
Drugs applied topically that penetrate into the eye across the
cornea will firstly enter the aqueous humor and then are distributed to
the surrounding tissues. The absorbed drugs in the eye tissues are
eliminated mainly via aqueous humor turnover and venous blood flow
in the anterior uvea [80]. Surfactants partitioned into the eye with
drugs follow the similar clearance path [110], which can be monitored
using microdialysis sampling of ocular tissues, the same technique
used to determine ocular drug movement locally [111,112].
IC50 (wt.%)
0.005
0.1
5. Safety
0.05
0.01–0.05 Topical ophthalmic drug delivery bears a resemblance to the other
routes of drug delivery with techniques aimed at facilitating drug
5.0
penetration through the skin and different epithelia (buccal, nasal,
 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673
intestinal, rectal, and pulmonary, etc). However, the unique char-
acteristics and high sensitivity of the corneal and conjunctival tissues
impose distinctive safety requirements and great restrictions on the
selection of the components that can be used in the topical ocular
preparations. A special consideration is given to the ability of the
dosage form inactive ingredients to affect the integrity of epithelial
surfaces, which causes irritation, burning, stinging, tearing, and
cytotoxic side effects to the eye. Some of the ingredients can disrupt
the pre-corneal tear film which acts as a lubricant and protective layer
for the epithelium, and lead to damage to the epithelial surface and
worsening of the dry-eye condition. Others have been associated with
inflammatory changes of the ocular surface after chronic use [113].
Surfactants as a whole can affect the corneal and conjunctival
epithelium, albeit to various degrees. They also have potential to cause
corneal stromal and endothelial cell changes. Over time, ocular
responses to surfactants dosed at high concentrations include epithelial
regeneration, edema, inflammation, neovascularization, keratocyte
regeneration, and conjunctivalization, which correlate with the extent
and severity of initial surfactant-induced injury that is dependent on
type and chemical structure of surfactants to which the eye is exposed
[114,115]. These responses are accompanied by clinical evidence of
irritation (corneal opacity, conjunctival redness or chemosis, and
discharge).
However, it has been noted since Draize [116,117] that nonionic
surfactants are relatively harmless to the eye compared to their ionic
counterparts when used properly. An ocular irritation ranking order of
cationic N anionic N nonionic surfactants was observed recently based
on a confocal microscopy/corneal fluorescein staining method which
allowed rabbit and mouse corneal lesions produced by the contact
with surfactants to be marked and detected in-vivo [118,119]. The
study demonstrated that the polyoxyethylated nonionic surfactants
tested (0.5% Tween 20, 0.5% Brij 35, and 20% Poloxamer 407) were
essentially equivalent to physiological saline solution in terms of the
corneal damage caused by repeated topical applications of the
surfactant solutions.
Monti et al. [120] studied a number of common ophthalmic
excipients/adjuvants including Cremophor EL and Polyoxyethylene-
20-stearyl ether using corneal hydration changes as toxicity/irritation
index. The hydration level of the corneal membrane that was in
contact with various excipient solutions was measured using a
differential scanning calorimetry and desiccation method. They
concluded that the nonionic surfactants studied showed the least
influence on the corneal hydration and hence the lowest cornea
damaging potential. The same research group also evaluated the
electrophysiological properties of cornea (electrical resistance and
capacitance) and timolol permeability as a function of the ocular
excipient types and contact time duration. It was observed that the
only group of the excipients that showed a promoting effect on the
timolol permeation without having an adverse effect on the corneal
electrophysiological properties was the nonionic surfactants [121,122].
Some polyoxyethylated nonionic surfactants have had a long
history of being safe in ophthalmic use. Polysorbate 80 was reported to
be non-irritating to the rabbit eye up to a concentration of 10% [123]
and has been used in a number of marketed ophthalmic solution
drops. Tyloxapol and Poloxamers are also used as formulation
components of several commercial topical ocular products and have
proven to be safe for use [124].
There have been controversial reports, however, on the ophthalmic
safety of Vitamin E TPGS, an increasingly popular nonionic surfactant
in pharmaceuticals. Vitamin E TPGS has been approved by the major
global medical regulatory authorities for use in oral and parenteral
pharmaceutical products [65,125]. Its ocular application was studied
[66,126–128] and approved by the US FDA as an inactive ingredient in
diclofenac sodium ophthalmic solution 0.1%, a generic version of the
NSAID Voltaren [129]. The market distribution of the generic
diclofenac ophthalmic was discontinued by the manufacturer after a
1671
report that some patients receiving the diclofenac ophthalmic drops
developed a corneal melt — corneal stromal ulceration that progres-
sively and severely damages the cornea.
Corneal melting was also observed with the brand name version of
diclofenac ophthalmic, Voltaren, manufactured in the United States by
Novartis Ophthalmics [130]. The complication was speculated to be a
result of the ophthalmic use of the topical nonsteroidal anti-inflamma-
tory drugs [131]. Consequently the safety of ophthalmic NSAIDs and the
pharmacology regarding NSAID action in the eye were subject to
regulatory scrutiny [132]. However, questions remain as to why generic
diclofenac was associated with more cases of corneal melting than
Voltaren. Both generic diclofenac and Voltaren consisted of 0.1%
diclofenac sodium, but their inactive ingredients, the buffers, solubili-
zers and preservatives, were entirely different. At least one group of
researchers has suggested that the inactive ingredients of generic
diclofenac may have been involved in the pathogenesis of the stromal
ulcers [133]. The solubilizer used in generic diclofenac, Vitamin E TPGS,
is a tocopherol derivative. Tocopherols have been demonstrated to
inhibit retinal pigment epithelial cell proliferation [134] and to induce
apoptosis in mouse mammary cells [135]. Unfortunately, there has been
no direct clinical evidence linking Vitamin E TPGS to the observed ocular
adverse effect. The exact relationship, if any, between the inactive
ingredient and corneal melts remains unclear [136].
6. Conclusions
Polyoxyethylated nonionic surfactants used in topical ocular drug
delivery systems play a critical role in relation to their success in
overcoming the constraints imposed by the eye and by the
physicochemical properties of drugs. It has been demonstrated that
these surfactants have a profound impact on the in-vitro and in-vivo
performance/characteristics of topically applied ophthalmic drugs/
products. Existing ocular drug delivery systems are fairly primitive
and inefficient, but the stage is set for the rational design of newer and
significantly improved systems. It is clear that better and more
effective ophthalmic surfactants need to be identified to improve the
delivery of ocular drugs to both the anterior and posterior chambers of
the eye from topical dosing while safely altering the protective
mechanisms of the eye to facilitate drug absorption.
Acknowledgements
The author is grateful to the opportunity of working with many
Pfizer colleagues on the formulation aspects of ophthalmic products.
Special thanks to Debra Pereira and Karl Gelotte for their review of the
manuscript and helpful suggestions.
References
[1] H. Van de Waterbeemd, in: H. Van de Waterbeemd, H. Lennernas, P. Artursson (Eds.),
Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and
Bioavailability, Wiley-VCH, New York, New York, 2006, pp. 3–14.
[2] G.L. Amidon, H. Lennernäs, V.P. Shah, J.R. Crison, A theoretical basis for a
biopharmaceutical drug classification: the correlation of in vitro drug product
dissolution and in vivo bioavailability, Pharm. Res. 12 (1995) 413–420.
[3] J. Hu, K.P. Johnston, R.O. William, Nanoparticle engineering process for enhancing
the dissolution rates of poorly water soluble drugs, Drug Dev. Ind. Pharm. 30
(2004) 233–245.
[4] N.M. Davies, Biopharmaceutical considerations in topical ocular drug delivery,
Clin. Exptal. Pharmacol. Physiol. 27 (2000) 558–562.
[5] G. Zografi, Interfacial phenomena, in: A.R. Gennaro (Ed.), Remington: The Science
and Practice Pharmacy, Mark Publishing, Easton, PA, 1995, pp. 241–251.
[6] D.G. Hall, Thermodynamics of micelle formation, in: M.J. Schick (Ed.), Nonionic
Surfactants: Physical Chemistry, Surfactant Science Series, vol. 23, Marcel Dekker,
New York, N.Y, 1987, pp. 233–296.
[7] M.J. Akers, V. Vasudevan, M. Stickelmeyer, Formulation development of protein
dosage form, in: S.L. Neil, M.J. Akers (Eds.), Development and Manufacture of
Protein Pharmaceuticals, Pharmaceutical Biotechnology, vol. 14, Kluwer Aca-
demic/Plenum Publishers, New York, N.Y, 2002, pp. 47–84.
[8] M. van Os Nico (Ed.), Nonionic Surfactants — Organic Chemistry, Surfactant
Science Series, vol. 72, Marcel Dekker, New York, 1998.
1672 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673
[9] T.F. Tadros (Ed.), Applied Surfactants: Principles and Applications, Wiley VCH,
New York, N.Y, 2005, pp. 1–16.
[10] W.C. Griffin, Calculation of HLB values of non-ionic surfactants, J. Soc. Cosmet.
Chem. 5 (1954) 259.
[11] J.T. Davies, A quantitative kinetic theory of emulsion type, I. Physical chemistry of
the emulsifying agent. Gas/liquid and liquid/liquid interface, Proc. Int. Congr. Surf.
Act. (1957) 426–438.
[12] P. Alexandridis, T.A. Hatton, Poly(ethylene oxide)-Poly(propylene oxide)-Poly
(ethylene oxide) block copolymer in aqueous solutions and at interfaces:
thermodynamics, structure, dynamics, and modeling, Colloid Surf.: A 96 (1995)
1–46.
[13] M.L. Adams, A. Lavasanifar, G.S. Kwon, Amphiphilic block copolymers for drug
delivery, J. Pharm. Sci. 92 (2003) 1343–1355.
[14] K.T. Shinoda, T. Nakagawa, B. Tamamushi, T. Isemura, Colloid Surfactant,
Academic Press, New York, 1963, pp. 50–65.
[15] K. Toerne, R. Rogers, R. von Wandruszka, Thermal stability of nonionic surfactant
aggregates, Langmuir 17 (2001) 6119–6121.
[16] J.R. Bloor, J.C. Morrison, C.T. Rhodes, Effect of pH on the micellar properties of a
nonionic surfactant, J. Pharm. Sci. 59 (1970) 387–391.
[17] A. Patist, S.G. Oh, R. Leung, D.O. Shah, Kinetics of micellization: its significance to
technological processes, Colloid Surf. A 176 (2000) 3–16.
[18] A. Patist, J.R. Kanicky, P.K. Shukla, D.O. Shah, Importance of micellar kinetics in
relation to technological processes, J. Colloid Interface Sci. 245 (2002) 1–15.
[19] N. Muller, Kinetics of micelle dissociation by temperature-jump techniques. A
reinterpretation, J. Phys. Chem. 76 (1972) 3017–3020.
[20] J. Lang, J.J. Auburn, E.M. Eyring, Kinetics of octylphenyl polyoxyethylene alcohol
micelle dissociation by a stopped-flow technique, J. Colloid Interface Sci. 41
(1972) 484–490.
[21] C.P. Singh, D.O. Shah, Surface chemical aspects of ocular drug delivery systems, in: I.K.
Reddy (Ed.), Ocular Therapeutics and Drug Delivery: A Multi-disciplinary Approach,
Technomic Publishing Co., Lancaster, Basel, 1995, pp. 31–50.
[22] S.R. Croy, G.S. Kwon, Polysorbate 80 and Cremophor EL micelles deaggregate and
solubilize nystatin at the core-corona interface, J. Pharm. Sci. 94 (2005)
2345–2354.
[23] O. Regev, R. Zana, Aggregation behavior of Tyloxapol, a nonionic surfactant
oligomer, in aqueous solution, J. Colloid Interface Sci. 210 (1998) 8–17.
[24] S. Tamilvanan, S. Benita, The potential of lipid emulsion for ocular delivery of
lipophilic drugs, Eur. J. Pharm. Biopharm. 58 (2004) 357–368.
[25] F.F. Lv, L.Q. Zheng, C.H. Tung, Phase behavior of the microemulsions and the
stability of the chloramphenicol in the microemulsion-based ocular drug delivery
system, Intern. J. Pharmaceutics 301 (2005) 237–246.
[26] Y. Ali, K. Lehmussaari, Industrial perspective in ocular drug delivery, Adv. Drug
Deliv. Rev. 58 (2006) 1258–1268.
[27] M.F. Saettone, G. Perini, M. Carafa, E. Santucci, F. Alhaique, Nonionic surfactant
vesicles as ophthalmic carriers for cyclopentolate: a preliminary evaluation, S.T.P.
Pharma Sci. 6 (1996) 94–98.
[28] H.E. Schaeffer, D. L Krohn, Liposomes in topical drug delivery, Investig.
Ophthalmol. Vis. Sci. 22 (1982) 220–227.
[29] D. Meisner, M. Mezei, Liposome ocular delivery systems, Adv. Drug Deliv. Rev. 16
(1995) 75–93.
[30] M.F. Saettone, P. Chetoni, R. Cerbai, G. Mazzanti, L. Braghiroli, Evaluation of ocular
permeation enhancers: in vitro effects on corneal transport of four β-blockers,
and in vitro/in vivo toxic activity, Int. J. Pharmaceutics 142 (1996) 103–113.
[31] P. Chetoni, L. Panichi, S. Burgalassi, U. Benelli, M.F. Saettone, Pharmacokinetics
and anti-inflammatory activity in rabbits of a novel indomethacin ophthalmic
solution, J. Ocular Pharmacol. Ther. 16 (2000) 363–372.
[32] I. Pepic, N. Jalsenjak, I. Jalsenjak, Micellar solutions of triblock copolymer
surfactants with pilocarpine, Int. J. Pharmaceutics 272 (2004) 57–64.
[33] M. Kuwano, H. Ibuki, N. Morikawa, A. Ota, Y. Kawashima, Cyclosporine a
formulation affects its ocular distribution in rabbits, Pharmaceutic Res. 19 (2002)
108–111.
[34] M. Yamaguchi, S. Yasueda, A. Isowaki, M. Yamamoto, M. Kimura, K. Inada, A.
Ohtori, Formulation of an ophthalmic lipid emulsion containing an anti-
inflammatory steroidal drug, difluprednate, Int. J. Pharmaceutics 301 (2005)
121–128.
[35] C. Carmignani, S. Rossi, M.F. Saettone, S. Burgalassi, Ophthalmic vehicles
containing polymer-solubilized tropicamide: “in vitro/in vivo” evaluation, Drug
Dev. Ind. Pharm. 28 (2002) 101–105.
[36] Thomson, Physicians' Desk Reference, 62nd Edition, Wadsworth, 2008.
[37] A.K. Zimmer, Philippe Maincent, Pierre Thouvenot, Jörg Kreuter, Hydrocortisone
delivery to healthy and inflamed eyes using a micellar polysorbate 80 solution or
albumin nanoparticles, Int. J. Pharmaceutics 110 (3) (1994) 211–222.
[38] P. Furrer, B. Plazonnetb, J.M. Mayera, R. Gurny, Application of in vivo confocal
microscopy to the objective evaluation of ocular irritation induced by surfactants,
Int. J. Pharmaceutics 207 (1–2) (2000) 89–98.
[39] A. Wade, P.J. Weller, Handbook of Pharmaceuticql Excipients, The American
Pharmaceutical Association, Washington D.C., USA and Royal Pharmaceutical
Society of Great Britain, London, England, 1994
[40] T. Loftsson, O. Stefansdottir, H. Frioriksdottir, O. Guomundsson, Interactions
between preservatives and 2-hydroxypropyl-β-cyclodextrin, Drug Dev. Ind.
Pharm. 18 (1992) 1477–1484.
[41] P.P. Deluca, H.B. Kostenbauder, Interaction of preservative with macromolecules
IV. Binding of quaternary ammonium compounds by nonionic agents, J. Amer.
Pharm. Assoc., 49 (1960) 430–437.
[42] R.M.E. Richards, Effect of hypromellose on the antibacterial activity of benzalk-
onium chloride, J. Pharm. Pharmacol. 28 (3) (1976) 264–269.
[43] S.J.A. Kazmi, A.G. Mitchell, Preservation of solubilized and emulsified systems. I:
Correlation of mathematically predicted preservative availability with antimi-
crobial activity, J. Pharmaceutical Sci. 67 (9) (1978) 1260–1266.
[44] S.J.A. Kazmi, A.G. Mitchell, Preservation of solubilized and emulsified systems. II:
Theoretical development of capacity and its role in antimicrobial activity of
chlorocresol in cetomacrogol-stabilized systems, J. Pharmaceutical Sci. 67 (9)
(1978) 1266–1271.
[45] A.G. Mitchell, S.J.A. Kazmi, Chemical preservation of emulsified and solubilized
disperse systems, Cosmet. Toilet. 92 (11) (1977) 33–34.
[46] T.J. McCarthy, Cosmetic and Drug Preservation: Principles and Practice, Marcel
Decker, New York, N.Y, 1984, pp. 359–368.
[47] H. Haque, A.D. Russel, Effect of chelating agents on the susceptibility of some
strains of gram-negative bacteria to some antibacterial agents, Antimicrob.
Agents Chemother. 6 (2) (1974) 200–206.
[48] T.R.R. Kurup, L.S.C. Wan, L.W. Chan, Effect of surfactants on the antibacterial
activity of preservatives, Pharm. Acta Helv. 66 (9–10) (1991) 274–280.
[49] S.J.A. Kazmi, A.G. Mitchell, Dialysis method for determining preservative
distribution in emulsions, J. Pharmaceutical Sci. 60 (1971) 1422–1424.
[50] S.J.A. Kazmi, A.G. Mitchell, Interaction of preservatives with cetomacrogol,
J. Pharm. Pharmacol, 23 (7) (1971) 482–489.
[51] S.J.A. Kazmi, A.G. Mitchell, The interaction of preservative and nonionic surfactant
mixtures, Canadian J. Pharm. Sci. 11 (1976) 10–17.
[52] W.R. Wasylaschuk, P.A. Harmon, G. Wagner, A.B. Harman, A.C. Templeton, H. Xu,
R.A. Reed, Evaluation of hydroperoxides in common pharmaceutical excipients,
J. Pharmaceutical Sci. 96 (1) (2007) 106–116.
[53] J. Jaeger, K. Sorensen, S.P. Wolff, Peroxide accumulation in detergents, J. Biochem.
Biophys. Methods 29 (1994) 77–81.
[54] S. Ahuja, K.M. Alsante (Eds.), Handbook of Isolation and Characterization of
Impurities in Pharmaceuticals, Separation Science and Technology, vol. 5,
Academic Press, 2003.
[55] M. Donbrow, E. Azaz, A. Pillersdorf, Autoxidation of polysorbates, J. Pharm. Sci. 67
(1978) 1676–1681.
[56] R. Hamburger, E. Azaz, M. Donbrow, Autoxidation of polyethylenic non-ionic
surfactants and of polyethylene glycols, Pharm. Acta. Helv. 50 (1975) 10–17.
[57] E. Azaz, M. Donbrow, R. Hamburger, Incompatibility of non-ionic surfactants with
oxidizable drugs, Pharm. J. 211 (1975) 15–25.
[58] L.V. Coates, M.M. Pahley, K. Tattersall, The stability of antibacterials in
polyethylene glycol mixtures, J. Pharm. Pharmacol. 13 (1961) 620–624.
[59] K.C. James, R.H. Leach, The stability of chloramphenicol in topical formulations,
J. Pharm. Pharmacol. 22 (1970) 607–611.
[60] V.M. Knepp, J.L. Whatley, A. Muchnik, T.S. Calderwood, Identification of
antioxidants for prevention of peroxide-mediated oxidation of recombinant
human ciliary neurotrophic factor and recombinant human nerve growth factor,
J. Pharm. Sci. Technol. 50 (1996) 163–171.
[61] A.C. Herman, T.C. Boone, H.S. Lu, Characterization, formulation, and stability of
neupogen (filgrastim), a recombinant human granulocyte-colony stimulating
factor, in: R. Pearlman, Y.J. Wang (Eds.), Formulation, Characterization, and
Stability of Protein Drugs, Plenum Press, New York, 1996, pp. 303–328.
[62] T. Miki, Y. Orii, The reaction of horseradish peroxidase with hydroperoxides
derived from triton x-100, Anal. Biochem. 146 (1985) 28–34.
[63] D.M. Johnson, W.F. Taylor, Degradation of fenprostalene in polyethylene glycol
400 solution, J. Pharm. Sci. 73 (1984) 1414–1417.
[64] E. Ha, W. Wang, Y.J. Wang, Peroxide formation in polysorbate 80 and protein
stability, J. Pharma. Sci. 91 (10) (2002) 2252–2264.
[65] P.P. Constantinides, J.H. Han, S.S. Davis, Advances in the use of tocols as drug
delivery vehicles, Pharm. Res. 23 (2) (2006) 243–255.
[66] A. Campana, G. Cavallo, E. Sodd, Uniquinone-containing water-soluble formula-
tion for ophthalmic use, EP-1464341. March 03, 2004
[67] R.J. Sokol, N. Butler-Simon, C. Conner, J.E. Heubi, F.R. Sinatra, F.J. Suchy, M.B.
Heyman, J. Perrault, R.J. Rothbaum, J. Levy, Multicenter trial of d-alpha-
tocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E
deficiency in children with chronic cholestasis, Gastroenterology 104 (6) (1993)
1727–1735.
[68] M.G. Traber, C.A. Thellman, M.J. Rindler, H.J. Kayden, Uptake of intact TPGS (d-alpha-
tocopheryl polyethylene glycol 1000 succinate) water — miscible form of vitamin E
by human cells in vitro, Am. J. Clin. Nutr. 48 (1988) 605–611.
[69] M. Umeda, K. Morishima, M. Kuwano, A. Kimura, H. Asada, Eye drops, PCT Int.
Appl. WO 2002022131 A1 20020321, 2002, pp. 21–25.
[70] V.L. Santvliet, L. Ludwig, Influence of the physico-chemical properties of
ophthalmic viscolysers on the weight of drops dispensed from a flexible dropper
bottle, Eur. J. Pharm. Sci. 7 (4) (1999) 339–345.
[71] B.I. Gaynes, R.M. Singa, G. Schaab, Y. Sorokin, Impact of administration angle on
the cost of artificial tear solutions: does bottle positioning minimize wastage?
J. Ocular Pharmacol. Ther. 23 (2) (2007) 196–201.
[72] R. Barreiro-Iglesias, C. Alvarez-Lorenzo, A. Concheiro, Incorporation of small
quantities of surfactants as a way to improve the rheological and diffusional
behavior of carbopol gels, J. Control. Release 77 (1–2) (2001) 59–75.
[73] H.R. Lin, K.C. Sung, Carbopol/pluronic phase change solutions for ophthalmic
drug delivery, J. Control. Release 69 (3) (2000) 379–388.
[74] I.P. Kaur, M. Kanwar, Ocular preparations: the formulation approach, Drug Dev.
Ind. Pharm. 28 (5) (2002) 473–493.
[75] N.L. Burstein, J.A. Anderson, Review: corneal penetration and ocular availability of
drugs, J. Ocul. Pharmacol. 1 (1985) 309–326.
[76] G. Wei, H. Xu, P.T. Ding, S.M. Li, J.M. Zheng, Thermosetting gels with modulated
gelation temperature for ophthalmic use: the rheological and gamma scinti-
graphic studies, J. Control. Release 83 (2002) 65–74.
 J. Jiao / Advanced Drug Delivery Reviews 60 (2008) 1663–1673
[77] R. Gurny, H. Ibrahim, A. Aebi, Design and evaluation of controlled release systems
for the eye, J. Control. Rel. 6 (1987) 367–373.
[78] A. Ludwig, The use of mucoadhesive polymers in ocular drug delivery, Adv. Drug
Deliv. Rev. 57 (2005) 1595–1639.
[79] I.P. Kaur, R. Smitha, Penetration enhancers and ocular bioadhesives: two new
avenues for ophthalmic drug delivery, Drug Dev. Ind. Pharm. 28 (4) (2002)
353–369.
[80] K. Jarvinen, T. Jarvinen, A. Urtti, Ocular absorption following topical delivery, Adv.
Drug Deliv. Rev. 16 (1995) 3–19.
[81] G.C.Y. Chiou, Y.Q. Zheng, Permeation enhancement via the ocular route, in: D.
Hsieh (Ed.), Drug Permeation Enhancement: Theory and Applications, Marcel
Dekker, New York, N. Y, 1994, pp. 405–406.
[82] R.J. Marsh, D.M. Maurice, Influence of nonionic detergents and other surfactants
on human corneal permeability, Exp. Eye Res. 11 (1) (1971) 43–48.
[83] S. Katragadda, R.S. Talluri, A.K. Mitra, Modulation of P-Glycoprotein-mediated
efflux by prodrug derivatization: an approach involving peptide transporter-
mediated influx across rabbit cornea, J. Ocular Pharmacol. Ther. 22 (2) (2006)
110–120.
[84] A.A. Shtil, T.M. Grinchuk, L. Tee, Overexpression of P-glycoprotein is associated
with a decreased mitochondrial transmembrane potential in doxorubixin-
selected K562 human leukemia cells, Int. J. Oncol. 17 (2000) 387–392.
[85] K. Ueda, N. Okamura, M. Hirai, Human P-glycoprotein transports cortisol,
aldosterone, and dexamethasone, but not progesterone, J. Biol. Chem. 267
(1992) 24248–24252.
[86] M.D. Perloff, L.L. Von Moltke, L.E. Marchand, Ritonavir induces P-glycoprotein
expression, multidrug resistance-associated protein (MRP1) expression, and drug
transporter-mediated activity in a human intestinal cell line, J. Pharm. Sci. 90
(2001) 1829–1837.
[87] M.T. Huisman, J.W. Smit, H.R. Wiltshire, Assessing safety and efficacy of directed
P-glycoprotein inhibition to improve the pharmacokinetic properties of saqui-
navir coadministered with ritonavir, J. Pharmacol. Exp. Ther. 304 (2003) 596–602.
[88] S. Duvvuri, M.D. Gandhi, A.K. Mitra, Effect of P-glycoprotein on the ocular
disposition of a model substrate, quinidine, Curr. Eye res. 27 (2003) 345–353.
[89] K. Kawazu, A. Oshita, T. Nakamura, N. Ichikawa, M. Nakashima, H. Sasaki, Transport
of acebutolol through rabbit corneal epithelium, Biol. Pharm. Bull. 29 (4) (2006)
846–849.
[90] E.M. Collnot, C. Baldes, M.F. Wempe, R. Kappl, J. Hüttermann, J.A. Hyatt, K.J. Edgar,
U.F. Schaefer, C.M. Lehr, Mechanism of inhibition of P-glycoprotein mediated
efflux by vitamin E TPGS: influence on ATPase activity and membrane fluidity,
Mol. Pharm. 4 (2007) 465–474.
[91] B.D. Rege, J.P. Kao, J.E. Polli, Effects of nonionic surfactants on membrane
transporters in Caco-2 cell monolayers, Eur. J. Pharm. Sci. 16 (2002) 237–246.
[92] J.M. Dintaman, J.A. Silverman, Inhibition of P-glycoprotein by D-alpha-tocopheryl
polyethylene glycol 1000 succinate (TPGS), Pharm. Res. 16 (1999) 1550–1556.
[93] M.T. Sheu, S.Y. Chen, L.C. Chen, H.O. Ho, Influence of micelle solubilization by
tocopheryl polyethylene glycol succinate (TPGS) on solubility enhancement and
percutaneous penetration of estradiol, J. Control. Release 88 (2003) 355–368.
[94] Manthena Varma, Ramesh Panchagnula, Enhanced oral paclitaxel absorption
with vitamin E-TPGS: effect on solubility and permeability in vitro, in situ and in
vivo, Eur. J. Pharm. Sci. 25 (4–5) (2005) 445–453.
[95] L. Yu, A. Bridgers, J. Polli, A. Vickers, S. Long, A. Roy, R. Winnike, M. Coffin, Vitamin
E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its
solubility and permeability, Pharm. Res. 16 (12) (1999) 1812–1817.
[96] E. Collnot, C. Baldes, M.F. Wempe, J. Hyatt, L. Navarro, K.J. Edgar, U.F. Schaefer, C.M.
Lehr, Influence of vitamin E TPGS poly(ethylene glycol) chain length on apical
efflux transporters in Caco-2 cell monolayers, J. Cont. Rel. 111 (2006) 35–40.
[97] Eastman Vitamin E TPGS NF, Applications and Properties.
[98] R.W. Yee, The effect of drop vehicle on the efficacy and side effects of topical
glaucoma therapy: a review, Curr. Opin. Ophthalmol. 18 (2007) 134–139.
[99] V.H. Lee, J.R. Robinson, Topical ocular drug delivery: recent developments and
future challenges, J. Ocul. pharmacol. 2 (1) (1986) 67–108.
[100] A. Urtti, Delivery of antiglaucoma drugs: ocular vs systemic absorption, J. Ocul.
Pharmacol. 10 (1) (1994) 349–357.
[101] A. Urtti, Challenges and obstacles of ocular pharmacokinetics and drug delivery,
Adv. Drug Deliv. Rev. 58 (2006) 1131–1135.
[102] M.F. Saettone, Progress and Problems in Ophthalmic Drug Delivery, Business
Briefing: Pharmatech, 2002, pp. 167–171.
[103] Z.J. Wang, I.J. Stern, Disposition in rats of a polyoxypropylene-polyoxyethylene
copolymer used in plasma fractionation, Drug Metab. Dispos. 3 (6) (1975)
536–542.
[104] M.J. Grindel, T. Jaworski, M.R. Emanuele, P. Culbreth, Pharmacokinetics of a novel
surface-active agent, purified poloxamer 188, in rat, rabbit, dog and man,
Biopharm. Drug Dispos. 23 (3) (2002) 87–103.
[105] L.K. Webster, M.E. Linsenmeyer, M.J. Millward, C. Morton, J. Bishop, D.M.
Woodcock, Measurement of Cremophor EL following Taxol: plasma levels
sufficient to reverse drug exclusion mediated by the multidrug-resistant
phenotype, J. Natl. Cancer Inst. 85 (20) (1993) 1685–1690.
[106] D. Kessel, Properties of Cremophor EL micelles probed by fluorescence,
Photochem. Photobiol. 56 (4) (1992) 447–451.
[107] A. Sparreboom, O. van Tellingen, W. Nooijen, J. Beijnen, Nonlinear pharmacoki-
netics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor
EL, Cancer. Res. 56 (1996) 2112–2115.
1673
[108] Olaf van Tellingen, Jos H. Beijnen, Jaap Verweij, Esther J. Scherrenburg, Willem J.
Nooijen, Alex Sparreboom, Rapid esterase-sensitive breakdown of polysorbate 80
and its impact on the plasma pharmacokinetics of docetaxel and metabolites in
mice, Clin. Cancer Res. 5 (10) (1999) 2918–2924.
[109] T.R. Bates, C.H. Nightingale, E. Dixon, Kinetics of hydrolysis of polyoxyethylene
(20) sorbitan fatty acid ester surfactants, J. Pharm. Pharmacol. 25 (1973) 470–477.
[110] N. Worakul, J.R. Robinson, Ocular pharmacokinetics/pharmacodynamics, Eur. J.
Pharma. Biopharma. 44 (1997) 71–83.
[111] A.K. Mitra (Ed.), Ophthalmic Drug Delivery Systems, Drugs and the Pharmaceu-
tical Sciences, Informa Healthcare, 2003.
[112] D. Aggarwal, D. Pal, A.K. Mitra, I.P. Kaur, Study of the extent of ocular absorption of
acetazolamide from a developed niosomal formulation, by microdialysis
sampling of aqueous humor, Int. J. Pharma. 338 (1–2) (2007) 21–26.
[113] R. Noecker, Ophthalmic preservatives: considerations for long-term use in
patients with dry eye or glaucoma, Rev. Ophthalmol. (2001) June.
[114] J.K. Maurer, R.D. Parker, G.J. Carr, Ocular irritation: microscopic changes occurring
over time in the rat with surfactants of known irritancy, Toxicol Pathol. 26 (2)
(1998) 217–225.
[115] J.V. Jester, W.M. Petroll, J. Bean, R.D. Parker, G.J. Carr, H.D. Cavanagh, J.K. Maurer,
Area and depth of surfactant-induced corneal injury predicts extent of
subsequent ocular responses, Investig. Ophthalmol. Vis. Sci. 39 (1998) 2610–2625.
[116] J.H. Draize, A. Kelley Elsie, Surface-active agents and the eye, Drug Cosmet. Ind. 71
(36) (1952) 118–120.
[117] J.H. Draize, A. Kelley Elsie, Toxicity to eye mucosa of certain cosmetic preparations
containing surface-active agents, Proc. Sci. Sec. Toilet Goods Assoc. 17 (1952) 1–4.
[118] P. Furrer, J.M. Mayer, R. Gurny, Ocular tolerance of preservatives and alternatives,
Eur. J. Pharm. Biopharm. 53 (2002) 263–280.
[119] Y. Rojanasakul, J.H. Liaw, J.R. Robinson, Mechanisms of action of some penetration
enhancers in the cornea: laser scanning confocal microscopic and electrophysiol-
ogy studies, Int. J. Pharm. 66 (1–3) (1990) 131–142.
[120] D. Monti, P. Chetoni, S. Burgalassi, M. Najarro, M.F. Saettone, Increased corneal
hydration induced by potential ocular penetration enhancers: assessment by
differential scanning calorimetry (DSC) and by desiccation, Int. J. Pharm. 232 (1–2)
(2002) 139–147.
[121] P. Chetoni, S. Burgalassi, D. Monti, M.F. Saettone, Ocular toxicity of some corneal
penetration enhancers evaluated by electrophysiology measurements on isolated
rabbit corneas, Toxicol. In. Vitro. 17 (4) (2003) 497–504.
[122] S. Burgalassi, P. Chetoni, D. Monti, M.F. Saettone, Cytotoxicity of potential ocular
permeation enhancers evaluated on rabbit and human corneal epithelial cell
lines, Toxicol. Lett. 122 (1) (2001) 1–8.
[123] L.W. Hazleton, Relation of surface-active properties of irritation of the rabbit eye,
Proc. Sci. Sect. T.G.A. (1952) 17–18.
[124] US Food and Drug Administration, Center for Drug Evaluation and Research
Database.
[125] Z. Zhang, S.H. Lee, S.S. Feng, Folate-decorated poly(lactide-co-glycolide)-vitamin
E TPGS nanoparticles for targeted drug delivery, Biomaterials 28 (2007)
1889–1899.
[126] S. Desai, R. Bawa, Topical ophthalmic acidic drug formulations. US5558876A. Sept
24, 1996.
[127] Manoj Maniar. Use of vitamin E tocopheryl derivatives in ophthalmic composi-
tions. US5886030. Mar 23, 1999.
[128] L. Mu, S.S. Feng, A novel controlled release formulation for the anticancer drug
paclitaxel Ta(xol): PLGA nanoparticles containing vitamin E TPGS, J. Cont. Rel. 86
(2003) 33–48.
[129] US Food and Drug Administration, Center for Drug Evaluation and Research,
Approved Drug Products with Therapeutic Equivalence Evaluations, Preface to
Twenty Second Edition, 2002.
[130] M. Zanini, G. Savini, P. Barboni, Corneal melting associated with topical diclofenac
use after laser-assisted subepithelial keratectomy, J. Cataract refract. Surg. 32 (9)
(2006) 1570–1572.
[131] A. Flach, Topically applied nonsteroidal anti-inflammatory drugs and corneal
problems: an interim review and comment, Ophthalmology 107 (7) (2000)
1224–1226.
[132] B.I. Gaynes, R. Fiscella, Topical nonsteroidal anti-inflammatory drugs for
ophthalmic use: a safety review, Drug Safety 25 (4) (2002) 233–250.
[133] S.L. Hargrave, J.C. Jung, M.E. Fini, H. Gelender, C. Cather, A. Guidera, I. Udell, S.
Fisher, J.V. Jester, R.W. Bowman, J.P. McCulley, H.D. Cavanagh, Possible role of the
Vitamin E solubilizer in topical diclofenac on matrix metalloproteinase expres-
sion in corneal melting: an analysis of postoperative keratolysis, Ophthalmology
109 (2) (2002) 343–350.
[134] T. Sakamoto, D.R. Hinton, H.K. Kimura, Vitamin E succinate inhibits proliferation
and migration of retinal pigment epithelial cells in vitro: therapeutic implication
for proliferative vitreoretinopathy, Graefes. Arch. Clin. Exp. Ophthalmol. 234
(1996) 186–192.
[135] B.S. Mclntyre, K.P. Briski, A. Gapor, P.W. Sylvester, Antiproliferative and apoptotic
effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse
mammary epithelial cells, Proc. Soc. Exp. Boil. Med. 224 (2000) 292–301.
[136] M. Abelson, L. Lilyestrom, Melting away the myths of NSAIDs: an in-depth look at
NSAIDs and the risk of side effects associated with their use, Rev. Ophthalmol. 14 (11)
(2007).