Cutaneous and Ocular Toxicology, 2009; 28(3): 93103

CRITICAL REVIEW

Ocular preservatives: associated risks and newer

options
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Indu Pal Kaur, Shruti Lal, Cheena Rana, Shilpa Kakkar and Harinder Singh
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

Abstract
Presence of a preservative in an ocular medication has often been considered a culprit in damaging the
epithelium. However, the inclusion of a preservative is equally necessary, especially in multiple-dose containers, in order to protect against dangerous organisms accidentally gaining access during instillation.
Benzalkonium chloride (BAK), chlorobutanol, chlorhexidine acetate (CHA), and phenylmercuric nitrate or
acetate are some commonly used preservatives in eye preparations. New preservatives with a wide range
of activity and good safety profiles have been introduced in the market, such as stabilized oxychloro complex (SOC), sofZia, and sodium perborate. In the present review, we discuss various conventional and newly
proposed and patented preservative molecules for ocular use. Reasons for discontinuing traditional preservatives and the need for less-toxic molecules are discussed at length, along with newer options coming
up in this area.
Keywords: Preservative; ocular; newer; toxicity

Introduction
In chronic eye diseases, for effective therapy, ophthalmic
medication is to be given regularly for longer durations
than usual dosing regimens. Typical examples of such
chronic pathologies are dry eye, glaucoma, and certain
eye infections, especially fungal infections. Preservative
is an important constituent of multiple-dose containers
that helps to minimize the risk associated with accidental microbial contamination, but its frequent use
has been associated with alteration in the precorneal
film. In patients suffering from dry eye, preservatives
tend to aggravate the already existing problem; and in
glaucoma patients, the prolonged use of eye drops with
preservatives has been associated with changes in ocular surface accompanied by inflammation. In fact, conjunctival biopsies in patients suffering from glaucoma
have revealed an increased number of immune cells and
fibroblasts (1,2).
Ocular medications are composed of unique
mixtures of the active drug, a preservative, the drug
delivery system, viscosity-increasing agents, buffers

and stabilizers, and a vehicle by which all the above

ingredients are carried. Of these, the preservative
has most often been considered the culprit in damaging the corneal epithelium, leading to disruption of
the glycocalyx, when drops are used beyond the recommended dosing. This sequence of repeated dosing
leaves the epithelium unable to keep the tear film in
place and can lead to ocular surface disease. This is
especially true for patients who overuse their artificial
tear products, use multiple ocular medications, suffer
from chronic eye diseases like dry eye or glaucoma, or
require postsurgery dosing of medication. In a way,
it is not incorrect to say that the preservatives are a
necessary evil.
Today, ophthalmologists have numerous antiglaucoma medications and artificial tears from which to
choose. Although topically administered medications
are increasingly used with apparent safety and good
tolerance, there is growing evidence that long-term use
of topical drugs can induce changes in the ocular surface and may often produce damage to conjunctival and
corneal epithelial cells. There have been several reports

Address for Correspondence: Indu Pal Kaur, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India. Tel.: 91 172
2534113 (0); Fax: 91 172 2541142; E-mail: indupalkaur@yahoo.com
(Received 06 January 2009; revised 24 April 2009; accepted 25 April 2009)
ISSN 1556-9527 print/ISSN 1556-9535 online 2009 Informa UK Ltd
DOI: 10.1080/15569520902995834

http://www.informahealthcare.com/cot

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94 I. P. Kaur etal.
of the toxic effects of prolonged topical treatments,
partly due to the preservatives associated with the formulation of such treatments (3,4). In the eye, preservative turnover is very slow, and quaternary ammonium
molecules can be retained in ocular tissues for up to 7
days (5). The lipophilic nature of some preservatives
causes them to bind to the ocular tissues immediately
after topical application. Previous studies by Burstein
(4,5) have shown that topically applied benzalkonium
chloride (BAK), the most commonly used preservative
in ophthalmic solutions, can cause morphologic disruption of the corneal epithelium at high concentrations. In
addition, there is evidence that clinical concentrations
of BAK may change the ionic resistance of the cornea by
intercalating into cellular membranes, which results in
increased permeability (7).
Three types of mechanisms have been described:
detergent effects causing loss of tear film stability, toxic
effects to the corneal and conjunctival epithelia, and
immunoallergic reactions (5,6). Furthermore, repeated
doses of preserved eye drops can have a cumulative
effect, because the preservatives are in prolonged contact with the epithelium. Several studies have confirmed
the participation of preservatives in induction of ocular
surface inflammation (7,8), allergy (8), fibrosis (9), and
dry eye syndrome (10,11). Preservatives are also suspected of strongly increasing the risk of failure of trabeculectomy in glaucoma (12,13).
In vitro models have been developed to predict the
cytotoxic potential of preservatives. These models were
essentially based on corneal epithelial cells (14,15) or
on other epithelial systems with characteristics similar
to those of the superficial layer of the corneal epithelium
(MadinDarby canine kidney cells) (16). The human
continuous conjunctival cell line has also been useful
for ocular toxicologic studies (17,18). It has been shown
that BAK is a strong proapoptotic agent in Changs conjunctival cells (19).
In the present review, we discuss conventional,
newly proposed, and patented preservative molecules
for ocular use. Reasons for discontinuing traditional
preservatives and the need for less-toxic molecules are
discussed at length, along with newer options coming
up in thisarea.

Mechanism of action of preservatives

Preservatives can be classified into 2 main categories, on
the basis of their mechanism of action:
DetergentsDetergent preservatives, such as BAK,
act upon microorganisms by altering cell membrane
permeability and lysing cytoplasmic contents (20).
Ocular toxicity can occur because some detergent preservatives can affect eukaryotic cells. Mammalian cells

cannot neutralize chemical preservatives, so the preservative is incorporated into the cell and causes cellular
damage(21).
OxidantsOxidative preservatives are usually small
molecules that penetrate cell membranes and interfere with cellular function (22). They can destabilize
cell membranes, but to a lesser degree than detergent
preservatives. Stabilized oxychloro complex (SOC)
and sodium perborate are 2 examples of oxidative preservatives. At low levels, oxidative preservatives have
an advantage over detergent preservatives because
they can provide enough activity against microorganisms while having only negligible toxicity on eukaryotic cells. This is because many microorganisms do not
have the ability to cope with oxidative stress, whereas
mammalian cells are equipped with antioxidants, oxidases, and catalases to neutralize the effect of a lowlevel oxidant.
This article concentrates on some of the most commonly used detergent and oxidative preservatives,
namely, BAK, phenyl mercuric nitrate or acetate, chorhexidine acetate (CHA), sorbic acid, chlorobutanol,
sodium perborate, SOC, and polyquaternium-1. Other
preservatives found in ophthalmic preparations include
benzododecinium bromide (BDD), cetrimonium chloride, thiomersal, methyl parahydroxybenzoate, polyquaternium ammonium chloride, polyaminopropyl
biguanide, and hydrogen peroxide. Tables 1 and 2 contain a list of commonly used products and associated
preservatives.
Table 1. Preservative-containing common glaucoma medications.
Trade name of
Sr.No. glaucoma formulations Manufacturer
Preservative
Allergan
0.005% BAK
1.
Alphagana
Allergan
0.005% SOC
2.
Alphagan Pa
Alcon Laboratories
0.01% BAK
3.
Azopta
Allergan
0.005% BAK
4.
Betagana
Alcon Laboratories
0.01% BAK
5.
Betoptic Sa
Merck & Co.
0.0075% BAK
6.
Cosopta
Novartis Ophthalmics 0.015% BAK
7.
Resculaa
Merck & Co.
0.01% BAK
8.
Timoptica
Merck & Co.
0.012% BDD
9.
Timoptic-XEa
Merck & Co.
0.0075% BAK
10.
Trusopta
Pfizer
0.02% BAK
11.
Xalatana
Merck & Co.
1:5,000 BAK
12.
Humorsolb
Alcon Laboratories
0.01% BAK
13.
Iopidine eye dropsb
Allergan
0.005% BAK
14.
Lumiganb
Bausch & Lomb
0.005% BAK
15.
Ocupressb
Bausch & Lomb
0.004% BAK
16.
Optipranololb
Allergan
0.04% BAK
17.
Propineb
a
Noecker R. Effects of common ophthalmic preservatives on ocular
health. Adv Ther 2001; 18:205-215.
b
http://www.rxlist.com. Accessed September 2008.
BAK=benzalkonium chloride; BDD=benzododecinium bromide;
SOC=stabilized oxychloro complex.

Ocular preservatives: risks and new options 95

Table 2. Multidose, over-the-counter medications for dry eye with or without preservatives.
Sr. No. Trade name
Manufacturer
Active ingredients(s)
Novartis
0.2% Hydroxypropyl methylcellulose
1.
GenTeal Milda
Novartis
Optics Laboratory
Bausch & Lomb

0.3% Hydroxypropyl methylcellulose

Polyvinylpyrrolidone, polyvinyl alcohol
0.95% Propylene glycol

5.
6.

GenTeal PFa
Minidrops Eye Therapya
Preservative Free
Moisture Eyesa
Refresh Plusa
Refresh Tearsa

Allergan
Allergan

0.5% Carboxymethylcellulose
0.5% Carboxymethylcellulose

7.
8.
9.

Refresh Celluvisca
Refresh Enduraa
Refresh Liquigela

Allergan
Allergan
Allergan

1% Carboxymethylcellulose
1% Polysorbate 80, 1% glycerin
1% Carboxymethylcellulose

10.
11.
12.
13.

Refresh PMa
TheraTearsa
TheraTears PFa
Systane Ultrab (High
Performance)
Systane Preservative Freeb

Allergan
Advanced Vision Research
Advanced Vision Research
Alcon

Systaneb (long lasting)

Alcon

Systane Nighttime Lubricant

Eye Ointmentb
Moisture Eyes PMa
Lacrisertc
Murine Tears Plus Lubricant
Redness Reliever Eye Dropsc
Murine Tears Lubricant
Eye Dropsc
AMO Blink Gel Tears
Lubricating Eye Dropsc
Murocel Methylcellulose
Lubricant Ophthalmic
Sterile Solution USPc
Clear Eyes for Dry Eyes Plus
ACR Reliefc
Allergan Optive Lubricant
Eye Dropsc
Tears Renewed Ophthalmic
Solutionc
Soothe Emollient
(Lubricant) Eye Dropsc

Alcon

Amo Sales and Service Inc

White petrolatum, mineral oil

0.25% Carboxymethylcellulose
0.25% Carboxymethylcellulose
0.3% Propylene glycol,
0.4% polyethylene glycol 400
0.3% Propylene glycol,
0.4% polyethylene glycol 400
0.3% Propylene glycol,
0.4% polyethylene glycol 400
3% Mineral oil, 94% white petrolatum,
3% anhydrous liquid lanolin
White petrolatum, mineral oil
Hydroxypropyl cellulose 5mg
0.5% Polyvinyl alcohol, 0.6% povidone,
0.05% tetrahydrozoline hydrochloride
0.5% Polyvinyl alcohol, 0.6% povidone,
sodium bicarbonate
0.25% Polyethylene glycol 400

Bausch & Lomb

Pharmaceuticals

1% Sodium chloride, sodium borate,

propylene glycol

Methylparaben,
propylparaben

Prestige Brands

0.012% Naphazoline hydrochloride,

0.2% glycerin, 0.25% zinc sulfate
1.4% Polyvinyl alcohol, 0.6% povidone

Benzalkonium chloride

Benzalkonium chloride

24.

Isopto Tearsc

Alcon

25.

Puralube Opthalmic
Ointmentc
Rohto V Arctic Cooling
Lubricant/Redness Reliever
Eye Dropsc
Lacri-Lube S.O.P. Lubricant
Eye Ointmentc
Allergan Optive Lubricant
Eye Dropsc
GenTeal Lubricant Eye Gel
for Severe Dry Eye Reliefc

Fougera

0.3% Hydroxypropyl methylcellulose,

0.1% dextran 70
0.4% Polysorbate 80, Restoryl
(consists of 15.1% Drakeol and
4.5% Drakeol-35)
0.5% Hydroxypropyl methylcellulose
2910
42.5% Mineral oil, 56.8% white
petrolatum
Hypromellose, tetrahydrozoline
hydrochloride

Chlorobutanol

Allergan Pharmaceutical

42.5% Mineral oil, 56.8% white

petrolatum
1.4% Polyvinyl alcohol, 0.6% povidone

Novartis Pharmaceutical

0.3% Hypromellose

None

2.
3.
4.

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Preservative
GenAqua (sodium
perborate)
None
None
None

14.
15.
16.
17.
18.
19.

20.
21.
22.
23.

26.

27.
28.
29.

Alcon

Bausch & Lomb

Aton Pharma
Prestige Brands
Medtech

Allergan Pharmaceutical
Akorn.
Alimera

Mentholatum Inc

Allergan

None
Purite (stabilized
oxychloro complex)
None
None
Purite (stabilized
oxychloro complex)
None
Sodium perborate
None
Polyquad
None
Polyquad
None
None
None
Benzalkonium chloride
Benzalkonium chloride
None

None

Polyhexamethylene
biguanide
Benzalkonium chloride
Chlorobutanol
Benzalkonium chloride

None

Table 2. continued on next page.

96 I. P. Kaur etal.

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Table 2. Continued.
S. No. Trade name
30.
Visine Tears Lasting Relief
Lubricant Eye Dropsc
31.
Hypo Tears Lubricant
Eye Dropsc
32.
Bausch & Lomb Soothe
Lubricant (Preservative
Free) Eye Dropsc
33.
Visine Pure Tears Lubricant
Eye Drops for Dry Eye Reliefc
34.
Bion Tearsc

Manufacturer
Pfizer Consumer
Novartis
Bausch & Lomb Personal
Product

Active ingredients(s)
Glycerin, hypromellose, polyethylene
glycol 400
1% Polyvinyl alcohol, 1% polyethylene
glycol 400
0.6% Glycerin, 0.6% propylene glycol

Preservative
Ascorbic acid,
benzalkonium chloride
Benzalkonium chloride
None

Pfizer Consumer

0.2% Glycerin, 0.2% hypromellose,

None
1% polyethylene glycol 400
Alcon Laboratories
70.01% Dextran, 0.3% hydroxypropyl
None
methylcellulose 2910
a
Optometric Study Center. How to Grade Dry Eyes. February 2006. http://www.revoptom.com/index.asp?ArticleType=SiteSpec&page=osc/1051
82/lesson.htm. Accessed September 2008.
b
http://www.systane.com. Accessed April 2009.
c
http://www.americarx.com. Accessed September 2008.

Some of the commonly used ocular

preservatives
Benzalkonium chloride
BAK is a quaternary ammonium compound and is the
most common antimicrobial preservative used in topical
multiuse ophthalmic preparations (23,24). The reasons
for the frequent use of BAK as a preservative include its
extreme efficacy in combating microbial contamination
of bottles and its ability to break cellcell junctions in the
corneal epithelium, thus allowing for antimicrobial and
antihypertensive drops to enter the anterior chamber, as
well as its familiarity among those formulating ophthalmic preparations in industry. The regulatory approval
from the FDA and its current widespread use in more
than 70% of existing multidose bottles constitute another
notable consideration. While the efficacy of BAK is well
known, a multitude of published studies document the
detrimental effects of BAK (23,27,3032). Benzalkonium
is known to induce necrosis (at concentrations of 0.05
0.1%) and cellular apoptosis (at concentrations of 0.01%)
by way of disturbing the cellular membrane in bacterial
cells (23). However, human ocular surface cells can also
absorb this detergent, and its effects on ocular surface
cells are similar to those seen in bacterial cells. The
potential of BAK-induced damage is clinically important
in patients who need eye drops several times a day for
years, who use multiple eye drops, or who have compromised corneas. The effects of the detergent are cumulative and become more severe with more concentrated
and frequent exposures (23). Breakdown of the corneal
epithelium and increased permeability of the cornea
as a result of BAK toxicity are well documented (30).
Ophthalmic preparations that contain high concentrations of BAK interfere with the integrity of the superficial
lipid layer of tear film and reduce its breakup time, thus
affecting its stability (3133). This is especially problematic in glaucoma patients, as they inherently have a

decreased rate of basal tear turnover (34). In one study,

it has been shown that ocular cells repeatedly exposed
to BAK can overexpress the cell marker Apo 2.7, which
has been implicated in apoptosis (32).
The epithelial cells of cornea are cemented together
by the apical portions of their plasma membranes. The
cells of corneal epithelium are tightly bound together
with intercellular cement similar to that of desmosomes.
The surfactant abilities of BAK solubilize the intercellular
cement of the corneal epithelium, thereby increasing its
penetration (3,26) and subsequent accumulation in the
ocular tissue when used for relatively lengthy periods
(3,27). Formulations containing BAK have been shown
to cause the duplex tear film to become unstable. The
tear film comprises an oily layer and an aqueous layer
that further consists of water and mucus. It keeps the eye
moist, creates a smooth surface for light to pass through
the eye, nourishes the front of the eye, and provides
protection from injury and infection. Tear film is compromised in patients suffering from dry eye syndrome,
which makes the cornea more vulnerable to deleterious
substances like preservatives. The degree of instability
induced by BAK, however, may not be physiologically
harmful under normal situations since the lipid layer of
the tear film is re-formed every 1530 seconds. However,
BAK-induced tear film instability needs to be considered when treating patients with a compromised tear
film as in the case of dry eye syndrome (32). It is also of
concern in situations where the medicament needs to
be instilled frequently and over a long period of time, as
in conditions like glaucoma (where very frequent use is
required) and dry eye (where no drop dilution occurs).
BAK is typically included in antiglaucoma medications at a concentration of 0.01%, with a range of 0.004%
to 0.02% (35). BAK in antiglaucoma ophthalmic preparations does not alter the ability of the medication to lower
intraocular pressure (IOP), but it can modify the ocular
surface (31). This effect has been demonstrated in many

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Ocular preservatives: risks and new options 97

studies and with several antiglaucoma medications that
contain BAK. For example, timolol maleate (Timoptic)
elicited cell damage along with a rapid decrease in
cell number and viability in a human conjunctival cell
line (32). Patients treated with timolol maleate exhibited BAK-induced ocular surface damage caused by
a decrease in the aqueous layer production rate and
impaired tear film mucus layer (36). Another study
found that 127 patients using BAK-containing glaucoma
drugs, alone or in combination, had a statistically significant degree of conjunctival metaplasia compared
with patients not using topical treatment (37). Another
study concluded that long-term use of antiglaucoma
medications containing BAK changes the conjunctival
surface and tear film function. This may increase the risk
associated with future glaucoma therapy (38).
In 1990, it was reported that a significantly greater
percentage of patients with aqueous tear-deficient dry
eye than normal control subjects showed inflammatory
cell infiltration of their conjunctival epithelium, and
based on this finding, it was speculated that inflammation plays an important role in the pathogenesis of
the conjunctival epithelial squamous metaplasia that
develops in dry eye (39). Three-fourths of the ophthalmologists surveyed (70%) reported that the preservatives in glaucoma medications are a significant cause
of the ocular surface disease they see in glaucoma
patients (40). Most believe each of the following is
related to the preservatives in glaucoma medications:
ocular surface disease (83%), conjunctival inflammation (75%), allergic reactions (71%), and dry eye (67%).
Chronic application of detergent preservatives can
lead to chronic lymphocytic infiltration in conjunctival
stroma in addition to deleterious changes to corneal
epithelium and tear film instability (41).
BAK use may be problematic in patients with dry eye
syndrome; they are often highly susceptible to its potentially harmful effects, because they lack natural tears to
dilute BAK (23). With chronic, long-term exposure or
in the setting of dry eye, BAK is reported to lessen the
integrity of epithelial cells, increase the number of conjunctival inflammatory cells, cause a loss of goblet cells
(16), reduce tear function (31), and decrease the tear
film breakup time (31). Research has shown that in cell
culture, animal, and human studies, BAK causes greater
cytotoxic effects than some of its alternatives, such as
SOC (2). Although intermittent use of preserved eye
drops in healthy individuals is probably not harmful, high
concentrations of some preservatives can cause damage
and irritation to the ocular tissue, particularly in patients
with dry eye. Frequent use of these can cause a higher
incidence of epithelial damage, edema, and bullous
keratopathy in patients with glaucoma, dry eye, infections, or iritis, who need to use eye drops for a long period
of time (3). Therefore, patients with dry eye syndrome

may be at greater risk of BAK-induced adverse effects. In

these patients, the cornea is particularly susceptible to
the effects of preservatives because the corneal epithelium is an exposed surface and meets the full strength of
topical ophthalmic preparations (20). Moreover, these
patients may not produce sufficient tears to dilute a
harmful preservative (20,29). Preservatives can disrupt
the precorneal tear filmwhich acts as a lubricant and
protective layer for the epitheliumand lead to damage
to the epithelial surface and worsening of the dry eye
condition (29). One study showed that artificial tears
containing BAK increased corneal epithelial permeability in patients with dry eye, indicating that BAK may
contribute to ocular surface disease (14). Often, allergic
complaints or chronic irritation of the conjunctivae and
eyelids declines when patients with glaucoma or dry eye
stop using preserved eye medications (3).
In a very recent study, where the authors have compared the toxicity of commonly used preservatives using
immortalized human conjunctival and corneal epithelial
cells, BAK (0.01%) showed a significantly higher toxicity
than most of its alternatives, and the order of toxicity was
as follows: thiomersal (0.01%)>BAK (0.01%)>chlorobutanol (0.5%)>methylparaben (0.01%)>sodium perborate
(0.02%)=ethylenediamine tetraacetic acid (EDTA)(42).
Phenylmercuric nitrate or acetate (0.002% w/v)
Phenylmercuric nitrate and, to a lesser extent, phenylmercuric acetate both are extensively used in eye
drops. Their solubilities are adequate (acetate: 1 in 500;
nitrate: 1 in 1,500) and they are nonirritant and stable.
They are effective against a wide range of bacteria and
fungi but are rather slow in action, particularly against
heavy inocula of Pseudomonas aeruginosa (43,44). Their
main disadvantages are their incompatibility with halides, strong absorption by rubber, and capacity to cause
mercurialentis.
Chlorhexidine acetate (0.01% w/v)
CHA is a nonirritant bactericide of low toxicity. It is most
effective against gram-positive bacteria but inactive
against spores. The susceptibility of some Proteus and
Pseudomonas species is low but is increased in the presence of EDTA. CHAs highest activity is shown in solutions with neutral or slightly alkaline pH (45).
Organic matter such as serum and, particularly,
phospholipids seriously reduces its efficiency, and, like
BAK, it is incompatible with anionic compounds and,
because of binding, with methylcellulose and hypromellose. Cork causes inactivation (46) and should not be a
component of wads of closures.
CHA forms sparingly soluble salts with bicarbonates,
borates, carbonates, chlorides, citrates, phosphates, and

98 I. P. Kaur etal.
sulfates, but precipitation (which is usually delayed for
about 24 hours) does not occur unless the concentration
of CHA is about 0.05%, except with sulfates, which cause
difficulty even when the preservative concentration is as
low as 0.005%. Consequently, CHA is not used for eye
drops containing the sulfates of atropine, neomycin,
physostigmine, and zinc (47).

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Chlorobutanol
Chlorobutanol is an alcohol-based preservative, with
no surfactant actions (26). Although the antimicrobial activity of chlorobutanol is extensive (27), its use
has been limited because it becomes unstable when
stored at room temperature for extended periods of
time. Unlike BAK, chlorobutanol does not act like a
surfactant (48). The method of action of chlorobutanol is cell lysis by way of disruption of microbial cell
membrane lipid configuration (48). Chlorobutanol
has been found to be safe in rabbit corneal cells, even
at 100 times the concentrations found in commercial
products (8).
Although chlorobutanol seems relatively safe as an
ophthalmic preservative, chlorobutanol 0.5% in artificial
tears has been shown to cause irritation in more than
50% of the subjects in a double-blind crossover study
(49). To this end, research has shown that in human
corneal cells, 0.5% chlorobutanol caused cell retraction
and cessation of normal cytokinesis, cell movement,
and mitotic activity (50). It also caused degeneration of
human corneal epithelial cells and the formation of conspicuous membranous blebs (48). Chlorobutanol does
not, however, affect the stability of the lipid component
of the tear film (48).
As compared with 0.0040.02% BAK, 0.20.5% chlorobutanol is less toxic to rabbit corneal epithelial cells
in vitro (51). In human corneal epithelial cells, the
cytotoxic effects of chlorobutanol occur less rapidly
than those of BAK, and the toxicity changes are less
severe (50). Therefore, ophthalmic solutions preserved
with chlorobutanol may be less damaging.
Polyquaternium-1
Polyquaternium-1 (Polyquad) is a polymeric quaternary
ammonium antimicrobial preservative. It is used in contact lens solutions and the artificial tear product Tears
Naturale II (Alcon Laboratories, Fort Worth, TX, USA).
Polyquaternium-1 has been proven to have less of an
effect on corneal epithelial cells than BAK. One rabbit
study showed that polyquaternium-1 produces a lesser
uptake of dye into the cornea than BAK and only superficial epithelial damage compared with BAK (52).
The main detriment associated with polyquaternium-1
is its tendency to reduce the density of conjunctival

goblet cells, thereby decreasing aqueous tear film

production (53).
Sorbate (sorbic acid)
Sorbate generally has limited antimicrobial activity, and
it is not able to eradicate many organisms on its own.
Sorbic acid molecules pass through the plasma membrane, dissociate in the cytoplasm, release protons, and
inhibit growth via acidification. This may activate energetically inefficient intracellular activities, such as energydependent ion pumps, wasting the cells energystores.
Whereas adverse reactions appear to be infrequent, a
reaction consisting of punctate keratitis may rarely result
from the use of sorbate. Still, sorbic acidpreserved
products are commonly promoted for sensitive eyes and
for contact lens wearers (54).
Sodium perborate
Sodium perborate (GenAqua) is a preservative contained
in Genteal lubricant eye drops (Novartis Ophthalmics,
East Hanover, NJ, USA). Sodium perborate was one
of the first oxidative preservatives to be developed. It
destroys numerous types of bacteria and can destroy
Aspergillus niger, a fungus that is otherwise difficult to
kill (55). Sodium perborate is typically found in lubricating drops used to combat dry eye. When sodium perborate is combined with water, it is converted to hydrogen
peroxide, an effective antimicrobial agent.
Sodium perborate oxidizes cell walls or membranes,
affects membrane-bound enzymes, and disrupts cellular function, such as protein synthesis. Once sodium
perborate enters the eye, it is decomposed to water and
oxygen by catalase and other enzymes present in the
conjunctival sac (55). The hydrogen peroxide allows low
levels of sodium perborate to be effective at destroying microbes while hydrogen peroxide as a byproduct also permits ocular comfort. However, hydrogen
peroxide levels above 100ppm or 3% can cause ocular
stinging(56,57).
Although gentler than some other preservatives,
sodium perborate may still cause ocular toxicity. Patients
with dry eye may frequently instill a preserved solution,
which increases the chance of aggravating the condition
by disrupting the precorneal tear film (29). In limited
testing, sodium perborate was found to be a direct-acting
in vitro mutagen (58). It can also destabilize cell walls
and membranes, but to a lesser degree than other types
of preservatives because it is an oxidative preservative.
Stabilized oxychloro complex
SOC (Purite, Bio-Cide International Inc., Norman, OK,
USA) was introduced into ophthalmic medicines in

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Ocular preservatives: risks and new options 99

the mid-1990s under the trade name Purite. SOC is an
oxidative ophthalmic preservative that destroys many
types of bacteria and can destroy the fungus Aspergillus
niger (56). SOC consists of an equilibrium mixture of
oxychloro species: 99.5% chlorite (ClO2), 0.5% chlorate
(ClO3), and trace amounts of chlorine dioxide (ClO2),
which have bactericidal, fungicidal, and virucidal activity (59). While the antimicrobial efficacy of SOC supports
its use as a preservative agent, its mechanism of action is
not fully elucidated. Most likely, the mechanism is due to
the oxidation potential of chlorite and possibly from the
generation of chlorine dioxide in the presence of microbial acidic environments, which leads to the disruption
of protein synthesis in the bacteria and ultimately its antimicrobial activity. SOC is capable of destroying microorganisms in fish, fruit, and vegetables without altering the
nutritive and organoleptic properties of the food (59).
SOC dissipates by converting into components normally
found in tears, such as sodium ions, chloride ions, oxygen, and water (56,59). This unique quality makes SOC
an unusually gentle preservative that is ideal for chronic
use. For this reason, products containing SOC may have
an improved tolerability profile, reduced toxicity, and,
ultimately, better patient compliance.
Although SOC is a chemical oxidant, there is no in
vivo or in vitro evidence of its mutagenicity or carcinogenicity (60). Accordingly, SOC has mild cytotoxic
effects and an excellent safety record. It has been given
an Environmental Protection Agency Category II rating
as a mild eye irritant based on rabbit studies (60). SOC
is efficacious at low concentrations (0.005% w/v). SOCis

safe and well tolerated when administered frequently,

as demonstrated in a 62-patient study in which Refresh
Tears containing an SOC-based preservative was administered 4 to 8 times daily for a 4-week period (61).
None of the currently available glaucoma medications contains SOC. However, the safety profile of SOC
makes it likely that novel ophthalmic products containing SOC will be developed. On March 19, 2001, the FDA
approved brimonidine tartrate ophthalmic solution
0.15%, preserved with SOC. This is the first glaucoma
medication to contain SOC.
A number of other preservatives have also been
investigated for use in eye drops and are discussed in
Table 3 (46).

Comparing safety/toxicity of preservatives

A direct comparison between preservatives can be seen
via scanning electron microscopy in a 2001 study conducted by Allergan (62). To evaluate toxicity, rabbits
were treated 4 times a day with products preserved with
0.001% polyquaternium-1, sodium perborate, or 0.005%
SOC, and the corneas were examined after 1 week of
treatment (62). The untreated rabbit corneal epithelium
had extensive microvilli and tight intercellular junctions. The rabbit eye treated with the product preserved
with SOC looked nearly identical to the untreated rabbit
eye, and the eye treated with the perborate-preserved
product also had a mostly normal epithelium with
extensive microvilli and tight epithelial junctions,

Table 3. Obsolete preservatives and reasons for their discontinuationa.

Sr. No. Preservative
Properties
1.
Hydroxybenzoates
Included in eye drops in 1949 but displaced in 1963.
Slow antibacterial activity, particularly against Pseudomonas aeruginosa.
Irritant to the eye.
2.
Chlorocresol (0.05% w/v) Replaced solution for eye drops in the 1963 British Pharmaceutical Codex, but reports of eye damage led
to its deletion within a few months.
It is a rapidly acting bactericide and fungicide, but a 0.05% solution is no more than marginally effective
against Pseudomonas aeruginosa.
Its efficiency is increased in acid solution.
It is more irritating than most preservatives.
3.
Thiomersal (0.01% w/v)
Its stability is low in acid solutions, and it is not widely used in eye drops.
Its antibacterial activity is slow, and its absorption by rubber is very high.
Less stable in solution (protection from light and heavy metals is necessary) and does not cause
mercurialentis.
Highly toxic to corneal and conjunctival cells.b
4.
Phenylethyl alcohol
Particularly effective against gram-negative bacteria, its action on Pseudomonas aeruginosa is rather slow.
(0.5% w/v)
Recommended as an eye drop preservative in the U.S. Pharmacopeia.
Often it is combined with another bactericide, such as benzalkonium chloride, phenylmercuric nitrate,
or chlorbutol, to confer enhanced activity against gram-negative organisms.
The solubility of chlorbutol is improved when used with phenylethyl alcohol.
a
Cooper JW, Gunn C. Ophthalmic products. In: Carter SL, ed. Dispensing for Pharmaceutical Students. 12th ed; Delhi, India: CBS Publisher and
Distributors. 2000:634-662.
b
Epstein EP, Ahdoot M, Marcus E, Asbell PA. Comparative toxicity of preservatives on immortalized corneal and conjunctival epithelial cells.
JOcul Pharmacol Ther 2009; 25:113-119.

100 I. P. Kaur etal.

90.00%

Sustained-release formulations

80.00%

One approach is to decrease the cumulative toxic

effects, hence a once-daily form of timolol maleate
(Timoptic-XE) with 0.012% BDD, a preservative similar
to BAK, was developed. In place of bromide, the benzododecinium cation may be used with chloride or another
anion. Chemically BDD is dimethyldodecylbenzylammonium bromide and, like BAK, is a quaternary ammonium compound having a property of cationic surfactant
and is primarily active against gram-positive microbes.
However, the gel-forming preparation may prolong
contact of the preservative with the eye, contributing to
greater toxic effects to the cornea. In this regard, it may
be noted that BDD, a preservative related to BAK, has
been shown to induce corneal epithelial damage when
incorporated into a gel (35). However, the concept of
using sustained release formulations may be extended
to newer and safer preservatives.

% Viable Cells

70.00%
60.00%
50.00%
40.00%
30.00%
20.00%

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10.00%
0.00%
24

48
Time (h)

Sodium Perborate

BAK

Figure 1. Toxicity profile of benzalkonium chloride (BAK) and

sodium perborate.

while the same workers reported that the rabbit eye

treated with polyquaternium-1-preserved product had
extensive superficial epithelial erosion and lack of protruding microvilli. This finding is in agreement with
another study that found that 0.001% polyquaternium-1
caused a small but significant degree of epithelial damage(52). However, another study has shown that 0.001%
polyquaternium-1 has a low potential for ocular irritation
(63). As compared with the untreated eye, damage to the
corneal epithelium was highest with polyquaternium-1,
followed by the sodium perborate product, and then by
the SOC-preserved product. Of the artificial tears compared in this study, the product with SOC caused the
least damage to corneal epithelial cells (62).
The superiority of sodium perborate has also been
established by us (64) using SIRC cell lines in a cell proliferation assay. Figure 1 depicts the comparison between
sodium perborate and BAK. The percentages of viable
cells that remain after 24 hours and 48 hours of exposure (positive control=100% and negative control=0%)
are significantly higher for sodium perborate than the
same concentration of BAK (p<.05). The 48-hour study
was designed to investigate possible delayed cytotoxicity
of preservatives and/or the recovery of damaged cells. It
was observed that after being incubated for 48 hours the
toxicity of sodium perborate decreases (p<.05%), which
indicates that the initial damage caused by sodium perborate is repairable with long-term use.

Future directions
The following methods are reported in the literature to
help reduce the toxic effects of preservatives:

Safe, mild, and less-toxic preservatives

All of the original formulations of the glaucoma medications commonly used today contain BAK. Several agents
available in the United States have been reformulated
without BAK, like SOC (Purite)-preserved brimonidine
tartrate (Alphagan P). These formulations appear to be
benign to the ocular surface. However, the efficacy of
the brimonidine class of antiglaucoma drugs is less than
that of prostaglandins, which are probably the first-line
monotherapy today; hence, it is important to reformulate these agents as well.
The preservative sofZia (Alcon) is a relatively new,
proprietary, ionic, buffered solution consisting of zinc,
borate, propylene glycol, and sorbitolchemical entities that are themselves not significantly toxic to the
ocular surface. sofZia, however, maintains an antimicrobial environment in the bottle, such that it meets the
U.S. Pharmacopeia standards for antimicrobial activity.
It produces more than a 3-log reduction (99.9% kill)
in surviving organisms after 8 days of incubation (65).
Recently, sofZia-preserved travoprost (Travatan Z,
Alcon) was introduced into the American market. This
formulation appears to have the same IOP-lowering efficacy as BAK-preserved travoprost in controlled clinical
trials (66). Arguably, this formulation is the most potent
non-BAK-containing glaucoma eye drop currently
available.
Preclinical studies comparing sofZia-preserved travoprost and latanoprost, which contains the highest
amount of BAK, demonstrated the relative safety to the
ocular surface of the non-BAK formulation (67). Cell
culture models and confocal studies of rabbit corneas
have shown that BAK-containing latanoprost caused
significant corneal epithelial cell death and loss with

Ocular preservatives: risks and new options 101

prolonged exposure times, whereas BAK-free travoprost
was fairly benign to these surface cells. Ongoing studies with more chronic dosing seem to confirm these
effects(68).
Travatan Z was introduced as the first prostaglandin
analogue to be preserved with a substance other than
BAK. The sofZia system effectively preserves the medicine while it is being stored; however, when the drug is
introduced into the eye, it is modified into harmless elements that are gentle on the ocular surface (64).

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Nonpreserved formulations
Preservative-free medications may eliminate the risk of
toxic side effects, which can make them attractive treatment options. For example, in a 1992 study conducted to
assess the corneal epithelial toxic effects of preservativefree tear preparations, researchers used scanning electron microscopy to evaluate the corneal epithelium of
rabbit eyes after the administration of 2 preservative-free
ocular lubricants. The 2 preservative-free preparations
were shown to be nontoxic to the corneal epithelium in
both the mild- and exaggerated-use protocols. The epithelial changes observed were no different from those
seen in control eyes. The study supported the belief that
preservative-free preparations are safe to use in patients,
especially with frequent dosing (20).
It has been reported by Pisella et al. (35) that using
unpreserved timolol may be beneficial for the long-term
treatment of glaucomatous patients because it increases
tear film stability and decreases epithelial permeability
and stromal aggression of the cornea. Baudouin and de
Lunardo (31) confirmed that carteolol is well tolerated,
either with or without preservative. The preservativefree group showed better stability of the tear film,
without loss of effect on IOP. Berdy etal. reported that
with frequent-dosage regimens, preservative-free Hypo
Tears PF and various forms of Refresh formulation(s) by
Allergan (Table 2) are free of the toxic effects associated
with preserved solutions (29).
Nonpreserved artificial tears have an extra advantage
over preserved ones: they may be the best choice for
patients immediately following eye surgery. Some nonpreserved artificial tears include GenTeal, TheraTears,
Refresh Tears, Moisture Eyes, and Bion Tears. These are
the most highly preferred ones because they contain
either no or mild and less-toxic preservatives like SOC
(Purite) and sodium perborate. Table 2 lists some of the
most common over-the-counter medications for dry eye
along with the preservative used.
Nonpreserved drugs are available only in unit-dose
vials and, as a result, the use of unit-dose bottles that
do not require preservatives will increase and become
more cost-effective while newer technologies will enable
multidose bottles to be constructed to inhibit microbial

invasion through inherent material properties independent of traditional preservatives (41). However, it may be
more difficult for a patient to use a unit-dose vial correctly, affecting compliance. Poor compliance may hinder
a nonpreserved drugs effectiveness, even if it is more
comfortable to use. This can be especially important
when it is used concomitantly with multidose glaucoma
medications, for which compliance is vital. Unit-dose
vials are also more expensive than multidose containers.
In addition, patients with advanced rheumatoid arthritis
may find it difficult to squeeze the drops from the singleuse vials. They may be tempted to use the multidose vials.
While it is true that a preservative may be the cause of an
allergic reaction, it is difficult to determine if the problem
is caused by the preservative, the drug, the drug delivery
system, the buffers, or the stabilizers. Hence, nonpreserved preparations still hold some risk.

Conclusions
At present, despite the numerous antiglaucoma medications and artificial tears in the market, none is risk-free.
In the future, manufacturers may reformulate existing products with less-toxic preservatives, offer lessconcentrated forms of current preservatives, or develop
new ones.

Acknowledgments
Declaration of interest: The authors report no conflicts
of interest.

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