ARTICLE
Choice of Artificial Tear Formulation for Patients With Dry
Eye: Where Do We Start?
Louis Tong, MBBS, FRCS, PhD,*†‡§ Andrea Petznick, Dipl-AO, PhD,§ SzeYee Lee, BOptom,§
and Jeremy Tan, MBBS¶k
Abstract: Dry eye is prevalent in many parts of the world. As
a result, ophthalmologists and other health care professionals, such
as optometrists and general practitioners, often help these patients
manage their symptoms. The most common form of treatment for
management of dry eye is over-the-counter tear lubricants. A number
of tear lubricant formulations are available that vary by their
mechanism of action. This article suggests simple guidelines on
how lubricants can be selected for patients with mild to moderate dry
eye. Side effects of lubricants, such as burning on instillation
because of mismatches of eye drop with tear acidity, are also
discussed.
Key Words: clinical science, dry eye, general practice, human tears,
ophthalmology
(Cornea 2012;31(Suppl. 1):S32–S36)
D ry eye is a multifactorial disease that affects the tears and
ocular surface. Symptoms of dry eye include discomfort,
visual disturbance, and tear film alterations caused by tear
deficiency and/or increased tear evaporation.1 Significant ocu-
lar surface damage may occur in patients with dry eye2 and
therefore is detrimental to their quality of life because it
interferes with the daily activities such as navigating stairs,
recognizing friends, reading, watching TV, computer-related
work, or driving, particularly at night.3 Dry eye is very com-
mon, affecting millions of people in the world with preva-
lence rates estimated to be as high as 5% to 35% of various
populations.4–7 Because of the sheer number of people with
dry eye, it is likely that in addition to ophthalmologists, other
health care professionals such as optometrists or general prac-
titioners would be involved in managing this condition.
This article provides suggestions to health care pro-
fessionals on how to select eye drops for the management of
From the *Department of Cornea and External Eye Disease, Singapore
National Eye Center, Singapore; †Office of Clinical Sciences, Duke–
National University of Singapore Graduate Medical School, Singapore;
‡Department of Ophthalmology, Yong Loo Lin School of Medicine,
National University of Singapore, Singapore; §Singapore Eye Research
Institute, Singapore; ¶Faith Medical Group, Singapore; and kDepartment
of Medicine, Yong Loo Lin School of Medicine, National University of
Singapore, Singapore.
The authors state that they have no conflicts of interest to disclose.
Reprints: Louis Tong, Department of Cornea and External Eye Disease,
Singapore National Eye Center, 11 Third Hospital Avenue, Singapore
168751 (e-mail: louis.tong.h.t@snec.com.sg).
Copyright © 2012 by Lippincott Williams & Wilkins
S32 | www.corneajrnl.com
patients with mild to moderate dry eye. After confirming the
diagnosis of dry eye, health care practitioners should try to
eliminate or modify the lifestyle and environmental factors that
may contribute to dry eye symptoms as part of a holistic
assessment. In the case of medical practitioners, this may
include assessment of contact lens use8 and the use of medica-
tion such as estrogenic hormonal replacement therapy,9 antide-
pressants,10 and antihistamines.11 In these cases, it is important
to know the patients’ history regarding ocular surgery, in par-
ticular laser corneal refractive surgery, which may cause or
aggravate dry eye.12 Smoking or alcohol consumption,13,14 sleep
apnea,15 computer-related tasks,16,17 and the effect of prolonged
working hours in air-conditioned facilities18 can worsen dry eye.
TOPICAL TREATMENT FOR DRY EYE: POSSIBLE
MECHANISMS OF ACTION
The first-line therapy for dry eye is topically administered
lubricants.19 Although there are numerous over-the-counter for-
mulations and prescription drugs, such as topical cyclosporine
and topical steroids,20 the current focus of this review is the
selection of nonprescription eye drops.
Mechanisms of Action
Commercially available tear lubricants differ in their
mechanisms of action. The beneficial mechanisms of tear
lubricants is incompletely understood but may be related to
tear volume replenishment, tear film stabilization, preserva-
tion of the smooth refracting surface, reduction of tear
osmolarity, and protection of the ocular surface by reducing
friction between the eyelids and the cornea.19
One mechanism of action of lubricants involves hydro-
gel, which is used to prepare hydroxypropyl-guar eye drops.
Hydrogel exists as monomers in a borate-containing solution
in the dispensing bottle. After instillation to the patient’s eye,
contact of hydrogel with the patient’s tear, which is at a dif-
ferent pH, causes the hydrogel to cross-link with borate (Sys-
tane or similar eye drops) to create a more viscous and elastic
matrix with an increased duration of effect compared with the
other eye drops.21 Another mechanistic strategy in lubricants
is to replace or augment tear components, such as the replen-
ishment of tear lipids important for maintaining tear stability.
In one study, improvement of tear film lipid layer thickness
was achieved with a castor oil emulsion (Refresh Endura).22
Cornea ! Volume 31, Number 11, Suppl. 1, November 2012
Cornea ! Volume 31, Number 11, Suppl. 1, November 2012
Composition of Lubricants
Eye drops vary in terms of composition, viscosity,
duration of action, presence and type of preservatives,
osmolarity/osmolality, and pH.23 The main ingredient of arti-
ficial tears are hydrogel polymers, so called because of their
ability to retain water.24 The following hydrogels have been
used in artificial tear substitutes: hydroxypropyl methylcellu-
lose, carboxy methylcellulose, polyvinyl alcohol, Carbopol,
polyvinylpyrrolidone, polyethylene glycol, dextran, hyalur-
onic acid, or carbomer 940 (polyacrylic acid).24
Viscosity of Eye Drop Preparations
Polymers may increase the viscosity of eye drops and
enhance adhesion to the mucus layer of tears. In practice,
there appears to be no advantage in using one lubricant over
another.24 The presence of hyaluronic acid, a naturally occur-
ring glycosaminoglycan contained in the commercial prepa-
ration Hialid, may facilitate wound healing,25 which is
disrupted in dry eye.
The optimal viscosity of an eye drop solution is often
a compromise between comfort and vision requirements.
Increased viscosity increases retention time26 but causes
unwanted visual disturbances, including optical aberrations.26
Higher viscosity eye drops may also precipitate as crystals
on the eyelids and lashes.27 The recommendation is that
low-viscosity drops are used in the daytime and highly viscous
preparations such as ointments and gels are instilled before sleep.
Preservatives in Eye Drop Preparations
Nonpreserved preparations are sold in small vials that
typically contain less than half a milliliter of solution each,
whereas preserved preparations are dispensed in the form of
eye drop bottles.19 Preservatives are added to increase the
shelf life of preparations and remove the need for refrigeration
after opening and during use.19 Provided there is no contact
between the bottle tip and the eye during instillation of eye
drops, the preservative can prevent contamination up to
1 month or more. The main disadvantage of preservatives
in eye drops is that they may cause preservative sensitivity,
especially when using the drops .6 times a day over long
periods.19 Benzalkonium chloride and chlorobutanol preser-
vatives can damage the corneal epithelium, causing symp-
toms similar to dry eye disease.28–30 Newer preservatives,
such as GenAqua (sodium perborate),31 Purite (sodium chlo-
rite),29 and Polyquad (polyquaternium-1)32 may be less harm-
ful to the ocular surface compared with benzalkonium
chloride. Purite is degraded to chloride ions and water after
administration of the eye drop, whereas GenAqua is degraded
to oxygen and water upon instillation.31
Nonpreserved preparations are at risk of microbial
contamination and therefore should be discarded within
a few hours of use, even though the vial may be recapped
after opening. When recommending preservative-free eye
drops to a patient, it is important to note that the overall
cost will be considerably higher than that of preserved eye
drops, in particular when the patient requires only 1 to 3
instillations per day. Therefore, preservative-free eye drops
! 2012 Lippincott Williams & Wilkins
Artificial Tear Formulation for Patients With Dry Eye
should be recommended to patients who require frequent
instillation of eye drops during the day, such as those with
severe dry eye.
Osmolarity/Osmolality of Eye
Drop Preparations
Tear lubricants are electrolyte solutions that consist of
different buffers, resulting in differences of osmolarity,19
a measurement to quantify solutes including electrolytes such
as sodium, potassium, and chloride in 1 L of solution. The
volume of water may change according to its temperature,
and therefore, osmolarity measurements are temperature-
dependent. In the current literature, the terms osmolarity
and osmolality are both used. However, osmolality is a more
accurate measure of solute concentration in tears because it
measures solutes per kilogram of solvent.
Changes in tear osmolarity may be a primary factor in
the initiation of dry eye and therefore may be an ideal
diagnostic marker.33,34 A common feature of dry eye is cor-
neal and conjunctival epithelial damage, which may be trig-
gered by increased osmolarity of the tear film.35 Accordingly,
increased osmolality has been measured in tears from dry eye
patients wearing contact lenses.8 Thus, a potential treatment
for dry eye is to lower tear osmolarity using hypo-osmolar
eye drops, such as TheraTears. Successful use of hypo-
osmolar eye drops has been observed in trials conducted
by Gilbard and Rossi36 and Lenton and Albietz.37 From the
patient’s point of view, hypo-osmolar eye drops were more
effective in relieving symptoms,38,39 although contrasting
results were reported by Wright et al.40
pH of Eye Drop Preparations
We measured the pH levels of the various over-the-
counter lubricant preparations (Table 1). The results of our
investigation and a study by López-Alemany et al41 showed
that commercially available lubricants have a wide range of
pHs. Natural tear pH can range from 6.9 6 0.242 to 7.5 6
0.243 in the normal population and is similar in patients with
dry eye.44 Differences or variability of tear pH may be related
to several factors including differences in carbon dioxide sat-
uration or in the meibomian lipids in the tear film.42 For
practical purposes, patients may experience a stinging sensa-
tion after eye drop use because of a mismatch between the pH
of the instilled eye drops and that of the patient’s tear.19 This
adverse effect may compromise compliance to treatment.
Because it is not practical to measure tear pH on a routine
basis, patients are recommended to try various tear lubricants
to identify the most comfortable solution, and which thus
matches the pH of their tear film. If a patient complains of
a stinging sensation after eye drop use, another lubricant
with a different pH should be recommended according to
our findings (Table 1). Some patients may need to use lu-
bricants of different pHs in different scenarios. For instance,
tear pH may be influenced by diurnal changes. In addition,
the wearing of contact lenses can significantly reduce tear
pH, which is a reversible phenomenon related to hypoxia
and hypercapnia.42
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Tong et al Cornea ! Volume 31, Number 11, Suppl. 1, November 2012

TABLE 1. Product Profile of the Various Over-the-Counter Preparations for Dry Eye Treatment
Product Active Ingredient Preservative pH* Osmolarity (mmol/kg)†
Bion Tears (single use) 0.3% HPMC, 0.1% dextran 70 None 7.53 246
Rohto C Cube 0.07% HEC Poloxamer 407 with 0.1% 7.33 352
potassium sorbate
Celluvisc (single use; Allergan) 1.0% CMC None 6.94 273
Computer Eye Drops (Bausch & Lomb) 1.0% glycerin 0.01% BAK 6.88 276
Dorama-Neo (Sato) 0.64% sodium chloride 0.005% BAK 7.18 350
Eye Mo (GlaxoSmithKline) 1.3% boric acid, 0.32% sodium 0.01% BAK 7.12 358
borate
Eye Mo Moist (GlaxoSmithKline) 0.3% HPMC 0.01% BAK 7.38 307
GenTeal (Novartis) 0.3% HPMC Sodium perborate 6.53 196
Optovisc (Ashford) 0.3% HPMC 0.0002 mL 50% BAK 6.40 242
Hialid 0.1 (Santen) 0.1% sodium hyaluronate BAK 6.57 261
HypoTears (Novartis) 1.0% PVA, 1.0% polyethylene glycol 0.01% BAK 6.10 213
Liquifilm Tears (Allergan) 1.4% PVA 0.005% BAK 6.80 206
Moisture Eyes (Bausch & Lomb) 0.3% glycerin, 1.0% propylene glycol 0.01% BAK 6.96 257
Oculotect Fluid Sine (Novartis) 5.0% polyvidone None 6.75 274
Optrex Hamamelis virginiana 0.005% BAK 7.22 283
Refresh Plus (single use; Allergan) 0.5% CMC None 6.52 276
Refresh (single use; Allergan) 1.4% PVA, 0.6% povidone None 5.64 246
Refresh Tears (Allergan) 0.5% CMC Purite 7.34 257
Salacyn 0.9% (Ashford) 0.9% sodium chloride 0.0002 mL 50% BAK 7.49 407
Systane (Alcon) 0.4% polyethylene glycol 400, 0.3% Hydroxypropyl guar, 7.07 255
propylene glycol polyquaternium-1
Tears Naturale II 0.3% HPMC, 0.1% dextran 70 0.001% polyquad 7.68 287
Tears Naturale Free 0.3% HPMC, 0.1% dextran 70 None 7.21 258
TheraTears 0.25% CMC None 8.95 145
Vidisept N 5.0% povidone 0.005% cetrimide 7.43 282
*The pH of formulations was tested using a pH meter (SevenEasy; Mettler Toledo). The reproducibility (95% confidence interval of differences) of the pH readings was 0.04.
†The osmolarity of formulations was measured using a vapor pressure osmometer (Vapro 5520; Wescor Inc) and the reproducibility (95% confidence interval of differences) of the
osmolarity readings was 9.6 mmol/kg.
BAK, benzalkonium chloride; CMC, carboxy methylcellulose; HEC, hydroxyethylcellulose; HPMC, hydroxypropyl methylcellulose; PVA, polyvinyl alcohol.

Limitations of Lubricant Treatment Preservative considerations should be borne in mind as

The use of artificial tear lubricants has obvious
limitations, and dry eye treatment with lubricants has been
suggested to be ineffective in many people.45 The tear film
consists of lipid, aqueous, and mucin layers, which cannot
be completely reproduced by artificial tear preparations.35
Artificial tears do not contain specific anti-inflammatory
proteins20 such as lysozyme, lactoferrin, immunoglobulin A,
and lipid-binding proteins.46
Suggested Guidelines on the Selection of
Tear Lubricants
There are a large variety of commercially available tear
lubricants and it may be difficult to identify one that is most
beneficial to a patient. The general principle is that a more
viscous tear lubricant is selected when there is an increased
severity of dry eye. In such cases, the frequency of instillation
should be increased. It may be necessary to try tear substitutes
with different mechanisms of action or properties to find
the optimal lubricant for an individual. In addition, this trial-
and-error approach may also involve titration of the frequency
of instillation and different combinations of lubricants.
discussed previously. Different viscosities of tear lubricants
may be used at different times of the day. For instance,
less viscous eye drops are advisable during the day and
a viscous ointment at night. If all other factors are the same,
hypo-osmolar eye drops may be preferred to other types of
eye drops.
Practitioners need to consider the patient’s needs and
this involves identification of patient activities and suggesting
the most suitable dosage according to their requirements or
symptoms on any given day. The frequency of eye drop
instillation may be increased if the patient anticipates working
at a computer for a prolonged period or driving at night.
PATIENT EXPECTATIONS AND SUCCESS
OF TREATMENT
Tear lubricants often require long-term usage and daily
administration. Patients with dry eye often discontinue use of
the recommended eye drops.47 Reasons for failure of treat-
ment include complicated regimens, high frequency of dos-
age, adverse effects, and the high cost of tear substitutes.48
Other contributing patient factors include the perception that

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Cornea ! Volume 31, Number 11, Suppl. 1, November 2012
the disease is mild, an inability to remember the regime, and
a lack of understanding of the objectives of the treatment. In
addition, patients may perceive that the prescribed tear lubri-
cants are not efficacious, leading to reduced compliance.47
Patients often require the help of family members to instill
eye drops, and such support may not always be available. In
other circumstances, health care practitioners may not have
explained the treatment aim and regime in sufficient detail to
the patient, resulting in a poor understanding by the patient,
causing dissatisfaction and discontinuation of the treatment.48
A more holistic approach by health care practitioners, pro-
viding an in-depth discussion of the treatment to educate the
patient and the rationale for selection of specific eye drops
and dosage, is critical to maximize compliance and increase
the success rate of dry eye treatment.47
CONCLUSIONS
In this review, we provide an overview of the available
over-the-counter treatments and their limitations. It is impor-
tant for health care professionals to understand the variations
between different compositions of tear lubricants, which will
help when counseling patients with dry eye and in the
selection of the appropriate treatment using these simple
guidelines. Patient education is a major component of success
because it determines compliance. Patient expectations need
to be realistic in that, although dry eye can be controlled, it
may not necessarily be curable.
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