Artificial tears potpourri: a literature review

Figures & data

Table 1 Summary of published papers and clinical trials comparing artificial tears

Comparison data between various brands of artificial tears
Drops examined	ST/SS	Trial results	P-value
Systane^® versus Refresh Tears^®,37	Double blinded RCT/87	After 14 days of daily therapy, Systane-treated patients exhibited decreased conjunctival staining and diminished temporal corneal staining compared to patients treated with Refresh Tears	Conjunctival stain: 0.025 Temporal stain: 0.024
Systane^® versus Refresh Tears^® versus\Refresh Endura^®,38	Double blinded, three-way cross-over, RCT/50	At 5, 10, 15, 20, and 60 minutes after application, Systane significantly prolonged tear break-up time compared to either Refresh therapies	5, 10, 15, 20, 60 minutes <0.05
Systane^® versus Refresh Liquigel^®,30	Open-label, RCT/60	Clinical trial revealed patient preference for Refresh Liquigel (36%) compared with Systane (24%). Mean corneal inferior staining was only significantly reduced in patients treated with Refresh Liquigel	Patient preference P not provided Corneal staining <0.001
Blink^Citation8 Intensive versus Systane^® versus\Refresh Celluvisc^®,44	Investigator masked RCT/60	At treatment day 30, the mean decrease in osmolarity 5 minutes postapplication was significantly greater with Blink Tears compared to Systane and Refresh	Osmolarity decrease <0.001
Blink^® Tears versus Systane^® Ultra^Citation45	Investigator masked, cross-over, RCT/40	After 1 month of therapy, TBUT was significantly increased by 2.4 seconds with Blink Tears while Systane Ultra showed no statistically significant increase in tear film	TBUT increase 0.003
Blink^® Tears versus Refresh Optive^®,31	Investigator masked, cross-over, RCT/50	After 16 days of therapy with either Blink Tears or Refresh Optive, patients reported similar improvement on the Dry Eye Disease Comfort Assessment questionnaire	P not provided
Refresh Liquigel^® versus Refresh Tears^®,41	Double blinded, cross-over, RCT/39	Refresh Liquigel (1.0% CMC) increased TBUT for a longer time when compared with Refresh Tears (0.5% CMC)	<0.05
Refresh Liquigel^® versus Refresh Tears^®,24	Subject masked, parallel-group, RCT/99	Corneal staining reduced greater from baseline with Refresh Liquigel than Refresh Tears, but more adverse events occurred with the Liquigel	Corneal staining 0.011 Adverse events 0.006
Refresh Plus^® versus Refresh Liquigel^® versus Refresh Celluvisc^®,42	Subject masked, controlled trial/20	Both Refresh Liquigel and Refresh Celluvisc significantly decreased contrast sensitivity	Decreased contrast sensitivity <0.001
Refresh Optive^® versus Systane^® versus Hylo-Comod^®,39	Open-label, observational study/5277	Questionnaire revealed 68.9% of Hylo-Comod users and 78.5% of Systane users had improvement of symptoms by switching to Refresh Optive. TBUT also improved with Refresh	Symptom improvement P not provided TBUT improvement <0.001
Refresh Tears^® versus Refresh Ultra^® versus Refresh Optive^®,43	Double-blinded, cross-over, RCT/38	Refresh Optive and Refresh Ultra improved patient symptoms greater than Refresh Tears	Optive 0.013 Ultra 0.011
Systane^® Ultra versus Refresh Optive^®,36	Double-blinded, cross-over RCT/48	At 90 minutes after application, Systane Ultra users maintained BCVA for 9.17±0.0365 seconds compared to 6.84±0.0365 seconds of maintained BCVA in Refresh Optive users	P not provided
Systane^® Ultra versus Refresh Optive^®,40	Double-blinded, parallel, RCT/109	On a unit scale of 0–15, with 0 being no staining and 15 the most staining, corneal staining after 42 days of treatment with Systane Ultra showed 2.9±1.8 units of corneal staining compared to 4.2±2.8 units of corneal staining in those treated with Refresh Optive	P not provided
Systane^® Ultra versus Refresh Optive^® versus GenTeal^® versus Blink^® Tears^Citation46	Double-blinded, cross-over, RCT/20	Posttherapeutic subjective comfort results revealed Systane Ultra outperformed Refresh Optive, GenTeal, and Blink Tears	P not provided
Soothe^® versus Refresh Optive^®,47	Double-blinded, cross-over, RCT/41	The mean lipid layer thickness increase was significantly greater in eyes treated with Soothe (60.0 nm) compared to eyes treated with Refresh (23.6 nm)	Refresh <0.0001 Soothe <0.0001 Comparison <0.0001
Soothe^® versus Systane^®,48	Double-blinded, cross-over, RCT/40	The lipid layer thickness increase was significantly greater in eyes treated with Soothe compared to eyes treated with Systane	Systane <0.0001 Soothe <0.0001 Comparison <0.0001
GenTeal^® Tears versus Naturale-Free^®,50	Open-label, cross-over, RCT/37	Results showed adequate improvement of Shirmer Test and TBUT, but only GenTeal showed reduction of erosions that affected >25% of the corneal surface	0.027
Tears Again^® versus Liposic^®,45	Investigator masked, cross-over, RCT/74	The tear break-up time in patients treated with Tears Again was increased greater than that of those treated with Liposic at 6 weeks	Both group improvement <0.001 Group difference 0.055

Notes: Manufacturers are as follows: Refresh^®, Allergan, Irvine, CA, USA; Systane^®, Alcon Laboratories, Inc., Fort Worth, TX, USA; Blink®, Abbott Laboratories Inc., Abbott Park, IL, USA; Hylo-Comod^®, URSAPHARM, Saarbrücken, Germany; GenTeal^®, Novartis Pharmaceuticals, East Hanover, NJ, USA; Soothe^®, Bausch & Lomb Incorporated, Bridgewater, NJ, USA; Liposic^®, Bausch & Lomb Incorporated; Naturale-Free^®, Alcon Laboratories, Inc.; Tears Again^®, OcuSoft, Rosenberg, TX, USA.

Abbreviations: BCVA, best-corrected visual acuity; CMC, carboxy methylcellulose; RCT, randomized controlled trial; SS, sample size; ST, study type; TBUT, tear film breakup time.

Table 2 Clinical data for performance of artificial tears and their corresponding percent improvement based upon respective subjective and objective criteria

Brand name	Pts treated (n)	Trials (n)	Improvement (%)
Thera Tears^®,^Citation80	2	1	100
Refresh Tears^®,^Citation68,Citation37,Citation41,Citation54,Citation47,Citation70,Citation30	739	7	100
Refresh Plus^®,^Citation69,Citation71,Citation72,Citation32,Citation82,Citation35	301	6	92.7
Refresh Celluvisc^®,^Citation80	11	1	100
Refresh Liquigel^®,^Citation41,Citation29,Citation30,Citation74	778	4	100
GenTeal^® Moderate to Severe^Citation50	37	1	100
Lacril^®,^Citation81	55	1	100
Isopto^® Alkaline^Citation80	2	1	100
Isopto^® Plain^Citation80	9	1	100
Blink^® Tears^Citation45	20	1	100
Blink^® Intensive Tears^Citation75,Citation44,Citation90	60	3	100
Systane^® Balance^Citation83,Citation84,Citation33	92	3	71.0
Systane^®,^Citation68,Citation37,Citation28,Citation85,Citation57,Citation34,Citation44,Citation86,Citation88,Citation89	502	10	87.3
Systane^® Ultra^Citation54,Citation79,Citation36,Citation40	130	4	100
Systane^®, preservative-free^Citation87	27	1	100
Soothe^®,^Citation47	30	1	100
GenTeal^® Gel^Citation55,Citation56	206	2	96.0
Viscotears^®,^Citation73,Citation80	456	2	100
Liposic^®,^Citation49	74	1	100
Refresh Lacrilube^®,^Citation80	239	1	100
Tears Again^® (Actimist in the UK)^Citation77,Citation78,Citation49	287	3	93.0
Refresh Optive^®,^Citation42,Citation36,Citation40,Citation31	5,430	4	75.8
Refresh Optive^® Sensitive^Citation82	114	1	100
Tears Naturale^® II^Citation80	68	1	100
Tears Naturale Free^®,^Citation68	22	1	100
Tears Naturale^® Forte^Citation71,Citation76	129	2	63.0

Notes: Improvement in DTS was defined in each study with the following subjective/objective criteria: subjective data: McMonnies Dry Eye Symptom survey, ODSI questionnaire, IDEEL questionnaire, SEE questionnaire, Ocular Discomfort Severity questionnaire, Direct Brand Comparison with drop preference selection, quality of life through the Measure Yourself Medical Outcome Profile-2 (MYMOP-2), Dry Eye Disease Comfort Assessment Score, and various custom questionnaires in addition to these. Objective data: McMonnies Dry Eye Symptom survey, ODSI questionnaire, IDEEL questionnaire, SEE Questionnaire, Ocular Discomfort Severity questionnaire, Direct Brand Comparison with drop preference selection, quality of life through the MYMOP-2, Dry Eye Disease Comfort Assessment Score, and various custom questionnaires in addition to these.^23–31 Manufacturers are as follows: Thera Tears^®, Advanced Vision Research, Ann Arbor, MI, USA; Refresh^®, Allergan, Irvine, CA, USA; GenTeal^®, Novartis Pharmaceuticals, East Hanover, NJ, USA; Lacril^®, Allergan; Isopto^®, Alcon Laboratories, Inc., Fort Worth, TX, USA; Blink^®, Abbott Laboratories Inc., Abbott Park, IL, USA; Systane^®, Alcon Laboratories, Inc.; Soothe^®, Bausch & Lomb Incorporated, Bridgewater, NJ, USA; Viscotears^®, Novartis Pharmaceuticals; Liposic^®, Bausch & Lomb Incorporated; Tears Again^®, OcuSoft, Rosenberg, TX, USA; Tears Naturale^®, Alcon Laboratories, Inc.

Abbreviations: DTS, dysfunctional tear syndrome; IDEEL, impact of dry eye on everyday life; ODSI, Ocular Surface Disease Index; pts, patients.

Figure 1 Treatment flowchart.

Notes: ^aContains 0.3% HPMC and 0.25% CMC; ^bPreservative-free option available; ^cPreservative-free option: Refresh Plus^®. Manufacturers are as follows: Refresh^®, Allergan, Irvine, CA, USA; GenTeal^®, Novartis Pharmaceuticals, East Hanover, NJ, USA; Lacril^®, Allergan; Blink^®, Abbott Laboratories Inc., Abbott Park, IL, USA; Systane^®, Alcon Laboratories, Inc.; Soothe^®, Bausch & Lomb Incorporated, Bridgewater, NJ, USA; Viscotears^®, Novartis Pharmaceuticals; Liposic^®, Bausch & Lomb Incorporated; Tears Again^®, OcuSoft, Rosenberg, TX, USA.
Abbreviations: CMC, carboxy methylcellulose; DTS, dysfunctional tear syndrome; HPMC, hydroxypropyl methylcellulose; PEG, polyethylene glycol; PG, propylene glycol.

Table S1 Methylcellulose-based artificial tears commercially available

Name	Active ingredients	Preservatives
GenTeal^® Mild	0.2% HPMC	GenAqua^® (sodium perborate)
GenTeal^® Moderate to Severe	0.3% HPMC 0.25% CMC	GenAqua^® (sodium perborate)
Ultra Tears^®	0.3% HPMC	BAK
Tearisol^®	0.3% HPMC	BAK
Lacril^®	0.5% HPMC	Chlorobutonal
Isopto^® Alkaline	1.0% HPMC	BAK
Isopto^® Plain	0.5% HPMC	BAK
Isopto^® Tears	0.5% HPMC	BAK
Nature’s Tears^®	0.4% HPMC	BAK
Natural Balance Tears	0.4% HPMC	BAK
Rohto^® Hydra	0.3% HPMC	Polyaminopropyl biguanide
Thera Tears^®	0.25% CMC	Preserved-forma Dequest (sodium perborate and phosphoric acid)
Refresh Tears^®	0.5% CMC	Purite (stabilized oxychloro complex)
Refresh Plus^®	0.5% CMC	None
Refresh Celluvisc^®	1.0% CMC	Preserved-forma Purite (stabilized oxychloro complex)
Refresh Liquigel^®	1.0% CMC	Preserved-forma Purite (stabilized oxychloro complex)
Just Tears	0.5% CMC	Purite (stabilized oxychloro complex)

Notes:

a Both preserved and preservative-free formulations commercially available. Manufacturers are as follows: GenTeal^®, Novartis Pharmaceuticals, East Hanover, NJ, USA; Ultra Tears^®, Alcon Laboratories, Inc., Fort Worth, TX, USA; Tearisol^®, Novartis Pharmaceuticals; Lacril^®, Allergan, Irvine, CA, USA; Isopto^®, Alcon Laboratories, Inc.; Nature’s Tears^®, Bio-Logic Aqua Technologies, Grants Pass, OR, USA; Natural Balance Tears, Major Pharmaceuticals, Livonia, MI, USA; Rohto^® Hydra, Rohto Laboratories Indonesia, Padalarang, Indonesia; Thera Tears^®, Advanced Vision Research, Ann Arbor, MI, USA; Refresh^®, Allergan; GenAqua^®, Novartis Ophthalmics, East Hanover, NJ, USA; Just Tears, Blairex, Columbus, IN, USA.

Abbreviations: BAK, benzalkonium chloride; CMC, carboxy methylcellulose; HPMC, hydroxypropyl methylcellulose.

Table S2 Polyvinyl alcohol-based artificial tears commercially available

Name	Active ingredients	Preservatives
Nutratear^®	0.4% PVA	Polexitonium
Murine Tears^®	0.5% PVA 0.6% povidone	BAK
Akorn^® Artificial Tears	1.4% PVA	BAK
MiniDrops^®	1.4% PVA 0.6% providone	None
Refresh Classic^®	1.4% PVA 0.4% povidone	None
Clear Eyes^® Artificial Tears	0.5% PVA 0.6% povidone	BAK
Freshkote^®	2.7% PVA 2.0% povidone	Polixetonium

Notes: Manufacturers are as follows: Nutratear^®, Medco Lab, Inc, Sioux City, IA, USA; Murine Tears^®, Prestige Brands Holdings, Inc., Tarrytown, NY, USA; Akorn^®, Akorn, Incorporated, Lake Forest, IL, USA; MiniDrops^®, Optics Laboratory, Inc., El Monte, CA, USA; Refresh^®, Allergan, Irvine, CA, USA; Clear Eyes^®, Prestige Brands Holdings, Inc., Tarrytown, NY, USA; Freshkote^®, FOCUS Laboratories, Inc., North Little Rock, AR, USA.

Abbreviations: BAK, benzalkonium chloride; PVA, polyvinyl alcohol.

Table S3 Liquid polyol-based artificial tears available on the market

Name	Active ingredients	Preservatives
Oasis^® Tears	0.2% glycerin (15%)	No
Oasis^® Tears Plus	0.2% glycerin (30%)	No
Advanced Eye Relief™ “Environmental”	1.0% glycerin	BAK
Advanced Eye Relief™ “Rejuvenation”	0.3% glycerin 1.0% propylene glycol	BAK
Blink^® Tears	0.25% polyethylene glycol 400	Preserved-forma
	Hyaluronic acid	OcuPure^® (stabilized oxychloro complex)
Blink^® Gel Tears	0.25% polyethylene glycol 400 Hyaluronic acid	OcuPure^® (stabilized oxychloro complex)
Systane^® Balance	0.6% propylene glycol	Polyquad^® (polyquaternium-1)
Systane^® Gel Drops	0.4% polyethylene glycol 400 0.3% propylene glycol	Polyquad^® (polyquaternium-1)
Systane^®	0.4% polyethylene glycol 400	Preserved-forma
	0.3% propylene glycol	Polyquad^® (polyquaternium-1)
Systane^® Ultra	0.4% polyethylene glycol 400	Preserved-forma
	0.3% propylene glycol	Polyquad^® (polyquaternium-1)
Soothe^®	0.6% glycerin 0.6% propylene glycol	No
Viva Drops^®	1.0% polysorbate 80	No

Notes:

a Both preserved and preservative-free formulations commercially available. Manufacturers are as follows: Oasis^®, Oasis Medical, Inc., Glendora, CA, USA; Advanced Eye Relief™, Bausch & Lomb Incorporated, Bridgewater, NJ, USA; Blink^®, Abbott Laboratories Inc., Abbott Park, Illinois, USA; Systane^®, Alcon Laboratories, Inc., Fort Worth, TX, USA; Soothe^®, Bausch & Lomb Incorporated; Viva Drops^®, Dakota Laboratories, LLC, Mitchell, SD, USA; Polyquad^®, Alcon Laboratories, Inc.; OcuPure^®, Abbott Laboratories Inc.

Abbreviation: BAK, benzalkonium chloride.

Table S4 Gels, ointments, sprays, and an ophthalmic insert for dysfunctional tear syndrome

Name	Active ingredients	Delivery	Preservatives
GenTeal^® Gel	0.3% HPMC	Gel	Preserved-forma
	Carbopol 980		GenAqua^®
Tears Again^® Night & Day Gel	1.5% CMC	Gel	Dissipate (stabilized oxyborate complex)
Hylo^®-Gel	0.2% hyaluronic acid	Gel	None
ViscoTears^® Liquid Gel	0.2% carbomer 980	Gel	None
Liquivisc™	0.25% carbomer 974P	Gel	BAK
Liposic^®	0.2% carbomer 980	Gel	None
Soothe^® Lubricant Eye Ointment	20% mineral oil 80% white petrolatum	Ointment	None
Akwa^® Tears Ointment	15% mineral oil 83% white petrolatum	Ointment	None
Rugby^® Artifical Tear Ointment	15% mineral oil 83% white petrolatum	Ointment	None
Puralube^® Ointment	15% mineral oil 85% white petrolatum	Ointment	None
Lubrifresh™ PM	15% mineral oil 83% white petrolatum	Ointment	None
Refresh PM^® Ointment	42.5% mineral oil 57.3% white petrolatum	Ointment	None
Tears Naturale^® PM	56.8% white petrolatum 42.5% mineral oil	Ointment	None
Refresh Lacrilube^®	42.5% mineral oil 56.8% white petrolatum	Ointment	Chlorobutanol
Systane^® Nighttime Ointment	3% mineral oil 94% white petrolatum	Ointment	None
Clarymist™	1.0% woy lecithin	Spray	Phenoxyethanol
Actimist™	1% woy Lecithin	Spray	Phenoxyethanol
Name	Active ingredients	Delivery	Preservatives
Tears Again^®	1.4% PVA	Spray	Dissipate (stabilized oxyborate complex)
Nature’s Tears^®	Bio-Logic Aqua^® tissue-culture grade water	Spray	None
Vizulize Dry Eyes Eye Mist	0.10% hyaluronate	Spray	N-IG
Lacrisert^®,b	5 mg HPMC	Insert	None

Notes:

a Both preserved and preservative-free formulations commercially available

b Prescription-only ophthalmic insert. Manufacturers are as follows: GenTeal^®, Novartis Pharmaceuticals, East Hanover, NJ, USA; Tears Again^®, OcuSoft, Rosenberg, TX, USA; Hylo^®-Gel, URSAPHARM, Saarbrücken, Germany; Viscotears^®, Novartis Pharmaceuticals; Liquivisc™, URSAPHARM; Liposic^®, Bausch & Lomb Incorporated, Bridgewater, NJ, USA; Soothe^®, Bausch & Lomb Incorporated; Akwa^®, Akorn, Incorporated, Lake Forest, IL, USA; Rugby^®, Rugby Laboratories, Livonia, MI, USA; Puralube^®, Fougera Pharmaceuticals Inc., Melville, NY, USA; Lubrifresh™, Major Pharmaceuticals, Livonia, MI, USA; Refresh^®, Allergan, Irvine, CA, USA; Systane^®, Alcon Laboratories, Inc., Fort Worth, TX, USA; Clarymist™, Savant Distribution, Leeds, UK; Actimist™, Reckitt Benckiser plc, Berkshire, UK; Nature’s Tears^®, Bio-Logic Aqua Technologies, Grants Pass, OR, USA; Lacrisert^®, Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA; GenAqua^®, Novartis Ophthalmics, East Hanover, NJ, USA; Tears Again^®, OcuSoft; Vizulize Dry Eyes Eye Mist, Butterflies Healthcare, Banbury, OX, UK; Bio-Logic Aqua^®, Bio-Logic Aqua Technologies.

Abbreviations: BAK, benzalkonium chloride; CMC, carboxy methylcellulose; HPMC, hydroxypropyl methylcellulose; N-IG, N-hydroxymethylglycinate; PVA, polyvinyl alcohol.

Table S5 Artificial tears with combinations of active ingredients

Name	Active ingredients	Preservatives
Refresh Optive^® Advanced	0.5% CMC	Preserved-forma
	1.0% glycerine	Purite^® (stabilized oxychloro complex)
Refresh Optive^®	0.5% polysorbate 80 0.5% CMC	Preserved-forma
Refresh Optive^® Sensitive	0.9% glycerine 0.5% CMC	Purite^® (stabilized oxychloro complex) None
Tears Naturale^® II	0.9% glycerine 0.3% HPMC	Polyquad^® (polyquaternium-1)
Tears Naturale^® Free	0.1% dextran 70 0.3% HPMC	None
Tears Naturale^® Forte	0.1% dextran 70 0.3% HPMC 0.1% dextran 70	Polyquad^® (polyquaternium-1)
Tears Naturale^® – Bion Tears	0.2% glycerin 0.3% HPMC 0.1% dextran 70 Zinc + bicarbonate	None
Tears Renewed^®	0.3% HPMC	BAK
Hypotears^®	0.1% dextran 70 1.0% PVA	BAK
Soothe^® XP	1.0% polyethylene glycol 1% light mineral oil 4.5% mineral oil	Polyhexamethylene biguanide
Hylo^®-Fresh	0.03% hyaluronic acid	None
Hylo-Comod^®	0.1% hyaluronic acid	None
Similasan^® Dry Eye Relief	Belladonna euphrasia Mercurius sublimatus	Silver sulfate
Similasan^® Irritated Eye Relief	Belladonna euphrasia Hepar sulfuris	Silver sulfate

Notes:

a Both preserved and preservative-free formulations commercially available. Manufacturers are as follows: Refresh^®, Allergan, Irvine, CA, USA; Tears Naturale^®, Alcon Laboratories, Inc., Fort Worth, TX, USA; Tears Renewed^®, Akorn, Incorporated, Lake Forest, IL, USA; Hypotears^®, Novartis Pharmaceuticals, East Hanover, NJ, USA; Soothe^®, Bausch & Lomb Incorporated, Bridgewater, NJ, USA; Hylo^®-Fresh and Hylo-Comod^®, URSAPHARM, Saarbrücken, Germany; Similasan^®, Similasan Corporation, Highlands Ranch, CO, USA; Polyquad^®, Alcon Laboratories, Inc.; Purite^®, Bio-Cide International Inc., Norman, OK, USA.

Abbreviations: BAK, benzalkonium chloride; CMC, carboxy methylcellulose; HPMC, hydroxypropyl methylcellulose; PVA, polyvinyl alcohol.

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