Lubricants are the first-line treatment for many causes of ocular irritation, in particular for dry eye. There are a multitude of artificial tear choices available. The goal of this tutorial is to provide information about the components that make up artificial tears, to discuss the functions of these components, and to explain which commercially available drops contain those components. The list is not exhaustive and you may feel free to send Dr. Tressa Larson (tressa-larson@uiowa.edu) information on additional drops.

Formalization of the Active Ingredients

The first important point when considering the large variety of artificial tears is that the Food and Drug Administration (FDA) created a drug monograph in the late 1980's to provide artificial tears a fast track to FDA approval [1]. The monograph states that an over-the-counter ophthalmic drug product in a form suitable for topical administration is generally recognized safe, effective and not misbranded if it contains the following ingredients and ingredient combinations.
This tutorial aims to familiarize the reader with the FDA approved active ingredients and then to discuss "inactive" ingredients.

FDA Monograph

1. Ophthalmic Astringent: A locally acting pharmacologic agent which, by precipitating protein, helps to clear mucous from the surface of the eye
   1. Zinc sulfate 0.25%
2. Ophthalmic Demulcent: An agent, usually a water soluble polymer, which is applied topically to the eye to protect and lubricate mucous membranes
   1. Cellulose derivatives
      1. Carboxymethcellulose sodium 0.2 to 2.5%
      2. Hydroxyethyl cellulose 0.2 to 2.5%
      3. Hydroxypropyl methylcellulose 0.2 to 2.5%
      4. Methylcellulose 0.2 to 2.5%
   2. Dextran 70: 0.1% when used with another polymeric demulcent agent in this section
   3. Gelatin 0.01%
   4. Polyols, liquid
      1. Glycerin 0.2 to 1%
      2. Polyethylene glycol 300: 0.2 to 1%
      3. Polyethylene glycol 400: 0.2 to 1%
      4. Polysorbate 80: 0.2 to 1%
      5. Polyvinyl alcohol 0.1 to 4%
      6. Povidone 0.1 to 2%
3. Ophthalmic emollients: An agent, usually a fat or oil which is applied locally to eyelids to protect or soften tissues and to prevent drying and cracking.
   1. Lanolin preparations
      1. Anhydrous lanolin 1 to 10% in combination with one or more oleaginous emollient agents included here
      2. Lanolin 1 to 10% in combination with one or more oleaginous emollient agents included here
   2. Oleaginous ingredients
      1. Light mineral oil up to 50% in combination with one or more other emollient agents included here
      2. Mineral oil up to 50% in combination with one or more other emollient agents included here
      3. Paraffin up to 5% in combination with one or more other emollient agents included here
      4. Petrolatum up to 100%
      5. White ointment up to 100%
      6. White petrolatum up to 100%
      7. White wax up to 5% in combination with one or more other emollient agents included here
      8. Yellow wax up to 5% in combination with one or more other emollient agents included here
4. Ophthalmic hypertonicity agent: Sodium chloride 2 to 5%
5. Ophthalmic vasoconstrictors
   1. Ephedrine hydrochloride 0.123%
   2. Naphazoline hydrochloride 0.01 to 0.03%
   3. Phenylephrine hydrochloride 0.08 to 0.2%
   4. Tetrahydrazoline hydrochloride 0.01 to 0.05%
6. Eyewashes: contain water tonicity agents and agents for establishing pH
7. Permitted combinations
   1. Any astringent + any vasoconstrictor
   2. Any 2-3 demulcents
   3. Any single demulcent + any single vasoconstrictor
   4. Any astringent + any vasoconstrictor + any demulcent
   5. Any 2+ emollients
8. Permitted Indications (Demulcents or emollients)
   1. For temporary relief of burning and irritation due to dryness of the eye
   2. For temporary relief of discomfort due to minor irritations of the eye
   3. For use as a protectant against further ocular irritation
   4. For use as a lubricant to prevent further ocular irritation

Goals of Artificial Tear Treatment

Although there are many patient related treatment goals, the most common purpose of artificial tears is to decrease dryness. Humectants are compounds which promote hydration and feel good upon application. Artificial tears are also lubricants meaning they decrease friction on the ocular surface caused by the eyelid. Another treatment goal in ocular surface disease is to increase tear retention. Artificial tears do this by increasing tear viscosity, increasing the adherence of the tears to the ocular surface, decreasing tear evaporation, and decreasing tear clearance. Additionally, inflammation is known to play a role in causing dry eyes and there are artificial tear components that decrease inflammation by disrupting the processes which promotes the recruitment of cytokines [2]. Artificial tears may also reduce redness and swelling and serve to protect the eye from hyperosmolarity. High osmolarity of the tear film causes water to diffuse out of epithelial cells, further dehydrating the surface. Finally, artificial tears may serve to soften and moisturize the ocular surface by forming an oily layer that traps existing moisture present in the tissues.

Demulcents

A demulcent is a soothing, usually mucilaginous substance that is used to relieve pain in inflamed or irritated mucous membranes.

Polyethylene glycol (PEG) is a demulcent that forms a protective layer over a mucous membrane to relieve inflammation or irritation and to preserve the ocular surface microenvironment. Demulcents are high molecular weight polymers that mimic mucins and act to lubricate, protect and provide viscosity to eye drops. Examples of artificial tears containing PEG are Blink Tears (Abbott), Blink Gel Tears (Abbott), Systane gel (Alcon), Systane preservative free (Alcon), and Soothe (B+L).

Propylene glycol also forms a protective layer over mucous membranes to relieve inflammation and/or irritation. It also increases the viscosity of the eye drop. In addition to its demulcent properties, propylene glycol is a humectant because it holds up to three times its own weight in water. Examples of artificial tears containing propylene glycol are B+L Advanced Eye Relief, Systane Balance, and Systane gel drops (Alcon).

Glycerin is a demulcent and lubricant as well as a humectant. Glycerin has the added properties of promoting epithelial cell growth and blunting the damaging effects of high osmolarity on the ocular surface. Povidone is a lipid that integrates with the existing oil layer of the tear film, thickening it to reduce evaporation. Dextran is a low molecular weight hydrophilic polymer that increases the mechanical strength of the tear film. Its low viscosity means that it is not useful in an artificial tear without a thickening agent. Examples of artificial tears containing Glycerin are Refresh Optive and Refresh Optive Advanced (Allergan), Oasis Tears (Oasis Medical Inc), Clear Eyes Pure Relief (Prestige Brands Inc.), and Tears Naturale Forte (Alcon).

There are a number of compounds that are cellulose derivatives that are approved for use in artificial tears. Carboxymethylcellulose (CMC) is the most commonly used polymeric viscosity agent in the United States. CMC binds to and is retained by corneal epithelial cells. It increases the viscosity and clearance times of an eye drop and is also widely used in foods, pharmaceuticals and non-food products such as tooth paste and detergents. Examples of artificial tears containing CMC are Thera Tears family (Advanced Vision Research), Refresh Tears and Refresh Plus tears (Allergan).

Hydroxymethylcellulose (HMC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC, aka. hypromellose) are all hydrophilic polymers that coat and protect the eye. They are hydrogels that crosslink upon contact with the ocular surface to increase tear clearance times. They must be mixed with other compounds because they are too viscous to instill alone onto the ocular surface. HMC is restores the protective effect of the mucous layer of the tears. Examples of artificial tears containing HMC and its related compounds are Tears Naturale II, Genteal Gel, and Genteal Liquid Gel Drops (Alcon) and in Clear Eyes Pure Relief (Prestige Brands Inc). Lacrisert is a solid piece of HPMC that is inserted into the fornix and left to dissolve slowly onto the surface of the eye.

Polyvinyl alcohol (PVA) is a demulcent that lowers the viscosity of a solution. Not found in any of the most up to date artificial tear brands due to the availability of more efficacious compounds, PVA is found in many older artificial tear preparations such as Refresh Classic (Allergan), Hypotears (Alcon), Fresh Kote (Focus Laboratories), and Visine Tears for Dry Eye and Visine for Contacts (Johnson + Johnson). PVA is also incorporated into Alcon's Dailies Aqua Comfort Plus contact lenses. The company claims that this daily disposable lens releases PVA for about twenty hours of wear to increase comfort. This in turn is thought to increase compliance with daily use since the lens becomes less comfortable once the PVA has diffused out of the lens.

Demulcents	Conc. Range	Function
Carboxymethylcellulose sodium	0.2 to 2.5%	Increase Viscosity (thickener) Stabilize emulsions
Dextran 70	0.1% when used with another Demulcent	Increase mechanical strength of tear film. Requires thickener due to low viscosity of compound
Gelatin	0.01%	seldom included gelling agent
Glycerin	0.2 to 1%	Blunts the damaging effects of high osmolarity on the ocular surface. Lubricant, humectant Promote epithelial cell growth
Hydroxyethyl cellulose Hydroxypropyl-methylcellulose Methylcellulose	0.2 to 2.5% 0.2 to 2.5% 0.2 to 2.5%	Cross links upon contact with tear film due to pH difference to increase viscosity. Too viscous to instill easily alone
Polyethylene glycol 300  Polyethylene glycol 400	0.2 to 1% 0.2 to 1%	Increases viscosity Forms protective layer over mucous membrane to relieve irritation
Polysorbate 80	0.2 to 1%	Stabilizes oil emulsions
Polyvinyl alcohol	0.1 to 4%	Lowers tear viscosity
Povidone	0.1 to 2%	Lubricating and soothing Lipid that integrates with existing oil layer, thickening it and reducing evaporation
Propylene glycol	0.2 to 1%	Forms a protective layer over mucous membranes relieving inflammation. Increases viscosity Holds up to 3x own weight in water

Emollients

Emollients are oily or fat based agents which are used to soften and protect tissues to prevent cracking or drying. Emollients are non-moisturizing, but they do function to seal in existing moisture. Mineral oils thicken or replace the lipid layer of the tear film to increase tear stability and tear break up time. White petrolatum and the lanolin preparations are lubricants. The majority of products containing mineral oil and white petrolatum contain only those two components in varying proportions. Examples of artificial tears containing these products include Systane Balance, Genteal PM, Hypotears Ointment, Systane Nighttime (Alcon), Soothe XP and Soothe PM (B+L), Retaine MGD and Retaine PM Nighttime Ointment (Ocusoft), and Refresh PM and Refresh Lacilube (Allergan)

Emollients	Conc. Range	Function
Anhydrous lanolin Lanolin	1-10% in combo with one+ listed oleaginous emollient	Lubrication and soothing Contributes to oil layer
Light mineral oil Mineral oil	up to 50% in combo with one+ listed emollient	Replace or thicken lipid layer to increase tear stability and TBUT.  Non-moisturizing, but does seal in existing moisture.
Paraffin	up to 5% in combo with one or more emollient	Waxy consistency Seal in moisture
Petrolatum White Ointment White Petrolatum	up to 100%	Lubricant Contributes to oil layer
White Wax  Yellow Wax	up to 5% in combo with one+ listed emollient	Contributes to oil layer

Inactive Ingredients

Sorbitol lowers the viscosity of gelling agents such as HP Guar (see below) and HPMC (see above) which are too viscous to instill directly on to the eye. Once instilled on the eye, sorbitol dissipates quickly which allows the solution to be more viscous than it is in the bottle. Sorbitol was the main addition to the solution Systane to produce Systane Ultra.

Hyaluronic Acid is a humectant that binds multiples of its weight in water to lower tear osmolarity. It also adheres to the ocular surface to stabilize the thickness of the tear film. This naturally highly viscous solution is thinned out by the blink action of the eyelids. It also improves cell-cell adhesions. While not currently found in any of the US artificial tear preparations, it is found in all of the Hylo-care products from Ursa Pharmaceuticals and is available in Europe.

Sodium hyaluronate is a derivative of hyaluronic acid and shares many of its beneficial properties. Sodium hyaluronate is a humectant, lubricant, and hypo-osmotic. It is found naturally in the eye where it is produced as a response to ocular surface damage. This hydrophilic polymer plays an important role in corneal wound healing as it promotes corneal epithelial repair and helps control localized inflammation. Sodium hyaluronate is also a lubricant with flow and deformation characteristics similar to those of the tear aqueous layer. Additionally, it reduces mucous strands in tears and is better at lowering tear osmolarity than glycerin. Examples of artificial tears containing sodium hyaluronate are Blink Tears, Blink Gel Tears, and Blink Tears Preservative free from Abbott and in Oasis Tears (Oasis Medical Inc).

L-carnitine and Erythritol are always seen in combination as osmoprotectants. Osmoprotectants blunt the damaging effects of high osmolarity on the ocular surface by preventing the activation of the stress cascade. L-carnitine and erythritol are absorbed by dehydrated cells where they promote hydration and prevent cell shrinkage and inflammation. Examples of artificial tears containing these compounds are Optive products from Allergan, Refresh Optive and Refresh Optive Advanced (added emollient).

Hydroxypropyl Guar (HP Guar) is a bean protein that is used as a thickening agent in both foods and pharmaceuticals. As a component in an artificial tear, it readily stabilizes the tear film by increasing viscosity. HP Guar mimics the mucin layer of the tears by binding to the cornea and strengthening the attachment of the aqueous layer to the glycocalyx-mucin interface. This attachment thickens the aqueous layer. HP Guar partially achieves this because it is pH sensitive, cross-linking and gelling when the pH is above 7. HP Guar also potentiates the active ingredients by prolonging their efficacy. Examples of artificial tears containing HP Guar are the entire Systane family of artificial tears from Alcon including Systane, Systane Ultra, Systane Balance, Systane gel, Systane Preservative Free, and Systane Nighttime.

Polyacrylic Acid has a longstanding reputation for being more efficacious to dry eye patients than PVA. It increases the viscosity and retention time of the artificial tear. Examples of artificial tears containing Polyacrylic Acid are Genteal gel and Genteal Liquid Gel Drops (Alcon) and in Viscotears (Novartis UK).

Tyloxapol is a surfactant, detergent, and mucolytic agent used to thin sputum in inhalation aerosols. As an artificial tear component, it helps to remove lipid and mucous from the surface of contact lenses. An example of an artificial tear containing Tyloxapol is Soothe Long Lasting (B+L). It is also in the contact lens rewetting drop Blink-n-Clean (Abbott).

Tromethamine, which is also found in the rewetting drop Blink-n-Clean, is an organic amine proton acceptor. It is most frequently used as an emulsifying agent for cosmetics, but it is also an alkalizer and biological buffer.

Inactive Ingredients	Function
Sorbitol	Lowers the viscosity of gelling agents Dissipates quickly, optimizing viscosity.
Hyaluronic acid	Binds multiples of its weight in water Lowers tear osmolarity Adheres to ocular surface Stabilizes and evens out the tear film Highly viscous until blink thins it out Improves cell-cell adhesion
Sodium Hyaluronate	Protects and promotes healing of corneal epithelium Changes viscosity upon blinking- more viscous while the eye is open Improves tear film break-up time and helps spreading Helps control localized inflammation Reduces mucous strands Lowers tear osmolarity Retains water, increasing surface wettability.
L-carnitine Erythritol	Blunts the damaging effects of high osmolarity by preventing stress activation. Absorbed by dehydrated cells to promote hydration Prevent cell shrinkage and inflammation
Hydroxypropyl Guar	Increasing viscosity Mimics the mucin layer of the eye Binds to cornea and aqueous layer       Prolongs the efficacy of active ingredients Actively cross links/gels at pH above pH 7
Polyacrylic acid	Increases viscosity/retention time of tears
Tyloxapol	Surfactant and mucolytic agent
Tromethamine	Organic amine proton acceptor. Emulsifying agent (thins waxy agents)
Boric acid Borate Buffer Sodium-citrate Phosphate Phosphate-acetate Phosphate-citrate Phosphate-citrate-bicarbonate Sodium hydroxide	Buffer systems used to obtain a pH for the artificial tear that is healthy and comfortable for the eye. pH ~8.5 is most comfortable for dry eye patients (normal tear pH is about 7.5)
Calcium chloride Magnesium chloride Potassium chloride Zinc chloride Sodium chloride Sodium citrate Sodium lactate Sodium bicarbonate	Electrolytes are added to maintain or lower tear osmolarity as high osmolarity products pull water from epithelial cells, interfering with metabolism. Some of the added electrolytes are also important for corneal epithelial metabolism. Some electrolytes are part of buffer systems.

Homeopathic drops

Homeopathic drops are not well studied, but products in this family, such as those from the company Similasan, are widely available. Tamarind seed polysaccharide is a gelling agent which contains a chemical similar to ocular mucin. Euphrasia, known as Eyebright, has been used in ocular poultices for centuries. It is thought to reduce inflammation and prevent mucous formation.

Preservatives

Preservatives are the component of artificial tears that may cause harm to the eye. Preservatives are important in eye drops because they prevent bacterial growth and subsequent infection.
There are three main types of preservatives: detergent type, oxidative type, and ionic buffering systems. Detergent-type preservatives cause bacterial cell death by interrupting the lipids in their cell membranes which causes the cells to break apart. These preservatives have a very broad spectrum of action making them fairly toxic to human cells [4]. Oxidative-type preservatives penetrate bacterial cell membranes to damage DNA, proteins, and lipids. Oxidative preservatives are less toxic to human cells than detergent preservatives. They are also effective against bacteria at very low concentrations which helps to minimize damage [5]. Ionic buffering systems are similar to oxidative preservatives, but have both antibacterial and antifungal properties [6]. SofZia, found in Travatan Z (Alcon), is the only ophthalmic preparation which uses an ionic buffering system type preservative.

Benzalkonium chloride (BAK) is the preservative currently in use in topical ocular preparations that is most likely to cause irritation, inflammation, and serious side effects. [4, 7, 8] This detergent-type preservative is a quaternary ammonium cationic surfactant that has a very long shelf life and is very effective against a broad spectrum of organisms. Additionally, it increases drug penetration. Unfortunately, BAK disrupts the tight junctions between human cells and accelerates desquamation of the epithelium. BAK promotes apoptosis at low concentrations and necrosis at higher concentrations [8]. It stimulates the production of inflammatory cytokines and causes reversible and non-reversible neurotoxicity which reduces cell density.[9, 10] BAK also decreases aqueous production. Many studies have shown that BAK is more toxic to the ocular surface than other preservatives such as Polyquad, SofZia, Purite, Gen Aqua, etc. [7, 11] BAK is found in more than 70% of all ophthalmic medications, but its use is much less frequent in artificial tears due to its surface toxicity. Examples of artificial tears that contain BAK are the Visine family of drops (Johnson and Johnson), the Clear Eyes family of drops (Prestige Brands Inc.), Rohto (Metholatum Company), Hypotears (Alcon), and Soothe Long Lasting (B+L).

Polyquad (Polyquaternium-1) is a detergent-type preservative derived from BAK. It is unique because bacterial cells attract Polyquad while human corneal epithelial cells tend to repel it. Despite causing some superficial epithelial damage, reducing goblet cell density, and decreasing aqueous production it results in less corneal epithelial staining and is better tolerated than Polyhexamethylene Biguanide (PHMB) or BAK [12]. Polyquad is very effective in contact lens solutions because the contact lens serves as a reservoir to slowly release the compound without it becoming excessively concentrated in the lens. Examples of artificial tears that contain Polyquad are most of the Alcon products, Tears Naturale II and Tears Naturale Forte as well as the entire Systane family of preserved drops. Polexitonium (Polyquaternium-42), the preservative found in Freshkote (Focus Laboratories), is closely related to Polyquad.

Sodium Perborate, known by the brand names GenAqua (Genteal family, Alcon) and Dequest (Thera Tears, Advanced Vision Research), is an oxidative-type preservative that releases hydrogen peroxide in a reversible reaction. Sodium perborate is broadly toxic to many pathogens by altering bacterial protein synthesis, oxidizing cell membranes, and altering membrane bound enzymes [12]. When exposed to the aqueous environment of the ocular surface, the reversible bacteriotoxic buffering reaction allows the sodium perborate to break down into hydrogen peroxide, oxygen, and water. Hydrogen peroxide is a very efficient antimicrobial, but in even small amounts, such as 30 parts per million (0.003%), is known to be harmful to the eye [12].

Stabilized Oxychloro Complex (Purite) is another oxidative-type preservative. When exposed to light, Purite degrades to water, oxygen, sodium, and chlorine free radicals. Purite has antibacterial, antifungal, and antiviral effects. It is effective at unusually low concentrations (0.005%). Chlorine free radicals inhibit microorganism protein synthesis within cells by oxidation of glutathione which causes cell death [10]. Examples of artificial tears that contain Purite are Refresh Tears, Refresh Optive, and Refresh Optive Advanced (Allergan).

Ocupure is a preservative closely related to Purite that is a stabilized oxychloro complex with sodium chlorite. Upon exposure to light, this preservative breaks down into sodium and chloride ions, oxygen, and water [13]. Mammalian cells have oxidases, catalases, and antioxidants that readily neutralize the small amount of stabilized oxychloro complex generally utilized as a preservative. Examples of artificial tears that contain Ocupure are Blink (Abbott) family of tears.

Polyhexamethylene Biguanide (PHMB) is the most commonly used preservative in contact lens solutions and historically has been a component of pool cleaners, skin disinfectants, and urinary catheter flush solutions. PHMB integrates into bacterial cell walls, disrupting the membrane and lethally altering DNA transcription in both bacteria and Acanthemoeba. PHMB is non-irritating to human corneal cells and also has limited antifungal activity [10]. PHMB is found in the artificial tear Soothe XP (B+L).

Chlorobutanol, a combination of acetone and chloroform, is a detergent-type preservative which is both less toxic and less effective than BAK [14]. It has broad anti-microbial activity. Its usefulness is limited by the need to be stored at lower temperatures than most drops. Chlorobutanol it is only found in Refresh Lacrilube (Allergan).

Edetate Disodium (EDTA) is a chelating agent that is used in a wide variety of products including hair conditioner, facial cleansers, aftershaves, deodorants, and ophthalmic drops. When added to topical medications, EDTA inactivates heavy metals, which prevents bacteria from using them to reproduce. EDTA is also used to remove corneal deposits in band keratopathy. Examples of artificial tears that contain EDTA are Soothe XP (B+L), Systane Ultra, Systane Balance (Alcon), and the Oasis Tears family (Oasis Medical Inc.)

Some of the information above is in table form in an article written by Christiansen and Larson for Review of Cornea & Contact Lens available from http://www.reviewofcontactlenses.com/content/d/featured_articles/i/3554/c/59277/ [15]

Preservative	Conc. Range	Additional Effects (+/-)
Benzalkonium chloride (BAK)	0.004 – 0.02%	Increases drug penetration Long shelf life Disrupts tight junctions Accelerate epithelial desquamation. Promotes apoptosis at lower conc. and necrosis at higher conc. Stimulates production of inflammatory cytokines. Reduces aqueous production. Causes reversible and non-reversible neurotoxicity, reducing nerve fiber density.
Polyquaternium-1 (Polyquad ®)	0.001%	Bacterial cells attract Polyquad, but human corneal epithelial cells tend to repel it. Causes superficial epithelial damage. Reduces the density of conjunctival goblet cells which decreases aqueous tear film production.
Sodium Perborate (Dequest ®, and GenAqua ®)		Vanishing preservative: Upon exposure to an aqueous environment, it is catalyzed into hydrogen peroxide, water and oxygen. Alters protein synthesis within bacterial cells by oxidizing cell membranes and altering membrane-bound enzymes, causing enzymatic inhibition.
Stabilized oxychloro complex (Purite ®)	0.005%	Degrades to water, oxygen, sodium and chlorine free radicals when exposed to light.  Chlorine free radicals are thought to inhibit microorganism protein synthesis within cells by way of glutathione oxidation, which causes microbe cell death.  Broad antimicrobial activity- includes antibacterial, antifungal and antiviral effects.
Sodium Chlorite (Ocupure ®)	0.005%	A mixture of 80% chlorite, 11% sodium chloride, water and trace electrolytes, it breaks down into sodium and chloride ions, oxygen and water when exposed to light.
Polyhexamethylene biguanide (PHMB)	0.02%	Has activity against bacteria and Acathemoeba, however, its antifungal activity is limited. Lethally alters the transcription of bacterial DNA. Nonirritating to human corneal cells. Integrates into bacterial cell walls, disrupting the membrane.
Chlorobutanol		Alcohol that increases lipid solubility and is able to cross the bacterial lipid layer. Has extensive anti-bacterial action, causing cell lysis by disruption of microbial cell membrane lipid configuration. Causes significant keratitis and irritation to the ocular surface, but less than BAK.
EDTA (Edetate disodium or EthyleneDiameneTetraacetic Acid)	1%	Chelating agent that binds metals which inactivates them. Enhances the activity of quaternary ammonium bases and sorbate.

References

1. Food and Drug Administration: "Ophthalmic Drug Products for Over-the-counter Human use; Final Monograph" 21 CFR Parts 349 and 369. Federal Register 1988, 53(43):7076-7093 Available from http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm094081.pdf.
2. Yagci A, Gurdal C: The role and treatment of inflammation in dry eye disease. Int Ophthalmol 2014, 34(6):1291-1301.
3. Segen JC: Concise dictionary of modern medicine: McGraw-Hill Medical; 2005.
4. Tu EY: Balancing antimicrobial efficacy and toxicity of currently available topical ophthalmic preservatives. Saudi J Ophthalmol 2014, 28(3):182-187.
5. Elder DP, Crowley PJ: Antimicrobial Preservatives Part One: Choosing a Preservative System. American Pharmaceutical Review 2012, available from http://www.americanpharmaceuticalreview.com/Featured-Articles/38886-Antimicrobial-Preservatives-Part-One-Choosing-a-Preservative-System/.
6. Freeman PD, Kahook MY: Preservatives in Topical Ophthalmic Medications: Historical and Clinical Perspectives. Expert Review of Ophthalmology 2009, 4 (1):59-64.
7. Becquet F, Goldschild M, Moldovan MS, Ettaiche M, Gastaud P, Baudouin C: Histopathological effects of topical ophthalmic preservatives on rat corneoconjunctival surface. Current eye research 1998, 17(4):419-425.
8. De Saint Jean M, Brignole F, Bringuier AF, Bauchet A, Feldmann G, Baudouin C: Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells. Invest Ophthalmol Vis Sci 1999, 40(3):619-630.
9. Kahook MY, Noecker RJ: Comparison of corneal and conjunctival changes after dosing of travoprost preserved with sofZia, latanoprost with 0.02% benzalkonium chloride, and preservative-free artificial tears. Cornea 2008, 27(3):339-343.
10. Kahook PDFMY: Preservatives in Topical Ophthalmic Medications: Historical and Clinical Perspectives. Expert Review of Ophthalmology 2009, 4 (1):59-64.
11. Ammar DA, Noecker RJ, Kahook MY: Effects of benzalkonium chloride-preserved, polyquad-preserved, and sofZia-preserved topical glaucoma medications on human ocular epithelial cells. Adv Ther 2010, 27(11):837-845.
12. Epstein SP, Ahdoot M, Marcus E, Asbell PA: Comparative toxicity of preservatives on immortalized corneal and conjunctival epithelial cells. J Ocul Pharmacol Ther 2009, 25(2):113-119.
13. Zheng LL, Myung D, Yu CQ, Ta CN: Comparative In vitro Cytotoxicity of Arti cial Tears. JSM Ophthalmol 2015, 3(1):1026.
14. Doughty MJ: Acute effects of chlorobutanol- or benzalkonium chloride-containing artificial tears on the surface features of rabbit corneal epithelial cells. Optom Vis Sci 1994, 71(9):562-572.
15. Christensen M, Larson TL: Artificial tears: looking beneath the surface. Review of Cornea & Contact Lenses 2016, 153(1):22-27 available from http://www.reviewofcontactlenses.com/content/d/featured_articles/i/3554/c/59277/.

Suggested Citation Format:

Larson T. Artificial Tears: A Primer. EyeRounds.org. November 23, 2016; Available from https://eyerounds.org/tutorials/artificial-tears.htm