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This is a LARGE extract but I wanted to put in one place the main information TFOS DEWS II has on artificial tears. I'll eventually have a home for this in the library of the Dry Eye Zone. This may be helpful for those who are trying to understand the differences between artificial tears and whether they should even be concerned with them.
TFOS DEWS II - Management and Therapy
2.1 Tear replacement approaches
Tear replacement with ocular lubricants is traditionally considered a mainstay of DED therapy and there are numerous topical formulations available. Over-the-counter (OTC) products are often termed “artificial tears” which, as their name suggests, attempt to replace and/or supplement the natural tear film. However, these products do not target the underlying pathophysiology of DED, and the mechanisms of any palliative actions are generally poorly understood.
2.1.1 Artificial tear substitutes
Tear substitutes comprise a wide variety of products, which typically aim to target one or more layers of the tear film. The wide variety of properties of these ocular lubricants has been reviewed elsewhere [11–15].
Ocular lubricants are largely regarded as safe, although there are some reported side effects, most notably blurred vision, variable levels of “ocular discomfort” and foreign body sensation [16]. There are relatively few randomized controlled trials (RCTs) that have compared the relative superiority of a particular OTC product to others for DED therapy [17]. A recent Cochrane systematic review, which sought to evaluate the effect of OTC tear supplement products for treating DED, included 43 randomized controlled trials that had compared artificial tear formulations to no treatment, or placebo [16]. The primary outcome measure was patient-reported symptoms. The authors reported that the overall quality of evidence was low for the various tear supplement formulations compared in the review, and concluded that while artificial tears may be effective for treating DED, there was still a need for future research to enable robust conclusions to be drawn about the effectiveness of individual OTC artificial tear formulations.
2.1.1.1 Aqueous supplementation
While ocular lubricant formulations may vary in osmolarity, viscosity and pH, most share similarities in their major components. The most abundant component in lubricant eye drops is the aqueous base. To enhance lubrication and prolong the retention time on the ocular surface, a variety of viscosity enhancing agents are frequently incorporated.
2.1.1.1.1 Viscosity-enhancing agents
The viscosity-enhancing agents used in tear supplement formulations include carbomer 940 (polyacrylic acid), carboxymethyl cellulose (CMC), dextran, hyaluronic acid (HA), HP-guar, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) and polyethylene glycol.
Viscosity enhancers are considered beneficial to the ocular surface in DED through a range of reported mechanisms. These include increasing tear film thickness, protecting against desiccation, promoting tear retention at the ocular surface, protecting the ocular surface, maintaining physiological corneal thickness, improving goblet cell density and relieving dry eye symptoms [18,19]. Although there are scores of formulations and products available, which vary by geographic region, there does not appear to be any substantial difference in effectiveness among them [16,20]. However, the differences in the viscosity of the drops can influence utilization. Eye drops with high viscosity can increase retention time on the ocular surface, but may also cause transient visual disturbances and result in unwanted debris on the eyelids and lashes, leading to decreased tolerance and compliance. Very high viscosity eye drops are typically recommended for overnight use, with low-viscosity drops being used in the daytime.
2.1.1.1.1.1 Carboxymethyl cellulose (CMC)
CMC is a cellulose derivative with carboxymethyl groups and is formed from the cell walls of plants. It is often used as its sodium salt, sodium carboxymethyl cellulose, and is also termed carmellose sodium. It is a very commonly used viscosity-enhancing agent in ocular lubricants as well as in pharmaceuticals, foods and cosmetics [21].
CMC can bind to corneal epithelial cells and promote epithelial cell healing [22,23]. CMC-based products have been proven to be successful in the management of mild-to-moderate dry eye in a number of studies [24–26].
2.1.1.1.1.2 Hydroxypropyl methylcellulose (HPMC)
Cellulose ethers are viscoelastic polysaccharides that increase the viscosity of the tears. Of these, HPMC has been used for many years in artificial lubricants and remains one of the most common ingredients. It is available in a wide variety of concentrations (from 0.2 to 0.8%) and is used in combination with many other components in modern ocular lubricants [11,14]. Due to its wide availability and use over many years, multiple studies have explored its potential to manage patients with DED [16]. A review of its performance shows that it is a safe and effective lubricant for those with low-to-moderate symptoms of DED [16].
2.1.1.1.1.3 Hyaluronic acid (HA)
Hyaluronic acid (HA), also termed hyaluron and sodium hyaluronate, is a naturally occurring anionic, non-sulfated glycosaminoglycan that is distributed widely throughout connective, epithelial, and neural tissues. It can be very large, with its molecular weight often reaching several million Daltons. HA is an important component of articular cartilage and is found in abundance in synovial fluid around joints, in the vitreous and aqueous humour [27]. A number of studies have demonstrated its ability to bind to ocular surface cells and its potential wound healing properties [28–33].
HA is used in a variety of tear supplements to increase viscosity and provide enhanced lubrication. HA exhibits non-Newtonian shear-thinning properties [34], where viscosity varies with shear rate. For HA-based solutions, the viscosity decreases with increasing shear rate, as occurs during a blink.
As the range of commercial products that contain HA increases, a growing number of Level 1 and 2 clinical studies have been published that demonstrate good tolerability and the ability to improve dry eye symptoms [35–42].
2.1.1.1.1.4 Combination of CMC and HA
As described above, there are a number of publications supporting the use of topical drops that contain CMC or HA in the management of DED. Optive Fusion™ (Allergan, Parkway Parsippany, NJ, USA)) contains a combination of 0.5% CMC and 0.1% HA in a single topical formulation. In a murine dry eye study, mice administered CMC + HA topically showed significantly lower corneal fluorescein staining and higher goblet cell density than mice treated with drops containing CMC or HA alone [43]. In a 3-month, double-masked, multicenter study involving 305 subjects with DED, the commercially available combination of CMC + HA improved symptoms and signs of DED more than a commercially available topical formulation based on CMC alone [44].
2.1.1.1.1.5 Hydroxypropyl-guar (HP-guar)
HP-guar is a non-ionic, polymeric thickener that can rapidly confer high viscosity, through a pH-dependent process [45,46]. One HP-guar-based product, Systane® ULTRA (Alcon, Ft Worth, TX, USA), includes two demulcents (polyethylene glycol 400 and propylene glycol), and sorbitol, and is buffered with borate, resulting in a partially crosslinked borate/HP-guar gel in the bottle [47]. The pH of Systane ULTRA is 7.9 but when instilled onto the ocular surface, the reduction in pH, and dilution of the sorbitol concentration, increases the density of the borate/hydroxypropyl-guar crosslinks, producing a very low viscosity gel [45].
HP-guar-based products have been shown to improve dry eye symptoms, increase mucous layer thickness, reduce inflammation and protect the ocular surface [47–53].
2.1.1.1.1.6 Combination of HA and HP-guar
A formulation containing the demulcents propylene glycol and polyethylene glycol and a dual polymer combination of HA and HP-guar (Systane® ULTRA HYDRATION; Alcon, Ft Worth, TX, USA) has been shown to be effective in desiccation protection and retention on the ocular surface in a corneal cell-based laboratory study [54].
2.1.1.1.1.7 Hydroxypropyl cellulose
The concept of using a dissolvable hydroxypropyl cellulose insert on the ocular surface to manage DED was first approved by the Food and Drug Administration (FDA) over 30 years ago, but for many years lost favour due to discomfort and relatively poor efficacy [55]. The newest version of this concept is LACRISERT™ (Bausch & Lomb, Rochester, NY, USA), which is a sterile, translucent, rod-shaped, water soluble, preservative-free, slow-release lubricant that is placed into the inferior cul-de-sac with the aid of a reusable applicator. It begins to soften within minutes, dissolving over the course of about 12 h and thickening the precorneal tear film. It is recommended for use in patients with moderate to severe DED, is usually inserted once a day and is contraindicated in patients who are hypersensitive to hydroxypropyl cellulose.
A multicenter, 2-visit, open-label, 4-week study was conducted to determine the acceptability of the inserts in 520 subjects with DED [56]. There was a significant improvement in symptoms, corneal fluorescein staining, conjunctival staining and tear volume. Contact lens wearers reported significant improvements, similar to non-wearers. Reported complications include transient blurring of vision, discomfort or irritation (particularly if not located appropriately), expulsion in patients with shallow conjunctival fornices and matting or stickiness of the eyelashes.
2.1.1.1.2 Osmotic agents
The original TFOS DEWS report drew attention to the importance of tear osmolarity, demonstrating that raised tear osmolarity is associated with DED [57]. Since that time, many studies have examined the link between DED and osmolarity. However, relatively few studies have investigated the impact of tear supplement hypo- or hyper-osmolar drops on tear osmolarity and any improvements in DED. Gilbard conducted a number of experiments to show that the use of a hypo-osmolar ocular lubricant could reverse various ocular surface changes (notably reduced goblet cell density) induced in a dry eye rabbit model [58–60]. Two more recent studies using hypotonic hyaluronic acid-based ocular lubricants demonstrated an improvement in both symptoms and various signs of DED [61,62]. However, more studies linking the ability of lubricants to reduce tear film osmolarity and their impact upon DED symptoms and signs are warranted.
A number of published studies demonstrate the potential to improve tear osmolarity with DED treatments [63–70], even in the absence of a change [71,72], or in association with negative outcomes [68,73,74], in other clinical features.
Since the publication of the first TFOS DEWS report, several examples of tracking dry eye therapy with tear osmolarity have been published. A study investigating the effects of a combination therapy of methylprednisolone and preservative-free 0.1% HA four times a day demonstrated a significant reduction in osmolarity at eight weeks that paralleled significant reductions in IL-1β and IL-8, as well as tear break up time (TBUT), corneal and conjunctival staining [75]. The authors concluded that measuring the changes in cytokine levels and tear osmolarity could objectively evaluate the anti-inflammatory effects of topical methylprednisolone applied in the treatment of patients with moderate to severe dry eye syndrome. A similar eight-week trial of a modified HA applied three times daily resulted in significant improvements in Ocular Surface Disease Index (OSDI) score, TBUT, conjunctival goblet cell density, corneal and conjunctival damage and tear osmolarity [66].
Tear osmolarity has also been shown to parallel improvements in dry eye symptoms and signs when patients use topical cyclosporine [63,76,77], HA [40,66,78–80], osmoprotective drops [40,67,69], and PEG/HP-Guar drops [81].
2.1.1.1.3 Osmoprotectants
Osmoprotectants (e.g., L-carnitine and betaine) are a group of compatible solutes that protect cells under extreme osmotic stress by balancing the osmotic pressure without disturbing cell metabolism [82–85]. The osmoprotective effect depends on the amount of drug uptake and its retention time, and combinations of osmoprotectants with different pharmaceutical kinetics may function better than individual osmoprotectants.
There are a number of studies demonstrating that osmoprotectants have a beneficial effect on the treatment of DED. An in vitro study showed that the osmoprotectants L-carnitine and erythritol can protect cultured human corneal epithelial cells from hyperosmolar conditions by lowering levels of activated mitogen-activated protein kinases [86]. The osmoprotectants also showed inflammatory-suppressing properties under hyperosmotic stress [87]. A dry eye mouse study showed that osmoprotectants can reduce corneal staining, decrease cell apoptosis and inflammatory cytokines and increase the number of goblet cells [88].
Trehalose is a naturally occurring dissacharide, present in numerous non-mammalian species, which allows cells to survive in unfavorable environments. It is implicated in anhydrobiosis, which relates to the ability of plants and animals to withstand prolonged periods of desiccation. It has very high water retention capabilities and has the dual properties of both bioprotection and osmoprotection [89–94]. In vitro and in vivo studies have shown that trehalose protects corneal cells from desiccation [95], as well as protecting corneal and conjunctival cells against apoptosis [90,96]. Trehalose has also been shown to protect corneal cells against ultraviolet (UV)-induced oxidative damage by accelerating corneal healing [97], and reducing conjunctival inflammatory cytokines in a murine model of DED [92]. It also helps to restore osmotic balance to the ocular surface, as well as preventing denaturation of cell membrane lipid bilayers and proteins to maintain the homeostasis of corneal cells [90–92].
A new eye drop formulation that contains both HA and trehalose has been developed to capitalize on the lubricant properties of HA and bioprotectant properties of trehalose [98].
2.1.1.1.4 Antioxidants
The presence of oxygen free radicals in the tears of patients with DED [99] has resulted in exploration of the potential application of antioxidants for the management of DED.
In an animal study, topical acetylcysteine, an amino acid with antioxidant activity, decreased inflammatory cytokine expression in ocular surface tissues of a mouse model of DED, but did not alter corneal staining [100]. Another antioxidant eye drop, vitamin A (retinyl palmitate), showed significant effects in improving blurred vision, TBUT, Schirmer score, and impression cytology findings in subjects with DED in a prospective, randomized, controlled, parallel study [101]. However, vitamin A metabolites are also known to cause MGD in animal models, including glandular keratinization and atrophy, reduced quality of meibum, reduced tear film break up time, increased tear film osmolarity, and dry eye symptoms (further details are included in the TFOS DEWS II Iatrogenic Dry Eye Report) [102].
A study using stratified human corneal limbal epithelial cells showed that several antioxidants may be beneficial if incorporated into topical ocular lubricants [103]. Quercetin, epigallocatechin gallate, n-propyl gallate, and gallic acid displayed good bioavailability, were effective at quenching reactive oxygen species and might be effective in protecting the corneal epithelium from oxidative damage.
Visomitin is the first registered drug with antioxidative properties that targets oxidative stress in mitochondria and is available as a topical drug in Russia. A recent multicenter, randomized, double-masked, placebo-controlled clinical study showed that a 6-week course of topical Visomitin reduced corneal staining and improved symptoms in 240 subjects with DED [104]. It may act through reducing reactive oxygen species on the ocular surface, but further studies are required to confirm this.
Selenoprotein P (SelP) is a secreted glycoprotein that is involved in the transport or storage of selenium, and is involved in oxidative stress metabolism [105]. In a rat dry eye model, the use of SelP eye drops for 3 weeks suppressed markers of oxidative stress and tears collected from human subjects with corneal staining were lower in SelP [106]. The authors concluded that tear SelP is a key molecule to protect the ocular surface against environmental oxidative stress.
2.1.1.1.5 Preservatives
Multidose artificial lubricants typically require a preservative to prevent microbial growth, whereas unit dose vials that are discarded after a single use do not. However, unit dose vials are more expensive and may be more difficult for less dextrous individuals to open. A number of new products are now available that utilise dispensers that incorporate unidirectional valves that allow multidose bottles to be unpreserved.
Increasing attention has been directed to the relationship between the chronic use of topical therapies, such as glaucoma medications, and OSD. Chronic exposure of the ocular surface to preservatives is now well recognized to induce toxicity and adverse changes to the ocular surface [107–112]. Benzalkonium chloride (BAK) is the most frequently used preservative in eye drop preparations. There are many in vitro and in vivo studies demonstrating that BAK can induce corneal and conjunctival epithelial cell apoptosis, damage the corneal nerves, delay corneal wound healing, interfere with tear film stability and cause loss of goblet cells [113–115]. In an in vitro study, a BAK concentration in excess of 0.005% significantly impaired lipid spreading and compromised the morphology of the tear lipid layer [116]. Sufficient evidence exists to confirm that patients with DED, particularly those with severe DED who require frequent dosing with lubricants or who use ocular lubricants in conjunction with other chronic topical therapies, such as glaucoma medications, should avoid the use of ocular lubricants preserved with BAK [102].
To avoid issues with long-term exposure to preservatives, newer variants of preservatives designed to have a lower impact on the ocular surface have been developed, including oxidative preservatives (sodium chlorite; Purite® and OcuPure™ and sodium perborate; GenAqua™), polyquaternium-1 (Polyquad®) and SofZia™. Sodium chlorite degrades to chloride ions and water upon exposure to UV light after instillation and sodium perborate is converted to water and oxygen on contact with the tear film. Some reports suggest that even these so-called “disappearing preservatives” can show some negative effects on the ocular surface [117]. Therefore, preservative-free drops may be a better choice for patients who have pre-existing ocular surface conditions and/or need frequent instillation of eye drops. Preservative-free eye drops have shown greater effectiveness than preserved drops in decreasing inflammation on the ocular surface and increasing the antioxidant contents in tears of patients with DED [118]. While ideally all prescribed dry eye products would be supplied in unit dose or unpreserved multi-dose bottles, cost considerations and product availability often prevent this from being possible.
Further information on preservative interactions with the ocular surface can be found in the TFOS DEWS II Iatrogenic Dry Eye Report [102].
2.1.1.1.6 Inactive agents
2.1.1.1.6.1 Buffers
The stability of commonly used ophthalmic solutions is controlled largely by the pH of their environment. In addition to stability, pH can influence comfort, safety, and activity of the product. Dry eye products contain a wide variety of buffers to control pH, including citrate, phosphate and borate buffers. The concentration of such buffers is critical, as reports exist of corneal calcification following extensive use of a dry eye product preserved with elevated levels of calcium phosphate [119].
Sodium borate, also known as sodium tetraborate or disodium tetraborate, is a salt of boric acid. Boric acid is a weak acid that is used as a buffering agent in some eye drops. Studies have shown that contact lens multipurpose solutions (MPS) containing boric acid may exhibit corneal epithelial cytotoxicity [120]. However, others have reported that MPS-induced ocular surface defects may be incorrectly attributed to boric acid [121]. The potential benefits, or otherwise, of boric acid or indeed any other buffers in dry eye formulations remain unclear. However, of note is that boric acid at ocular surface pH also acts as a cross-linking agent and electrostatically binds to hydroxypropyl guar (HP-guar) [122,123].
2.1.1.1.6.2 Excipients
Due to the delicate structure of the ocular tissues, the number of acceptable excipients for eye drops is limited, and consists mainly of ionic and non-ionic isotonic agents. There are limited published studies concerning the effect of excipients on the ocular surface [124]. Recently, macrogolglycerol hydroxystearate 40 (MGH 40), has been used in preservative-free eye drops as a solubilizing excipient. An animal study showed that MGH 40 is well tolerated [125]. However, a prior in vitro study revealed that MGH 40 triggers similar detrimental effects in cells as that seen with BAK [126]. Another study examined the role of poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) as a novel polymer excipient in artificial tears [127]. A single-center study showed that PLL-g-PEG was effective in prolonging non-invasive break up time (NIBUT) 15 min after instillation [127]. More studies are needed to clarify the impact of the various excipients on the ocular surface.
2.1.1.1.6.3 Electrolytes
The pre-corneal tear film is a complex milieu that is rich in electrolytes, including sodium, potassium, chlorine, magnesium and calcium [128]. When secreted, tears are isotonic with serum, although the proportions of ions are somewhat different, especially potassium [129,130]. In DED, the concentration of electrolytes in the tear film typically increases due to evaporation and/or reduced aqueous production.
Electrolytes perform critical roles in ocular surface homeostasis. Observations suggest that the relatively high potassium levels in tears may play a role in protecting the corneal epithelium from UV-B radiation [131,132]. Potassium has also been shown to be necessary to maintain normal corneal thickness, and decreases in the potassium concentration may result in an increase in corneal thickness [133]. Finally, the quality of the corneal epithelial surface integrity and light scattering properties, as measured by specular microscopy, have been shown to be dependent on electrolyte composition [134]. The epithelial surface is best maintained with a buffered solution containing potassium, calcium, magnesium, phosphate, bicarbonate and sodium chloride, with potassium being particularly important [134].
Certain tear lubricants, such as TheraTears® (Akorn Lake Forrest, IL, USA) and Bion® Tears (Alcon Ft Worth, TX, USA), have an electrolyte profile that is intended to reflect that of the tear film. Some of the commonly used electrolyte salts include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, sodium borate, sodium phosphate and boric acid. Sodium bicarbonate is used to buffer the solution, but also has an electrolyte effect [135]. An electrolyte-based artificial tear formulation has been shown to increase conjunctival goblet cell density and corneal glycogen content in a rabbit model of DED [58,59]. Other studies have shown that the inclusion of potassium with HA in non-preserved artificial tears enhances corneal wound healing in a mechanical scraping model [33]. The addition of bicarbonate to an isotonic, non-preserved artificial tear solution promotes recovery of the corneal epithelium compared with the same solution buffered with borate or without a buffer [136]. A separate study showed that addition of bicarbonate promoted recovery of epithelial barrier function and maintained normal corneal and mucin layer ultrastructure after exposure to BAK [137]. To date, in vitro, animal and human studies would suggest that certain electrolyte compositions could have a positive role in the management of DED with ocular lubricants.
2.1.1.2 Lipid supplementation
The lipid layer of the tear film has an important role to play in preventing tear evaporation [138]. Lipid-containing eye drops are growing in both availability and popularity [139,140], primarily due to the increased attention being paid to MGD and lipid deficiency. A variety of oils, such as mineral oils and phospholipids, have been incorporated in ocular lubricant formulations to help restore the lipid layer of the tear film [46,141,142].
Lipid-containing drops are formulated as emulsions. Emulsions are defined as non-soluble liquids that are finely dispersed within another liquid, such as oil and water [143]. Emulsions are not readily formed and extreme shear forces and pressure must be applied with the appropriate surfactants to overcome the effects of surface tension [143].
Emulsions can be broadly categorized into three types, based upon the droplet size. Macroemulsions contain droplets larger than 100 nm (nm), nanoemulsions have droplets between 10 and 100 nm and microemulsions have droplets < 10 nm. Macroemulsions are cloudy because the large droplet sizes scatter light and these formulations can induce blur when applied topically. To minimize the potential blurring effect on vision, as well as the stability of the emulsion upon instillation, particle size, concentration and type of lipids can be manipulated. Smaller droplet sizes minimize blurring on installation because the droplet structures are smaller than visible wavelengths, which prevents scattering. A number of commercial products employ meta-stable emulsions to minimize blur time and therefore require the dispensing bottle to be inverted or shaken to enhance uniformity of the emulsion prior to application.
Emulsions have been demonstrated to effectively deliver lipophilic drugs, a task that is challenging for aqueous-based carriers. Newer approaches employ cationic submicron oil-in-water (o/w) vectors, which exploit the negative charges at the mucin layer [144]. A cationic o/w nanoemulsion is a biphasic formulation that comprises positively charged oil nanodroplets (the oil phase) dispersed in water (the continuous phase). The positive charge of the oil nanodroplets is brought about by a cationic surfactant that localizes itself at the oil interface. It is believed that when a cationic o/w nanoemulsion eye drop is instilled, the resultant electrostatic attraction between the positively charged oil nanodroplets and the negatively charged ocular surface mucins manifests itself macroscopically as an improved spreading and retention time [145]. It is possible that this interaction could be modified by exposure to cationic tear film proteins, such as lysozyme. This is of particular interest for patients with MGD who exhibit reduced tear film stability due to lipid deficiency within their tears [146].
Even in the absence of an active ingredient, these cationic o/w nanoemulsions have been observed in preclinical studies to have an inherent benefit on the ocular surface [147,148]. Cationorm® (Santen Osaka, Japan) is a preservative-free cationic emulsion indicated for the treatment of DED. The cationic excipient is cetalkonium chloride, an alkyl derivative of BAK that is lipophilic [148]. Some studies have shown that Cationorm is well tolerated by human corneal epithelial cells in culture [146,149]. However, another in vitro study demonstrated that corneas treated with Cationorm suffered epithelial loss and alterations to the superficial corneal stroma [150]. Cationic-based nanosystems incorporating chitosan provide alternative formulation strategies [151–153].
The long-term safety of nanoemulsions on the ocular surface remains to be evaluated.
2.1.1.2.1 Types and properties of lipids
Different types of lipids have been proposed to try to best mimic natural meibum. The types of lipids used include phospholipids, saturated and unsaturated fatty acids, and triglycerides [154]. Mineral oil in various concentrations, castor oil, olive oil, glycerin carbomers, coconut oil, soybean oil and lecithin, in combination with various emulsifying agents and surfactants, have been described [155–161].
Phospholipids can be neutral (zwitterionic), negatively (anionic) or positively (cationic) charged. Systane® Balance (Alcon Ft Worth, TX, USA) contains a polar phospholipid, DMPG (dimyristoylphosphatidylglycerol). Many types of phospholipids exist and, of these, two are commonly found in the tears - phosphatidylcholine and phosphatidylethanolamine [162–172]. It appears that anionic phospholipids have a greater ability to increase lipid layer thickness than zwitterionic compounds [46,173]. A possible reason is that negatively charged phospholipids contribute to a stable interface between non-polar lipids at the surface of the hydrophilic aqueous layer [174]. This supports a suggestion that polar phospholipids help to form a stable multi-molecular lipid film [175]. Studies suggest that lower levels of the two polar phospholipids are present in individuals with tear film deficiencies [165,176]. Further information can be obtained in the TFOS DEWS II Tear Film Report [128].
Multiple studies have shown that lipid-based drops and liposomal sprays can improve signs and symptoms of dry eye (Table 2) [65,141,142,177–182].
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TFOS DEWS II - Management and Therapy
2.1 Tear replacement approaches
Tear replacement with ocular lubricants is traditionally considered a mainstay of DED therapy and there are numerous topical formulations available. Over-the-counter (OTC) products are often termed “artificial tears” which, as their name suggests, attempt to replace and/or supplement the natural tear film. However, these products do not target the underlying pathophysiology of DED, and the mechanisms of any palliative actions are generally poorly understood.
2.1.1 Artificial tear substitutes
Tear substitutes comprise a wide variety of products, which typically aim to target one or more layers of the tear film. The wide variety of properties of these ocular lubricants has been reviewed elsewhere [11–15].
Ocular lubricants are largely regarded as safe, although there are some reported side effects, most notably blurred vision, variable levels of “ocular discomfort” and foreign body sensation [16]. There are relatively few randomized controlled trials (RCTs) that have compared the relative superiority of a particular OTC product to others for DED therapy [17]. A recent Cochrane systematic review, which sought to evaluate the effect of OTC tear supplement products for treating DED, included 43 randomized controlled trials that had compared artificial tear formulations to no treatment, or placebo [16]. The primary outcome measure was patient-reported symptoms. The authors reported that the overall quality of evidence was low for the various tear supplement formulations compared in the review, and concluded that while artificial tears may be effective for treating DED, there was still a need for future research to enable robust conclusions to be drawn about the effectiveness of individual OTC artificial tear formulations.
2.1.1.1 Aqueous supplementation
While ocular lubricant formulations may vary in osmolarity, viscosity and pH, most share similarities in their major components. The most abundant component in lubricant eye drops is the aqueous base. To enhance lubrication and prolong the retention time on the ocular surface, a variety of viscosity enhancing agents are frequently incorporated.
2.1.1.1.1 Viscosity-enhancing agents
The viscosity-enhancing agents used in tear supplement formulations include carbomer 940 (polyacrylic acid), carboxymethyl cellulose (CMC), dextran, hyaluronic acid (HA), HP-guar, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) and polyethylene glycol.
Viscosity enhancers are considered beneficial to the ocular surface in DED through a range of reported mechanisms. These include increasing tear film thickness, protecting against desiccation, promoting tear retention at the ocular surface, protecting the ocular surface, maintaining physiological corneal thickness, improving goblet cell density and relieving dry eye symptoms [18,19]. Although there are scores of formulations and products available, which vary by geographic region, there does not appear to be any substantial difference in effectiveness among them [16,20]. However, the differences in the viscosity of the drops can influence utilization. Eye drops with high viscosity can increase retention time on the ocular surface, but may also cause transient visual disturbances and result in unwanted debris on the eyelids and lashes, leading to decreased tolerance and compliance. Very high viscosity eye drops are typically recommended for overnight use, with low-viscosity drops being used in the daytime.
2.1.1.1.1.1 Carboxymethyl cellulose (CMC)
CMC is a cellulose derivative with carboxymethyl groups and is formed from the cell walls of plants. It is often used as its sodium salt, sodium carboxymethyl cellulose, and is also termed carmellose sodium. It is a very commonly used viscosity-enhancing agent in ocular lubricants as well as in pharmaceuticals, foods and cosmetics [21].
CMC can bind to corneal epithelial cells and promote epithelial cell healing [22,23]. CMC-based products have been proven to be successful in the management of mild-to-moderate dry eye in a number of studies [24–26].
2.1.1.1.1.2 Hydroxypropyl methylcellulose (HPMC)
Cellulose ethers are viscoelastic polysaccharides that increase the viscosity of the tears. Of these, HPMC has been used for many years in artificial lubricants and remains one of the most common ingredients. It is available in a wide variety of concentrations (from 0.2 to 0.8%) and is used in combination with many other components in modern ocular lubricants [11,14]. Due to its wide availability and use over many years, multiple studies have explored its potential to manage patients with DED [16]. A review of its performance shows that it is a safe and effective lubricant for those with low-to-moderate symptoms of DED [16].
2.1.1.1.1.3 Hyaluronic acid (HA)
Hyaluronic acid (HA), also termed hyaluron and sodium hyaluronate, is a naturally occurring anionic, non-sulfated glycosaminoglycan that is distributed widely throughout connective, epithelial, and neural tissues. It can be very large, with its molecular weight often reaching several million Daltons. HA is an important component of articular cartilage and is found in abundance in synovial fluid around joints, in the vitreous and aqueous humour [27]. A number of studies have demonstrated its ability to bind to ocular surface cells and its potential wound healing properties [28–33].
HA is used in a variety of tear supplements to increase viscosity and provide enhanced lubrication. HA exhibits non-Newtonian shear-thinning properties [34], where viscosity varies with shear rate. For HA-based solutions, the viscosity decreases with increasing shear rate, as occurs during a blink.
As the range of commercial products that contain HA increases, a growing number of Level 1 and 2 clinical studies have been published that demonstrate good tolerability and the ability to improve dry eye symptoms [35–42].
2.1.1.1.1.4 Combination of CMC and HA
As described above, there are a number of publications supporting the use of topical drops that contain CMC or HA in the management of DED. Optive Fusion™ (Allergan, Parkway Parsippany, NJ, USA)) contains a combination of 0.5% CMC and 0.1% HA in a single topical formulation. In a murine dry eye study, mice administered CMC + HA topically showed significantly lower corneal fluorescein staining and higher goblet cell density than mice treated with drops containing CMC or HA alone [43]. In a 3-month, double-masked, multicenter study involving 305 subjects with DED, the commercially available combination of CMC + HA improved symptoms and signs of DED more than a commercially available topical formulation based on CMC alone [44].
2.1.1.1.1.5 Hydroxypropyl-guar (HP-guar)
HP-guar is a non-ionic, polymeric thickener that can rapidly confer high viscosity, through a pH-dependent process [45,46]. One HP-guar-based product, Systane® ULTRA (Alcon, Ft Worth, TX, USA), includes two demulcents (polyethylene glycol 400 and propylene glycol), and sorbitol, and is buffered with borate, resulting in a partially crosslinked borate/HP-guar gel in the bottle [47]. The pH of Systane ULTRA is 7.9 but when instilled onto the ocular surface, the reduction in pH, and dilution of the sorbitol concentration, increases the density of the borate/hydroxypropyl-guar crosslinks, producing a very low viscosity gel [45].
HP-guar-based products have been shown to improve dry eye symptoms, increase mucous layer thickness, reduce inflammation and protect the ocular surface [47–53].
2.1.1.1.1.6 Combination of HA and HP-guar
A formulation containing the demulcents propylene glycol and polyethylene glycol and a dual polymer combination of HA and HP-guar (Systane® ULTRA HYDRATION; Alcon, Ft Worth, TX, USA) has been shown to be effective in desiccation protection and retention on the ocular surface in a corneal cell-based laboratory study [54].
2.1.1.1.1.7 Hydroxypropyl cellulose
The concept of using a dissolvable hydroxypropyl cellulose insert on the ocular surface to manage DED was first approved by the Food and Drug Administration (FDA) over 30 years ago, but for many years lost favour due to discomfort and relatively poor efficacy [55]. The newest version of this concept is LACRISERT™ (Bausch & Lomb, Rochester, NY, USA), which is a sterile, translucent, rod-shaped, water soluble, preservative-free, slow-release lubricant that is placed into the inferior cul-de-sac with the aid of a reusable applicator. It begins to soften within minutes, dissolving over the course of about 12 h and thickening the precorneal tear film. It is recommended for use in patients with moderate to severe DED, is usually inserted once a day and is contraindicated in patients who are hypersensitive to hydroxypropyl cellulose.
A multicenter, 2-visit, open-label, 4-week study was conducted to determine the acceptability of the inserts in 520 subjects with DED [56]. There was a significant improvement in symptoms, corneal fluorescein staining, conjunctival staining and tear volume. Contact lens wearers reported significant improvements, similar to non-wearers. Reported complications include transient blurring of vision, discomfort or irritation (particularly if not located appropriately), expulsion in patients with shallow conjunctival fornices and matting or stickiness of the eyelashes.
2.1.1.1.2 Osmotic agents
The original TFOS DEWS report drew attention to the importance of tear osmolarity, demonstrating that raised tear osmolarity is associated with DED [57]. Since that time, many studies have examined the link between DED and osmolarity. However, relatively few studies have investigated the impact of tear supplement hypo- or hyper-osmolar drops on tear osmolarity and any improvements in DED. Gilbard conducted a number of experiments to show that the use of a hypo-osmolar ocular lubricant could reverse various ocular surface changes (notably reduced goblet cell density) induced in a dry eye rabbit model [58–60]. Two more recent studies using hypotonic hyaluronic acid-based ocular lubricants demonstrated an improvement in both symptoms and various signs of DED [61,62]. However, more studies linking the ability of lubricants to reduce tear film osmolarity and their impact upon DED symptoms and signs are warranted.
A number of published studies demonstrate the potential to improve tear osmolarity with DED treatments [63–70], even in the absence of a change [71,72], or in association with negative outcomes [68,73,74], in other clinical features.
Since the publication of the first TFOS DEWS report, several examples of tracking dry eye therapy with tear osmolarity have been published. A study investigating the effects of a combination therapy of methylprednisolone and preservative-free 0.1% HA four times a day demonstrated a significant reduction in osmolarity at eight weeks that paralleled significant reductions in IL-1β and IL-8, as well as tear break up time (TBUT), corneal and conjunctival staining [75]. The authors concluded that measuring the changes in cytokine levels and tear osmolarity could objectively evaluate the anti-inflammatory effects of topical methylprednisolone applied in the treatment of patients with moderate to severe dry eye syndrome. A similar eight-week trial of a modified HA applied three times daily resulted in significant improvements in Ocular Surface Disease Index (OSDI) score, TBUT, conjunctival goblet cell density, corneal and conjunctival damage and tear osmolarity [66].
Tear osmolarity has also been shown to parallel improvements in dry eye symptoms and signs when patients use topical cyclosporine [63,76,77], HA [40,66,78–80], osmoprotective drops [40,67,69], and PEG/HP-Guar drops [81].
2.1.1.1.3 Osmoprotectants
Osmoprotectants (e.g., L-carnitine and betaine) are a group of compatible solutes that protect cells under extreme osmotic stress by balancing the osmotic pressure without disturbing cell metabolism [82–85]. The osmoprotective effect depends on the amount of drug uptake and its retention time, and combinations of osmoprotectants with different pharmaceutical kinetics may function better than individual osmoprotectants.
There are a number of studies demonstrating that osmoprotectants have a beneficial effect on the treatment of DED. An in vitro study showed that the osmoprotectants L-carnitine and erythritol can protect cultured human corneal epithelial cells from hyperosmolar conditions by lowering levels of activated mitogen-activated protein kinases [86]. The osmoprotectants also showed inflammatory-suppressing properties under hyperosmotic stress [87]. A dry eye mouse study showed that osmoprotectants can reduce corneal staining, decrease cell apoptosis and inflammatory cytokines and increase the number of goblet cells [88].
Trehalose is a naturally occurring dissacharide, present in numerous non-mammalian species, which allows cells to survive in unfavorable environments. It is implicated in anhydrobiosis, which relates to the ability of plants and animals to withstand prolonged periods of desiccation. It has very high water retention capabilities and has the dual properties of both bioprotection and osmoprotection [89–94]. In vitro and in vivo studies have shown that trehalose protects corneal cells from desiccation [95], as well as protecting corneal and conjunctival cells against apoptosis [90,96]. Trehalose has also been shown to protect corneal cells against ultraviolet (UV)-induced oxidative damage by accelerating corneal healing [97], and reducing conjunctival inflammatory cytokines in a murine model of DED [92]. It also helps to restore osmotic balance to the ocular surface, as well as preventing denaturation of cell membrane lipid bilayers and proteins to maintain the homeostasis of corneal cells [90–92].
A new eye drop formulation that contains both HA and trehalose has been developed to capitalize on the lubricant properties of HA and bioprotectant properties of trehalose [98].
2.1.1.1.4 Antioxidants
The presence of oxygen free radicals in the tears of patients with DED [99] has resulted in exploration of the potential application of antioxidants for the management of DED.
In an animal study, topical acetylcysteine, an amino acid with antioxidant activity, decreased inflammatory cytokine expression in ocular surface tissues of a mouse model of DED, but did not alter corneal staining [100]. Another antioxidant eye drop, vitamin A (retinyl palmitate), showed significant effects in improving blurred vision, TBUT, Schirmer score, and impression cytology findings in subjects with DED in a prospective, randomized, controlled, parallel study [101]. However, vitamin A metabolites are also known to cause MGD in animal models, including glandular keratinization and atrophy, reduced quality of meibum, reduced tear film break up time, increased tear film osmolarity, and dry eye symptoms (further details are included in the TFOS DEWS II Iatrogenic Dry Eye Report) [102].
A study using stratified human corneal limbal epithelial cells showed that several antioxidants may be beneficial if incorporated into topical ocular lubricants [103]. Quercetin, epigallocatechin gallate, n-propyl gallate, and gallic acid displayed good bioavailability, were effective at quenching reactive oxygen species and might be effective in protecting the corneal epithelium from oxidative damage.
Visomitin is the first registered drug with antioxidative properties that targets oxidative stress in mitochondria and is available as a topical drug in Russia. A recent multicenter, randomized, double-masked, placebo-controlled clinical study showed that a 6-week course of topical Visomitin reduced corneal staining and improved symptoms in 240 subjects with DED [104]. It may act through reducing reactive oxygen species on the ocular surface, but further studies are required to confirm this.
Selenoprotein P (SelP) is a secreted glycoprotein that is involved in the transport or storage of selenium, and is involved in oxidative stress metabolism [105]. In a rat dry eye model, the use of SelP eye drops for 3 weeks suppressed markers of oxidative stress and tears collected from human subjects with corneal staining were lower in SelP [106]. The authors concluded that tear SelP is a key molecule to protect the ocular surface against environmental oxidative stress.
2.1.1.1.5 Preservatives
Multidose artificial lubricants typically require a preservative to prevent microbial growth, whereas unit dose vials that are discarded after a single use do not. However, unit dose vials are more expensive and may be more difficult for less dextrous individuals to open. A number of new products are now available that utilise dispensers that incorporate unidirectional valves that allow multidose bottles to be unpreserved.
Increasing attention has been directed to the relationship between the chronic use of topical therapies, such as glaucoma medications, and OSD. Chronic exposure of the ocular surface to preservatives is now well recognized to induce toxicity and adverse changes to the ocular surface [107–112]. Benzalkonium chloride (BAK) is the most frequently used preservative in eye drop preparations. There are many in vitro and in vivo studies demonstrating that BAK can induce corneal and conjunctival epithelial cell apoptosis, damage the corneal nerves, delay corneal wound healing, interfere with tear film stability and cause loss of goblet cells [113–115]. In an in vitro study, a BAK concentration in excess of 0.005% significantly impaired lipid spreading and compromised the morphology of the tear lipid layer [116]. Sufficient evidence exists to confirm that patients with DED, particularly those with severe DED who require frequent dosing with lubricants or who use ocular lubricants in conjunction with other chronic topical therapies, such as glaucoma medications, should avoid the use of ocular lubricants preserved with BAK [102].
To avoid issues with long-term exposure to preservatives, newer variants of preservatives designed to have a lower impact on the ocular surface have been developed, including oxidative preservatives (sodium chlorite; Purite® and OcuPure™ and sodium perborate; GenAqua™), polyquaternium-1 (Polyquad®) and SofZia™. Sodium chlorite degrades to chloride ions and water upon exposure to UV light after instillation and sodium perborate is converted to water and oxygen on contact with the tear film. Some reports suggest that even these so-called “disappearing preservatives” can show some negative effects on the ocular surface [117]. Therefore, preservative-free drops may be a better choice for patients who have pre-existing ocular surface conditions and/or need frequent instillation of eye drops. Preservative-free eye drops have shown greater effectiveness than preserved drops in decreasing inflammation on the ocular surface and increasing the antioxidant contents in tears of patients with DED [118]. While ideally all prescribed dry eye products would be supplied in unit dose or unpreserved multi-dose bottles, cost considerations and product availability often prevent this from being possible.
Further information on preservative interactions with the ocular surface can be found in the TFOS DEWS II Iatrogenic Dry Eye Report [102].
2.1.1.1.6 Inactive agents
2.1.1.1.6.1 Buffers
The stability of commonly used ophthalmic solutions is controlled largely by the pH of their environment. In addition to stability, pH can influence comfort, safety, and activity of the product. Dry eye products contain a wide variety of buffers to control pH, including citrate, phosphate and borate buffers. The concentration of such buffers is critical, as reports exist of corneal calcification following extensive use of a dry eye product preserved with elevated levels of calcium phosphate [119].
Sodium borate, also known as sodium tetraborate or disodium tetraborate, is a salt of boric acid. Boric acid is a weak acid that is used as a buffering agent in some eye drops. Studies have shown that contact lens multipurpose solutions (MPS) containing boric acid may exhibit corneal epithelial cytotoxicity [120]. However, others have reported that MPS-induced ocular surface defects may be incorrectly attributed to boric acid [121]. The potential benefits, or otherwise, of boric acid or indeed any other buffers in dry eye formulations remain unclear. However, of note is that boric acid at ocular surface pH also acts as a cross-linking agent and electrostatically binds to hydroxypropyl guar (HP-guar) [122,123].
2.1.1.1.6.2 Excipients
Due to the delicate structure of the ocular tissues, the number of acceptable excipients for eye drops is limited, and consists mainly of ionic and non-ionic isotonic agents. There are limited published studies concerning the effect of excipients on the ocular surface [124]. Recently, macrogolglycerol hydroxystearate 40 (MGH 40), has been used in preservative-free eye drops as a solubilizing excipient. An animal study showed that MGH 40 is well tolerated [125]. However, a prior in vitro study revealed that MGH 40 triggers similar detrimental effects in cells as that seen with BAK [126]. Another study examined the role of poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) as a novel polymer excipient in artificial tears [127]. A single-center study showed that PLL-g-PEG was effective in prolonging non-invasive break up time (NIBUT) 15 min after instillation [127]. More studies are needed to clarify the impact of the various excipients on the ocular surface.
2.1.1.1.6.3 Electrolytes
The pre-corneal tear film is a complex milieu that is rich in electrolytes, including sodium, potassium, chlorine, magnesium and calcium [128]. When secreted, tears are isotonic with serum, although the proportions of ions are somewhat different, especially potassium [129,130]. In DED, the concentration of electrolytes in the tear film typically increases due to evaporation and/or reduced aqueous production.
Electrolytes perform critical roles in ocular surface homeostasis. Observations suggest that the relatively high potassium levels in tears may play a role in protecting the corneal epithelium from UV-B radiation [131,132]. Potassium has also been shown to be necessary to maintain normal corneal thickness, and decreases in the potassium concentration may result in an increase in corneal thickness [133]. Finally, the quality of the corneal epithelial surface integrity and light scattering properties, as measured by specular microscopy, have been shown to be dependent on electrolyte composition [134]. The epithelial surface is best maintained with a buffered solution containing potassium, calcium, magnesium, phosphate, bicarbonate and sodium chloride, with potassium being particularly important [134].
Certain tear lubricants, such as TheraTears® (Akorn Lake Forrest, IL, USA) and Bion® Tears (Alcon Ft Worth, TX, USA), have an electrolyte profile that is intended to reflect that of the tear film. Some of the commonly used electrolyte salts include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, sodium borate, sodium phosphate and boric acid. Sodium bicarbonate is used to buffer the solution, but also has an electrolyte effect [135]. An electrolyte-based artificial tear formulation has been shown to increase conjunctival goblet cell density and corneal glycogen content in a rabbit model of DED [58,59]. Other studies have shown that the inclusion of potassium with HA in non-preserved artificial tears enhances corneal wound healing in a mechanical scraping model [33]. The addition of bicarbonate to an isotonic, non-preserved artificial tear solution promotes recovery of the corneal epithelium compared with the same solution buffered with borate or without a buffer [136]. A separate study showed that addition of bicarbonate promoted recovery of epithelial barrier function and maintained normal corneal and mucin layer ultrastructure after exposure to BAK [137]. To date, in vitro, animal and human studies would suggest that certain electrolyte compositions could have a positive role in the management of DED with ocular lubricants.
2.1.1.2 Lipid supplementation
The lipid layer of the tear film has an important role to play in preventing tear evaporation [138]. Lipid-containing eye drops are growing in both availability and popularity [139,140], primarily due to the increased attention being paid to MGD and lipid deficiency. A variety of oils, such as mineral oils and phospholipids, have been incorporated in ocular lubricant formulations to help restore the lipid layer of the tear film [46,141,142].
Lipid-containing drops are formulated as emulsions. Emulsions are defined as non-soluble liquids that are finely dispersed within another liquid, such as oil and water [143]. Emulsions are not readily formed and extreme shear forces and pressure must be applied with the appropriate surfactants to overcome the effects of surface tension [143].
Emulsions can be broadly categorized into three types, based upon the droplet size. Macroemulsions contain droplets larger than 100 nm (nm), nanoemulsions have droplets between 10 and 100 nm and microemulsions have droplets < 10 nm. Macroemulsions are cloudy because the large droplet sizes scatter light and these formulations can induce blur when applied topically. To minimize the potential blurring effect on vision, as well as the stability of the emulsion upon instillation, particle size, concentration and type of lipids can be manipulated. Smaller droplet sizes minimize blurring on installation because the droplet structures are smaller than visible wavelengths, which prevents scattering. A number of commercial products employ meta-stable emulsions to minimize blur time and therefore require the dispensing bottle to be inverted or shaken to enhance uniformity of the emulsion prior to application.
Emulsions have been demonstrated to effectively deliver lipophilic drugs, a task that is challenging for aqueous-based carriers. Newer approaches employ cationic submicron oil-in-water (o/w) vectors, which exploit the negative charges at the mucin layer [144]. A cationic o/w nanoemulsion is a biphasic formulation that comprises positively charged oil nanodroplets (the oil phase) dispersed in water (the continuous phase). The positive charge of the oil nanodroplets is brought about by a cationic surfactant that localizes itself at the oil interface. It is believed that when a cationic o/w nanoemulsion eye drop is instilled, the resultant electrostatic attraction between the positively charged oil nanodroplets and the negatively charged ocular surface mucins manifests itself macroscopically as an improved spreading and retention time [145]. It is possible that this interaction could be modified by exposure to cationic tear film proteins, such as lysozyme. This is of particular interest for patients with MGD who exhibit reduced tear film stability due to lipid deficiency within their tears [146].
Even in the absence of an active ingredient, these cationic o/w nanoemulsions have been observed in preclinical studies to have an inherent benefit on the ocular surface [147,148]. Cationorm® (Santen Osaka, Japan) is a preservative-free cationic emulsion indicated for the treatment of DED. The cationic excipient is cetalkonium chloride, an alkyl derivative of BAK that is lipophilic [148]. Some studies have shown that Cationorm is well tolerated by human corneal epithelial cells in culture [146,149]. However, another in vitro study demonstrated that corneas treated with Cationorm suffered epithelial loss and alterations to the superficial corneal stroma [150]. Cationic-based nanosystems incorporating chitosan provide alternative formulation strategies [151–153].
The long-term safety of nanoemulsions on the ocular surface remains to be evaluated.
2.1.1.2.1 Types and properties of lipids
Different types of lipids have been proposed to try to best mimic natural meibum. The types of lipids used include phospholipids, saturated and unsaturated fatty acids, and triglycerides [154]. Mineral oil in various concentrations, castor oil, olive oil, glycerin carbomers, coconut oil, soybean oil and lecithin, in combination with various emulsifying agents and surfactants, have been described [155–161].
Phospholipids can be neutral (zwitterionic), negatively (anionic) or positively (cationic) charged. Systane® Balance (Alcon Ft Worth, TX, USA) contains a polar phospholipid, DMPG (dimyristoylphosphatidylglycerol). Many types of phospholipids exist and, of these, two are commonly found in the tears - phosphatidylcholine and phosphatidylethanolamine [162–172]. It appears that anionic phospholipids have a greater ability to increase lipid layer thickness than zwitterionic compounds [46,173]. A possible reason is that negatively charged phospholipids contribute to a stable interface between non-polar lipids at the surface of the hydrophilic aqueous layer [174]. This supports a suggestion that polar phospholipids help to form a stable multi-molecular lipid film [175]. Studies suggest that lower levels of the two polar phospholipids are present in individuals with tear film deficiencies [165,176]. Further information can be obtained in the TFOS DEWS II Tear Film Report [128].
Multiple studies have shown that lipid-based drops and liposomal sprays can improve signs and symptoms of dry eye (Table 2) [65,141,142,177–182].
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