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`characterised by modification or reduction of tear fluid lipids, due to which, integrity and
`quality of the tear fluid may be compromised [9,10]. A number of pathological mecha-
`nisms, including inflammation, microbial contamination and lipid deficiencies can trigger
`MGD [11]. Although traditionally, DED has been classified into these two subtypes, it
`is acknowledged that there is considerable overlap between them [2]. As such, chronic
`conditions are most often characterised by a “hybrid” or “mixed” form of the disease,
`wherein each DED subtype eventually adopts some clinical features of the other [12,13].
`It is now understood that the various DED pathologies are not exclusive of each other,
`but rather, they tend to initiate and exacerbate each other forming a “vicious circle” of
`DED and MGD [2,14]. Consequently, multiple therapeutic strategies are often employed
`simultaneously to target DED pathologies with topically applied tear supplements typically
`being the first line of intervention.
`Topical application, being simple, convenient, and painless, is the preferred route
`for administration of prescription drugs to treat ocular surface conditions as it reduces
`systemic side effects by localising the drug close to the target site. Moreover, for a number
`of drugs, it is the only means of achieving therapeutic concentrations in the eye, since the
`blood-aqueous barrier otherwise prevents systemically administered drugs from reaching
`anterior segment tissues [15]. Not surprisingly, over 90% of ophthalmic formulations
`currently on the market are topical eyedrops [16]. However, the efficacy of topically applied
`formulations is limited by the various protective mechanisms of the eye which reduce
`drug bioavailability, thus necessitating frequent eyedrop administration over prolonged
`periods. This in turn is often associated with reduced patient compliance further limiting
`treatment efficacy. Concomitant administration of multiple eyedrops, as is often necessary
`to manage DED, may further complicate the treatment regimen and reduce compliance.
`This review discusses the challenges encountered in developing topical formulations,
`specifically highlighting those attenuated by the ocular surface compromise typically
`observed in DED. Additionally, formulations generally used in the management of DED to
`target the different underlying pathologies, their postulated benefits and their formulation
`characteristics are also discussed.
`
`2. Formulation Challenges
`2.1. Rapid Precorneal Clearance
`The dynamic nature of the ocular surface results in rapid clearance of foreign sub-
`stances from the eye due to blinking, nasolacrimal drainage and reflex and basal tearing.
`The conjunctival sac, which serves as a reservoir for topically applied formulations, has a
`volume of approximately 7–8 µL and can distend to a maximum capacity of 30 µL without
`blinking [17]. Meanwhile, eyedrops instilled with commercial droppers typically have a
`volume of 40 µL or more [18]. The eye attempts to achieve homeostasis immediately after
`eyedrop instillation by reflex blinking and tearing to expel foreign substances and restore
`the normal tear volume, which results in immediate overflow and expulsion of excess
`fluid [17,19]. It has been estimated that less than 10 µL of the applied dose remains on the
`ocular surface following a single blink, leaving a short window of approximately 5–7 min
`for drug absorption, especially when the rapid tear fluid turnover (19.7 ± 6.5%/min) is
`taken into account [20].
`Concomitant administration of two or more eyedrops, as is often necessary for DED,
`can further reduce precorneal residence time and ocular bioavailability by increasing
`competition for volume in the precorneal space [21], with the time interval between eyedrop
`administration negatively correlating with corneal bioavailability [22,23]. On the other
`hand, corneal drug concentration post-administration of a single eyedrop formulation
`containing two drugs is reportedly similar to that observed after administration of eyedrops
`containing equivalent amounts of each drug, individually [22]. Thus, combination eyedrop
`formulations capable of simultaneously treating more than one of the underlying DED
`pathologies could potentially improve the ocular bioavailability and treatment efficacy.
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`2.2. Poor Drug Penetration
`In addition to the rapid clearance of topically applied medications from the ocular
`surface, the ocular bioavailability of drugs from medicated eyedrops is further limited by
`the nature of the tear fluid and ocular tissues, which together pose a formidable barrier to
`intraocular transport of drugs (Figure 1).
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`Figure 1. Penetration barriers to topical drug delivery.
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`The tear film is the eye’s first line of defence with its various components working
`synergistically to minimise exposure to foreign substances. Superficially, it comprises a thin
`lipid layer which limits access of aqueous formulations to the corneal interface while also
`minimising excessive tear evaporation. Underlying the lipid layer is the aqueous phase of
`the tear film, rich in enzymes, proteins, and mucins that can inactivate drugs by protein
`binding or enzymatic degradation, and thus reduce their bioavailability [24]. The region
`of the aqueous layer closest to the goblet cells is the most concentrated in mucins which
`can entrap drug particles by the formation of low affinity polyvalent adhesive interactions,
`rapidly eliminating them from the ocular surface [25,26].
`The cornea is the most anterior ocular tissue and consists of alternating hydropho-
`bic and hydrophilic layers. The hydrophobic corneal epithelium is the major barrier to
`drug transport. It is composed of 5–7 layers of epithelial cells with tight intercellular
`junctions, therefore, only very small molecules can traverse paracellularly through the
`cornea. Transcellular transport, on the other hand, is generally only possible for smaller
`molecular weight lipophilic drugs [27]. Underlying the hydrophobic epithelium is the
`hydrophilic stroma which favours the penetration of low molecular weight hydrophilic
`drugs while hindering the passage of lipophilic drugs. Therefore, hydrophobic drugs tend
`to be retained in the corneal epithelium from where they are released very slowly into
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`Pharmaceutics 2021, 13, 207
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`4 of 19
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`the posterior tissues [28]. Overall, it has been estimated that less than 10% of a topically
`applied dose reaches the intraocular environment through the cornea [29].
`While traditionally not considered a major drug delivery route, ocular drug penetra-
`tion may also occur via the conjunctival-scleral pathway which provides a much larger
`surface area for drug absorption than the cornea [28]. The conjunctival epithelium is rela-
`tively leaky and hydrophilic, with intercellular spaces being approximately 230-fold larger
`than those in the cornea, rendering it permeable even to large biomolecules, such as pro-
`teins and peptides [30,31]. The conjunctival epithelium is more permeable to hydrophilic
`drugs with the permeability of hydrophilic polyethylene glycol mixtures reportedly being
`the highest in the conjunctiva, followed by the sclera and cornea, respectively [31]. How-
`ever, since the sclera and conjunctiva are richly perfused by blood vessels, a large fraction
`of drug absorbed via this route may be lost to the systemic circulation [32].
`
`2.3. Dose Volume
`Due to limited precorneal space, a smaller eyedrop volume (5–15 µL) is preferable
`to minimise drug wastage and reduce the risk of systemic toxicity. The dose-volume can
`be controlled to some extent by training the patient in eyedrop administration and by
`modifying the dropper tip and angle [33,34]. Piezoelectric micro-dosing systems have
`also been developed to consistently deliver a very small eyedrop volume [35]; however,
`these devices are rather expensive. Physical characteristics of the formulation, such as
`surface tension, cohesive forces, viscosity and density can also influence the drop size [36].
`For instance, in situ gelling systems, such as hydroxypropyl-guar Systane®, by virtue of
`their lower viscosity, reduce dosing errors in comparison to viscous gels [37]. Surfactants
`and penetration enhancers, such as tetracaine, polysorbate 80 and benzalkonium chloride
`(BAK), can also reduce the drop size to some extent by reducing the surface tension of the
`formulation [33]; however, due to the toxicity typically associated with these excipients,
`their inclusion is rarely justified for the purpose of reducing drop size alone. Certain
`non-aqueous liquids, such as semifluorinated alkanes (SFAs), which inherently have lower
`surface tension and viscosity than aqueous eyedrops, may help in achieving a smaller drop
`size and minimise overflow [38].
`
`2.4. Visual Disturbance
`Transiently reduced visual acuity post-instillation is another limitation of eyedrops
`that correlates with their viscosity and refractive index. For example, mid-viscosity Refresh
`Liquigel® can cause more blurring than low viscosity Refresh Tears® [39]. Blurring of
`vision is also commonly reported with in situ gelling systems, likely due to a sudden
`change in viscosity post-instillation [40]. To minimise visual disturbance, topically applied
`eyedrops should be optically transparent and ideally have a refractive index identical
`to that of the tear fluid (1.336–1.338) [41]. Nevertheless, the refractive index of most
`formulations currently on the market is relatively high (oily eyedrops typically have a
`refractive index of 1.44–1.50), resulting in frequent complaints of blurred vision and foreign
`body sensation [42].
`
`2.5. Preservative Toxicity
`Several experimental and clinical studies have demonstrated that most preservatives
`used in ophthalmic formulations have pronounced ocular toxicity. BAK, the most com-
`monly used preservative in topical eyedrops, has repeatedly been shown to be toxic to the
`ocular surface, leading to exacerbated DED symptoms [43,44]. BAK disrupts the integrity
`of corneal tight junctions which may compromise its barrier properties and elevate the
`toxicity potential of other drugs and excipients. Therefore, eyedrops preserved with BAK
`not only have a direct detrimental effect on the ocular surface but may also potentiate the
`toxicity of other excipients in the same formulation or those applied concomitantly. In fact,
`one study has suggested that with each additional dose, eyedrops containing BAK increase
`the risk of ocular surface disease two-fold [45]. However, despite the overwhelming evi-
`
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`Pharmaceutics 2021, 13, 207
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`5 of 19
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`dence of its toxicity, a number of products containing BAK remain commercially available
`and are not infrequently used in the treatment of DED [46].
`Significant ocular toxicity has also been associated with other antimicrobial agents
`used in eyedrops, including parabens, sodium perborate, chlorobutanol, stabilised thiom-
`ersal, and ethylenediamine tetraacetic acid (EDTA) [47]. Meanwhile, the cytotoxic effect
`of newer generation preservatives, such as Polyquad®, Purite®
`, and SofZia®, is compara-
`tively low [48], although their long-term effect on tear film stability is currently unknown.
`It should be noted that the toxicity of preservatives may incidentally be enhanced by
`viscosity-building agents present in eyedrops. For instance, corneal epithelial damage
`has been observed when the thickening agent hydroxyethylcellulose is used with BAK,
`although no such effect was observed when either excipient was used alone [49]. Similarly,
`punctal plugs, commonly used in DED therapy to reduce tear drainage, can increase the
`exposure to toxic preservatives enhancing their detrimental effects.
`To enable the delivery of preservative-free eyedrops to the ocular surface, preparations
`may be supplied in single-dose units; however, such eyedrops can cost 5–10 times more than
`multidose formulations and are often difficult to handle [50]. Multidose preservative-free
`dosing systems have thus been developed to overcome these limitations. One such dosing
`system is the third generation ABAK® bottle (Théa Laboratories, Clermont-Ferrand, France)
`which uses a bi-functional membrane with antimicrobial properties to maintain sterility
`for up to three months after opening. Sterile filters are also used in the Clear Eyes® bottle
`(Prestige Consumer Healthcare, Greenburgh, NY, USA) and the hydraSENSE® delivery
`system (Bayer, Leverkusen, Germany), while the COMOD® dosage system (Ursapharm,
`Saarbrücken, Germany) uses a one-way valve to maintain sterility for up to six months
`after opening [46]. Although these systems reduce the difficulties associated with handling
`single-dose products, their cost remains significantly higher than that of conventionally
`preserved eyedrops.
`
`2.6. Poor Tolerability of Formulation Excipients
`In view of recent clinical experience and literature evidence, the TFOS DEWS II
`Iatrogenic Subcommittee listed several formulation excipients, including surfactants, pH
`modifiers and antioxidants, in addition to preservatives, as agents with the potential to
`cause DED [51]. However, almost all of these compounds are commonly found in over-
`the-counter artificial tear supplements and DED medications currently on the market. An
`increased incidence of local adverse effects, such as stinging, burning and excessive tearing,
`has been reported due to high surfactant concentrations in topical formulations. The risk of
`toxicity is particularly high in novel colloidal drug delivery systems, such as micelles, micro-
`or nanoemulsions, liposomes and nanoparticles, due to the higher proportion of surfactants
`and co-surfactants used compared to conventional formulations [52,53]. Surfactants and
`co-surfactants can further destabilise the tear film exacerbating DED symptoms [51,54].
`Consequently, iatrogenic ocular surface disease, caused by “commission” rather than the
`“omission” of treatment, is a significant concern with eyedrops.
`As discussed earlier, excipient toxicity too may be exacerbated by concomitant admin-
`istration of multiple eyedrops. For example, Restasis® and Refresh® Endura artificial tear
`supplements both contain polysorbate 80, which can reportedly trigger DED [51]. However,
`these eyedrops are frequently recommended in combination for DED therapy [55] and this
`practice may significantly increase the toxicity potential by increasing the overall expo-
`sure. Finally, adverse effects may also become more pronounced on exposure to multiple
`iatrogenic excipients (in addition to preservatives) simultaneously.
`
`2.7. Poor Patient Compliance
`Non-compliance with treatment regimens is one of the biggest challenges in treating
`ocular surface disorders. In a phone survey performed in 239 patients [56], 37–53% of
`patients with prescribed topical eyedrops had discontinued use.
`Inter-day and inter-
`individual variability appeared to be high with most patients arbitrarily titrating the dose
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`Pharmaceutics 2021, 13, 207
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`6 of 19
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`to the severity of symptoms on any given day. The chief reasons for discontinuing treatment
`were reportedly failure to purchase a new dosage unit followed by failure to perceive any
`improvement [56]. In DED, therapeutic outcomes generally become evident only after
`long-term treatment. Reduced corneal sensitivity in late stages of the disease may also
`result in failure to notice any change in symptoms, which ironically results in worsening of
`patient compliance as the severity of the disease progresses [57]. Adverse effects associated
`with eyedrops can also reduce the patient’s willingness to continue the treatment. The
`absence of adverse effects is reportedly one of the most desirable product characteristics
`from the patients’ perspective with almost 85% of patients willing to pay more for eyedrops
`that have fewer adverse effects [58,59].
`DED therapy usually involves frequent administration of eyedrops over a prolonged
`period of time, which further reduces patient compliance. Socioeconomic studies analysing
`patients’ responses to eyedrops have shown that patient preference increases as the dosing
`frequency reduces [58]. For many patients, adding a second eyedrop adversely affects
`compliance by increasing the complexity of the dosing regimen, potentially also increasing
`dosing errors [60,61]. Meanwhile, patient preference analysis using a “willing-to-pay”
`questionnaire has shown that patients strongly prefer combination eyedrops which can be
`administered from a single bottle over having to use multiple eyedrops [58].
`The long-term financial burden of DED treatment is another major reason for poor
`patient compliance. The annual cost of DED treatment in the US in 2008 was estimated to
`range between USD 438–2964 per patient, depending upon the severity of the disease, the
`recommended treatment plan and the number of specialist visits, with the acquisition of
`Restasis eyedrops being the single most significant contributor to the treatment cost [57].
`
`3. Management of Dry Eye Disease
`The eye is a complex and dynamic organ with robust homeostatic mechanisms de-
`signed to optimise its function. Disruption to the homeostasis of the ocular surface leads
`to multiple downstream effects resulting in the development of a self-sustained vicious
`circle of DED pathologies. Therefore, concurrent management of the different underlying
`pathologies, such as hyperosmolarity, apoptosis and inflammation, as well as tear film
`instability (Figure 2), is desirable [10,62].
`Selecting therapeutic interventions based on disease severity is generally recom-
`mended to ensure that desirable effects of the intervention outweigh undesirable adverse
`events (Table 1). Moderate lifestyle changes along with artificial tear supplementation are
`generally adequate in mild or preclinical DED (Grade I). Prescription drugs for pathogenic
`treatment may additionally be needed for management of moderate to severe conditions
`(Grades 2 and 3). Surgical intervention is considered only if these treatment recommenda-
`tions fail to yield any positive results (Grade 4).
`
`Table 1. Staged management and treatment recommendations of DED.
`
`Stage 1
`Education
`
`Environmental modification
`
`Lifestyle modification
`
`Dietary changes
`
`Medication review
`
`Lid hygiene
`Tear supplementation
`
`Provide information on the condition, its management, treatment and prognosis
`Minimize exposure to high temperature/low-humidity environments and air conditioning/forced hot-air
`systems;
`use humidifiers and air filters indoors; avoid exposure to pollutants, volatile organic compounds and wind
`drafts
`Lower video display terminals to below the eye level; take periodic breaks; increase blink frequency (blinking
`exercises); avoid smoking and alcohol consumption
`Increase dietary intake of omega-3 essential fatty acids
`Identify and potentially modify/eliminate any offending systemic and topical medications (e.g.,
`antihistamines, antidepressants,
`anxiolytics, oestrogen-containing hormone replacement therapy)
`Apply warm compresses and lid massage
`Apply low viscosity eyedrops; consider lipid-containing eyedrops for patience with evidence of MGD
`
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`Pharmaceutics 2021, 13, 207
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`Table 1. Cont.
`
`Tear conservation
`
`In-office treatments (for MGD)
`
`Stage 2 (If Above Options Are Inadequate or Insufficient):
`Tear supplementation
`Apply low to moderate viscosity preservative-free eyedrops to minimise preservative-induced toxicity
`Use moisture chamber spectacles/goggles and/or punctal occlusion (collagen plugs-short term/silicone
`plugs-long term)
`Apply heat and express meibomian glands (including device-assisted therapies, such as LipiFlow); use
`intense pulsed light
`Consider one or more of the following:
`•
`Topical antibiotic or antibiotic/steroid combination applied to the lid margins for anterior blepharitis (if
`present)
`•
`Topical secretagogues (such as diquafosol)
`•
`Topical corticosteroid (short-term) and non-glucocorticoid immunomodulatory drugs (such as
`cyclosporine A)
`•
`Topical LFA-1# antagonist drugs (such as lifitegrast)
`•
`Oral macrolide or tetracycline antibiotics
`•
`Oral omega-3 fatty acid supplements
`Stage 3 (If Above Options Are Insufficient or Inadequate):
`Tear stimulation
`Take oral secretagogues
`Biological tear substitutes
`Apply autologous/allogeneic serum eyedrops
`Therapeutic contact lenses
`Use soft bandage lenses; rigid mini-scleral and scleral contact lenses
`Stage 4 (If Above Options Are Insufficient or Inadequate):
`Prescription medicine
`Use topical corticosteroid (for longer duration) and systemic anti-inflammatory agents
`Surgical intervention
`Consider punctal cautery; amniotic membrane grafts; tarsorrhaphy; salivary gland transplantation
`Table adapted from the report of the TFOS DEWS II Management and Therapy Subcommittee [62] and the report of the Management
`and Treatment Subcommittee, International Workshop on Meibomian Gland Dysfunction [63]. LFA-1#: Lymphocyte function-associated
`antigen 1.
`
`Prescription medicine
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`Figure 2. Therapeutic management strategies for dry eye disease (DED). Adapted with permission from [14]; Published by
`Elsevier, 2013.
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`Eye Therapies Exhibit 2030, 7 of 19
`Slayback v. Eye Therapies - IPR2022-00142
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`

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`Pharmaceutics 2021, 13, 207
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`8 of 19
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`Topically applied aqueous and/or lipid-based tear supplements, along with lid hy-
`giene, are the mainstay of DED therapy [64]. The next line of treatment generally involves
`medicated topical eyedrops containing antibiotics and/or anti-inflammatory agents, corti-
`costeroids, omega-3 fatty acids or tear secretagogues, as further discussed below.
`
`3.1. Tear Supplementation
`3.1.1. Aqueous Tear Supplementation
`Aqueous tear supplementation is often the first line of treatment comprising either
`isotonic or hypotonic aqueous eyedrops which typically function by augmenting the
`aqueous layer and transiently reducing tear fluid osmolarity. Thus, osmolarity balanced
`artificial tear supplements are a preferred treatment in individuals with low baseline tear
`volume [65]. Artificial tear supplements with an electrolyte balance similar to human tears,
`such as Conheal™ eyedrops (Pannon Pharma Ltd., Pécsvárad, Hungary) and BION Tears®
`(Alcon, Fort Worth, TX, USA), can improve corneal integrity [66,67].
`Hypotonic tear substitutes are believed to be more efficient in ameliorating dry eye
`symptoms [68]; however, their effect is generally short-lived due to rapid clearance from
`the eye. Consequently, baseline tear osmolarity values are restored within 1–2 min af-
`ter instillation [69]. The level of hypotonicity may be crucial in determining therapeutic
`outcomes. While no significant difference was observed between moderately hypotonic
`(215 mOsm/L) and isotonic (305 mOsm/L) sodium hyaluronate solutions [70], further re-
`duction in osmolarity to 150 mOsm/L significantly improved therapeutic outcomes [68,71].
`A placebo-controlled clinical study performed in 444 subjects using a patented formula-
`tion of 0.18% sodium hyaluronate with an osmolarity of 150 mOsm/L has also shown a
`statistically significant reduction in DED symptoms [72]. Although no adverse effects were
`observed in this study, recent concerns over the potential of hypotonic solutions to cause
`microcystic corneal oedema to warrant further long-term safety evaluations [14].
`More recently, “osmoprotectants”, which are naturally occurring small molecules that
`purportedly reduce the concentration of intracellular organic salts without disturbing cellu-
`lar macromolecular components, have also been investigated for their potential to reduce
`tear fluid hyperosmolarity [14,73]. Osmoprotectants may be weak polyelectrolytes, such
`as carbohydrates (e.g., trehalose and hypromellose) and polyols (e.g., glycerol, erythritol,
`inositol and sorbitol), or zwitterions, such as amino acids (e.g., glycine, betaine, proline,
`taurine) and methylamines/methylsulfonium solutes (e.g., L-carnitine), that function by a
`variety of mechanisms to prevent cell death and reduce inflammation [74–76]. Erythritol
`and L-carnitine are currently used as osmoprotectants in Refresh Optive® lipid based
`eyedrops (Allergan, Irvine, CA, USA), which reportedly improves DED symptoms due to
`the combined effect of lipid and osmoprotectant [77,78]. A 3% trehalose solution, marketed
`as Thealoz® (Théa Laboratories, Clermont-Ferrand, France) can also significantly improve
`DED symptoms [79] and has shown prophylactic benefits in preventing DED secondary to
`laser eye surgery [80].
`To prolong the symptomatic relief provided by eyedrops, artificial tear supplements
`are often formulated with viscosity-building macromolecules, such as sodium hyaluronate
`(e.g., Hylo-Vision® HD Eye Drops, OmniVision GmbH, Puchheim, Germany), polyethylene
`glycol (e.g., Blink® Tears, Abbot Vision, Green Oaks, IL, USA), carboxymethyl cellulose
`(e.g., Refresh Liquigel® Drops, Allergan, Irvine, CA, USA), polyvinylalcohol (e.g., Blink®
`Refreshing, Abbot Vision, Green Oaks, IL, USA), carbomers (e.g., Artelac® Nighttime Gel,
`Bausch & Lomb, Rochester, NY, USA) and natural gums (e.g., Systane®, Alcon, Fort Worth,
`TX, USA) [81]. Hydroxypropylcellulose ophthalmic inserts (Lacrisert®; Bausch & Lomb,
`Rochester, NY, USA) that are intended to be placed in the cul-de-sac and slowly dissolve in
`the tear fluid may be recommended in moderate-to-severe dry eye to provide sustained
`lubrication [82,83]. In addition to prolonging the precorneal residence time, viscosity-
`building polymers also exhibit mucomimetic properties and form a protective layer on the
`ocular surface reducing surface desiccation, friction and epithelial cell death [84]. However,
`blurring of vision and difficulty in instillation are major drawbacks of viscous solutions. In
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`Eye Therapies Exhibit 2030, 8 of 19
`Slayback v. Eye Therapies - IPR2022-00142
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`

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`Pharmaceutics 2021, 13, 207
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`9 of 19
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`situ gelling bioadhesive systems based on hydroxypropyl guar (HP-Guar Systane®, Alcon,
`Fort Worth, TX, USA) which form a soft gel at physiological tear pH (approximately 7.4)
`have thus been developed to minimise dosing difficulties [85].
`
`3.1.2. Lipoidal Tear Supplementation
`Excessive evaporation of tears due to a compromised or absent lipid layer is a hallmark
`characteristic of EDE [86], often associated with MGD. Patients with a baseline lipid layer
`deficiency generally observe greater benefit with lipoidal tear supplementation [87] as
`these eyedrops replenish the tear fluid lipid layer, potentially improving its stability and
`reducing evaporation of the underlying aqueous phase [65,88]. Consequently, lipid-based
`eyedrops can also help in relieving DED symptoms in the presence of desiccating stress [89].
`Lipid-based (lipomimetic) eyedrops are most frequently available in the form of oil-in-
`water emulsions (e.g., Cationorm®, Santen SAS, Évry Cedex, France), or ointments (e.g.,
`VitA-POS®, AFT Pharmaceuticals, Auckland, New Zealand). These eyedrops usually
`contain amphipathic lipids which reduce the interfacial tension between the aqueous and
`lipid components of the tear film to improve tear film stability and continuity [90,91].
`Polar lipids, such as phospholipids and ω-hydroxy fatty acids, although present in
`a relatively small concentration in the tear film, play a critical role in determining its
`surface properties and stability. It has been suggested that polar lipid abnormalities may
`have aetiological roles in EDE [92]; hence, lipomimetic eyedrops are often formulated
`with phospholipids. Alcon’s Systane Balance, for instance, is based on the patented Lip-
`iTech™ system and is a microemulsion of mineral oils and a polar phospholipid surfactant
`(phosphatidylcholine) specifically designed to minimise the evaporative loss of tears from
`the ocular surface [91]. Studies comparing Systane Balance to the non-lipid containing
`Systane Ultra showed that the lipomimetic eyedrop provides a more consistent barrier to
`excessive tear evaporation and has superior prophylactic efficacy in an adverse environ-
`ment [93]. Similar prophylactic benefits in a simulated adverse environment have also
`been observed with Systane Complete [94], which too is based on the LipiTech system but
`contains nano-sized lipid droplets that are anticipated to have better patient tolerance due
`to lower opacity.
`Liposomal sprays, such as ActiMist™ (Optrex Ltd., Berkshire, UK) and Tears Again®
`(Optima Pharmazeutische GmbH, Hallbergmoos, Germany) also contain a relatively large
`proportion of phospholipids, which can accumulate at the interface of the aqueous and
`lipoidal phase of the tear fluid and improve its integrity [95,96]. An in situ gelling hybrid
`artificial tear supplement with liposomes containing phosphatidylcholine, cholesterol,
`vitamins A and E, suspended in an aqueous phase consisting of gellan gum and the
`osmoprotectants L-carnitine and trehalose has also been designed to replenish both aqueous
`and lipid components of the tear film [97].
`SFAs are synthetic pharmacologically inert hydrophobic liquids that reportedly sta-
`bilize the tear film lipid layer. Due to their unique surface properties and extremely low
`surface tension, SFAs spread rapidly on the ocular surface with their contact angle on the
`cornea being virtually zero (Figure 3), thus they have the potential to improve continuity
`and integrity of the tear film and fortify the barrier to tear evaporation [38].
`The SFA, perfluorohexyloctane, is currently marketed as a lipid layer stabilizing
`eyedrop (EvoTears™, URSAPHARM in Europe and NovaTears™, AFT Pharmaceuticals
`in Australia and New Zealand). Based on the patented EyeSol® technology (Novaliq
`GmbH, Heidelberg, Germany), this eyedrop is preservative-free and is believed to have
`slower precorneal clearance than aqueous eyedrops. Preclinical and clinical studies have
`shown that NovaTears can improve lipid layer thickness and integrity and minimise tear
`fluid evaporation, thus improving clinical signs of mild to moderate EDE associated with
`MGD [98,99].
`As discussed previously, considerable overlap exists between the various subtypes
`of DED and it is not uncommon to see features of aqueous and lipid deficient DED
`simultaneously [2]. Scifo et al. [100] compared the efficacy of lipid-based eyedrop Emustil®
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`Eye Therapies Exhibit 2030, 9 of 19
`Slayback v. Eye Therapies - IPR2022-00142
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`

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`Pharmaceutics 2021, 13, 207
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`10 of 19
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`(SIFI, Aci Sant’Antonio, Italy), which is an oil-in-water emulsion containing soybean oil
`and egg yolk phospholipids, and aqueous sodium hyaluronate eyedrops in a mouse model
`of DED. They reported a significant improvement in tear volume after administration of the
`lipid-based eyedrop but not with the aqueous eyedrops. However, when the two eyedrops
`were administered concomitantly, improvement in clinical signs of DED was observed
`more rapidly, thus demonstrating the rationale for concomitant administration of aqueous
`and lipid-based eyedrops when both evaporative and the aqueo