Ophthalmic formulations and related methods

Abstract

The present disclosure relates to ophthalmic suspensions for dry eye and other ocular indications that provide long-lasting benefits to the eye. The present disclosure provides methods of increasing lipid layer thickness and methods of lubricating an eye. The disclosure also provides methods of maintaining the integrity of the tear film layer of the eye, increasing the lipid layer thickness of the eye, and methods of reconstructing or establishing one or more layers of the tear film of the eye.

Description

Technical Field

[0001] The present disclosure provides a long-acting ophthalmic suspension for ocular therapy of dry eye and other ocular indications. The ophthalmic suspension described herein provides relief for dry eye that lasts two to ten times longer on the eye than currently marketed products. Background Art

[0002] The tear film is produced by secretions of different glands of the eye during normal blinking. These secretions or components constitute a healthy and stable tear film. The aqueous part of the tears is mainly produced by the tear glands activated by blinking. The outer tear film layer is a lipid layer, which is mainly secreted from the meibomian glands located in the eyelids during blinking. The lipid layer provides a protective layer on the top of the tear film, aiming to reduce the evaporation of the aqueous liquid of the tear film. The thinning of the lipid layer increases the evaporation of the aqueous layer, resulting in dry eyes on the corneal surface between blinks. The evaporation rate of the tear film of such dry eye patients increases by 30% to 38% at a relative humidity of less than 50%. The secretions from the tear glands and meibomian glands, coupled with these collections of eyelids that provide a wiper effect during normal blinking, provide a normal, lasting and stable tear film in the eye. Although the normal production of components continues to repair and replace the tear film, the loss of key components due to dysfunction or no secretion makes the tear film unstable and quickly leads to the loss of tear film structure, resulting in dry eye.

[0003] The tear film protects, lubricates, nourishes and cleanses the surface of the eye. An important role is to prevent dehydration of the underlying corneal and conjunctival tissues, as well as to provide a lubricated surface during blinking. The tear film has many different functions. One of the most important functions of the tear film is its role in reducing evaporation from the surface of the eye, thereby preventing the cornea and conjunctiva from drying out. The failure of the tear film to keep the eye adequately hydrated and lubricated may lead to epithelial cell damage and inflammation. This in turn may lead to severe discomfort or pain, and even severe corneal damage. The tear film lubricates the eyelids, ensuring smooth and comfortable blinking. If the surface of the cornea and eyelids is not smooth or lubricated enough, abrasive damage may result, causing problems similar to those of corneal and conjunctival dryness as described above, and has been described as eyelid brush epitheliopathy. Since the cornea is an avascular structure, the tear film contains nutrients to nourish the corneal epithelium and remove cellular waste and debris. The tear film also provides oxygen to the corneal and conjunctival epithelium and removes carbon dioxide from it. If the cornea becomes malnourished, blood vessels may grow into it in order to provide the necessary nutrients. These blood vessels may obstruct vision and are a feature of very severe dry eye.

[0004] The tear film contains antibacterial and antiviral substances that protect the eye from infection. Tears are buffered and are able to neutralize weak acids and bases, allowing the eye to tolerate instillations of substances with a pH range of 6.6 to 7.8. The tear film refracts (bends) light and aids visual acuity by forming a smooth, clear optical surface on the cornea, smoothing out minor surface irregularities in the corneal epithelium. The tear film has a refractive index ranging between 1.3345 and 1.3360 (by comparison, the refractive index of air is 1.0).

[0005] It should be understood that the tear film is composed of five different layers, each of which plays a key role in maintaining the tear film. The outer (oily) lipid layer, which lubricates the movement of the eyelids and reduces the evaporation of the aqueous (watery) layer. The next layer, which constitutes the largest part of the tear film, is the aqueous (watery) layer, which hydrates and provides nutrients to the avascular cornea while removing cellular byproducts and debris. Finally, the inner mucin layer secreted by the cornea, which reduces the surface tension of the tear film so that it can be evenly spread on the surface of the eye. The outer interstitial layer is located between the lipid layer and the aqueous layer. The inner interstitial layer is located between the aqueous layer and the mucin layer.

[0006] The continuous basal secretion of tear components at all times of the day and night normally ensures that the tear film provides adequate lubrication and protection for most environments. However, the production and maintenance of the tear film is not simply dependent on the production of sufficient amounts of tears. The quality (i.e., composition) of the tears and the blinking process also play an important role in maintaining a healthy tear film.

[0007] Normal tears with the correct balance of lipid, aqueous and mucin components combined during blinking form a stable and protective tear film. Between blinks, the tear film thins due to evaporation, and the lipid molecules of the outer layer begin to migrate through the aqueous layer toward the mucin layer. The aqueous portion of the tears is also exchanged on the eye at approximately 16% by volume per minute, while the lipid layer is exchanged on the eye at a rate of approximately 2% per minute. Contamination of the mucin layer by the lipid layer increases the surface tension of the tear film and eventually causes the tear film to rupture (rupture / break-up) and aggregate into beads on the corneal surface, forming dry spots. Subsequent blinks usually repair the rupture by removing lipid contaminants from the mucin layer and restoring the normal aqueous layer. However, repeated ruptures may result in loss of the mucin layer and show staining when observed using fluorescein.

[0008] Due to aging, disease, glandular dysfunction, medications, preservatives in ophthalmic preparations or wearing contact lenses, no proper blinking, and eyelid closure or sealing problems, the balance between tear film components is disrupted, the tear film becomes less stable, and may break up in just a few seconds (i.e., before the next blink). When this happens, the breakup time is shorter than the blink interval (whether due to sufficient tear film or insufficient blinking), dry spots are formed on the ocular surface of the eye, and this becomes the first stage of ocular surface disease or dry eye development. Ideally, the breakup time should be equal to or longer than the normal blink interval.

[0009] The loss of tear film structure leads to dry eye, which is an ophthalmic medical condition currently manifested in more than 350 million patients worldwide and more than 50 million in the United States (equivalent to 15% of the U.S. population). Discomfort caused by dry eye conditions may include dryness of the eyes, gritty sensations, burning sensations, pain, itching (scratching) or foreign body reactions. The degree of discomfort depends on the subject and the subject's condition. The main cause of dry eye is the loss of the lipid layer due to meibomian gland dysfunction, which is estimated to be up to 86% of all dry eyes. The change in composition is reflected in the loss of meibum and / or glands that produce meibum as a viscous / semi-solid material. In addition, although many authors have discussed the differences in the formation of the lipid layer of various components, little is known about the importance of various components. The importance of the lipid layer in the maintenance of the tear film has been well studied, which shows that the lipid layer is crucial in preventing the loss of the aqueous layer due to evaporation. It is believed that the thinning of the lipid layer aggravates the symptoms of dry eye caused by the evaporation of the aqueous component of the tear film.

[0010] The most common treatment for dry eye involves temporarily relieving dry eye symptoms by topical application of artificial tear substitutes, which provide a certain volume of liquid to the surface of the eye and adjacent tissues (e.g., eyelids, cornea). Typical commercially available tear substitute compositions include water-soluble polymer solutions. Examples of such solutions include saline solutions of polyvinyl alcohol, hydroxypropyl methylcellulose, or carboxymethylcellulose. U.S. Patent No. 4,421,748 teaches an artificial tear composition comprising a hypotonic aqueous solution of lecithin and a viscosity modifier, such as a soluble cellulose solution. The aqueous tear film extends over the surface of the eye and maintains a moist and lubricated surface of the eye. It is also known that dehydration of eye moisture may cause discomfort. In addition, compositions intended for the treatment of dry eye are available on the market. Commercially available compositions are mainly aqueous materials that supplement the tear film by adding a water-soluble polymer film on the surface of the eye. These films have a short lifespan and provide limited relief.

[0011] Many improved compositions for the treatment of dry eye are disclosed in U.S. Pat. Nos. 4,914,088; 5,278,151; 5,294,607; 5,578,586 and 9,161,905, each of which is incorporated herein by reference for its teachings on how to form an oil film on the surface of the eye, including compositions and uses. U.S. Pat. No. 4,914,088 teaches the use of certain charged phospholipids for treating symptoms of dry eye. It is believed that the addition of charged phospholipids to the eye helps replicate the tear film that would naturally exist in the eye. According to the patent, a phospholipid composition, preferably in the form of an aqueous emulsion, is topically applied to the eye, where it is believed to disperse on the surface of the eye and form a film that replicates the lipid layer that would be formed by the spreading of naturally occurring lipids secreted primarily from the meibomian glands during blinking. Because the phospholipids carry a net negative charge when applied to the eye, it is believed that the oriented molecules repel each other, preventing the formation of complex aggregates, thereby resulting in a stable phospholipid interface between the lipid and aqueous phases. The patent theorizes that the film formed from the charged phospholipids helps form a barrier membrane, reducing evaporation of the aqueous layer, thereby maintaining the tear film. Others have theorized that the phospholipids also act as surfactants, maintaining emulsion stability.

[0012] The above-cited U.S. Patent Nos. 5,278,151; 5,294,607; 5,578,586; 9,279,095; and 9,375,401 disclose additional improvements in the treatment of dry eye. In these patents, the dry eye treatment composition of U.S. Patent No. 4,914,088 is improved by adding oil, preferably non-polar oil such as mineral oil composed of hydrocarbon components, to the eye treatment composition. The oil is added to improve the performance of the dry eye treatment composition by increasing the life of the tear film formed on the eye due to the formation of an oil film that acts as an evaporation barrier on the surface of the eye (i.e., by providing and / or thickening the dehydration barrier (oil layer) on the outer surface of the tear film). Therefore, the oil increases the efficacy of the dry eye treatment solution and reduces the performance variation between subjects. It also supplements the oil provided by the meibomian glands, which in many cases of dry eye cannot provide enough oil to provide a sufficient lipid tear layer. The preferred embodiment disclosed in the above-referenced patents is a dry eye treatment composition comprising a metastable oil-in-water emulsion wherein the aqueous phase comprises a charged phospholipid believed to act both as an emulsifier and a surfactant, which helps the oil spread on the eye to form an unclouded film, binding the oil to the aqueous layer of the tear film. The emulsion is desirably "metastable" so that when the emulsion is applied to the eye, it will quickly break and spread on the ocular surface after it first contacts the ocular environment.

[0013] U.S. Patent Nos. 5,371,108, 5,278,151 and U.S. Patent Publication No. 2016 / 03389952 issued to Korb teach a method or formulation for producing an emulsion or gel containing oil and wax to form a tear film on the surface of the eye to extend the residence time of the oil. However, wax-containing gels have not yet been produced and commercially sold because it is difficult to homogenize the wax in a manner that does not cause visual blur beyond what is acceptable to most consumers. Specifically, autoclaving wax-containing formulations results in increased particle size, which causes irritation and blurred vision. Gels are semisolid formulations with high viscosity. In contrast, the present disclosure relates to metastable emulsions that behave as flowing liquids at room temperature. Emulsions behave as liquids and therefore do not exhibit static internal structures or have high viscosity. Korb also utilizes preservatives at levels known to be toxic to corneal cells after application, and does not disclose a vehicle that will exhibit a persistent residence time.

[0014] Many ophthalmic formulations and compositions for use take note of the use of zeta potential and are disclosed in WO2016209555, WO 2015057847, WO 2011098578, WO 2011084509, WO 03053405, US2012328702, US2012225834, and U.S. Pat. Nos. 7,060,285, 9,827,191, 8,298,569, 7,893,040, 7,834,172, and 10,137,083, each of which is incorporated herein by reference for its teachings regarding the use of zeta potential.

[0015] Currently commercially available products (including oil and water emulsion products) generally supplement one or more layers of the tear film through various combinations of oils, aqueous solutions and mucus mimetics. These lipid emulsions provide adequate lubrication and prevent drying, but they are still insufficient in their ability to remain on the eye and provide lasting relief, which is the most desired clinical outcome. In addition, these compositions cannot completely reconstruct the tear film, causing these layers to lose their natural stability on the surface of the eye, and therefore have limited relief due to their on-eye residence time of less than 30 minutes. Without connecting to each subsequent layer of the film, the lipid layer, aqueous layer, and mucin layer (whether natural, artificial, or some combination thereof) are often squeezed out in too short a period of time to provide lasting comfort for dry eye. Figure 1A magnified view of the components of the layers and interfaces of the eye and the tear film is provided. A normal tear film is 3-6 μM thick. Two insets with lines to the tear film show magnified views of the lipid / aqueous interface and the aqueous / mucin interface. The third inset shows the thinning of the layers and interfaces associated with dry eye. In particular, it shows the thinning of the bound mucin layer on the surface of (i) the aqueous layer, (ii) the unbound mucin layer, and (iii) the corneal epithelial cells. Existing products cannot stabilize the different layers and interfaces of the tear film (including the lipid layer). Therefore, existing products cannot produce a stable lipid layer and cannot provide long-term benefits. Summary of the invention

[0016] The tear film of human eyes includes three different layers, and recent studies and research have determined that the tear film has two additional layers that are interstitial layers. These interstitial layers of tear film come from other glands in the eyelids that are different from the lacrimal glands and meibomian glands of the eyelids. The components secreted by these interstitial layers provide healthy, normal, and stable tear film. These glands include Krause glands, Wolfring glands, Moll glands, and Heine glands, which secrete wax, wax esters, and other surfactants and chemicals, which enhance the Velcro effect of the interface between the tear film layers, and establish and thicken the tear film to reduce tear film evaporation. These two interstitial layers each play a key role in maintaining the tear film. In a word, the tear film is incorporated with five layers, wherein the outer (oily) lipid layer is secreted by the meibomian glands. The first interstitial layer is secreted by the meibomian glands and the Wolffning, Clause, More's, and Heine glands and includes anionic polar phospholipids (i.e., connecting the lipid layer to the aqueous layer), wax esters, and surfactants (i.e., thickening and enhancing the lipid layer and interstitial attachment), which connect the lipid layer of the tear film to the aqueous layer to maintain a stable tear film. The next layer, which makes up the largest part of the tear film, is the aqueous (watery) layer, which hydrates and provides nutrients to the avascular cornea while removing cellular byproducts and debris. The second interstitial layer, secreted by the Wolffning, Clause, More's, and Heine glands, is composed of wax esters and surfactants, which thicken the aqueous layer and enhance the connection with the mucin secreted by the cornea, which connects the aqueous layer to the cornea to maintain a stable tear film. Finally, the inner mucin layer secreted by the cornea attaches to the cornea and reduces the surface tension of the tear film so that the tear film can spread evenly on the surface of the eye. Waxes and wax esters, as well as surfactants and other agents, combine with the lipid-secreting meibomian glands and the aqueous secretions of the lacrimal glands, which have a lip wiper effect due to the normal blinking action, to establish a normal, stable and long-lasting tear film on the eye. Thus, the addition of wax esters and their partial hydrolysates, such as beeswax, with their normal distribution throughout the various phases of the suspension, has the same effect of improving the efficacy of the composition by allowing the lubricating component to remain on the eye for an extended period of time similar to a normal tear film.

[0017] Disclosed herein is an ophthalmic suspension that simulates a natural tear film (including three different layers and two interstitial layers) to rebuild or otherwise increase the thickness of the lipid layer of the eye over an extended period of time, thereby reducing tear film evaporation and maintaining normal ocular tear structure in the eye. The ophthalmic suspension provided herein can serve as a substitute for each tear film layer (lipid layer, aqueous layer, interstitial layer, and mucin layer), which enhances the tear film, thereby improving the natural function of the tear film to produce significantly longer eye residence time and improved patient comfort. By providing a more lasting effect on the eye, patients in need of treatment need to use fewer applications or drops. By replacing the lipid (outer) layer, enhancing the aqueous (middle) layer, simulating the mucin (inner) layer, and incorporating an interstitial layer, the ophthalmic suspension of the present invention simulates natural tears and acts as a true artificial tear.

[0018] The present invention provides an ophthalmic suspension comprising an emulsified oil-in-water suspension containing a wax ester, or a suitable combination of wax esters, a surfactant, and other components as provided herein, which simulates the body's natural tear film and provides a tear film that maintains its structure on the eye for an extended period of time.

[0019] According to one aspect, the present disclosure provides an ophthalmic suspension comprising: i) an aqueous phase comprising water and one or more components selected from the group consisting of: at least one wax ester, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt, and at least one phosphate; and ii) an oil phase comprising at least one mineral oil and optionally at least one wax ester. According to one embodiment, the wax ester exhibits an average particle size determined via a Microtrac particle analyzer. The wax ester exhibits an average particle size of at least about 2.0 microns. According to one embodiment, the wax ester exhibits an average particle size distribution of at least about 2.0 microns to about 20.0 microns. According to one embodiment, the wax ester exhibits an average particle size distribution of at least about 5.0 microns. According to one embodiment, the ophthalmic suspension has an osmolality of about 245mOsmol / kg to about 315mOsmol / kg. According to one embodiment, the ophthalmic suspension is formulated as an emulsified suspension that flows freely at about 30°C. According to one embodiment, the wax ester is present in a concentration of about 0.8 wt % to about 1.2 wt %. According to one embodiment, the wax ester is natural beeswax. According to one embodiment, the wax ester is synthetic beeswax. According to one embodiment, the ophthalmic suspension exhibits a negative zeta potential of about -60 mV to about -110 mV. According to one embodiment, the ophthalmic suspension exhibits an ion mobility of about -5.9 (μms) / (V / cm) to about -7.4 (μms) / (V / cm). According to one embodiment, the oil is a mixture of light mineral oil and heavy mineral oil. According to one embodiment, the light mineral oil exhibits an ion mobility of about 3.0 mm at 40°C.2 s -1 to about 34.4mm 2 s -1 The dynamic viscosity of heavy mineral oil is about 34.5 mm at 40 °C. 2 s -1 To about 150mm 2 s -1 According to one embodiment, the ophthalmic suspension further comprises an anionic polar surfactant, the anionic polar surfactant comprising a polysorbate nonionic surfactant at a concentration of about 0.35% by weight to about 0.45% by weight and a mixture of anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35% by weight to about 0.55% by weight. According to one embodiment, the ophthalmic suspension is packaged as a sterile multiple-use or sterile disposable container. According to one embodiment, the ophthalmic suspension is packaged in a multi-dose non-preservative (MDNP) container or a container comprising at least one preservative. According to one embodiment, the ophthalmic suspension increases the lipid layer thickness by at least 20 nanometers five minutes after administration. According to one embodiment, the ophthalmic suspension increases the lipid layer thickness by at least 20 nanometers 60 minutes after administration. According to one embodiment, the ophthalmic suspension increases the lipid layer thickness by at least 25 nanometers of the control net value five minutes after administration. According to one embodiment, the ophthalmic suspension increases the lipid layer thickness by at least 20 nanometers four hours after administration. According to one embodiment, the ophthalmic suspension increases lipid layer thickness by at least 25 nanometers above a control net value four hours after administration.

[0020] According to another aspect, a method for increasing lipid layer thickness is provided. The method comprises the step of applying an ophthalmic suspension as provided herein to the eyes of a patient in need of treatment. According to one embodiment, the lipid layer thickness increases by at least 20 nm from the baseline within five minutes of application. According to one embodiment, the lipid layer thickness increases by at least 20 nm from the baseline four hours after application. According to one embodiment, the lipid layer thickness increases by at least 25 nm from the baseline four hours after application.

[0021] According to one aspect, a method for lubricating an eye is provided. The method comprises the step of applying an ophthalmic suspension as provided herein to the eye of a patient in need of treatment. According to one embodiment, the ophthalmic suspension reconstructs or rebuilds one or more layers of the tear film of the eye and maintains the integrity of the tear film for more than 60 minutes. According to one embodiment, the ophthalmic suspension reconstructs or rebuilds one or more layers of the tear film of the eye and maintains the integrity of the tear film for more than 90 minutes. According to one embodiment, the ophthalmic suspension reconstructs or rebuilds one or more layers of the tear film of the eye and maintains the integrity of the tear film for more than 120 minutes. According to one embodiment, the ophthalmic suspension reconstructs or rebuilds one or more layers of the tear film of the eye and maintains the integrity of the tear film for more than 150 minutes.

[0022] According to one aspect, a method for alleviating dry eye symptoms is provided. The method comprises the step of administering an ophthalmic suspension as provided herein to an eye of a patient in need of treatment.

[0023] According to one aspect, a method for maintaining the integrity of the tear film layer of an eye and increasing the thickness of the lipid layer of the eye is provided. The method comprises the step of applying an ophthalmic suspension as provided herein to the eye of a patient in need of treatment. According to one embodiment, 60 minutes after application, the integrity of the tear film is maintained and the lipid layer thickness is increased by at least 20 nm.

[0024] According to one aspect, a method for reconstructing or establishing one or more layers of the tear film of an eye is provided. The method comprises the step of applying an ophthalmic suspension as provided herein to the eye of a patient in need of treatment. After application, the ophthalmic suspension reconstructs or rebuilds one or more layers of the tear film of the eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Magnified views of tear films with different regions are shown. A normal tear film is 3-6 microns thick. The figure shows a lipid layer, a lipid / aqueous interface, an aqueous layer, an aqueous / mucin interface, a mucin layer, and a cornea. Two of the illustrations show magnified views of the lipid / aqueous interface and the aqueous / mucin interface. The third illustration shows thinning of layers and interfaces associated with dry eye. In particular, the third illustration shows thinning of (i) an aqueous layer, (ii) an unbound mucin layer, and (iii) a bound mucin layer bound to the surface of corneal epithelial cells. Methods for evaluating tear films are further provided in U.S. Serial No. 16 / 708,120 (U.S. Publication No. 2020 / 0179281), the entire contents of which are incorporated herein by reference. DETAILED DESCRIPTION

[0026] While the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[0027] As used herein, the terms "about" and / or "approximately" can be used in conjunction with numerical values ​​and / or ranges. The term "about" is understood to mean those values ​​that are close to the recited values. Alternatively, depending on the context, the term "about" can mean ± half a standard deviation, ± one standard deviation, or ± two standard deviations. In addition, the phrase "less than about [value]" or "greater than about [value]" should be understood according to the definition of the term "about" provided herein. The terms "about" and "approximately" can be used interchangeably. Throughout this specification, numerical ranges are provided for certain quantities.

[0028] As used herein, the verb "comprise" and its conjugations as used in the specification and claims are used in their non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.

[0029] As used herein, the word "comprising" or variations such as "comprises / comprising" will be understood to imply the inclusion of the stated elements, integers, or steps, or groups of elements, integers, or steps, but not the exclusion of any other elements, integers, or steps, or groups of elements, integers, or steps. The present disclosure may appropriately "comprise / comprises," "consist of," or "consist essentially of," the steps, elements, and / or agents described in the claims.

[0030] It is further noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended to serve as antecedent basis for use of exclusive terminology such as "solely," "only" and the like in connection with the recitation of claim elements or use of a "negative" limitation.

[0031] As used herein, the term "weight percent" refers to the amount based on the ophthalmic suspension, unless otherwise specified.

[0032] As used herein, the term "wax ester" refers to esters of fatty acids and fatty alcohols. Wax esters provided herein can include long carbon chains. Wax esters provided herein can exist as solid particles, and the solid particles exhibit a melting point of about 60°C to about 100°C. Wax esters provided herein can be natural beeswax. Natural beeswax can also be purchased as white beeswax (Cera Alba) or yellow beeswax (Cera Flava) (white or yellow beeswax). The use of natural beeswax can include hydrocarbons as components. During the preparation of an embodiment of the ophthalmic suspension of the present disclosure, as part of the method, wax esters can be hydrolyzed to form additional acids and / or alcohols. The terms "wax ester dispersion" and "wax dispersion" can be used interchangeably.

[0033] As used herein, the term "particle size" refers to the size of wax ester particles alone or in combination with one or more oils, phospholipids, surfactants, hyaluronic acid (HA), sodium hyaluronate, or any other ophthalmic suspension components provided herein.

[0034] As used herein, the term "residence time" refers to the time (e.g., minutes or hours) that an ophthalmic suspension remains on the eye after a single application when the level or amount of lipid layer thickness is evaluated from a baseline on the eye. The lipid layer thickness can be determined by an interferometric instrument to measure the residence time on the eye.

[0035] As used herein, the term "persistent" refers to an increase in retention time observed over a period of time and demonstrated compared to an untreated eye.

[0036] As used herein, the term "stable" refers to the time that the tear film maintains its structure between blinks.

[0037] As used herein, the term "tear film" refers to the entire protective coating provided to the eye by the eye, e.g. Figure 1 As shown in the figure.

[0038] As used herein, the term "dry eye" refers to a condition of the eye in which the tear film fails to perform its lubricating function and may be caused by a lack of key components that form a stable tear film.

[0039] As used herein, the terms "light mineral oil" and "light mineral oil" are used interchangeably and refer to low viscosity mineral oils as defined in the NF or USP formularies.

[0040] As used herein, the terms "heavy mineral oil" and "heavy mineral oil" are used interchangeably and refer to high viscosity mineral oil variants that meet the requirements of the NF or USP monographs for mineral oils.

[0041] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0042] The present disclosure relates to ophthalmic suspensions and related methods. Ophthalmic suspensions are particularly suitable for increasing the lipid layer thickness on the eye relative to the baseline lipid layer thickness. The ophthalmic suspensions provided herein form an artificial tear film on the ocular surface of the eye and provide enhanced ocular lubrication while reducing evaporation. The ophthalmic suspensions are retained on the eye and exhibit significantly longer residence times than any commercially available product currently on the market. The ophthalmic suspensions provided herein not only replicate the discrete layers of the tear film, but also supplement the interstitial binding properties and establish and thicken the tear film. Therefore, a significant improvement in the duration of dry eye relief is provided.

[0043] The ophthalmic suspension provided comprises an aqueous phase and an oil phase. The aqueous phase may comprise water and one or more of: at least one wax ester, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt and at least one phosphate. The water utilized in the ophthalmic suspension vehicle provided herein may be purified water or deionized water. The oil phase may comprise at least one mineral oil and optionally at least one wax ester. Therefore, the at least one wax ester may be present in the aqueous phase, the oil phase, or both the aqueous phase and the oil phase. According to specific embodiments, at least one wax ester is in the aqueous phase or the oil phase.

[0044] The ophthalmic suspension provided herein can be formulated as an oil-in-water emulsion suspension. As the term is used herein, an emulsion suspension is a suspension comprising an aqueous phase and an oil phase, wherein the aqueous phase and the oil phase are incorporated with a wax ester microparticle component. The wax ester microparticles in the aqueous phase are preferably aggregated but insoluble in water. The lack of solubility is attributable to the significant charge stabilization of the wax ester particles. The wax ester microparticles in the oil phase do not appear to aggregate or mix with water.

[0045] When the emulsified suspension is added to the eye as standard drops, the emulsified suspension rapidly differentiates, thereby permitting rapid formation of an oil film on the corneal surface without expelling excessive oil due to blinking. The emulsified suspension can differentiate within about 10 blinks after application to the eye, more preferably within a time of less than about 1 minute. During and after differentiation of the emulsified suspension, the formation of the oil film is aided by the use of a surfactant combination that is used to help form the emulsified suspension and promote spreading of the oil on the surface of the eye when the emulsified suspension breaks.

[0046] Compared to emulsified ophthalmic suspensions, stable emulsions will not differentiate quickly when applied to the ocular surface. Due to the presence of two different phases, emulsions are typically optically opaque. Therefore, opaque emulsions on the surface of the eye may cause blurring. The duration of blurring depends on the time required for the emulsion to differentiate and form a separate layer that replicates the tear film. In addition, emulsions are most easily added to the eye as standard drops from an eye dropper. The eye is able to accommodate a limited volume of fluid with a volume of less than 25 μL. The volume of 25 μL is substantially less than the volume of standard drops. Therefore, if the emulsion is stable and fails to differentiate quickly after being applied to the eye, excess emulsion will be discharged from the eye during blinking. The discharge of the emulsion from the eye will cause the effective components of the therapeutic suspension to be discharged from the eye before a lasting tear film can be formed. For this reason, the effective components may not be obtained in sufficient amounts to form the desired tear film.

[0047] Ophthalmic suspensions as provided herein are free-flowing liquids at room temperature, such as between about 20° C. to about 30° C. Emulsified suspensions as provided herein separate into an oil phase and an aqueous phase upon contact with the eye. The surface of the eye typically exhibits a temperature of about 32° C. to about 36° C.

[0048] According to specific embodiments, ophthalmic suspension provided herein comprises water-in-oil emulsion. The water-in-oil emulsion comprises at least one oil and water. The water can be purified water or deionized water. The oil for forming water-in-oil emulsion can be derived from animals, plants, nuts or other suitable sources. The oil derived from animals, plant seeds and nuts is similar to fat, and is mainly glyceride or fatty acid, and therefore contains a large amount of acid and / or ester groups, so that oil has polarity. The example of these oils is safflower oil, corn oil, canola oil, whale oil and seal oil or chemically similar oil. The other oil that can be used for preparing water-in-oil emulsion as provided herein comprises vegetable oil such as castor oil, almond oil, geranium oil, corn oil, peanut oil, canola oil, safflower oil, cola nut oil, light olive oil, bay leaf oil or other generally recognized safety (GRAS) oils that are listed as being suitable for eye preparations. Alternatively, oil can be an oil suitable for forming liposomes. According to one embodiment, the oil is a straight chain hydrocarbon oil having 10 to 150 carbon atoms, more preferably, the oil is a saturated normal alkane or isoalkane having 10 to 26 carbon atoms. Unsaturated olefins can be used, but the chemical stability is poor.

[0049] According to one embodiment, the oil as provided herein is a mineral oil. According to one embodiment, the oil as provided herein is a light mineral oil. According to one embodiment, the oil as provided herein is a heavy mineral oil.

[0050] According to one embodiment, the oil comprises a mixture of a light mineral oil and a heavy mineral oil, each having a different viscosity. According to a specific embodiment, the light mineral oil exhibits a viscosity of about 3.0 mm at 40°C. 2 s -1 to about 34.4mm 2 s -1 According to a specific embodiment, the heavy mineral oil exhibits a dynamic viscosity of about 34.5 mm at 40°C. 2 s -1 To about 150mm 2 s -1 According to yet another embodiment, the light mineral oil exhibits a dynamic viscosity of about 28 mm at 40°C. 2 s -1 To about 30mm 2 s -1 According to yet another embodiment, the heavy mineral oil exhibits a dynamic viscosity of about 65 mm at 40°C. 2 s -1 To about 71mm 2 s -1 The viscosity of the dynamic viscosity.

[0051] The amount of oil in the oil-in-water emulsion can vary within reasonable limits so that no more than 25 μL is administered to the eye. According to one embodiment, the volume does not exceed 15 μL. According to one embodiment, the volume varies between about 1 μL and 10 μL. According to one embodiment, the volume varies between about 1 μL and 30 μL.

[0052] The total amount of the oil or combination of oils may be present in the ophthalmic suspension in an amount of at least about 0.1% by weight based on the total weight of the ophthalmic suspension. According to one embodiment, the oil or combination of oils is present in an amount of at least about 0.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount of at least about 1.0% by weight. According to one embodiment, the oil or combination of oils is present in an amount of at least about 1.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 12.5% ​​by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 10.0% by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 7.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 6.6% by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 6.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 0.5% by weight and about 12.5% ​​by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 1.0% by weight and about 8.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 3.5% by weight and about 7.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 4.0% by weight and about 7.0% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 4.4% by weight and about 6.6% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 4.95% by weight and about 6.05% by weight.

[0053] According to one embodiment, the oil comprises a mixture of two or more oils of different weights. According to such an embodiment, the oil is a mixture of at least one light oil and at least one heavy oil. According to a specific embodiment, the oil is sold under the trade name 15 (light mineral oil) and According to one embodiment, the light mineral oil may be present in an amount of about 0.5% by weight to about 1.5% by weight. According to one embodiment, the light mineral oil may be present in an amount of about 0.6% by weight to about 1.4% by weight. According to one embodiment, the light mineral oil may be present in an amount of about 0.7% by weight to about 1.3% by weight. According to one embodiment, the light mineral oil may be present in an amount of about 0.8% by weight to about 1.2% by weight.

[0054] According to one embodiment, the heavy mineral oil may be present in an amount of about 2.7% by weight to about 6.5% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 2.9% by weight to about 6.3% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 3.1% by weight to about 6.1% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 3.3% by weight to about 5.9% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 3.5% by weight to about 5.7% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 3.7% by weight to about 5.5% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 4.05% by weight to about 4.95% by weight.

[0055] According to one embodiment, the light mineral oil may be present in an amount of about 1.0% by weight, and the heavy mineral oil may be present in an amount of about 4.5% by weight.

[0056] The ophthalmic suspension provided herein comprises a wax ester dispersion. The wax dispersion comprises at least one wax ester. Although not bound by a particular theory, it is believed that the role of the wax ester and its hydrolyzate is to maintain the integrity of the interstitial layer itself, to bind the mucin layer to the aqueous layer and to bind the aqueous layer to the lipid layer. In addition, the wax ester is used to thicken the mucin, aqueous layer, and lipid layer itself. The binding process and subsequent steady state achieved by the wax ester allow the layers of the tear film to adhere to each other, thereby allowing the entire tear film to remain on the eye for an extended period of time. The ophthalmic suspension provided herein penetrates all layers of the tear film, including five interstitial layers that were not previously incorporated with the product.

[0057] According to one embodiment, at least one wax ester is present in an amount of at least about 0.2% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.3% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.4% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.5% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.6% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.7% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.8% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.9% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 1.0% by weight. According to one embodiment, at least one wax ester is present in an amount of less than about 1.8% by weight. According to one embodiment, at least one wax ester is present in an amount of about 0.2% by weight to about 1.8% by weight. According to one embodiment, at least one wax ester is present in an amount of about 0.4% by weight to about 1.6% by weight. According to one embodiment, the at least one wax ester is present in an amount of about 0.6 wt % to about 1.4 wt %. According to one embodiment, the at least one wax ester is present in an amount of about 0.8 wt % to about 1.2 wt %. According to one embodiment, the at least one wax ester is present in an amount of about 1.0 wt %.

[0058] According to one embodiment, at least one wax ester is beeswax. According to one embodiment, the beeswax is natural beeswax. The beeswax can be white beeswax, yellow beeswax, or a combination thereof. The beeswax can be USDA certified organic beeswax or regular natural beeswax. According to one embodiment, at least one wax ester is synthetic beeswax.

[0059] According to one embodiment, wax ester particles can be emulsified in an ophthalmic suspension to form a series of specific particle sizes. The irregular shape and charge of the particles themselves allow wax ester particles to have more surface area to interact with oil as provided herein, and allow wax ester particles to decompose at a variable rate, wherein smaller wax ester particles and oil particles decompose quickly, and larger wax ester particles decompose more slowly. When wax ester particles decompose, it is believed that oil and wax ester particles interact with natural tear film to support a more stable barrier of an aqueous tear film that is easy to evaporate.

[0060] The ophthalmic suspensions provided herein include wax ester particles that exhibit a particle size that allows the wax ester particles to remain on the eye. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 2.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 3.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 4.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 5.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 30.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 25.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 24.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 23.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 22.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 21.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 20.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 2.0 microns but less than about 25.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 2.0 microns but less than about 20.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 2.0 microns but less than about 15.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 3.0 microns but less than about 24.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 4.0 microns but less than about 23.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 5.0 microns but less than about 22.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 6.0 microns but less than about 21.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 7.0 microns but less than about 20.0 microns.

[0061] The wax ester dispersion comprises at least one surfactant. According to one embodiment, the wax dispersion comprises two or more surfactants. According to one embodiment, the wax dispersion comprises a combination of surfactants for the dual purpose of stabilizing the suspension and spreading and maintaining the suspension on the ocular surface after being applied to the eyes. The surfactant combination may include a primary surfactant and a secondary surfactant. At least one surfactant is capable of forming a suspension that is stable during manufacture and storage, but is expected to be metastable when applied to the ocular surface. At least one surfactant as provided herein is suitable for rapid differentiation when applied to the eyes, thereby rapidly forming a non-fuzzy film of oil on the ocular surface, and the wax esters are spread through each phase of the emulsified suspension.

[0062] According to one embodiment, at least one surfactant includes at least one polyoxyethylene sorbitan monooleate, such as polyoxyethylene-sorbitan-20 monooleate, which is commercially available as polysorbate 80 or Tween 80. According to one embodiment, polyoxyethylene sorbitan monooleate may be present in the ophthalmic suspension in an amount of about 0.1% by weight to about 0.7% by weight. According to one embodiment, polyoxyethylene sorbitan monooleate may be present in the ophthalmic suspension in an amount of about 0.2% by weight to about 0.6% by weight. According to one embodiment, polyoxyethylene sorbitan monooleate may be present in the ophthalmic suspension in an amount of about 0.3% by weight to about 0.6% by weight. According to one embodiment, polyoxyethylene sorbitan monooleate may be present in the ophthalmic suspension in an amount of about 0.4% by weight to about 0.6% by weight.

[0063] According to one embodiment, at least one surfactant includes diphosphatidylglycerol, such as commercially available dimyristoylphosphatidylglycerol or 1,2-dimyristoyl-sn-glycero-3-phosphatidylglycerol sodium salt (DMPG). The surfactant can be lysophosphatidylcholine, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, or phosphatidylserine. In other embodiments, the surfactant includes at least one anionic surfactant. According to one embodiment, the anionic surfactant can be one or more of anionic polar phospholipids, such as lysophosphatidylcholine, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, or phosphatidylserine. According to another embodiment, the anionic polar phospholipid can be one or more of the following: phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), and its phosphorylated derivative phosphoinositide (e.g., phosphatidylinositol-4-phosphate [PI4P] and phosphatidylinositol-4,5-bisphosphate), and dimyristoylphosphatidylglycerol. According to one embodiment, the anionic surfactant is dimyristoylphosphatidylglycerol. According to one embodiment, the surfactant is a mixture of two surfactants as provided herein. According to one embodiment, the surfactant is a combination of two anionic polar phospholipids. According to one embodiment, the anionic polar surfactant is a mixture of Tween 80 and anionic polar dimyristoylphosphatidylglycerol.

[0064] According to one embodiment, dimyristoyl phosphatidylglycerol may be present in the ophthalmic suspension in an amount of about 0.1% to about 0.7% by weight. According to one embodiment, dimyristoyl phosphatidylglycerol may be present in the ophthalmic suspension in an amount of about 0.2% to about 0.6% by weight. According to one embodiment, dimyristoyl phosphatidylglycerol may be present in the ophthalmic suspension in an amount of about 0.3% to about 0.6% by weight. According to one embodiment, dimyristoyl phosphatidylglycerol may be present in the ophthalmic suspension in an amount of about 0.4% to about 0.6% by weight.

[0065] According to one embodiment, the ophthalmic suspension provided herein comprises one or more phosphate salts.According to one embodiment, the ophthalmic suspension comprises both monobasic phosphate salts and dibasic phosphate salts.

[0066] According to a specific embodiment, the monobasic phosphate is monosodium phosphate (sodium dihydrogen phosphate), such as NaH2PO4. According to one embodiment, the monobasic phosphate may be present in an amount of about 0.01% by weight to about 0.05% by weight. According to one embodiment, the monobasic phosphate may be present in an amount of about 0.02% by weight to about 0.04% by weight. According to one embodiment, the monobasic phosphate may be present in an amount of about 0.03% by weight.

[0067] According to a specific embodiment, the dibasic phosphate is disodium phosphate (sodium hydrogen phosphate or disodium hydrogen phosphate), such as Na2HPO4. According to one embodiment, the dibasic phosphate may be present in an amount of about 0.1% by weight to about 0.5% by weight. According to one embodiment, the dibasic phosphate may be present in an amount of about 0.2% by weight to about 0.3% by weight. According to one embodiment, the dibasic phosphate may be present in an amount of about 0.25% by weight.

[0068] According to one embodiment, the ophthalmic suspension provided herein comprises at least one salt. According to one embodiment, at least one salt is sodium chloride or other salt suitable for ophthalmic administration. At least one salt may be present in an amount of about 0.50% by weight to about 0.75% by weight. According to another embodiment, at least one salt may be present in an amount of about 0.55% by weight to about 0.70% by weight. According to another embodiment, at least one salt may be present in an amount of about 0.55% by weight. According to another embodiment, at least one salt may be present in an amount of about 0.67% by weight.

[0069] According to one embodiment, ophthalmic suspension provided herein includes at least one glycosaminoglycan. Suitable glycosaminoglycans include hyaluronic acid (HA), corresponding sodium salt sodium hyaluronate, or a combination thereof. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension in an amount of about 0.06% by weight to about 0.5% by weight. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension in an amount of about 0.07% by weight to about 0.4% by weight. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension in an amount of about 0.08% by weight to about 0.3% by weight. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension in an amount of about 0.09% by weight to about 0.2% by weight. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension in an amount of about 0.1% by weight.

[0070] According to one embodiment, the ophthalmic suspension provided herein optionally includes ethylenediaminetetraacetic acid (EDTA). According to one embodiment, EDTA can be present in the ophthalmic suspension in an amount of about 0.007% by weight to about 0.02% by weight. According to one embodiment, EDTA can be present in the ophthalmic suspension in an amount of about 0.008% by weight to about 0.015% by weight. According to one embodiment, EDTA can be present in the ophthalmic suspension in an amount of about 0.01% by weight.

[0071] According to one embodiment, the ophthalmic suspension provided herein optionally comprises at least one anti-inflammatory compound, such as inactivated brewer's yeast or adenosine diphosphate ribose. When present, the at least one anti-inflammatory compound does not affect the stability or ocular performance of the ophthalmic suspension. According to one embodiment, the anti-inflammatory compound may be present in the ophthalmic suspension in an amount of about 0.02% by weight to about 1.0% by weight.

[0072] Other additives may be present in the ophthalmic suspension. Such additives include small amounts of neutral lipids and oils, such as one or more triglycerides, partially hydrolyzed esters, cholesterol esters, high molecular weight isoprenoids; stabilizers, additional surfactants; mucus mimetics (e.g., HP guar gum); preservatives; pH adjusters; salts, buffers, glycerol, sugars, in concentrations sufficient to form a mild hypotonic composition so that the emulsion is unstable in the ocular environment; emollients; demulcents; polymers of ethylene oxide, propylene oxide, or butylene oxide; carboxymethylcellulose (CMC); hydroxypropyl methylcellulose (HPMC); polyacrylic acid (PAA); polyethylene glycol (PEG); propylene glycol (PG); or polyvinyl alcohol (PVA).

[0073] The ophthalmic suspensions provided herein have an osmotic pressure molar concentration, which can be adjusted by the concentration of salts such as NaCl. According to one embodiment, the ophthalmic suspensions provided herein have an osmotic pressure molar concentration of at least about 245mOsmol / kg. According to one embodiment, the ophthalmic suspensions provided herein have an osmotic pressure molar concentration of at least about 260mOsmol / kg. According to one embodiment, the ophthalmic suspensions provided herein have an osmotic pressure molar concentration of about 245mOsmol / kg to about 315mOsmol / kg. According to one embodiment, the ophthalmic suspensions provided herein have an osmotic pressure molar concentration of about 245mOsmol / kg to about 310mOsmol / kg. According to one embodiment, the ophthalmic suspensions provided herein have an osmotic pressure molar concentration of about 255mOsmol / kg to about 305mOsmol / kg. According to one embodiment, the ophthalmic suspensions provided herein have an osmotic pressure molar concentration of about 270mOsmol / kg to about 300mOsmol / kg. According to one embodiment, the ophthalmic suspension provided herein has an osmotic pressure molar concentration of about 275mOsmol / kg to about 295mOsmol / kg. According to one embodiment, the ophthalmic suspension provided herein has an osmotic pressure molar concentration of about 280mOsmol / kg to about 290mOsmol / kg. According to one embodiment, the ophthalmic suspension provided herein has an osmotic pressure molar concentration of about 282mOsmol / kg to about 289mOsmol / kg. According to one embodiment, the ophthalmic suspension provided herein has an osmotic pressure molar concentration of about 285mOsmol / kg to about 287mOsmol / kg. According to one embodiment, the ophthalmic suspension provided herein has an osmotic pressure molar concentration of about 286mOsmol / kg.

[0074] According to one embodiment, the ophthalmic suspension provided herein has a pH between about 6.8 and 7.8. According to one embodiment, the ophthalmic suspension provided herein has a pH between about 6.9 and 7.7. According to one embodiment, the ophthalmic suspension provided herein has a pH between about 7.0 and 7.6. According to one embodiment, the ophthalmic suspension provided herein has a pH between about 7.0 and 7.4. According to one embodiment, the ophthalmic suspension provided herein has a pH between about 7.1 and 7.5. According to one embodiment, the ophthalmic suspension provided herein has a pH between about 7.2 and 7.4. According to one embodiment, the ophthalmic suspension provided herein has a pH of about 7.2. According to one embodiment, the ophthalmic suspension provided herein has a pH of about 7.3. The pH can be adjusted by adding a pH adjusting agent such as HCl or citric acid or a base such as NaOH.

[0075] The viscosity of the ophthalmic suspension described herein can vary, but will show a viscosity that allows appropriate drop sizes to be applied to eyes. According to one embodiment, the viscosity of the ophthalmic suspension provided herein shows a viscosity of about 5 centipoise at 25 ° C to about 8 centipoise at 25 ° C. The viscosity of the ophthalmic suspension described herein can be measured using technology well known to those skilled in the art. The non-limiting examples of the method for measuring viscosity include a falling ball viscometer, a viscosity cup, a consistency meter (measuring flow on an inclined plane), a capillary glass viscometer, or a rotational viscometer. Various instruments are commercially available (Cole-Palmer Instrument Co., Ltd., Vernon Hills, IL, USA).

[0076] The ophthalmic suspension provided herein is preservative-free. In certain embodiments, due to the risk of bacterial contamination associated with conventional multiple use applications, the ophthalmic suspension without preservatives is delivered in a disposable package. In another embodiment, the ophthalmic suspension is delivered in a sterile multi-dose bottle. Examples include Aptar Pharma (Crystal Lake, IL, USA) multi-dose squeeze dispenser, which is mechanically operated and utilizes a filter membrane (see PCT Publication No. WO 2017 / 074420 and WO 2017 / 132190 (Aptar Group, Inc.); Nemera La Verpillier (France) multi-dose squeeze bottle (see PCT Publication WO 2013 / 140069)).

[0077] According to alternative embodiments, the ophthalmic suspensions provided herein may comprise at least one preservative.According to alternative embodiments, the ophthalmic suspensions provided herein may comprise at least one borate buffer.

[0078] A method for preparing an ophthalmic suspension vehicle is provided. According to one embodiment, the method for preparing an ophthalmic suspension vehicle comprises the following steps: preparing a mixture of oils (e.g., heavy mineral oil and light mineral oil) separately and adding a wax ester component such as beeswax, and heating the mixture to a temperature above the melting point of the wax ester (e.g., about 63°C to about 71°C). In a separate water / aqueous phase, salts, phosphates, surfactants, and any other water-soluble ingredients can be prepared and heated to about 85°C. The oil phase can then be slowly added to the water / aqueous phase, mixed, and homogenized to form an ophthalmic suspension vehicle. The resulting ophthalmic suspension vehicle is autoclaved. Throughout the process, the ophthalmic suspension vehicle is continuously mixed.

[0079] According to one embodiment, a method of preparing an ophthalmic suspension vehicle comprises the steps of separately preparing an oil phase (e.g., heavy mineral oil and light mineral oil) and heating to a temperature of about 63° C. to about 71° C. The step of preparing the oil phase may optionally include the steps of adding or introducing at least one wax ester to the oil phase and then heating the mixture to a temperature above the melting point of the wax ester (e.g., about 63° C. to about 71° C.).

[0080] According to one embodiment, the method of preparing an ophthalmic suspension vehicle includes a step of separately preparing an aqueous phase. The aqueous phase can be prepared by mixing at least one wax ester, at least one salt, at least one phosphate, at least one surfactant, and any other water-soluble ingredients, followed by heating the mixture to a temperature above the melting point of the wax ester (e.g., about 63° C. to about 71° C.).

[0081] According to one embodiment, the oil phase as provided herein can then be slowly added to the aqueous phase, mixed, and homogenized to form an ophthalmic suspension vehicle. The resulting ophthalmic suspension vehicle can then be autoclaved. Therefore, according to such an embodiment, the separate oil phase and aqueous phase are not autoclaved separately before combination. According to one embodiment, the resulting ophthalmic suspension vehicle is not autoclaved and is sterilized according to an alternative method such as, for example, electron beam or gamma irradiation, or filtration.

[0082] According to an alternative embodiment, a method for preparing an ophthalmic suspension vehicle is provided. The alternative method includes the step of preparing a wax dispersion by mixing or dissolving at least one wax ester (such as natural beeswax) with a surfactant and purified water or deionized water. According to one embodiment, the at least one wax ester can be mixed or dissolved in such a manner that the natural wax ester can be delivered in a controlled manner, resulting in an increased residence time on the eye. According to one embodiment, the step of preparing the wax dispersion includes dissolving one or more salts and one or more phosphates (such as monosodium phosphate and disodium phosphate) in purified water or deionized water. According to one embodiment, the step of preparing the wax dispersion includes heating the one or more salts, phosphates, surfactants and wax esters and stirring the resulting dispersion. According to one embodiment, the dispersion is heated to about 70°C to about 90°C. According to a particular embodiment, the wax particle dispersion can be prepared by homogenizing melted beeswax (about 1.0%) in purified or distilled water containing salts, phosphates and added Octoxynol-40 (about 0.2% 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol sodium salt (DMPG)) at about 75° C. The high cloud point (>100° C.) of Octoxynol-40 allows for emulsification efficiency at higher temperatures by reducing its water solubility (effective reduction of the HLB value).

[0083] An alternative method includes the steps of preparing an oil-in-water emulsion. According to one embodiment, the step of preparing the oil-in-water emulsion includes mixing mineral oils as described herein of different weights or viscosities, and heating the mixture of mineral oils to a temperature of about 65° C. to about 75° C. According to one embodiment, the step of preparing the oil-in-water emulsion includes introducing the heated mixture of mineral oils dropwise into purified water or deionized water, and homogenizing the water and mineral oil mixture to form the oil-in-water emulsion. The pH of the oil-in-water emulsion can be adjusted to a range of about 6.8 to about 7.8.

[0084] An alternative method includes the steps of separately autoclaving the wax dispersion and the oil-in-water emulsion. The integrity of the emulsion is maintained during autoclaving.

[0085] While not being bound by a particular theory, it is believed that the mechanism involved in the irreversible aggregation of wax (wax cracking) under autoclave conditions involves the presence of relatively high (nearly isotonic) salt concentrations. It is believed that this high ion loading significantly reduces the zeta potential of the wax ester particles, which eliminates an important stabilization mechanism when these dispersions are subjected to autoclave conditions.

[0086] An alternative method includes the step of aseptically blending an autoclaved beeswax dispersion and an oil-in-water emulsion to prepare an ophthalmic suspension vehicle as provided herein. According to one embodiment, the wax ester particles can be stabilized by a surfactant in the oil phase to prevent flocculation and droplet aggregation during cooling.

[0087] In order to maintain a storage-stable suspension, separate preparation and autoclaving of wax ester particle dispersion and emulsion components are carried out, followed by aseptic blending steps to ensure product sterility. The aseptic blending steps of autoclaved beeswax dispersion and oil-in-water emulsion ensure that the mineral oil, beeswax and other components of the desired final concentration are present in the ophthalmic suspension. According to one embodiment, the oil-in-water emulsion is formulated with an increased component level, and the beeswax particles are emulsified in water with an added surfactant. The concentration of various components in two parts (before autoclaving) can be customized to allow a relatively wide variation of the final emulsified suspension composition.

[0088] According to one embodiment, the preparation method includes the following steps: separately preparing a mixture of oils (e.g., heavy mineral oil and light mineral oil) and adding a wax ester component such as beeswax, and heating the mixture to a temperature above the melting point of the wax ester (e.g., 63° C. to 71° C.). In a separate phase, salts, phosphates, surfactants, and any other water-soluble ingredients are prepared and heated to about 85° C. The oil phase is slowly added to the water phase, mixed, and homogenized. The resulting preparation is autoclaved. Throughout the process, the preparation is continuously mixed.

[0089] According to one embodiment, the preparation method comprises the following steps: mixing an oil phase containing light minerals, mineral oils and wax esters (e.g., natural or synthetic beeswax) with an aqueous phase containing salts, phosphates, surfactants and water-soluble glycosaminoglycans, followed by homogenization and autoclaving to form a complex combination of particles. According to particle analysis via particle size analysis by Maiqike, larger particles of about 2 microns to about 15 microns were observed in the resulting preparation. According to one embodiment, the measurement of the zeta potential or surface charge of the particles shows that the zeta potential is greater than -60mV. According to one embodiment, the measurement of the zeta potential or surface charge of the particles shows that the zeta potential is about -60mV to about -110mV. In the preparation, there are both charged particles that may be found in the aqueous phase and particles of submicron size found in the oil phase. The particles in the oil phase can be wax-ester particles or oil wax-ester mixtures, which can have a neutral charge or a surface charge.

[0090] In the absence of added surfactants, large-sized particle dispersions cannot be prepared. The particle formation mechanism in operation is different from the simple nucleation and particle growth model used in the formation of submicron-sized dispersions. The added surfactant stabilizes the growing beeswax droplets during homogenization. The surfactant prevents the droplets from aggregating during the cooling period after autoclaving. The chemical properties of the system produce particle dispersions that are stable in the autoclave (as molten wax droplets), but once the sample temperature, which is reduced during sample cooling, approaches the melting point (crystallization temperature) of beeswax, these particle dispersions are irreversibly aggregated. Specifically, the presence of surfactants such as DMPG is also believed to help stabilize beeswax emulsions at high temperatures present in autoclaves. In particular, it is believed that surfactants stabilize the molten wax droplets by redistributing from the dissolved state in the aqueous phase to the particle / droplet surface and preventing flocculation. As the temperature increases continuously during the autoclave process, the surfactant becomes increasingly insoluble in water and tends to migrate toward the particle surface (droplet / aqueous interface), helping to stabilize the molten wax droplets.

[0091] Although the zeta potential value cannot be measured under autoclave conditions, the sealed beeswax particle / droplet dispersion remains stable at 121° C. (with mild stirring) when dispersed in water. In addition, the oil-in-water emulsions provided herein do not undergo a significant amount of particle aggregation when prepared according to the methods of the present invention. It is believed that the strong long-term stability characteristics are a result of such methods. Examples Ophthalmic suspension preparations

[0092] The ophthalmic suspensions utilized in the examples provided herein are described in Table 1 below. Table 1

[0093] To prepare a 500 gram batch of ophthalmic suspension, dissolve NaCl, dimyristoylphosphatidylglycerol (DPMG), NaH2PO4, and Na2HPO4 in purified water in a beaker. Add Tween 80, DPMG, and sodium hyaluronate to the aqueous solution and heat to 85°C (+ / - 2°C) with continuous stirring. In a separate glass beaker, 15. 35 and wax esters are mixed and heated to 71°C (+ / -2°C) for 10 minutes (+ / -20 seconds) under continuous stirring. The aqueous phase is homogenized for 30 seconds (+ / -5 seconds). The oil phase is preheated to 71°C (+ / -2°C) and added dropwise to the aqueous phase at 85°C (+ / -2°C) while the homogenizer is running. After the addition of the oil is complete, the homogenizer is run. The target homogenization speed is about 10,000RPM (+ / -400RPM) and the target homogenization time is about 4min (+ / -20 seconds). The homogenization procedure is terminated and stirring is continued until the suspension reaches room temperature (approximately 4 hours). While stirring, the pH and osmolality are checked and adjusted (target pH: 7.2-7.4; osmolality is 240mOsmol / kg-290mOsmol / kg). While stirring, the suspension mixture is dispensed into autoclavable bottles using a syringe and a magnetic stirring bar is loaded. The bottle and autoclave were sealed for 35 minutes (+ / - 1 minute) and heated to 121°C / heated at 121°C and 15 psi while stirring. The suspension was allowed to cool to room temperature (approximately 6 hours) while stirring. Example 1 Effects of wax esters on retention of eye emulsions

[0094] Tests were performed to determine the effect of wax esters on lipid layer thickness. Blurring and comfort scores were recorded when a single drop was instilled, and then interferometric measurements of lipid layer thickness were performed on both eyes at intervals of 5, 30, 60, and 120 minutes. The improvement in lipid layer thickness over baseline was calculated, and the net result of the control drops at each time interval was subtracted (or added). The results for the ophthalmic solutions of Table 1 are shown in Table 2. Ophthalmic solutions without wax esters (as XP is commercially available) and two other commercially available solutions - Refresh Advanced and Balance, wherein the results are shown in Tables 2, 3, 4 and 5 below, respectively. Table 2 Ophthalmic Suspension Table 3Refresh Advanced Table 4 XP (no wax) Table 5 Balance

[0095] Testing determined that mineral oil added alone to the ocular environment is rapidly lost, most likely by regular replacement of the tear film or ocular drainage through the lacrimal gland. The addition of wax esters was shown to provide an ophthalmic suspension that remains in the ocular environment for an extended period of time, thereby allowing the ophthalmic suspension to continue to grow with the increase in lipid layer. Example 2 Wax and Surfactant Selection

[0096] The inclusion of different wax esters provides an indication of the key properties required to maintain the effect of adding wax esters to the ocular environment. In order to understand the effect of lipid layer enhancement that exhibits enhancement, the effect of the use of wax ester ingredients and surfactant ingredients was evaluated. The following wax esters were evaluated: wax esters, Kester K-24, Branched Kester BK-40, and synthetic wax esters.

[0097] One or more of the following surfactants were used with the wax esters mentioned: DMPG dimyristoylphosphatidylglycerol (anionic phospholipid); IGEPAL CA 897 ethoxylated (40)-1,1,3,3-tetramethylbutylphenol; Phospholipon 90G phosphatidylcholine (zwitterionic charged phospholipid); and IGEPAL CO-890 branched polyoxyethylene (40) nonylphenyl ether. The results are summarized in Tables 6-10 below. Table 6 Beeswax Table 7 BK Kester Table 8 BK Kester / Kester K24 Table 9Kester K24 Table 10 Synthetic beeswax

[0098] The foregoing results demonstrate that the lower melting wax esters have no significant ocular effects relative to the control product and are similar to the commercially available product. Improved results were seen with natural and synthetic beeswax wax esters, with all surfactant combinations with natural beeswax wax esters showing the best results overall. Example 3 Choice of wax and surfactant combination

[0099] Natural and synthetic beeswax wax esters were tested to identify which surfactants allowed for rapid improvement of the lipid layer and prolonged residence time on the eye (in addition to in-bottle stability). One or more of the following surfactants were used with the wax esters mentioned: DMPG dimyristoylphosphatidylglycerol (anionic phospholipid); IGAPEL CA 897 ethoxylated (40)-1,1,3,3-tetramethylbutylphenol; Phospholipon 90G phosphatidylcholine (zwitterionic charged phospholipid); and IGEPAL CO-890 branched polyoxyethylene (40) nonylphenyl ether. The results for natural beeswax are summarized in Table 11 below. The results for synthetic beeswax are summarized in Table 12 below. Table 11. Table 12.

[0100] Natural beeswax wax esters and the anionic surfactant DMPG were shown to provide excellent results at all time intervals. In general, natural beeswax showed an average increase in lipid layer thickness that was achieved and maintained after 120 minutes. Example 4 granularity

[0101] In order to provide the desired properties, the oil and wax ester portions of the ophthalmic suspension should remain in the ocular environment for an extended period of time. The wax ester particle size is preferably maintained to provide a persistent lipid layer increase on the eye over time.

[0102] Particle size was determined using a Microtrac Sync 3R Flow device. Particle size analysis was performed using approximately 6.0 mL of sample, which can be stored in plastic bottles until testing. Each bottle was shaken 10 times prior to testing. The entire cap was then removed and approximately two drops of sample were transferred to the Microtrac Sync 3R Flow device using a plastic pipette. The sample was loaded into the particle size analyzer. Approximately two drops (0.060 g) of sample were injected into the 200 mL deionized water circulation chamber and the test was started.

[0103] The results for mineral oil alone indicate that the loss of added mineral oil will not exceed 30 minutes, as in competitive products The results are summarized in Table 13.

[0104] The processing parameter marked as "homogenizer" in Table 13 refers to processing only by the homogenizer in the range of about 10k rpm to about 18k rpm for about 4 minutes to about 8 minutes. Other processing parameters refer to the pressure of the microfluidizer system used to evaluate uniformity. This additional processing is added after the initial homogenization and results in a reduction in particle size but reduces clinical performance (average increase over baseline). More specifically, based on the particle size analysis performed on several test formulations, the processing of the homogenizer alone produces an average particle size in the range of 2 microns to 20 microns, while the samples further processed with the microfluidizer produce an average particle size of ≤1 micron. The actual measurement of the formulations determines a significant range of particle size and distribution. Specifically, formulations with an average particle size of about 1 micron will not remain in the eye, while the best performing formulations have an average particle size in the range of 5 microns to 20 microns under the measurement conditions. Table 13. Example 5 Ocular performance of ophthalmic suspensions

[0105] The study was conducted to evaluate the ocular performance of the ophthalmic suspensions as described in Table 1. Positive results were obtained in both the properties of the emulsified suspension and the ocular performance. In particular, patients who exhibited a reduction in tear film and a low lipid layer thickness (LLT) level were studied based on previous and current screening. The lipid layer thickness of the tear film at baseline was measured using interferometry. The range of the baseline lipid layer thickness of these patients was 25nm to 70nm, with an average of 45nm. A lipid layer thickness of less than 70nm was considered insufficient.

[0106] After baseline measurements were taken, a single test drop of the ophthalmic suspension of Table 1 (Example 1) and a single control drop were self-instilled into the contralateral eye. The control drops were selected as Ultra PF commercial solution (commercially available, preservative-free, lipid-free drops).

[0107] The primary objective was to evaluate increases in lipid layer thickness, and the first challenge was to develop strict inclusion and exclusion criteria for patient recruitment to select subjects with a chronically dry tear film due to evaporative dry eye (e.g., meibomian gland dysfunction or MGD), rather than subjects with partial blinking or a side effect of another medication or procedure. Primarily, the study looked for subjects with a baseline lipid layer thickness of less than 55 nm and a partial blink rate of less than 50% in at least one eye, both measured using LipiView (Johnson and Johnson). Additionally, patients with elevated risk factors such as other ocular diseases, pregnancy, or recent use of certain medications were not considered for the evaluation.

[0108] Once the inclusion criteria have been established, a formal protocol must be created for clinicians and staff to follow. In this document, each step of the patient evaluation process is listed in a checkbox format; from the initial patient evaluation and confirmation date of inclusion to the actual evaluation and measurement process. Each step is documented for physicians and staff to follow in order: 1. Confirmation of inclusion 2. Exclusion confirmation 3. Eye health examination (evaluation details to be determined by the physician) 4. Baseline LLT Reading 5. SPEED pre-assessment (Standardized patient assessment of dry eyes), see Korb et al. Lid wiper epitheliopathy and dryeye symptoms. Eye Contact Lens. 2005 Jan;31(1):2-8; and Korb et al. The effect of two novel lubricanteye drops on tear film lipid layer thickness in subjects with dry eyesymptoms. Optom Vis Sci. 2005 Jul;82(7):594-601, each incorporated by reference with respect to such investigational testing. 6. Test and Control Drop Instillation 7.Measure at 5, 30, 60, 120, 180, and 240 minute intervals 8. Post-SPEED evaluation

[0109] The drops were masked to the patients but not to the physicians and staff.All study results were recorded on a data record form, with the patient identity masked.

[0110] In two weeks, 12 patients completed the study. As shown in Tables 14 and 15, the results show the original average lipid layer thickness readings of 12 patients measured. The ophthalmic suspension of Table 1 shows a significant increase in lipid layer thickness at 5 minutes and 30 minutes. At all time points, there is a significant distinction between the ophthalmic suspension and the control drops. Compared with 61.8 (+ / - 2.2) nm of the control, the ophthalmic suspension maintains an average lipid layer thickness of 72.5 (+ / - 3.8) nm at the 4 hour mark. Table 14 Ophthalmic Suspension Time interval Lipid layer thickness (nm) Baseline 49.5 5 minutes 79.2 30 minutes 77.6 60 minutes 70.2 120 minutes 74.0 180 minutes 70.4 240 minutes 72.5 Table 15 Ultra Time interval Lipid layer thickness (nm) Baseline 57.6 5 minutes 66.8 30 minutes 66.2 60 minutes 61.3 120 minutes 61.1 180 minutes 63.5 240 minutes 61.2

[0111] Based on the raw data from the fellow eye, the mean baseline lipid layer thickness in the test eye and the control eye differed. Therefore, in addition to using the lipid layer thickness at each time point as the key indicator, the mean increase in lipid layer thickness from baseline was also evaluated for patients using both the test and control drops. Table 16 provides the increase in lipid layer thickness obtained from the ophthalmic suspensions as set forth in Table 1. Table 17 provides the increase in lipid layer thickness from the ophthalmic suspensions as set forth in Table 1. The thickness of the lipid layer obtained with Ultra PF solution was increased.

[0112] Clear differentiation of the test and control drops at each time point was demonstrated, with the ophthalmic suspension showing a nearly 50% increase in lipid layer thickness at the 4 hour mark. Thus, the decrease in lipid layer thickness was delayed to return to baseline well beyond the 4 hour mark. If the degradation rate remained linear, significant lipid layer thickness increases would likely occur well beyond 8 hours using only a single drop of the ophthalmic suspension. Table 16 Ophthalmic Suspension Table 17 Ultra

[0113] Immediately after the drops were instilled in each eye, the patients were asked two subjective questions. The first question asked the patients to rate their initial comfort from 0-100. The second question was to report the duration of any visual blur they noticed. For the ophthalmic suspension, the average patient comfort rating was noted to be 85 points (out of 100) and the minimum visual blur time was 5.6 seconds. For the control drops, the average results were 92 points (out of 100) and 2.9 seconds. Although there were differences in both indicators between the test and the control, the blur time for the ophthalmic suspension was less than 3 seconds, while the initial comfort rating differed by 7 points (out of 100).

[0114] Most patients reported no clouding with the ophthalmic suspension, with the longest duration of clouding being 30 seconds (one in the test eye and one in the control eye). Patient comfort ratings were similar and ranged from 45 to 100 in the test eye and 50 to 100 in the control eye. Based on thousands of hours of in-house testing, comfort and clouding were similar to the control solution.

[0115] The self-administered SPEED dry eye symptom questionnaire was incorporated into this study. A score of 8 or higher indicated the presence of dry eye. At the beginning of the test, before the drops were instilled, the patients responded with an average SPEED score of 13.58. All patients tested reported an initial SPEED score greater than 8.

[0116] After 4 hours had passed after the drops were instilled, the patients were retested using the SPEED. The average result of the post-evaluation was a score of 10.5, with no patients reporting an increase in the score and five patients reporting a score of less than 8. The evaluation did not differentiate symptoms between eyes. Because the experiments were performed in the fellow eye, it is difficult to delineate the effects of the ophthalmic suspension relative to control drops. The SPEED evaluation is designed to measure symptoms over a period of weeks or months, so the immediate results may not accurately reflect the symptoms a patient has. Finally, the time of day was a variable that was not controlled in this study and could have had an impact on the symptoms reported by the patients.

[0117] In summary, this study demonstrated that lipid layer thickness increased significantly over a four-hour interval relative to controls in an independent (arms-length), physician-managed study. Specifically, in the on-eye patient evaluation of the controls, the ophthalmics demonstrated a nearly 50% increase in lipid layer thickness at the 4-hour mark, resulting in a reduction in patient-reported dry eye symptoms. These benefits were observed without significant effects associated with initial drop comfort and visual blur.

[0118] While not being bound by a particular theory, as the wax ester particles dissolve, it is believed that the oil bound to the wax ester particles is released into the tear film and migrates to the surface, continuously replenishing the patient's weakened evaporative lipid barrier. Particles of different sizes dissolve at different rates. In fact, the widespread distribution of oil-bound wax ester particles creates a controlled release mechanism, delivering lipids to the tear film with each blink as the wax ester particles dissolve. Wax esters are believed to act as a mechanism to slow the drainage of the lipid layer through the puncta during the regular tear turnover process. Example 6 Comparison of ophthalmic suspensions with commercial artificial tears

[0119] A study was conducted to evaluate the ophthalmic suspensions as described in Table 1 in comparison with different commercially available artificial tear products ( Tears Again, Complete, Balance, XP, MGD and Refresh Advanced) on-eye performance.

[0120] The lipid layer thickness of the commercial product was measured up to 60 minutes. The ophthalmic suspension was measured up to 120 minutes and above. The test was open label and utilized Systane Ultra As a control. A total of 93 observations (n=93) were made in 12 commercially available products. The results showed that no product was able to increase the lipid layer thickness by more than 13 nm over the control at a 5-minute time interval, and the best performing commercial product showed a 10 nm increase over the control at a 60-minute time interval.

[0121] On average, there was an increase of 21 nm over the control at the 5 minute time interval, and at the 60 minute time point, the lipid layer thickness continued to increase to 24.7 nm (n=78). The pooled data are summarized in Tables 18 and 19. Table 18 Ophthalmic Suspension (n=78) Table 19 Commercial products (n=93)

[0122] Overall, the ophthalmic suspension showed a five-fold (5×) improvement in immediate lipid layer thickness increase in 78 cumulative observations compared to 93 cumulative observations for the 12 commercially available products. At the 60 minute mark, the difference in lipid layer thickness increase was eleven-fold (11×), with the ophthalmic suspension showing a 23 nm increase over baseline relative to the control compared to the commercial product which only showed a 2 nm increase over baseline relative to the control. Example 7 Tear film stability

[0123] The oil-in-water suspension containing the wax esters was compared with several other commercially available products.

[0124] Ophthalmic suspension containing beeswax: H714: 5.0 Dr-21, 10.0% Beeswax (Beeswax, Sesame Oil, Lecithin, Methyl Paraben, and Water) (Koster Keunen), 0.18 Tween-80, 0.1 EDTA, and ba / NaCl to 100 mOsm.

[0125] Water-soluble polymer solution No. 1: *DUASORB* (polymer system containing 0.1% dextran 70, 0.3% hydroxypropyl methylcellulose 2910), 0.001% polyquaternium-1, sodium borate, KCl, NaCl, H2O, and HCl and / or NaOH.

[0126] Tear film performance was evaluated by observing interference patterns using a standard fellow eye.For delivery methods, approximately 50 μL of standard full drops were delivered to the eyes of five subjects.

[0127] Wax-ester formulation H714 compared to water-soluble polymer solution No. 1: H714 performed very well in the interferometric analysis of tear film thickness. Initially, H714 scored 2.5 levels higher than baseline in the first two hours and returned to baseline after three hours. On the other hand, in one set of experiments, the water-soluble polymer solution was initially 2.0 levels higher than baseline, but weakened quite quickly within 30 minutes. In another set of experiments, after instillation, both H714 and the water-soluble polymer were about 1.8 levels higher than baseline. After 15 minutes, water-soluble polymer solution No. 1 was almost back to baseline, while H714 (about 1% beeswax) remained on the eyes for more than two hours. Water-soluble polymer No. 1, which showed an initial 2.0 score change, showed a substantial return to baseline at 1 hour. (See Figure 2). Example 8 Zeta potential and ion mobility analysis

[0128] Zeta potential testing was performed to evaluate the performance of various ophthalmic suspensions as Balance particle performance and stability of commercially available ophthalmic drops. Zeta potential indicates the degree of electrostatic repulsion between similarly charged particles in a dispersion. Typically, a high negative zeta potential is associated with stability (e.g., a dispersion will resist aggregation). In an ophthalmic context, the applicant has demonstrated that a higher negative potential translates directly into a longer residence time of an ophthalmic suspension on the eye.

[0129] For the same ophthalmic suspension and Balance Eye Drops was subjected to ion mobility testing to evaluate the particle velocity generated by the electric field.

[0130] The contents of the ophthalmic suspensions (Samples AF) tested are shown in Table 20. Sample A was homogenized at 10,000 RPM for two minutes with beeswax added to the water phase. Sample B was homogenized at 20,000 RPM for eight minutes with beeswax added to the water phase. Samples C and D were homogenized at 18,000 RPM for eight minutes with beeswax added to the water phase. Samples E and F were homogenized at 18,000 RPM for eight minutes with beeswax added to the oil phase and the oil and water phases were separated and tested. Balance eye drops contain propylene glycol (0.6%) lubricant as the main active ingredient and various inactive ingredients including boric acid, dimyristoyl phosphatidylglycerol, disodium EDTA, hydroxypropyl guar gum, mineral oil, polyoxyl 40 stearate, (Polyquaternium-1) 0.001% preservatives, sorbitan tristearate, sorbitol and purified water, and hydrochloric acid and / or sodium hydroxide to adjust pH.

[0131] The results of the zeta potential and ion mobility tests are provided in Table 21. Table 20 Table 21

[0132] Ophthalmic suspensions AF all exhibited a zeta potential of about -75 to about -95 and an ion mobility of about -6 to about -7.5. These results demonstrate that the ophthalmic suspensions as provided herein provide considerable stabilization of large particles and sustained thickening of the tear film, unlike Balance eye drops, which exhibit distinctly different zeta potentials and ion mobilities. Example 9 Suspension separation

[0133] The preparations of the formula in Table 1 were allowed to stand for at least two hours. The preparations showed separation of suspensions, which were shown as different regions of the oil phase to the water phase. The preparations were then dyed using a solid oil red dye, which preferentially dyed the oils of hydrocarbon oils in the preparations without dyeing the wax ester components. Microscopic observation of each phase showed different regions of the separated product, including an oil phase containing mineral oil and discrete undyed wax particles, which mainly had an estimated particle size of 200nm to 500nm, with some of the larger particles being greater than two microns. The samples of the preparations were separated into an oil phase and an water phase. Each was tested in the eye, where the results showed that the particles associated with the oil phase showed the main activity associated with the product enhancing the time of the lipid layer thickness. Example 10 USP (87) Biological Reactivity Test - Benzalkonium Chloride (BAK)

[0134] The test was conducted by a neutral third-party laboratory to determine the cytotoxicity of benzalkonium chloride (BAK) when used as a preservative in a standard topical saline ophthalmic solution vehicle. At the typical storage concentration (50ppm) used in ophthalmic products, BAK test solutions of various dilutions were subjected to USP (87) biological reactivity testing and graded according to reactivity. All solutions contained EDTA as an adjuvant to enable BAK to effectively fight Gram-negative bacteria. All negative and positive controls were nominal. All test solutions were graded as showing "severe" reactivity, which means that all cell layers were almost completely destroyed, and therefore the use of BAK did not meet USP requirements. Therefore, in summary, according to the USP (87) biological reactivity test, BAK (containing EDTA) causes severe reactivity at a concentration of 5% of the "use concentration" in typical ophthalmic products.

[0135] It should be understood that the above description represents only illustrative embodiments and examples. For the convenience of the reader, the above description focuses on a limited number of representative examples of all possible embodiments, examples of the principles of the present disclosure. This description does not attempt to exhaustively list all possible variations or even combinations of those variations described. Alternative embodiments may not be proposed for a specific portion of the present disclosure, or other alternative embodiments that may be available that are not described for a part should not be considered as a waiver of those alternative embodiments. Those of ordinary skill will understand that many embodiments in those undescribed embodiments relate to differences in technology and materials, rather than differences in the application of the principles of the present disclosure. Therefore, the present disclosure is not intended to be limited to less than the scope set forth in the following claims and equivalents.

[0136] It is to be understood that while the disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to be illustrative and not limiting of the scope. Other aspects, advantages and modifications are within the scope of the claims set forth below. General Statement of This Disclosure

[0137] The following numbered statements provide a general description of the disclosure and are not intended to limit the appended claims.

[0138] Statement 1. An ophthalmic suspension is provided comprising: i) an aqueous phase comprising water and one or more components selected from the group consisting of at least one wax ester, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt, and at least one phosphate; and ii) an oil phase comprising at least one mineral oil and optionally at least one wax ester. The wax ester exhibits an average particle size of at least about 5.0 microns using a Microtrac Particle Analyzer procedure to determine particle size.

[0139] Statement 2. The present disclosure provides an ophthalmic emulsified suspension as described in Statement 1.

[0140] Statement 3. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-2, wherein the ophthalmic suspension has an osmolality of about 245 mOsmol / kg to about 315 mOsmol / kg.

[0141] Statement 4. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-3, wherein the ophthalmic suspension is formulated as a free-flowing emulsified suspension at about 30°C.

[0142] Statement 5. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-4, wherein the wax ester is present at a concentration of about 0.8 weight % to about 1.2 weight %.

[0143] Statement 6. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-5, wherein the wax ester is natural beeswax.

[0144] Statement 7. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-6, wherein the ophthalmic suspension exhibits a negative zeta potential of about -60 mV to about -110 mV.

[0145] Statement 8. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-7, wherein the ophthalmic suspension exhibits an ion mobility of about -5.9 (μms) / (V / cm) to about -7.4 (μms) / (V / cm).

[0146] Statement 9. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-8, wherein the oil is a mixture of light mineral oil and heavy mineral oil.

[0147] Statement 10. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-9, wherein the light mineral oil exhibits a viscosity of about 3.0 mm at 40°C. 2 s -1 to about 34.4mm 2 s -1 The heavy mineral oil exhibits a dynamic viscosity of about 34.5 mm at 40°C. 2 s -1 To about 150mm 2 s -1 The viscosity of the dynamic viscosity.

[0148] Statement 11. The present disclosure provides an ophthalmic suspension as described in any of Statements 1-10, further comprising an anionic polar surfactant comprising a mixture of a polysorbate nonionic surfactant at a concentration of about 0.35 weight % to about 0.45 weight % and an anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 weight % to about 0.55 weight %.

[0149] Statement 12. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-11, which is packaged in a sterile multiple-use or sterile single-use container.

[0150] Statement 13. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-12, packaged in a multi-dose non-preserved (MDNP) container or a container comprising at least one preservative.

[0151] Statement 14. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-13, wherein the ophthalmic suspension increases the thickness of the lipid layer by at least 20 nanometers five minutes after administration.

[0152] Statement 15. The present disclosure provides an ophthalmic suspension as described in any one of Statements 1-14, wherein the ophthalmic suspension increases the thickness of the lipid layer by at least 20 nanometers four hours after administration.

[0153] Statement 16. A method of increasing lipid layer thickness is provided, and the method comprises the step of administering to an eye of a patient in need of treatment the ophthalmic suspension of any one of Statements 1-15.

[0154] Statement 17. The present disclosure provides a method of increasing lipid layer thickness as described in Statement 16, wherein the lipid layer thickness is increased by at least 20 nm within five minutes of administration.

[0155] Statement 18. The present disclosure provides a method of increasing lipid layer thickness as described in any of Statements 16-17, wherein the lipid layer thickness is increased by at least 20 nm four hours after administration.

[0156] Statement 19. The present disclosure provides a method of lubricating an eye, the method comprising administering to an eye of a patient in need of treatment the ophthalmic suspension of any one of Statements 1-15.

[0157] Statement 20. The present disclosure provides a method for alleviating symptoms of dry eye disease, the method comprising administering to an eye of a patient in need of treatment the ophthalmic suspension of any one of Statements 1-15.

[0158] Statement 21. An ophthalmic suspension is provided, comprising a wax dispersion comprising (a) water; (b) at least one oil; (c) a surfactant; and (d) at least one wax ester present at a concentration of about 0.5% to about 1.5% by weight. The at least one wax ester in the ophthalmic suspension binds to the mucin layer, the aqueous layer, and the lipid layer in the eye of a subject and functions to maintain or enhance the integrity of the interstitial layer between the mucin layer and the aqueous layer, and the interstitial layer between the aqueous layer and the lipid layer.

[0159] Statement 22. The present disclosure provides an ophthalmic solution as described in Statement 21, wherein the at least one wax ester acts to increase the thickness of the mucin layer, the aqueous layer, the lipid layer, or a combination thereof.

[0160] Statement 23. The present disclosure provides an ophthalmic suspension as described in any of Statements 21-22, wherein the binding and stabilization achieved by the wax, wax ester or hydrolysate allows the mucin layer, aqueous layer and lipid layer of the tear film to interact with each other, thereby allowing the tear film to be retained on the eye for an extended period of time (e.g., at least two hours).

[0161] Statement 24. An ophthalmic suspension is provided which exhibits a zeta potential of about -60 mV to about -110 mV.

[0162] Statement 25. An ophthalmic suspension is provided which forms a metastable emulsion which separates into an oil phase and an aqueous phase upon contact with the eye and provides lubrication on the eye for about 2 hours to about 12 hours.

[0163] Statement 26. A method for alleviating symptoms of dry eye is provided, the method comprising the step of contacting the eye with the ophthalmic suspension of any one of Statements 21-25.

[0164] Statement 27. The present disclosure provides a method for alleviating symptoms of dry eye as described in Statement 26, wherein upon contact with the eye, the ophthalmic suspension interacts with: the lipid layer; the aqueous layer; the mucin layer; the interface between the lipid layer and the aqueous layer; and the interface between the aqueous layer and the mucin layer of the eye and unprotected corneal cells.

[0165] Statement 28. The present disclosure provides a method of alleviating symptoms of dry eye as described in any of Statements 26-27, wherein the wax ester of the ophthalmic suspension is natural beeswax or synthetic beeswax.

[0166] Statement 29. The present disclosure provides a method of alleviating dry eye symptoms as described in any of Statements 26-28, wherein the oil is a mixture of a lighter mineral oil and a heavier mineral oil.

[0167] Statement 30. The present disclosure provides a method of alleviating dry eye symptoms as described in any of Statements 26-29, wherein the oil is present at a concentration of about 1.0 wt % to about 5 wt %.

[0168] Statement 31. The present disclosure provides a method of alleviating dry eye symptoms as described in any of Statements 26-30, wherein the surfactant is a mixture of two or more surfactants.

[0169] Statement 32. The present disclosure provides a method for relieving symptoms of dry eye as described in any of Statements 26-31, wherein (i) the oil is a mixture of a lighter oil and a heavier oil and is present at a concentration of about 1.0 weight % to about 5.5 weight %; (ii) the surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 weight % to about 0.45 weight % and dimyristoylphosphatidylglycerol at a concentration of about 0.3 weight % to about 0.5 weight %; (iii) the wax ester is natural or synthetic beeswax, which is present at a concentration of about 0.5 weight % to about 1.0 weight %; and the ophthalmic suspension has a weight osmotic pressure molar concentration of about 245 mOsmol / kg to about 310 mOsmol / kg.

[0170] Statement 33. The present disclosure provides a method of alleviating dry eye symptoms as described in any one of Statements 26-32, wherein the ophthalmic suspension is packaged in a sterile multiple-use or sterile single-use container.

[0171] Statement 34. The present disclosure provides a method of alleviating dry eye symptoms as described in any of Statements 26-33, wherein the ophthalmic suspension is packaged in a multi-dose non-preserved (MDNP) container or a container comprising at least one preservative.

[0172] Statement 35. The present disclosure provides a method for preparing an ophthalmic suspension comprising the steps of: (a) preparing a suspension of a wax ester and a surfactant in purified or deionized water; (b) preparing an oil-in-water emulsion comprising a suspension of oil in purified or deionized water; (c) separately autoclaving the beeswax dispersion and the oil-in-water emulsion; and (d) aseptically blending the autoclaved beeswax dispersion and the oil-in-water emulsion to prepare a metastable oil-in-water emulsion ophthalmic suspension.

[0173] Statement 36. The present disclosure provides a method of preparing an ophthalmic suspension as described in Statement 35, wherein the ophthalmic solution provides lubrication on the eye for at least about 2 hours.

[0174] Statement 37. The present disclosure provides a method of preparing an ophthalmic suspension as described in any of Statements 35-36, wherein the ophthalmic solution provides lubrication on the eye for at least about 12 hours.

[0175] Statement 38. The present disclosure provides a method for preparing an ophthalmic suspension as described in any of Statements 35-37, wherein upon contact with the eye, the ophthalmic suspension penetrates: the lipid layer; the aqueous layer; the mucin layer; the interface between the lipid layer and the aqueous layer; and the interface between the aqueous layer and the mucin layer of the eye and unprotected corneal cells.

[0176] Statement 39. The present disclosure provides a method of preparing an ophthalmic suspension as described in any one of Statements 35-38, wherein the wax ester is natural beeswax.

[0177] Statement 40. The present disclosure provides a method of preparing an ophthalmic suspension as described in any one of Statements 35-39, wherein the beeswax is synthetic beeswax.

[0178] Statement 41. The present disclosure provides a method of preparing an ophthalmic suspension as described in any of Statements 35-40, wherein the oil is a mixture of a lighter oil and a heavier oil.

[0179] Statement 42. The present disclosure provides a method of preparing an ophthalmic suspension as described in any of Statements 35-41, wherein the surfactant is a mixture of two or more surfactants.

[0180] Statement 43. The present disclosure provides a method for preparing an ophthalmic suspension as described in any of Statements 35-42, wherein (i) the oil is a mixture of light oil and heavy oil and is present at a concentration of about 1.0 weight % to about 5.5 weight %; (ii) the surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 weight % to about 0.45 weight % and dimyristoylphosphatidylglycerol at a concentration of about 0.3 weight % to about 0.5 weight %; (iii) the wax ester is natural beeswax or synthetic beeswax, which is present at a concentration of about 0.25 weight % to about 1.0 weight %; and the ophthalmic suspension has a weight osmotic pressure molar concentration of about 245 mOsmol / kg to about 310 mOsmol / kg.

[0181] Statement 44. The present disclosure provides a method of preparing an ophthalmic suspension as described in any one of Statements 35-43, wherein the ophthalmic suspension is packaged in a sterile multiple-use or sterile single-use container.

[0182] Statement 45. The present disclosure provides a method of preparing an ophthalmic suspension as described in any of Statements 35-44, wherein the ophthalmic suspension is packaged in a multi-dose non-preserved (MDNP) container or a container comprising at least one preservative.

[0183] Statement 46. The present disclosure provides a method of preparing an ophthalmic suspension as described in any one of Statements 35-44, wherein the ophthalmic suspension is packaged in a container containing a preservative.

[0184] Statement 47. The present disclosure provides a method of preparing an ophthalmic suspension as described in any of Statements 35-46, wherein the wax ester acts to increase the thickness of the mucin layer, the aqueous layer, the lipid layer, or a combination thereof.

[0185] Statement 48. The present disclosure provides a method for preparing an ophthalmic suspension as described in any of Statements 35-47, wherein the binding and stabilization achieved by the wax ester allows the mucin layer, aqueous layer, and lipid layer of the tear film to interact with each other, thereby allowing the tear film to remain on the eye for at least two hours.

[0186] Statement 49. The present disclosure provides a method of preparing an ophthalmic suspension, the method comprising the steps of: (a) preparing an oil phase; (b) preparing an aqueous phase; (c) mixing the oil phase and the aqueous phase to form the ophthalmic suspension; (d) and autoclaving the ophthalmic suspension.

[0187] Statement 50. The present disclosure provides a method of preparing an ophthalmic suspension as described in Statement 49, wherein the step of preparing the oil phase (e.g., heavy mineral oil and light mineral oil) comprises heating to a temperature of about 63°C to about 71°C.

[0188] Statement 51. The present disclosure provides a method for preparing an ophthalmic suspension as described in Statements 49-50, wherein the step of preparing the oil phase includes the steps of adding or introducing at least one wax ester into the oil phase and then heating the mixture to a temperature above the melting point of the wax ester (e.g., from about 63°C to about 71°C).

[0189] Statement 52. The present disclosure provides a method for preparing an ophthalmic suspension as described in Statements 49-51, wherein the aqueous phase can be prepared by mixing at least one wax ester, at least one salt, at least one phosphate, at least one surfactant, and any other water-soluble ingredients, and then heating the mixture to a temperature above the melting point of the wax ester (e.g., from about 63°C to about 71°C).

[0190] Statement 53. The present disclosure provides a method of preparing an ophthalmic suspension as described in Statements 49-52, wherein the separate oil phase and aqueous phase are not separately autoclaved prior to combining.

[0191] Statement 54. The present disclosure provides an ophthalmic suspension consisting of: a wax dispersion comprising natural beeswax particles, an anionic polar surfactant and water; Sodium hyaluronate; and Oil-in-water emulsions comprising oil and water; and Optionally, at least one preservative selected from the group consisting of polyhexamethylene biguanide, a stable oxychloro complex and polyquaternium-1, in: (i) the oil is a mixture of a lighter molecular weight mineral oil and a heavier molecular weight mineral oil and is present in a concentration of about 4.0 weight percent to about 6.25 weight percent; (ii) the anionic polar surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 wt % to about 0.45 wt % and anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 wt % to about 0.50 wt %; and (iii) the natural beeswax particles are solid up to about 60°C and are present in a concentration of about 0.50% to about 1.25% by weight; and Ophthalmic suspension vehicle: (i) forms a metastable emulsion which separates into an oily and aqueous phase upon contact with the eye; (ii) provides a residence time on the eye of at least two hours; (iii) formulated to be a free-flowing liquid at room temperature; (iv) has an osmolarity of about 230 mOsmol / kg to about 260 mOsmol / kg; and (v) has a pH of about 6.5 to about 7.8.

[0192] Statement 55. The present disclosure provides an ophthalmic suspension as described in Statement 54, wherein the beeswax is present at a concentration of about 1.0 weight %.

[0193] Statement 56. The present disclosure provides an ophthalmic suspension as described in Statements 54-55, wherein the beeswax is white beeswax or yellow beeswax.

[0194] Statement 57. The present disclosure provides an ophthalmic suspension as described in Statements 1-56, which is packaged in a sterile single-use container.

[0195] Statement 58. The present disclosure provides an ophthalmic suspension as described in Statements 1-56, which is packaged in a sterile multi-dose container.

[0196] Statement 59. The present disclosure provides a finished pharmaceutical product comprising an ophthalmic suspension vehicle as described in Statements 1-56.

[0197] Statement 60. The present disclosure provides a finished pharmaceutical product comprising an ophthalmic suspension vehicle as described in Statements 1-56.

[0198] Statement 61. The present disclosure provides a finished pharmaceutical product comprising an ophthalmic suspension vehicle as described in Statements 1-56.

Claims

1. An ophthalmic suspension comprising i) an aqueous phase comprising water and one or more components selected from the group consisting of at least one wax ester, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt, and at least one phosphate; and ii) an oily phase comprising at least one mineral oil and optionally at least one wax ester, wherein the suspension exhibits an average particle size of at least about 2.0 microns.

2. The ophthalmic suspension of claim 1 having an average particle size distribution of at least about 2.0 microns to about 20.0 microns.

3. The ophthalmic suspension according to claim 1, wherein The ophthalmic suspension has an osmolarity of about 245 mOsmol / kg to about 315 mOsmol / kg.

4. The ophthalmic suspension according to claim 1, wherein The ophthalmic suspension is formulated as a free-flowing emulsified suspension at about 30°C.

5. The ophthalmic suspension according to claim 1, wherein The wax ester is present in a concentration of about 0.8 wt % to about 1.2 wt %.

6. The ophthalmic suspension according to claim 1, wherein The ophthalmic suspension exhibits a negative zeta potential of about -60 mV to about -110 mV.

7. The ophthalmic suspension according to claim 1, wherein The ophthalmic suspension exhibits an ion mobility of about -5.9 (μms) / (V / cm) to about -7.4 (μms) / (V / cm).

8. The ophthalmic suspension according to claim 1, wherein The oil is a mixture of light mineral oil and heavy mineral oil.

9. The ophthalmic suspension according to claim 8, wherein The light mineral oil exhibits a viscosity of about 3.0 mm at 40°C. 2 s- 1 to about 34.4mm 2 s- 1 The heavy mineral oil exhibits a dynamic viscosity of about 34.5 mm at 40°C. 2 s- 1 To about 150mm 2 s- 1 The viscosity of the dynamic viscosity.

10. The ophthalmic suspension of claim 1 further comprising an anionic polar surfactant comprising a mixture of a polysorbate nonionic surfactant at a concentration of about 0.35 wt % to about 0.45 wt % and an anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 wt % to about 0.55 wt %.

11. The ophthalmic suspension of claim 1, packaged in a sterile multiple-use or sterile single-use container.

12. The ophthalmic suspension of claim 1 packaged in a multi-dose non-preserved (MDNP) container or a container comprising at least one preservative.

13. The ophthalmic suspension according to claim 1, wherein The ophthalmic suspension increases the lipid layer thickness by at least 20 nanometers 60 minutes after administration.

14. The ophthalmic suspension according to claim 1, wherein The ophthalmic suspension increases the lipid layer thickness by at least 20 nanometers two hours after administration.

15. A method for maintaining the integrity of the tear film layer of an eye and increasing the thickness of the lipid layer of the eye, the method comprising the steps of: The ophthalmic suspension of claim 1 is administered to the eye of a patient in need of treatment.

16. The method of claim 15, wherein: The integrity of the tear film was maintained 60 minutes after application and the lipid layer thickness was increased by at least 20 nm.

17. A method of recreating or building one or more layers of the tear film of an eye, the method comprising the steps of: administering the ophthalmic suspension of claim 1 to the eye of a patient in need of treatment, wherein, upon administration, the ophthalmic suspension reconstitutes or rebuilds one or more layers of the tear film of the eye.

18. A method for lubricating an eye, the method comprising the steps of: administering the ophthalmic suspension of claim 1 to the eye of a patient in need of treatment, wherein, upon administration, the ophthalmic suspension reconstructs or rebuilds one or more layers of the tear film of the eye and maintains the integrity of the tear film for more than 60 minutes.

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