Sustained release of oleic acid from contact lenses

Abstract

Oleic acid releasing contact lenses and methods of making the same are described. The oleic acid releasing contact lenses comprise glycerophospholipids containing an oleoyl group at the sn-2 position and sustain the release of oleic acid in the presence of sPLA2 enzymes present in human tears. The oleic acid releasing contact lenses may increase the duration of comfortable wear and / or reduce lens sensation events in symptomatic contact lens wearers.

Description

[Technical field]

[0001] The field of the invention relates to contact lenses, and in particular to contact lenses that are more comfortable for the contact lens wearer. [Background technology]

[0002] An estimated 50% of all contact lens wearers experience discomfort while wearing their lenses, and approximately 25% of these contact lens wearers permanently discontinue wearing lenses. The primary reason for contact lens dissatisfaction among contact lens wearers is the sensation of lens sensitivity. Despite advances in contact lens materials, a need exists for improved contact lenses that are comfortable to wear for contact lens wearers who experience the sensation of lens sensitivity while wearing currently available contact lenses. Fatty acids are known to act as comfort agents that can provide lubrication and reduce discomfort when administered to the eye. Fatty acids acting as comfort agents can be released from contact lenses in sufficient amounts to soothe the eye during wear, thus reducing discomfort (US Patent Publication No. 20220187620). However, some contact lens materials cannot sustain fatty acid release throughout the day. It would be desirable to obtain a sustained release rate of fatty acids from contact lenses, thereby enhancing the comfort of contact lens wear in contact lens wearers and increasing the duration over which contact lens wearers can comfortably wear the contact lenses. Alternatively or additionally, it would be desirable to provide improved contact lenses that can be worn by contact lens wearers. Summary of the Invention

[0003] It is a feature of the present invention to provide a hydrogel contact lens capable of releasing oleic acid and its salts during lens wear. The term "oleic acid" is used herein to refer to both oleic acid in its free acid form and as a salt. A further feature of the present invention is to provide a contact lens that is comfortable to wear for the contact lens wearer. A further feature of the present invention is to increase the duration of comfortable lens wear and / or reduce lens sensation events in contact lens wearers. Additional features and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The objectives and other advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims.

[0004] To achieve these and other advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, the invention relates, in part, to a hydrogel contact lens comprising a polymeric lens body loaded with 2-oleoyl phospholipids. The 2-oleoyl phospholipids are advantageously susceptible to digestion by secretory phospholipase 2-acyl hydrolase (sPLA2) enzymes, particularly group IIA secretory phospholipase 2-acyl hydrolase (sPLA2-IIA), found in human tears. The 2-oleoyl phospholipids present in the contact lens body are advantageously susceptible to digestion by sPLA2 enzymes, particularly sPLA2-IIA, found in human tears when the 2-oleoyl phospholipids are present in the polymeric lens body of a silicone hydrogel contact lens, e.g., a stenfilcon A contact lens. A 2-oleoylphospholipid may be considered susceptible to digestion by sPLA2 enzyme if the amount of oleic acid released from a stenfilcon A lens loaded with at least 200 μg of 2-oleoylphospholipid in a release medium containing sPLA2 enzyme is at least twice, e.g., at least three times, the amount of oleic acid released in an otherwise identical control release medium lacking phospholipase A2 enzyme after identical stenfilcon A contact lenses loaded with each of said 2-oleoylphospholipids are immersed in each release medium at 35° C. for 4 hours. The release medium containing sPLA2 enzyme may be an artificial tear solution (ATF) such as that defined in Table 1 below, further containing 50 ppm recombinant human sPLA2-IIA, and the control release medium lacking phospholipase A2 enzyme may be an otherwise identical ATF release medium lacking phospholipase A2 enzyme. Alternatively, the release medium containing sPLA2 enzyme may be a reflex tear solution and the control release medium may be an ATF.For the avoidance of doubt, while the determination of whether a 2-oleoylphospholipid is susceptible to digestion by sPLA2 enzymes can be performed by loading the 2-oleoylphospholipid into a stenfilcon A lens, the contact lenses of the present invention, including those containing a 2-oleoylphospholipid determined to be susceptible to digestion by sPLA2 enzymes, do not have to be stenfilcon A lenses, but can be silicone hydrogel lenses of any formulation. In all aspects of the present invention, the contact lenses loaded with 2-oleoylphospholipids susceptible to digestion by sPLA2 enzymes can be any contact lens described herein. For comparison, one example of a phospholipid that has been found not to be susceptible to digestion by sPLA2 enzymes found in human tears when present in a silicone hydrogel contact lens body is dimyristoylphosphatidylcholine, i.e., 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). The phospholipid can be an anionic glycerophospholipid or a zwitterionic glycerophospholipid. Anionic glycerophospholipids have a phospholipid head group (i.e., R in formula (I) below). 3 2-oleoyl phospholipids contain an anionic (negatively charged) substrate group attached at the aryl group (position).

[0005] [ka] Formula (I) [wherein X is either -O- or -O(CO)-; R 1 is C 11-25 is alkyl, R 2 is CH3(CH2)7CH=CH(CH2)7-, and R 3 is hydrogen, C 1-10 polyols (e.g., glycerol or inositol), ethanolamine (-CHCHNH) and serine (-CHCH(NH)COOH), and salts of phospholipids of formula (I) (e.g., 3 is a negative charge, or a deprotonated anionic group, e.g., -CHCH(NH)COO -The hydrogel contact lenses of the present invention have been found to sustain the release of oleic acid, thereby enhancing contact lens comfort in the lens wearer and / or increasing the duration of comfortable contact lens wear in the contact lens wearer.

[0006] In one example, the hydrogel contact lens is capable of releasing 0.05 μg to 50 μg, 0.1 μg to 25 μg, 0.5 μg to 10 μg, particularly 1 to 5 μg of oleic acid after 1 hour of immersion in an in vitro release medium including ATF containing 50 ppm sPLA2-IIA enzyme solution in phosphate buffered saline (PBS) at 35° C.

[0007] The present invention further relates to a method of making the hydrogel contact lenses of the present invention, the method comprising the steps of: a) polymerizing a polymerizable composition (as described herein) in a contact lens mold to obtain a polymeric lens body, b) removing the polymeric lens body from the contact lens mold, c) extracting the polymeric lens body in an organic solvent containing 2-oleoyl phospholipid, d) hydrating the polymeric lens body in a hydration liquid to obtain a hydrogel contact lens, e) sealing the hydrogel contact lens in a package with a packaging solution, and f) autoclaving the package. The hydration step d) may be performed before the extraction step c) in which the 2-oleoyl phospholipid is loaded into the polymeric lens body. If the hydration step d) is performed before the extraction step c) in which the 2-oleoyl phospholipid is loaded into the polymeric lens body, a further hydration step may be performed after step c). The present invention further relates to a method of correcting the vision of a symptomatic contact lens wearer by providing the symptomatic contact lens wearer with an oleic acid releasing hydrogel contact lens comprising a polymeric lens body loaded with 2-oleoylphospholipid. Advantageously, the oleic acid releasing hydrogel contact lens increases the duration of comfortable contact lens wear and / or reduces lens sensation events in the symptomatic contact lens wearer compared to a control lens not containing the 2-oleoylphospholipid. Advantageously, the 2-oleoylphospholipid, e.g., the 2-oleoylphospholipid of formula (I), when present in a polymeric lens body, is susceptible to digestion by sPLA2 enzymes, particularly sPLA2-IIA, found in human tears.

[0008] Additionally, the present invention relates to the use of oleic acid releasing hydrogel contact lenses containing 2-oleoyl phospholipid by a contact lens wearer to increase the duration of comfortable contact lens wear and / or reduce lens sensation events compared to control lenses not containing 2-oleoyl phospholipid. The present invention further relates to the use of a contact lens comfort enhancing amount of 2-oleoyl phospholipid, wherein the phospholipid is associated with a polymeric lens body of the contact lens. The present invention further relates to a hydrogel composition for use in reducing the sensation of lens sensation in a contact lens wearer, thereby enhancing contact lens comfort in a contact lens wearer and / or increasing the duration of comfortable contact lens wear in a contact lens wearer, the hydrogel composition comprising a polymeric lens body that is the reaction product of (a) a polymerizable composition loaded with (b) an amount of 2-oleoyl phospholipid.

[0009] In all aspects of the present invention, the 2-oleoylphospholipid is advantageously susceptible to digestion by sPLA2 enzymes found in human tears, particularly Group IIA sPLA2, when the 2-oleoylphospholipid is present in the polymeric lens body of a silicone hydrogel contact lens. In all aspects of the invention, contact lenses comprising polymeric lens bodies loaded with 2-oleoyl phospholipids may be characterized in that (a) when the contact lens is immersed two, e.g., three times, for 4 hours in human reflex tears at 35° C., a greater amount of oleic acid is detected in the reflex tears than when the lens is immersed for 4 hours at 35° C. in a release medium lacking phospholipase A2 enzyme, and / or (b) when the contact lens is immersed two, e.g., three times, for 4 hours at 35° C. in artificial tears (ATF) containing 50 ppm recombinant human Group IIa secretory phospholipase A2, a greater amount of oleic acid is detected in the ATF than when the lens is immersed for 4 hours at 35° C. in an equivalent ATF release medium lacking phospholipase A2 enzyme.

[0010] Further aspects of the invention are provided in the following numbered paragraphs. 1. An unworn silicone hydrogel contact lens sealed in a package, the unworn silicone hydrogel contact lens comprising a polymeric lens body loaded with an amount of 2-oleoyl phospholipid. 2. A silicone hydrogel contact lens of paragraph 1, wherein the 2-oleoyl phospholipid, when present in the polymer lens body, is susceptible to digestion by the secretory phospholipase A2 (sPLA2) enzyme found in human tears. 3. A contact lens according to item 1 or 2, which releases oleic acid when the hydrogel contact lens comes into contact with a solution containing sPLA2-IIA. 4. A silicone hydrogel contact lens of any preceding paragraph, which when contacted with artificial tear fluid (ATF) containing 50 ppm human sPLA2 for 4 hours at 37°C releases at least two times more oleic acid than when contacted with ATF containing no human sPLA2. 5. The silicone hydrogel contact lens of any preceding paragraph, wherein the 2-oleoyl phospholipid is phosphatidylserine, phosphatidylethanolamine, or phosphatidylglycerol. 6. The silicone hydrogel contact lens of any preceding clause, wherein the 2-oleoyl phospholipid is selected from 1,2-dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoylphosphatidylserine (DOPS), and 1,2-dioleoylphosphatidylethanolamine (DOPE). 7. The silicone hydrogel contact lens of any preceding paragraph, wherein the polymeric lens body is the reaction product of a polymerizable composition comprising at least one hydrophilic monomer containing a vinyl group. 8. The silicone hydrogel contact lens of any preceding clause, wherein the polymeric lens body is the reaction product of a polymerizable composition comprising, by weight, 25% to 55% siloxane monomers, 30% to 55% vinyl monomers selected from N-vinylpyrrolidone, N-vinyl-N-methylacetamide, or combinations thereof, and optionally, about 1% to about 20% hydrophilic monomers selected from N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), or ethylene glycol methyl ether methacrylate (EGMA), or any combinations thereof, and optionally about 1% to about 20% hydrophobic monomers selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), or 2-hydroxybutyl methacrylate (HOB), or any combinations thereof. 9. The polymeric lens body is represented by the formula (II)

[0011] [ka] Formula (II) A first siloxane having a structure represented by: and formula (III)

[0012] [ka] Formula (III). A second siloxane having a structure represented by The contact lens of any preceding claim, which is the reaction product of a polymerizable composition comprising: 10. A contact lens of any preceding clause, wherein the polymeric lens body is loaded with at least 10 μg of 2-oleoyl phospholipid, in particular at least 10 μg of 2-oleoyl phosphatidylserine, 2-oleoyl phosphatidylethanolamine, or 2-oleoyl phosphatidylglycerol, e.g., at least 10 μg of 1,2-dioleoyl phosphatidylserine (DOPS), 1,2-dioleoyl phosphatidylethanolamine (DOPE), or 1,2-dioleoyl phosphatidylglycerol (DOPG). 11. The contact lens according to item 10, wherein the amount of the 2-oleoyl phospholipid is 10 μg to 1000 μg, preferably 25 μg to 250 μg. 12. A contact lens of any preceding clause, wherein when immersed in a release medium comprising an artificial tear solution containing 50 ppm sPLA2 at 35°C, the contact lens sustains release of at least 0.1 μg / hour of oleic acid for at least 4 hours, e.g., at least 8 hours, optionally at least 10 hours. 13. Packaging (a) a base member having a cavity for holding a packaging solution and a flange surrounding the cavity; (b) a cover that forms a liquid-tight seal with a flange of the base member; A contact lens according to any preceding claim. 14. A method of making a hydrogel contact lens of any preceding paragraph, comprising the steps of: a) polymerizing a polymerizable composition in a contact lens mold to obtain a polymeric lens body; b) removing the polymeric lens body from the contact lens mold; c) extracting the polymeric lens body in an organic solvent containing 2-oleoyl phospholipid; d) hydrating the polymeric lens body in a hydration solution to obtain a hydrogel contact lens; e) sealing the hydrogel contact lens in a package with a packaging solution; and, optionally, f) autoclaving the package. 15. A method for correcting vision in a symptomatic contact lens wearer, comprising a step of the symptomatic contact lens wearer wearing a hydrogel contact lens according to any one of items 1 to 13. 16. The method of paragraph 15, wherein a symptomatic contact lens wearer has an increased duration of comfortable contact lens wear compared to the control lenses. 17. The method of paragraph 15 or paragraph 16, wherein symptomatic contact lens wearers have reduced lens sensation and / or fewer "lens sensation events" over the course of a day compared to control lenses. 18. Use of a 2-oleoyl phospholipid in an amount that enhances contact lens comfort, wherein the phospholipid is associated with a polymeric lens body of the contact lens. 19. The use according to item 18, wherein the contact lens is a hydrogel contact lens according to any one of items 1 to 13. 20. Use of paragraph 18 or 19, wherein the sensation of lens sensation is reduced and / or the duration of comfortable contact lens wear is increased in symptomatic contact lens wearers. 21. A hydrogel composition for use in reducing the sensation of lens sensation in a contact lens wearer, thereby enhancing contact lens comfort in a contact lens wearer and / or increasing the duration of comfortable contact lens wear in a contact lens wearer, the hydrogel composition comprising: a polymeric lens body that is the reaction product of (a) a polymerizable composition loaded with (b) an amount of 2-oleoyl phospholipid. 22. The composition for use according to item 21, which is in the form of a contact lens according to any one of items 1 to 13. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 shows that dioleoylphosphatidylglycerol (DOPG) at the sn-2 ester bond is enzymatically cleaved by sPLA2 to produce oleic acid and lysophosphatidylglycerol (LOPG). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Described herein are silicone hydrogel contact lenses that sustain the release of oleic acid during wear, and methods for their manufacture. The contact lenses may be referred to herein as oleic acid-releasing contact lenses. Oleic acid is released from the lenses during wear in an amount that may enhance the comfort of contact lens wear in the contact lens wearer and increase the duration that the contact lens wearer can comfortably wear the contact lens. In particular, the oleic acid-releasing lenses of the present invention may increase the end-of-day comfort of lens wear in symptomatic patients. The silicone hydrogel contact lenses of the present invention advantageously provide sustained release of oleic acid during lens wear. Silicone hydrogel contact lenses contain oleoyl groups (i.e., *OC(O)CH 14 CH=CHC8H 17) at the sn-2 position, which glycerophospholipid is referred to hereinafter as "2-oleoyl phospholipid." 2-oleoyl phospholipids that are susceptible to digestion by human secretory phospholipase A2 (human sPLA2) present in tears can be used in the contact lenses of the present invention. The susceptibility of phospholipids to degradation by human sPLA2 present in tears can be determined using commercially available recombinant human PLA2G2A, as described in Example 1 below.

[0015] The 2-oleoyl phospholipid may be, for example, phosphatatidic acid, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or phosphatidylglycerol. Preferably, the 2-oleoyl phospholipid is other than phosphatidylcholine. Phosphatidylcholine has been found to be less susceptible than other glycerophospholipids to degradation by the group IIA secretory phospholipase A2 (sPLA2-IIA) enzyme found in human tears, as demonstrated in Example 1 below. Advantageously, the 2-oleoyl phospholipid is selected from phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylglycerol, especially phosphatidylethanolamine or phosphatidylglycerol. By "susceptible to digestion," it is meant that sPLA2 present in human tears hydrolyzes the acyl group at the sn2 position of 2-oleoylphospholipids to produce free fatty acids and lysophospholipids. 2-oleoyl phospholipids are digestible by human tears. 2-oleoyl phospholipids are digestible at least from sPLA2 present in human tears. The 2-oleoyl phospholipid may contain another oleoyl group at the sn-1 position, i.e. it may be a dioleoyl phospholipid, e.g. 1,2-dioleoylphosphatidylglycerol. Alternatively, the 2-oleoyl phospholipid may contain a different fatty acid group at the sn-1 position. The fatty acid at the sn-1 position may be C 12-26 Fatty acids, e.g., C14-22 It may be a fatty acid.

[0016] Preferred dioleoyl phospholipids include dioleoyl phosphatidylserine (DOPS), dioleoyl phosphatidylglycerol (DOPG), and dioleoyl phosphatidylethanolamine (DOPE). Other exemplary 2-oleoyl phospholipids include 1-palmitoyl-2-oleoyl phosphatidylethanolamine, 1-palmitoyl-2-oleoyl phosphatidylglycerol, 1-palmitoyl-2-oleoyl phosphatidylserine, 1-myristoyl-2-oleoyl phosphatidylethanolamine, 1-myristoyl-2-oleoyl phosphatidylglycerol, 1-myristoyl-2-oleoyl phosphatidylserine, 1-pentadecanoyl-2-oleoyl phosphatidylethanolamine ... oleoyl phosphatidylglycerol, 1-pentadecanoyl-2-oleoyl phosphatidylserine, 1-didocosahexaenoyl-2-oleoyl phosphatidylethanolamine, 1-didocosahexaenoyl-2-oleoyl phosphatidylglycerol, 1-didocosahexaenoyl-2-oleoyl phosphatidylserine, 1-stearoyl-2-oleoyl phosphatidylethanolamine, 1-stearoyl-2-oleoyl phosphatidylglycerol, and 1-stearoyl-2-oleoyl phosphatidylserine.

[0017] Optionally, one or more 2-oleoyl phospholipids as described herein may be present in the oleic acid releasing contact lenses of the present invention (e.g., two different, three different, or more 2-oleoyl phospholipids as described herein). The oleic acid at the sn-2 position is advantageously released and eluted from the lens, while the remaining phospholipids (i.e., lysophospholipids) are retained within the lens. The release rate of oleic acid may depend on the kinetics of the enzymatic reaction of the 2-oleoyl phospholipid, as well as the diffusion rate of oleic acid itself through the contact lens.

[0018] The hydrogel contact lens may be a silicone hydrogel. As an example, a silicone hydrogel contact lens comprises a polymeric lens body that is the reaction product of a polymerizable composition that includes at least one siloxane monomer or macromer and at least one hydrophilic monomer and / or at least one hydrophobic polymer. Advantageously, as described in more detail below, a cured polymeric lens body of silicone hydrogel may be extracted with an extraction solvent, such as ethanol, containing 2-oleoyl phospholipid. Thus, the extraction step may serve both to extract unreacted monomers and other materials from the cured polymeric lens body, and to load the 2-oleoyl phospholipid into the polymeric lens body. Instead of or in addition to including the 2-oleoyl phospholipid in the extraction solvent, the 2-oleoyl phospholipid may be included in the polymerizable composition. In either case, the 2-oleoyl phospholipid may be associated with the polymeric lens body by electrostatic and / or hydrophobic interactions, and / or may be physically encapsulated by the polymeric network of the polymeric lens body. Thus, the term "associated" refers to the non-covalent interactions between the 2-oleoyl phospholipid and the polymeric lens body, and is used interchangeably with the terms "attached" and "loaded."

[0019] The amount of 2-oleoyl phospholipid loaded into the polymeric lens body refers to the total amount of phospholipid that can be extracted from the contact lens by the isopropyl alcohol (IPA) extraction method as described in Example 2 below. Advantageously, the 2-oleoyl phospholipid associated with the polymeric lens body is not removed when the lens is immersed in deionized water or a standard contact lens packing solution, such as phosphate or borate buffered saline. In one example, the 2-oleoyl phospholipid is loaded into the polymeric lens body using a loading solution that includes an alcohol, such as ethanol, and the 2-oleoyl phospholipid is at a concentration ranging from about 0.01 mg / mL to about 10 mg / mL, or from about 0.05 mg / mL to about 5 mg / mL, or from about 0.1 mg / mL to about 2.5 mg / mL. The loading solution includes, for example, any mixture of ethanol (EtOH) and water that can solubilize the 2-oleoyl phospholipid and swell the lens material, for example, about 10% to 95% EtOH in water. The lenses are immersed in the loading solution for a period of time necessary to achieve the desired loading level of 2-oleoylphospholipid in the polymeric lens body, which can be determined by routine experimentation, such as by the method of Example 2 below. In some examples, the amount of 2-oleoylphospholipid associated with the polymeric lens body can be at least about 1 μg, 10 μg, 25 μg, 50 μg, or 100 μg up to about 250 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, or 1000 μg. In one example, the amount of 2-oleoylphospholipid associated with the polymeric lens body is from about 25 μg / lens to about 250 μg / lens.

[0020] As used herein, unless the context dictates to the contrary, the amount of oleic acid released from a 2-oleoylphospholipid-containing contact lens over a particular duration, or the "release profile" of oleic acid, refers to the amount of oleic acid released from the lens as measured using an in vitro release medium (ATF as described in Table 2 below containing 50 ppm sPLA2) and the method described in Example 3 below. The contact lens may have an in vitro oleic acid release profile of about 0.05 μg / hr to 50 μg / hr of oleic acid from the lens, e.g., 0.1 μg / hr to 25 μg / hr, or 0.5 μg / hr to 10 μg / hr, or 1 μg / hr to 5 μg / hr, after initial immersion in the release medium at 35° C. Advantageously, the contact lens sustains release of oleic acid for at least 4 hours, e.g., at least 8 hours, optionally at least 10 hours or at least 12 hours. Advantageously, the contact lens sustains release of 0.05 μg to 25 μg of oleic acid per hour, e.g., 0.1 μg to 10 μg, or 0.1 μg to 5 μg of oleic acid per hour for at least the first 10 hours after immersion in the release medium at 35° C., as determined by the method of Example 3. Oleic acid release rates as low as 0.05 μg / hour may be beneficial for some wearers. Release rates greater than 50 μg / hour may cause irritation for some wearers, and some wearers may not experience additional beneficial effects when the oleic acid release rate is increased to greater than 25 μg / hour. Optionally, the contact lenses of the present invention do not contain any comfort agents, except for the presence of 2-oleoyl phospholipid as described herein. Optionally, the contact lenses of the present invention may contain one or more comfort agents other than the 2-oleoyl phospholipid as described herein. The amount of any other comfort agent may be less than the amount of 2-oleoyl phospholipid present. The amount of any other comfort agent may be less than 300 μg, less than 100 μg, less than 50 μg, less than 10 μg, or less than 1 μg. Optionally, the packaging solutions as described herein do not contain any comfort agents.

[0021] Optionally, the packaging solutions as described herein do not contain any comfort agents, except for the possible presence of 2-oleoyl phospholipid and / or oleic acid resulting from the 2-oleoyl phospholipid originally present in the contact lens. Alternatively, the only phospholipid present in or associated with the contact lens is a 2-oleoyl phospholipid. Alternatively, the only source of fatty acids released or present with the contact lenses is from the 2-oleoyl phospholipids present. The present invention has the ability to provide improved controlled release of oleic acid compared to free oleic acid (not derived from 2-oleoyl phospholipids) associated with contact lenses, e.g., the release can be more linear compared to free fatty acids only used / associated with contact lenses.

[0022] The release of fatty acids from the digestion of 2-oleoylphospholipids can be considered a tear-controlled release of fatty acids.

[0023] Silicone hydrogel materials of contact lenses are typically formed by curing a polymerizable composition (i.e., a monomer mixture) that includes at least one siloxane monomer or macromer, and at least one hydrophilic monomer or at least one hydrophobic polymer, or a mixture thereof. As used herein, the term "siloxane monomer" refers to a molecule that contains at least one Si-O group and at least one polymerizable functional group. "Siloxane macromer" refers to a silicon-containing molecule that has at least one polymerizable functional group, which is used as a monomer, but has a high enough molecular weight and enough internal monomer units to be considered a polymer. Typically, siloxane macromers contain siloxane chains with at least five siloxane (-Si-O-) units and / or have a molecular weight of at least 500 Daltons.

[0024] Siloxane monomers and macromers used in contact lens compositions are well known in the art (see, for example, U.S. Pat. Nos. 8,658,747 and 6,867,245). (All patents and publications cited herein and throughout are incorporated by reference in their entirety.) In some examples, the polymerizable composition comprises a total amount of siloxane monomers or macromers of at least 10%, 20%, or 30% by weight up to about 40%, 50%, 60%, or 70% by weight. Unless otherwise specified, as used herein, a given weight percentage (wt%) of a component of a polymerizable composition is relative to the total weight of all polymerizable components and IPN polymers (as further described below) in the polymerizable composition. The weight of the polymerizable composition contributed by components such as diluents that are not incorporated into the final contact lens product is not included in the weight% calculation.

[0025] In a particular example, the polymerizable composition comprises a hydrophilic vinyl monomer. As used herein, a "hydrophilic vinyl monomer" is any siloxane-free (i.e., does not contain a Si-O group) hydrophilic monomer having a polymerizable carbon-carbon double bond (i.e., a vinyl group) present in its molecular structure that is not part of an acrylic group, and the carbon-carbon double bond of the vinyl group is less reactive under free radical polymerization than the carbon-carbon double bond present in a polymerizable methacrylate group. As used herein, the term "acyl group" refers to a polymerizable group present in acrylates, methacrylates, acrylamides, and the like. Thus, carbon-carbon double bonds are present in acrylate and methacrylate groups, and as used herein, such polymerizable groups are considered not to be vinyl groups. Furthermore, as used herein, a monomer is "hydrophilic" if at least 50 grams of the monomer is completely soluble in 1 liter of water at 20°C (i.e., about 5% soluble in water), as determined visually using a standard shake flask method. In various examples, the hydrophilic vinyl monomer is N-vinyl-N-methylacetamide (VMA), or N-vinylpyrrolidone (NVP), or 1,4-butanediol vinyl ether (BVE), or ethylene glycol vinyl ether (EGVE), or diethylene glycol vinyl ether (DEGVE), or any combination thereof. In one example, the polymerizable composition comprises at least 10%, 15%, 20%, or 25% by weight up to about 45%, 60%, or 75% by weight of the hydrophilic vinyl monomer. As used herein, a given weight percentage of a particular class of component (e.g., hydrophilic vinyl monomer or siloxane monomer, etc.) in the polymerizable composition is equal to the sum of the weight percentages of each component in that class in the composition. Thus, for example, a polymerizable composition that comprises 5% by weight BVE and 25% by weight NVP, but no other hydrophilic vinyl monomers, is said to comprise 30% by weight of the hydrophilic vinyl monomer. In one example, the hydrophilic vinyl monomer is a vinylamide monomer. Exemplary hydrophilic vinylamide monomers are VMA and NVP. In an embodiment, the polymerizable composition comprises at least 25% by weight of the vinylamide monomer.In further specific examples, the polymerizable composition comprises from about 25% to up to about 75% by weight VMA or NVP, or a combination thereof. Additional hydrophilic monomers that can be included in the polymerizable composition are N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), ethylene glycol methyl ether methacrylate (EGMA), and combinations thereof.

[0026] In addition to or as an alternative to the hydrophilic monomer, the polymerizable composition may include a non-polymerizable hydrophilic polymer, resulting in a polymeric lens body comprising an interpenetrating polymer network (IPN) in which the non-polymerizable hydrophilic polymer interpenetrates the silicone hydrogel polymer matrix. In this example, the non-polymerizable hydrophilic polymer is referred to as an IPN polymer, which acts as an internal wetting agent in the contact lens. In contrast, the polymer chains within the silicone hydrogel network that form by polymerization of the monomers present in the polymerizable composition are not considered to be IPN polymers. The IPN polymer may be a high molecular weight hydrophilic polymer, for example, from about 50,000 to about 500,000 Daltons. In a specific example, the IPN polymer is polyvinylpyrrolidone (PVP). In another example, the polymerizable composition is substantially free of polyvinylpyrrolidone or other IPN polymers.

[0027] Optionally, one or more non-silicon-containing hydrophobic monomers may be present as part of the polymerizable composition. A hydrophobic monomer may be understood to be any monomer in which 50 grams of the monomer is not visually completely soluble in 1 liter of water at 20° C. using the standard shake flask method. Examples of suitable hydrophobic monomers include methyl acrylate, or ethyl acrylate, or propyl acrylate, or isopropyl acrylate, or cyclohexyl acrylate, or 2-ethylhexyl acrylate, or methyl methacrylate (MMA), or ethyl methacrylate, or propyl methacrylate, or butyl methacrylate, or 2-hydroxybutyl methacrylate, or vinyl acetate, or vinyl propionate, or butyl butyrate, or vinyl valerate, styrene, or chloroprene, or vinyl chloride, or vinylidene chloride, or acrylonitrile, or 1-butene, or butadiene, or methacrylonitrile, or vinyl toluene, or vinyl ethyl ether, or perfluorohexylethylthiocarbonylaminoethyl methacrylate, or isobornyl methacrylate (IBM), or trifluoroethyl methacrylate, or hexafluoroisopropyl methacrylate, or tetrafluoropropyl methacrylate, or hexafluorobutyl methacrylate, or any combination thereof.

[0028] When used, the hydrophobic monomer may be present in the reaction product of the polymerizable composition in an amount of 1% by weight to about 30% by weight, for example, 1% by weight to 25% by weight, 1% by weight to 20% by weight, 1% by weight to 15% by weight, 2% by weight to 20% by weight, 3% by weight to 20% by weight, 5% by weight to 20% by weight, 5% by weight to 15% by weight, or 1% by weight to 10% by weight, based on the total weight of the polymerizable composition. The polymerizable composition may further comprise at least one crosslinker. As used herein, "crosslinker" refers to a molecule having at least two polymerizable groups. Thus, the crosslinker can react with the functional groups of two or more polymer chains to crosslink one polymer with another. The crosslinker may comprise an acrylic group or a vinyl group, or both an acrylic group and a vinyl group. In certain instances, the crosslinker does not comprise a siloxane moiety, that is, the crosslinker is a non-siloxane crosslinker. A variety of crosslinkers suitable for use in silicone hydrogel polymerizable compositions are known in the art (see, for example, U.S. Pat. No. 8,231,218, which is incorporated herein by reference). Examples of suitable crosslinking agents include, without limitation, lower alkylene glycol di(meth)acrylates, such as triethylene glycol dimethacrylate, diethylene glycol dimethacrylate, poly(lower alkylene) glycol di(meth)acrylates, and lower alkylene di(meth)acrylates; divinyl ethers, such as triethylene glycol divinyl ether, diethylene glycol divinyl ether, 1,4-butanediol divinyl ether, and 1,4-cyclohexanedimethanol divinyl ether; divinyl sulfone; di- and trivinylbenzene; trimethylolpropane tri(meth)acrylate; pentaerythritol tetra(meth)acrylate; bisphenol A di(meth)acrylate; methylene bis(meth)acrylamide; triallyl phthalate; 1,3-bis(3-methacryloxypropyl)tetramethyldisiloxane; diallyl phthalate; and combinations thereof.

[0029] As will be appreciated by those skilled in the art, the polymerizable composition may include one or more of the additional polymerizable or non-polymerizable components conventionally used in contact lens formulations, such as a polymerization initiator, a UV absorber, a colorant, an oxygen scavenger, or a chain transfer agent. In some examples, the polymerizable composition may include an amount of organic diluent that prevents or minimizes phase separation between the hydrophilic and hydrophobic components of the polymerizable composition, thereby resulting in an optically clear lens. Diluents commonly used in contact lens formulations include hexanol, ethanol, and / or other primary, secondary, or tertiary alcohols. In other examples, the polymerizable composition is free or substantially free (e.g., less than 500 ppm) of organic diluents. In such examples, the use of siloxane monomers containing hydrophilic moieties such as polyethylene oxide groups, pendant hydroxyl groups, or other hydrophilic groups may eliminate the need to include a diluent in the polymerizable composition. Non-limiting examples of these and additional components that may be included in the polymerizable composition are provided in U.S. Pat. No. 8,231,218.

[0030] Non-limiting examples of silicone hydrogels that can be used include comfilcon A, fanfilcon A, stenfilcon A, senofilcon A, senofilcon C, somofilcon A, narafilcon A, delefilcon A, narafilcon A, lotrafilcon A, lotrafilcon B, balafilcon A, samfilcon A, galyfilcon A, and asmofilcon A. Specific examples of hydrogel contact lenses of the present invention are based on a polymerizable composition comprising 25% to 55% by weight of a siloxane monomer or macromer, 30% to 55% by weight of a vinyl monomer selected from NVP, VMA, or a combination thereof, and optionally, about 1% to about 20% by weight of a hydrophilic monomer selected from N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), or ethylene glycol methyl ether methacrylate (EGMA), or any combination thereof, and optionally, about 1% to about 20% by weight of a hydrophobic monomer selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), or 2-hydroxybutyl methacrylate (HOB), or any combination thereof. Silicone hydrogel materials made from this particular embodiment of the polymerizable composition include stenfilcon A, comfilcon A, somofilcon A, fanfilcon A, and enfilcon A. In a further example, the polymerizable composition may comprise stenfilcon A siloxanes, specifically, siloxanes of formula (II):

[0031] [ka] Formula (II) A first siloxane having a structure represented by: and formula (III) [ka] Formula (III). A second siloxane having a structure represented by Includes.

[0032] Conventional methods can be used to manufacture the contact lenses of the present invention. As an example, a polymerizable composition for a hydrogel composition is dispensed into a female mold member having a concave surface that defines the front surface of the contact lens. A male mold member having a convex surface that defines the rear surface, i.e., the corneal contact surface, of the contact lens is combined with the female mold member to form a contact lens mold assembly that is subjected to curing conditions, e.g., UV or thermal curing conditions, under which the curable composition is formed into a polymer lens body. The female and male mold members can be of a non-polar or polar type. The mold assembly is disassembled (i.e., demolded), and the polymer lens body is removed from the mold and contacted with a solvent, e.g., an organic solvent such as ethanol, to extract unreacted components from the lens body. After extraction, the lens body is hydrated in one or more hydrating liquids, such as water or an aqueous solution, and packaged. An exemplary method for manufacturing silicone hydrogel contact lenses is described in U.S. Pat. No. 8,865,789.

[0033] The 2-oleoyl phospholipid is typically loaded into the polymer lens during the extraction step. Generally, after curing, the polymer lens body is swollen in an extraction solvent, such as a mixture of ethanol and water containing the 2-oleoyl phospholipid. When the extracted polymer lens body is subsequently placed in a hydration solution, such as deionized (DI) water, the extraction solvent is removed and the 2-oleoyl phospholipid remains associated with the polymer lens body. Examples of extraction solvents and hydration liquids used in the extraction and hydration process may consist of denatured ethanol, a mixture of denatured ethanol and deionized water, and deionized water. By way of example, the extraction and hydration process may include at least one extraction step in denatured ethanol (EtOH), followed by one extraction step with a mixture of EtOH and water, such as about 10%-95% EtOH in water, such as about 30%-80% EtOH in water, followed by at least one hydration step in deionized water, each extraction and hydration step may last from about 15 minutes to about 3 hours at a temperature of about 20° C. to about 30° C. The extraction solvent may contain 2-oleoyl phospholipid to achieve loading of the 2-oleoyl phospholipid into the polymer lens body.

[0034] Any extraction solvent used as the loading solution for 2-oleoylphospholipid may contain 2-oleoylphospholipid at a concentration of about 0.01 μg / ml to 10 mg / ml, e.g., 0.1 μg / ml to 5 mg / ml. The amount of 2-oleoylphospholipid loaded into the polymer lens body may be 10 μg to 1000 μg, e.g., about 25 μg to 500 μg, or 50 μg to 250 μg. As part of the present invention, the contact lens may be sealed in a contact lens package. The packaging solution sealed in the contact lens package may be any conventional contact lens compatibility solution. In one example, the packaging solution comprises, consists of, or consists essentially of an aqueous solution of a buffer and / or an isotonicity agent. In another example, the packaging solution contains additional agents, such as one or more additional antimicrobial agents, and / or comfort agents, and / or hydrophilic polymers, and / or surfactants, and / or other beneficial agents. In some examples, the packaging solution may include polysaccharides (e.g., hyaluronic acid, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, etc.), or other high molecular weight polymers, such as polyvinylpyrrolidone, which are commonly used as comfort polymers or thickeners in eye drops and contact lens packaging solutions. In other examples, the packaging solution may include an ophthalmic drug. The packaging solution may have a pH ranging from about 6.8 or 7.0 up to about 7.8 or 8.0. In one example, the packaging solution includes a phosphate buffer or a borate buffer. In another example, the packaging solution includes a tonicity agent selected from sodium chloride or sorbitol in an amount to maintain an osmolality in the range of about 200-400 mOsm / kg, typically about 270 mOsm / kg up to about 310 mOsm / kg.

[0035] With respect to contact lens packaging, the packaging may include or comprise a cavity configured to hold a contact lens and a packaging solution, and a plastic base member including a flange region that flares outwardly around the cavity. A removable foil is attached to the flange region to provide a sealed contact lens package. Such contact lens packages are commonly referred to as "blister packs" and are well known in the art (see, e.g., U.S. Pat. No. 7,426,993). It is recognized that conventional manufacturing methods can be used to manufacture the sealed contact lens package. In the method of manufacturing the contact lens package, the method includes the steps of placing an unworn contact lens and a contact lens packaging solution into a receptacle, placing a cover in the receptacle, and sealing the cover on the receptacle. Generally, the receptacle is configured to receive a single contact lens and a sufficient amount of packaging solution to completely cover the contact lens, typically about 0.5 to 1.5 ml. The receptacle may be made of any suitable material, such as glass or plastic. In one example, the receptacle includes a plastic base member including a cavity configured to hold the contact lens and the packaging solution, and a flange region that extends outwardly around the cavity, and the cover includes a removable foil attached to the flange region to provide a sealed contact lens package. The removable foil may be sealed by any conventional method, such as heat sealing or gluing. In another example, the receptacle is in the form of a plastic base member including a plurality of threads, and the cover includes a plastic cap member including a matching set of threads for mating with the threads of the base member, thereby providing a resealable cover. It will be appreciated that other types of packaging can also be used to provide a resealable package. For example, the contact lens package may include a plastic cover including features that mate with matching features of the receptacle to form an interference fit. The method of producing a sealed contact lens package may further include sterilizing an unworn contact lens by autoclaving the sealed contact lens package. Autoclaving generally includes subjecting the sealed contact lens package to a temperature of at least 121° C. for at least 20 minutes.

[0036] The contact lenses may be provided unworn (i.e., new contact lenses not previously used by a patient) impregnated with the packaging solution and sealed in a package. The package may be a blister pack, glass vial, or other suitable container. The package may include a base member having a cavity for holding the packaging solution, a cover forming a fluid-tight seal with the base member, and an unworn contact lens. The sealed package may be sterilized by irradiation with a sterilizing amount including heat or steam, for example, by autoclaving, or by gamma irradiation, e-beam irradiation, ultraviolet irradiation, and the like.

[0037] In a specific embodiment, the packaged contact lenses are sterilized by autoclaving. The final product can be a sterile packaged contact lens (eg, a silicone hydrogel contact lens) having an ophthalmically acceptable surface wettability. The oleic acid releasing hydrogel contact lenses described herein can be used to correct the vision of a symptomatic contact lens wearer. For example, the oleic acid releasing hydrogel contact lenses of the present invention can increase the duration of comfortable contact lens wear in a symptomatic contact lens wearer. References herein to "symptomatic contact lens wearer" or "symptomatic subject" refer to lens wearers who are classified as symptomatic using the CLDEQ-8 as described by Chalmers et al. (See Chalmers et al., Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) and opinion of contact lens performance. Optom Vis Sci 2012; 89(10):1435-1442).

[0038] The oleic acid releasing hydrogel contact lenses described herein can be worn by a contact lens wearer to reduce lens sensation and / or provide fewer "lens sensation events" throughout the day compared to a control lens or a lens that the contact lens wearer is accustomed to wearing. References herein to a "control lens" refer to a contact lens that does not contain phospholipids or oleic acid but is otherwise identical to the oleic acid releasing lens to which it is compared. Reduction in lens sensation and / or lens sensation events during contact lens wear can be determined using a "lens sensation logger" as described by Read et al. (See, Read et al., Monitoring ocular discomfort using a wrist-mounted electronic logger. Contact Lens and Anterior Eye Vol. 43 (2020) 476-483). The following examples are illustrative of certain aspects and advantages of the present invention, but it should be understood that they are not limiting thereby. EXAMPLES

[0039] Example 1: Oleic acid release from stenfilcon A lenses loaded with different 2-oleoylphospholipids. The phospholipids shown in Table 1 were obtained from Avanti Polar Lipids. A 3 mg / ml loading solution of the phospholipids shown in Table 1 was prepared by adding 2.4 mL of ethanol to 9 mg of phospholipid, sonicating (up to 15 minutes), then adding 0.6 mL of DI water and sonicating again (up to 15 minutes) to dissolve the phospholipid.

[0040] [Table 1] Hydrated contact lenses made from stenfilcon A were washed in 3 mL of purified water three times for 30 minutes each time. Each washed lens was placed in 3 mL of phospholipid loading solution and incubated at room temperature for 3 hours with gentle shaking at 75 rpm. The loaded lenses were then rinsed and hydrated with several changes of DI water. The lenses were packaged in buffered saline contact lens packaging solution and autoclaved. Artificial tears (ATF) were prepared by adding the first three components listed in Table 2 to a clean glass vial, then adding 30 mL of the fourth component.

[0041] [Table 2] After autoclaving, each lens was removed from its packaging, placed into a 6 mL glass vial containing 5 mL of ATF at room temperature, and placed on a shaker at 125 rpm overnight to dissolve any free oleic acid that may be present in the lens. Each lens was rinsed for 30 minutes in a 6 ml glass vial containing a fresh aliquot of 5 ml of ATF before the digestion assay was performed. A 50 ppm sPLA2 solution in ATF was prepared by adding 200 μl ATF to a tube containing 10 μg recombinant human PLA2G2A (Creative BioMart, Catalog No. PLA2G2A-669H). This solution is referred to as ATF+sPLA2. Two 4 mm pieces were cut from each lens. One piece of each lens was placed in a tube with 100 μL ATF and the other piece was placed in a tube containing 100 μL ATF+sPLA2. The tubes were incubated at 35±2° C. for 4 hours without shaking.

[0042] At T=4 hours, 50 μl of release medium from each lens was transferred to an HPLC vial and 500 μl of isopropanol (IPA) was added and mixed thoroughly. An HPLC vial at T=0 hours was also prepared (50 μl ATF + 500 μl IPA). All vials were sonicated for 15 minutes and centrifuged. The supernatant was removed for LCMS injection. The supernatant was injected into an LCMS instrument equipped with an ACQUITY UPLC BEH C18 1.7 μg, 2.1 mm x 15 cm column and run with a mobile phase gradient of 65% A to 90% B at a flow rate of 0.35 mL / min, where A = 40% acetonitrile in water with 10 mM ammonium acetate and 0.2% (v / v) ammonium hydroxide, B = 10% acetonitrile in IPA with 10 mM ammonium acetate and 0.2% (v / v) ammonium hydroxide. The mass spectrometer detector was run in negative electrospray mode. The oleic acid (OA) peak in the supernatant was measured (m / z trace = 281.24). The ratio of the OA peak area in ATF with and without sPLA2 was calculated. The results are shown in Table 3.

[0043] [Table 3] The results suggest that contact lenses filled with 2-oleoylphosphatidylcholine are less susceptible to sPLA2-mediated degradation and fatty acid release, whereas contact lenses filled with phosphatidylglycerol, phosphatidylethanolamine, and phosphatidylserine are more susceptible to sPLA2-mediated fatty acid release.

[0044] Example 2: DOPG filled Stenfilcon A contact lenses. 1,2-Dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG) from Sigma-Aldrich was dissolved in 50% by volume of ethanol (EtOH), 50% by volume of deionized water, and sonicated until DOPG was completely dissolved to obtain DOPG loading solutions with concentrations ranging from 1 mg / ml to 10 mg / ml. Silicone hydrogel contact lenses were prepared by curing a formulation of stenfilcon A in a polypropylene contact lens mold. The cured stenfilcon A was removed from the mold and each lens was extracted with EtOH to remove unreacted monomer. The lenses were then placed in DOPG loading solution for approximately 90 minutes and then hydrated with several changes of DI water. The lenses were packaged in plastic blisters with approximately 1.2 ml of packaging solution containing phosphate buffered saline (PBS) and autoclaved.

[0045] The amount of DOPG in each lens was determined by extracting the lens with isopropanol (IPA) and measuring the DOPG in the extract by LCMS. Briefly, each lens was removed from its blister pack, lightly blotted to remove excess packaging solution, and placed in a 20 mL glass vial containing 10 mL of 100% IPA. The vial was placed on a benchtop shaker at 300 rpm at room temperature overnight (approximately 16 hours). For stenfilcon A, a single 2 hour extraction step is sufficient to extract virtually all of the DOPG from the lens. More hydrophobic silicone hydrogel lens materials may require a second overnight extraction to extract all of the DOPG, in which case the IPA from the first extraction step is removed and replaced with 3 mL of fresh IPA and shaken overnight at room temperature at 300 rpm. The amount of DOPG in the IPA extract from each lens was determined by LCMS in comparison to a DOPG standard solution. The DOPG loading concentration and average DOPG for each lens are shown in Table 4.

[0046] [Table 4]

[0047] Example 3: Determination of oleic acid release profile To determine the oleic acid release profile of silicone hydrogel contact lenses loaded with 2-oleoyl phospholipid, the lenses were removed from their packaging, placed in a 6 mL glass vial containing 5 mL of ATF (described in Example 1) at room temperature, and placed on a shaker at 125 rpm overnight to dissolve any free oleic acid that may be present in the lenses.

[0048] Each lens was then transferred to a 6 mL glass vial containing 3 mL of in vitro release medium with ATF containing 50 ppm recombinant human PLA2G2A at 35° C. Alternatively, phospholipase A2 from honeybee venom (CAS number 9001-84-7) may be used at the same concentration (50 ppm) instead of recombinant human PLA2G2A. The vials were placed in a 35° C. incubator at 50 rpm and 2.5 ml of in vitro release medium was removed from each vial at 2-hour intervals (e.g., 2 hours, 4 hours, 6 hours, 8 hours, and 10 hours) and sent for analysis. If the release medium was not analyzed immediately at its designated time point, a sample was taken and mixed with IPA (1:10 v / v ratio) to stop the enzyme activity. Following this, 2.5 ml of fresh in vitro release medium with ATF containing 50 ppm recombinant human PLA2G2A was added back to each vial and the lenses continued to incubate. At the end of the release experiment, the amount of OA in the release medium at each time point is analyzed by LCMS using the method described in Example 1.

[0049] It should be understood that the disclosure herein refers to certain illustrated examples, which are presented by way of example and not by way of limitation. The intent of the foregoing detailed description, although discussing illustrative examples, is to be construed to encompass all modifications, alternatives, and equivalents of those examples as may fall within the spirit and scope of the invention as defined by the appended claims. Reference herein to an "example" or "embodiment" or "aspect" or "embodiment" or similar phrase is intended to introduce a feature or features of the inventive oleic acid releasing hydrogel contact lenses or components thereof, the sealed contact lens packaging or components thereof, or the method of making the inventive oleic acid releasing hydrogel contact lenses (as the context requires), which may be combined in any combination of the examples, aspects, embodiments (i.e., features) described above or subsequently, unless a particular combination of features is mutually exclusive or the context indicates otherwise. Furthermore, as used herein, the singular forms "a," "an," and "the" include plural references (e.g., at least one or more) unless the context clearly dictates otherwise. Thus, for example, reference to a "contact lens" includes a single lens as well as two or more of the same or different lenses.

[0050] The entire contents of all references cited in this disclosure are incorporated herein by reference to the extent they are not inconsistent with this disclosure. The present invention may include any combination of the various features or embodiments described above, including any numbered clauses above, and / or in the following claims, as set forth in sentences and / or paragraphs. Any combination of features disclosed herein is considered to be part of the invention, and no limitations as to which features may be combined are intended. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims and equivalents thereof. Yet another aspect of the present invention may be as follows. [1] An unworn silicone hydrogel contact lens sealed in a package, comprising a polymer lens body loaded with at least one 2-oleoyl phospholipid, and containing 50 ppm of human sPLA. 2 When exposed to artificial tear fluid (ATF) containing human sPLA for 4 hours at 37°C, 2 1. An unworn silicone hydrogel contact lens that releases at least two times more oleic acid than when in contact with an ATF that does not contain [2] The silicone hydrogel contact lens according to [1] above, wherein the 2-oleoyl phospholipid is phosphatidylserine, phosphatidylethanolamine, or phosphatidylglycerol. [3] The silicone hydrogel contact lens according to [1] above, wherein the 2-oleoyl phospholipid is selected from DOPG, DOPS, and DOPE. [4] The silicone hydrogel contact lens according to [1] above, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising 25% to 55% by weight of a siloxane monomer, 30% to 55% by weight of a vinyl monomer selected from N-vinylpyrrolidone, N-vinyl-N-methylacetamide, or a combination thereof, and optionally about 1% to about 20% by weight of a hydrophilic monomer selected from N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), ethylene glycol methyl ether methacrylate (EGMA), or any combination thereof, and optionally about 1% to about 20% by weight of a hydrophobic monomer selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), 2-hydroxybutyl methacrylate (HOB), or any combination thereof. [5] The polymer lens body is represented by the formula (II) [C1] JPEG0007659135000010.jpg34110 Formula (II) A first siloxane having a structure represented by: and formula (III) [Case 2] JPEG0007659135000011.jpg24120 Formula (III). A second siloxane having a structure represented by The silicone hydrogel contact lens according to [1] above, which is a reaction product of a polymerizable composition comprising: [6] The silicone hydrogel contact lens according to the above [1], which is filled with 10 μg to 1000 μg, preferably 25 μg to 250 μg, of 2-oleoylphospholipid. [7] 50 ppm sPLA 2 The silicone hydrogel contact lens according to [1], wherein the contact lens sustains release of at least 0.1 μg / hour of oleic acid for at least 4 hours, for example at least 8 hours, and optionally at least 10 hours, when immersed in a release medium containing an artificial tear solution containing the compound at 35° C. [8] An unworn silicone hydrogel contact lens sealed in a package, comprising a polymer lens body loaded with at least 10 μg of 2-oleoyl phospholipid, wherein the 2-oleoyl phospholipid is phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or phosphatidylglycerol. [9] The silicone hydrogel contact lens according to [8] above, wherein the 2-oleoyl phospholipid is selected from DOPG, DOPS, and DOPE.

[10] The silicone hydrogel contact lens according to [8] above, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising 25% to 55% by weight of a siloxane monomer, 30% to 55% by weight of a vinyl monomer selected from N-vinylpyrrolidone, N-vinyl-N-methylacetamide, or a combination thereof, and optionally about 1% to about 20% by weight of a hydrophilic monomer selected from N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), ethylene glycol methyl ether methacrylate (EGMA), or any combination thereof, and optionally about 1% to about 20% by weight of a hydrophobic monomer selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), 2-hydroxybutyl methacrylate (HOB), or any combination thereof.

[11] The polymer lens body is represented by the formula (II) [C3] JPEG0007659135000012.jpg34110 Formula (II) A first siloxane having a structure represented by: and formula (II) [C4] JPEG0007659135000013.jpg24120 Formula (III). A second siloxane having a structure represented by The contact lens according to [8] above, which is a reaction product of a polymerizable composition comprising:

[12] The contact lens according to the above [8], which is filled with 10 μg to 1000 μg, preferably 25 μg to 250 μg, of 2-oleoylphospholipid.

[13] 50 ppm sPLA 2 The contact lens according to [8], wherein when immersed in a release medium containing an artificial tear solution containing the compound at 35°C, the contact lens sustains a release of at least 0.1 μg / hour of oleic acid for at least 4 hours, for example at least 8 hours, and optionally at least 10 hours.

Claims

1. An unworn silicone hydrogel contact lens sealed in a package, comprising a polymer lens body loaded with at least one 2-oleoyl phospholipid, and containing 50 ppm of human sPLA. 2 When contacted with artificial tear fluid (ATF) containing human sPLA for 4 hours at 37°C, 2 An unworn silicone hydrogel contact lens that releases at least two times more oleic acid than when contacted with an ATF that does not contain the compound.

2. 2. The silicone hydrogel contact lens of claim 1, wherein the 2-oleoyl phospholipid is phosphatidylserine, phosphatidylethanolamine, or phosphatidylglycerol.

3. 2. The silicone hydrogel contact lens of claim 1, wherein the 2-oleoyl phospholipid is selected from 1,2-dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoylphosphatidylserine (DOPS), and 1,2-dioleoylphosphatidylethanolamine (DOPE).

4. 10. The silicone hydrogel contact lens of claim 1, wherein the polymeric lens body is the reaction product of a polymerizable composition comprising 25% to 55% by weight of a siloxane monomer, 30% to 55% by weight of a vinyl monomer selected from N-vinylpyrrolidone, N-vinyl-N-methylacetamide, or a combination thereof.

5. The polymeric lens body is represented by the formula (II) 【Chemistry 1】 Formula (II) A first siloxane having a structure represented by: and formula (III) 【Chemistry 2】 Formula (III) A second siloxane having a structure represented by 2. The silicone hydrogel contact lens of claim 1 which is the reaction product of a polymerizable composition comprising:

6. 10. The silicone hydrogel contact lens of claim 1 loaded with 10 μg to 1000 μg of 2-oleoyl phospholipid.

7. 50 ppm sPLA 2 2. The silicone hydrogel contact lens of claim 1, wherein the contact lens sustains release of at least 0.1 μg / hr of oleic acid for at least 4 hours when immersed in a release medium comprising an artificial tear solution containing at 35° C.

8. An unworn silicone hydrogel contact lens sealed in a package, comprising a polymer lens body loaded with at least 10 μg of 2-oleoyl phospholipid, the 2-oleoyl phospholipid being phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or phosphatidylglycerol.

9. 9. The silicone hydrogel contact lens of claim 8, wherein the 2-oleoyl phospholipid is selected from 1,2-dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoylphosphatidylserine (DOPS), and 1,2-dioleoylphosphatidylethanolamine (DOPE).

10. 9. The silicone hydrogel contact lens of claim 8, wherein the polymeric lens body is the reaction product of a polymerizable composition comprising 25% to 55% by weight of a siloxane monomer, 30% to 55% by weight of a vinyl monomer selected from N-vinylpyrrolidone, N-vinyl-N-methylacetamide, or a combination thereof.

11. The polymeric lens body is represented by the formula (II) 【Chemistry 3】 Formula (II) A first siloxane having a structure represented by: and formula (III) 【Chemistry 4】 Formula (III) A second siloxane having a structure represented by The contact lens of claim 8 which is the reaction product of a polymerizable composition comprising:

12. 9. The contact lens of claim 8, loaded with 10 μg to 1000 μg of 2-oleoyl phospholipid.

13. 50 ppm sPLA 2 9. The contact lens of claim 8, wherein the contact lens sustains release of at least 0.1 μg / hour of oleic acid for at least 4 hours when immersed in a release medium comprising an artificial tear solution containing at 35° C.

14. The silicone hydrogel contact lens of claim 4, wherein the polymerizable composition further comprises 1% to 20% by weight of a hydrophilic monomer selected from N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), or ethylene glycol methyl ether methacrylate (EGMA), or any combination thereof.

15. The silicone hydrogel contact lens of claim 4 or 14, wherein the polymerizable composition further comprises 1% to 20% by weight of a hydrophobic monomer selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), or 2-hydroxybutyl methacrylate (HOB), or any combination thereof.

16. The silicone hydrogel contact lens of claim 10, wherein the polymerizable composition further comprises 1% to 20% by weight of a hydrophilic monomer selected from N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), or ethylene glycol methyl ether methacrylate (EGMA), or any combination thereof.

17. The silicone hydrogel contact lens of claim 10 or 16, wherein the polymerizable composition further comprises 1% to 20% by weight of a hydrophobic monomer selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), or 2-hydroxybutyl methacrylate (HOB), or any combination thereof.

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