Sustained Release of Oleic Acid from Contact Lenses

Abstract

The present invention describes an oleic acid-releasing contact lens and a method for manufacturing the same. The oleic acid-releasing contact lens contains glycerophospholipids having an oleoyl group at the sn-2 position and continuously releases oleic acid in the presence of sPLA2 enzyme present in human tears. The oleic acid-releasing contact lens can increase the duration of comfortable contact lens wear and / or reduce contact lens awareness events in symptomatic contact lens wearers.

Description

Technical Field

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

[0002] It is estimated that 50% of all contact lens wearers experience discomfort when wearing their lenses, and approximately 25% of these contact lens wearers permanently stop wearing lenses. Lens awareness sensations are the primary cause of contact lens dissatisfaction among contact lens wearers. Despite advancements in contact lens materials, there is still a need for improved contact lenses that can be comfortably worn by contact lens wearers who otherwise experience lens awareness sensations when wearing currently available commercial contact lenses.

[0003] Fatty acids are known to be used as comfort agents that can provide lubrication and relieve discomfort when administered to the eye. Fatty acids used as comfort agents can be released from contact lenses during contact lens wear in an amount sufficient to desensitize the eye and thus reduce discomfort (U.S. Patent Application Publication No. 20220187620). However, some contact lens materials cannot maintain fatty acid release throughout the day.

[0004] It is desirable to obtain a sustained release rate of fatty acids from contact lenses, thereby enhancing the comfort of contact lens wear among contact lens wearers and increasing the duration for which contact lens wearers can comfortably wear contact lenses. Alternatively or additionally, it is desirable to provide an improved contact lens that can be worn by contact lens wearers. Summary of the Invention

[0005] One feature of the present invention is to provide a hydrogel contact lens that can release oleic acid and its salts during lens wear. As used herein, the term "oleic acid" refers to both oleic acid in the form of the free acid and the salts of oleic acid.

[0006] Another feature of the present invention is to provide contact lenses that can be comfortably worn by contact lens wearers.

[0007] Another feature of the present invention is to increase the duration of comfortable lens wear and / or reduce lens awareness events among contact lens wearers.

[0008] Additional features and advantages of the present invention will be set forth in part in the following description, and in part will be obvious from the description, or may be learned by practice of the present invention. The objectives and other advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in this description and the appended claims.

[0009] To achieve these and other advantages and in accordance with the purpose of the present invention, as embodied and broadly described herein, the present invention in part relates to a hydrogel contact lens comprising a polymeric lens body loaded with 2-oleoylphospholipid. The 2-oleoylphospholipid is advantageously readily digested by the secretory phospholipase 2-acyl hydrolase (sPLA2) enzyme, especially the group IIA secretory phospholipase 2-acyl hydrolase (sPLA2-IIA), found in human tears. The 2-oleoylphospholipid present in the contact lens body is advantageously readily digested by the sPLA2 enzyme (especially sPLA2-IIA) found in human tears when the 2-oleoylphospholipid is present in the polymeric lens body of a silicone hydrogel contact lens, such as a stenfilcon A contact lens. After immersing each of the same stenfilcon A contact lenses loaded with the 2-oleoylphospholipid in each release medium at 35 °C for 4 hours, the 2-oleoylphospholipid can be considered readily digested by the sPLA2 enzyme when the amount of oleic acid released from the stenfilcon A lens loaded with at least 200 μg of 2-oleoylphospholipid into the release medium containing the sPLA2 enzyme is at least twice (e.g., at least three times) the amount of oleic acid released into an otherwise identical control release medium lacking the phospholipase A2 enzyme. The release medium containing the sPLA2 enzyme can be an artificial tear fluid (ATF), such as the artificial tear fluid additionally containing 50 ppm recombinant human sPLA2-IIA defined in Table 1 below, and the control release medium lacking the phospholipase A2 enzyme can be an otherwise identical ATF release medium lacking the phospholipase A2 enzyme. Alternatively, the release medium containing the sPLA2 enzyme can be a reflex tear solution and the control release medium can be an ATF. To avoid doubt, although the determination of whether the 2-oleoylphospholipid is readily digested by the sPLA2 enzyme can be carried out by loading the 2-oleoylphospholipid into the stenfilcon A lens, the contact lenses of the present invention (including contact lenses comprising 2-oleoylphospholipid that has been determined to be readily digested by the sPLA2 enzyme) need not be stenfilcon A lenses and can be silicone hydrogel lenses of any formulation. In all aspects of the present invention, the contact lenses in which the 2-oleoylphospholipid is readily digested by the sPLA2 enzyme can be any of the contact lenses described herein. For comparison, an example of a phospholipid that has been found to be not readily digested by the sPLA2 enzyme 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 include anionic (negatively charged) substrate groups attached to the phospholipid head group (i.e., the R 3 position) in the following formula (I). The 2-oleoylphospholipid can be of formula (I):

[0010]

[0011] wherein X is –O– or –O(CO)–, R 1 is C 11-25 alkyl, R 2 is CH3(CH2)7CH=CH(CH2)7–, R 3 is selected from hydrogen; C 1-10 polyols (such as glycerol or inositol); ethanolamine (–CH2CH2NH2); and serine (–CH2CH(NH2)COOH) and salts of phospholipids of formula (I) (such as where R 3 is a negatively charged or deprotonated anionic group (such as –CH2CH(NH2)COO - –)). It has been found that the hydrogel contact lenses of the present invention continuously release oleic acid, thereby enhancing the comfort of the contact lenses in contact lens wearers and / or increasing the duration of comfortable contact lens wearing time in contact lens wearers.

[0012] In one example, after being immersed in an in vitro release medium of ATF containing a solution of 50 ppm sPLA2-IIA enzyme in phosphate buffered saline (PBS) at 35 °C for 1 hour, the hydrogel contact lenses are capable of releasing 0.05 μg to 50 μg, 0.1 μg to 25 μg, 0.5 μg to 10 μg, especially 1 to 5 μg of oleic acid.

[0013] Furthermore, the present invention relates to a method for manufacturing the hydrogel contact lenses of the present invention. The method comprises the steps of: a) polymerizing a polymerizable composition (as described herein) in a contact lens mold to obtain a polymer contact lens body, b) removing the polymer contact lens body from the contact lens mold, c) extracting the polymer contact lens body in an organic solvent containing 2-oleoylphospholipid, d) hydrating the polymer contact lens body in a hydrating liquid to obtain a hydrogel contact lens, e) sealing the hydrogel contact lens in a package with a packaging solution, and f) heat pressing the package. The hydration step d) may occur before the extraction step c) in which 2-oleoylphospholipid is loaded onto the polymer contact lens body. If the hydration step d) occurs before the extraction step c) in which 2-oleoylphospholipid is loaded onto the polymer contact lens body, then an additional hydration step may be carried out after step c).

[0014] Furthermore, the present invention relates to a method of correcting vision in a symptomatic contact lens wearer by providing a hydrogel contact lens that releases oleic acid and comprises a polymeric contact lens body loaded with 2 - oleoyl phosphatide to the symptomatic contact lens wearer. Advantageously, the hydrogel contact lens that releases oleic acid increases the duration of comfortable contact lens wear and / or reduces contact lens awareness events in the symptomatic contact lens wearer as compared to a control contact lens without 2 - oleoyl phosphatide. The 2 - oleoyl phosphatide is advantageously readily digested by sPLA2 enzymes (especially sPLA2 - IIA) found in human tears when present in the polymeric contact lens body, such as 2 - oleoyl phosphatide of formula (I).

[0015] Furthermore, the present invention relates to the use of a hydrogel contact lens that releases oleic acid and contains 2 - oleoyl phosphatide by a contact lens wearer to increase the duration of comfortable contact lens wear and / or reduce contact lens awareness events as compared to a control contact lens without 2 - oleoyl phosphatide.

[0016] Furthermore, the present invention relates to the use of a certain amount of 2 - oleoyl phosphatide in enhancing the comfort of a contact lens, wherein the phosphatide is associated with the polymeric contact lens body of the contact lens.

[0017] Furthermore, the present invention relates to a hydrogel composition for reducing contact lens awareness sensations in a contact lens wearer, thereby enhancing the comfort of the contact lens and / or increasing the duration of comfortable contact lens wear in a contact lens wearer, the composition comprising (a) a polymeric contact lens body that is a reaction product of a polymerizable composition, loaded with (b) a certain amount of 2 - oleoyl phosphatide.

[0018] In all aspects of the present invention, the 2 - oleoyl phosphatide is advantageously readily digested by sPLA2 enzymes (especially group IIA sPLA2) found in human tears when the 2 - oleoyl phosphatide is present in the polymeric contact lens body of a silicone hydrogel contact lens. In all aspects of the present invention, a contact lens comprising a polymeric contact lens body loaded with 2 - oleoyl phosphatide is characterized in that: (a) when the contact lens is immersed in human reflex tears at 35 °C for 4 hours, the amount of oleic acid detected in the reflex tears is two times (e.g., three times) that when the contact lens is immersed in a release medium lacking phospholipase A2 enzyme at 35 °C for 4 hours; and / or (b) when the contact lens is immersed in artificial tears (ATF) containing 50 ppm recombinant human group IIa secreted phospholipase A2 at 35 °C for 4 hours, the amount of oleic acid detected in the ATF is two times (e.g., three times) that when the contact lens is immersed in an equivalent ATF release medium lacking phospholipase A2 enzyme at 35 °C for 4 hours.

[0019] Other aspects of the invention are provided in the numbered clauses below:

[0020] 1. An unworn silicone hydrogel contact lens sealed in a package, the contact lens comprising a polymeric lens body loaded with an amount of 2 - oleoyl phosphatide.

[0021] 2. The silicone hydrogel contact lens of clause 1, wherein the 2 - oleoyl phosphatide is readily digested by the secretory phospholipase A2 (sPLA2) enzyme found in human tears when present in the polymeric lens body.

[0022] 3. The contact lens of clause 1 or 2, wherein the hydrogel contact lens releases oleic acid when contacted with a solution containing sPLA2 - IIA.

[0023] 4. The silicone hydrogel contact lens of any of the preceding clauses, wherein the contact lens releases from one to two times more oleic acid when contacted with artificial tear serum (ATF) containing 50 ppm human sPLA2 at 37°C for four hours than when contacted with ATF without human sPLA2.

[0024] 5. The silicone hydrogel contact lens of any of the preceding clauses, wherein the 2 - oleoyl phosphatide is phosphatidylserine, phosphatidylethanolamine or phosphatidylglycerol.

[0025] 6. The silicone hydrogel contact lens of any of the preceding clauses, wherein the 2 - oleoyl phosphatide is selected from 1,2 - dioleoyl phosphatidylglycerol (DOPG), 1,2 - dioleoyl phosphatidylserine (DOPS) and 1,2 - dioleoyl phosphatidylethanolamine (DOPE).

[0026] 7. The silicone hydrogel contact lens of any of the preceding clauses, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising at least one hydrophilic monomer containing a vinyl group.

[0027] 8. A silicone hydrogel contact lens as in any of the preceding clauses, wherein the polymeric contact lens body is the reaction product of a polymerizable composition comprising 25 wt% to 55 wt% of a siloxane monomer, 30 wt% to 55 wt% of a vinyl monomer selected from N-vinylpyrrolidone, N-vinyl-N-methylacetamide, or a combination thereof, and optionally about 1 wt% to about 20 wt% 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 wt% to about 20 wt% of a hydrophobic monomer selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), or 2-hydroxybutyl methacrylate (HOB) or any combination thereof.

[0028] 9. A contact lens as in any of the preceding clauses, wherein the polymeric contact lens body comprises a first siloxane having a structure represented by formula (II),

[0029]

[0030] and is the reaction product of a polymerizable composition comprising a second siloxane having a structure represented by formula (III),

[0031]

[0032] 10. A contact lens as in any of the preceding clauses, wherein the polymeric contact lens body is loaded with at least 10 μg of 2-oleoylphospholipid, especially at least 10 μg of 2-oleoylphosphatidylserine, 2-oleoylphosphatidylethanolamine, or 2-oleoylphosphatidylglycerol, such as at least 10 μg of 1,2-dioleoylphosphatidylserine (DOPS), 1,2-dioleoylphosphatidylethanolamine (DOPE), or 1,2-dioleoylphosphatidylglycerol (DOPG).

[0033] 11. A contact lens as in clause 10, wherein the amount of 2-oleoylphospholipid is from 10 μg to 1000 μg, preferably from 25 μg to 250 μg.

[0034] 12. A contact lens as in any of the preceding clauses, wherein when immersed in a release medium comprising an artificial tear solution containing 50 ppm sPLA2 at 35 °C, the contact lens continuously releases at least 0.1 μg / hr of oleic acid for at least 4 hours, such as at least 8 hours, optionally at least 10 hours.

[0035] 13. A contact lens as in any of the preceding clauses, wherein the package comprises:

[0036] (a) A base member having a cavity for holding a packaging solution and a flange surrounding the cavity; and

[0037] (b) A cap that forms a liquid-tight seal with the flange of the base member.

[0038] 14. A method of manufacturing a hydrogel contact lens as described in any one of the preceding items, the method comprising: 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 phosphatide, d) hydrating the polymeric lens body in a hydrating liquid to obtain the hydrogel contact lens, e) sealing the hydrogel contact lens in a package with a packaging solution, and optionally, f) heat-pressing the package.

[0039] 15. A method of correcting the vision of a symptomatic contact lens wearer, the method comprising having the symptomatic contact lens wearer wear a hydrogel contact lens as described in any one of items 1 to 13.

[0040] 16. The method of item 15, wherein the symptomatic contact lens wearer has an increased duration of comfortable contact lens wear compared to a control lens.

[0041] 17. The method of item 15 or 16, wherein the symptomatic contact lens wearer has a reduced lens awareness and / or fewer "lens awareness events" during the day compared to a control lens.

[0042] 18. Use of a certain amount of 2-oleoyl phosphatide in enhancing the comfort of a contact lens, wherein the phosphatide associates with the polymeric lens body of the contact lens.

[0043] 19. The use of item 18, wherein the contact lens is a hydrogel contact lens as described in any one of items 1 to 13.

[0044] 20. The use of item 18 or 19, wherein in a symptomatic contact lens wearer, the lens awareness sensation is reduced, and / or the duration of comfortable contact lens wear is increased.

[0045] 21. A hydrogel composition for reducing lens awareness sensation in a contact lens wearer, thereby enhancing the comfort of the contact lens in the contact lens wearer and / or increasing the duration of comfortable contact lens wear in the contact lens wearer, the composition comprising (a) a polymeric lens body as a reaction product of a polymerizable composition, loaded with (b) a certain amount of 2-oleoyl phosphatide.

[0046] 22. A composition as used in item 21, wherein the composition is in the form of a contact lens as in any one of items 1 to 13. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 Depicts the enzymatic hydrolysis of dioleoylphosphatidylglycerol (DOPG) at the sn-2 ester bond to produce oleic acid and lysophosphatidylglycerol (LOPG). DETAILED DESCRIPTION

[0048] Described herein are silicone hydrogel contact lenses that continuously release oleic acid during wear and methods of making the same. 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 enhances the comfort of contact lens wear in contact lens wearers and may increase the duration for which a contact lens wearer can comfortably wear a contact lens. In particular, the oleic acid-releasing lenses of the present invention may increase the all-day comfort of lens wear in symptomatic patients.

[0049] The silicone hydrogel contact lenses of the present invention advantageously provide continuous oleic acid release during lens wear. The silicone hydrogel contact lenses comprise a polymeric lens body loaded with glycerophospholipids having an oleoyl group (i.e., *OC(O)C7H 14 CH=CHC8H 17 ) at the sn-2 position (hereinafter referred to as "2-oleoyl phospholipids"). Any 2-oleoyl phospholipid that is readily degradable by human secretory phospholipase A2 (human sPLA2) present in tears can be used in the contact lenses of the present invention. The susceptibility of a phospholipid to degradation by human sPLA2 present in tears can be determined using commercially available recombinant human PLA2G2A as described in Example 1 below.

[0050] The 2-oleoyl phospholipid may be, for example, phosphatidic acid, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or phosphatidylglycerol. Preferably, the 2-oleoyl phospholipid is not phosphatidylcholine. It has been found that phosphatidylcholine is less readily degradable by group IIA secretory phospholipase A2 (sPLA2-IIA) enzymes found in human tears, as demonstrated in Example 1 below. Advantageously, the 2-oleoyl phospholipid is selected from phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylglycerol, particularly phosphatidylethanolamine or phosphatidylglycerol.

[0051] With respect to "readily digestible", sPLA2 present in human tears will hydrolyze the acyl group at the sn2 position of the 2-oleoyl phospholipid to produce free fatty acids and lysophospholipids.

[0052] The 2-oleoyl phospholipid can be digested by human tears. The 2-oleoyl phospholipid can be digested by at least sPLA2 present in human tears.

[0053] The 2-oleoyl phospholipid may comprise another oleoyl group at the sn-1 position, i.e., it may be a dioleoyl phospholipid, such as 1,2-dioleoyl phosphatidylglycerol. Alternatively, the 2-oleoyl phospholipid may comprise a different fatty acid group at the sn-1 position. The fatty acid at the sn-1 position may be a C 12-26 fatty acid, such as a C 14-22 fatty acid.

[0054] 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, 1-pentadecanoyl-2-oleoyl phosphatidylglycerol, 1-pentadecanoyl-2-oleoyl phosphatidylserine, 1-di(docosahexaenoyl)-2-oleoyl phosphatidylethanolamine, 1-di(docosahexaenoyl)-2-oleoyl phosphatidylglycerol, 1-di(docosahexaenoyl)-2-oleoyl phosphatidylserine, 1-stearoyl-2-oleoyl phosphatidylethanolamine, 1-stearoyl-2-oleoyl phosphatidylglycerol, and 1-stearoyl-2-oleoyl phosphatidylserine.

[0055] As an option, 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).

[0056] The oleic acid at the sn-2 position is advantageously released and eluted from the lens, while the remainder of the phospholipid (i.e., lysophospholipid) remains within the lens. In addition to the diffusion rate of oleic acid itself through the contact lens, the release rate of oleic acid may depend on the kinetics of the enzymatic reaction of the 2-oleoyl phospholipid.

[0057] The hydrogel contact lens can be a silicone hydrogel. As an example, the silicone hydrogel contact lens comprises a polymeric lens body that is a reaction product of a polymerizable composition comprising at least one siloxane monomer or macromonomer and at least one hydrophilic monomer and / or at least one hydrophilic polymer. Conveniently, as described in more detail below, the cured polymeric lens body for the silicone hydrogel can be extracted in an extraction solvent containing 2-oleoyl phosphatide (e.g., ethanol). Thus, the extraction step can be used to extract unreacted monomers and other materials from the cured polymeric lens body and to load the 2-oleoyl phosphatide into the polymeric lens body. Alternatively or in addition to including the 2-oleoyl phosphatide in the extraction solvent, the 2-oleoyl phosphatide can be included in the polymerizable composition. In both cases, the 2-oleoyl phosphatide can become associated with the polymeric lens body by electrostatic and / or hydrophobic interactions and / or can be physically entrapped by the polymer network of the polymeric lens body. Thus, the term "associated with" refers to the non-covalent interaction between the 2-oleoyl phosphatide and the polymeric lens body and can be used interchangeably with the terms "attached to" and "loaded into".

[0058] The amount of 2-oleoylphosphatidylcholine loaded into the polymeric ocular lens body refers to the total amount of phosphatidylcholine extractable from the contact lens by the isopropanol (IPA) extraction method as described in Example 2 below. Advantageously, when the ocular lens is immersed in deionized water or a standard contact lens packaging solution (such as phosphate or borate buffered saline), the 2-oleoylphosphatidylcholine associated with the polymeric ocular lens body is not removed. In one example, the 2-oleoylphosphatidylcholine is loaded into the polymeric ocular lens body using a loading solution comprising an alcohol (such as ethanol), and the concentration of the 2-oleoylphosphatidylcholine ranges 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 can, for example, comprise any mixture of ethanol (EtOH) and water that can dissolve the 2-oleoylphosphatidylcholine and swell the lens material, such as an aqueous solution of about 10% to 95% EtOH. The ocular lens is immersed in the loading solution for a time required to achieve the desired loading level of the 2-oleoylphosphatidylcholine in the polymeric ocular lens body, which can be determined by routine experimentation (such as by following the method of Example 2). In some examples, the amount of 2-oleoylphosphatidylcholine associated with the polymeric ocular lens body can be at least about 1 μg, 10 μg, 25 μg, 50 μg, or 100 μg up to a maximum of 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-oleoylphosphatidylcholine associated with the polymeric ocular lens body is from about 25 μg / lens to about 250 μg / lens.

[0059] As used herein and unless the context indicates otherwise, reference to the amount of oleic acid released from the 2 - oleoylphospholipid - containing contact lens over a specified duration or reference to the "release profile" of said oleic acid refers to the amount of oleic acid released from the lens measured using an in vitro release medium (ATF containing 50 ppm sPLA2 as described in Table 2 below) and the method described in Example 3 below. The contact lens may have an in vitro oleic acid release profile of from about 0.05 μg / hr to 50 μg / hr of oleic acid from the lens, such as 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 initially being immersed in the release medium at 35°C. Advantageously, the contact lens continuously releases oleic acid for at least 4 hours, such as at least 8 hours, optionally at least 10 hours or at least 12 hours. Advantageously, the contact lens continuously releases from 0.05 μg to 25 μg of oleic acid per hour, such as 0.1 μg to 10 μg, or 0.1 μg to 5 μg of oleic acid, for at least the first 10 hours after being immersed in the release medium at 35°C, as determined by the method of Example 3. An oleic acid release rate as low as 0.05 μg / hr may be beneficial for some wearers. A release rate above 50 μg / hr may cause irritation in some wearers and as the oleic acid release rate increases above 25 μg / hr, some wearers may not experience any additional beneficial effects.

[0060] As an option, in addition to the presence of 2 - oleoylphospholipid as described herein, the contact lenses of the present invention do not contain any comfort agents.

[0061] As an option, the contact lenses of the present invention may contain one or more comfort agents different from the 2 - oleoylphospholipid as described herein. The amount of any other comfort agent may be less than the amount of 2 - oleoylphospholipid 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.

[0062] As an option, the packaging solution as described herein does not contain any comfort agents.

[0063] As an option, the packaging solution as described herein does not contain any comfort agents, except possibly for the presence of 2 - oleoylphospholipid and / or oleic acid resulting from the 2 - oleoylphospholipid initially present in the contact lens.

[0064] As an option, the only phospholipid present in or associated with the contact lens is 2 - oleoylphospholipid.

[0065] As an option, the only source of fatty acids released or present in the contact lens is from the 2 - oleoylphospholipid present.

[0066] The present invention is capable of providing improved controlled release of oleic acid as compared to free oleic acid (not derived from 2-oleoylphospholipid) associated with the contact lens. For example, the release may be more linear as compared to free fatty acid used / associated with the contact lens only.

[0067] The release of fatty acid from digestion of 2-oleoylphospholipid can be regarded as a tear controlled release of fatty acid.

[0068] Silicone hydrogel materials for contact lenses are generally formed by curing a polymerizable composition (i.e., monomer mixture) comprising at least one siloxane monomer or macromonomer and at least one hydrophilic monomer or at least one hydrophilic polymer or a combination thereof. As used herein, the term "siloxane monomer" refers to a molecule comprising at least one Si-O group and at least one polymerizable functional group. A "siloxane macromonomer" refers to a silicon-containing molecule having at least one polymerizable functional group, which although used as a monomer has a high enough molecular weight and enough internal monomer units to be regarded as polymeric. Generally, siloxane macromonomers contain a siloxane chain having at least 5 siloxane (-Si-O-) units and / or having a molecular weight of at least 500 daltons.

[0069] Siloxane monomers and macromonomers for contact lens compositions are well known in the art (see, for example, U.S. Patent No. 8,658,747 and U.S. Patent No. 6,867,245). (The entire texts of all patents and publications mentioned herein and throughout are incorporated by reference.) In some instances, the polymerizable composition comprises a total amount of at least 10 total %, 20 total %, or 30 total % up to about 40 total %, 50 total %, 60 total %, or 70 total % of siloxane monomer or macromonomer. Unless otherwise specified, as used herein, a given weight percentage (wt%) of a component of the polymerizable composition is based on the total amount of all polymerizable components and IPN polymers (described further below) in the polymerizable composition. The weight of the polymerizable composition contributed by components that are not incorporated into the final contact lens product (e.g., diluents) is not included in the wt% calculation.

[0070] In one specific example, the polymerizable composition comprises a hydrophilic vinyl monomer. As used herein, a "hydrophilic vinyl monomer" is any siloxane-free (i.e., Si-O-free) hydrophilic monomer having a polymerizable carbon-carbon double bond (i.e., a vinyl group) that is not part of an acrylic group in its molecular structure, wherein the carbon-carbon double bond of the vinyl group is not as reactive as the carbon-carbon double bond present in a polymerizable methacrylate group under free radical polymerization. As used herein, the term "acrylic group" refers to a polymerizable group present in acrylates, methacrylates, acrylamides, and the like. Therefore, although carbon-carbon double bonds are present in acrylate and methacrylate groups, such polymerizable groups are not considered vinyl groups as used herein. In addition, as used herein, if at least 50 grams of the monomer is completely soluble in 1 liter of water (i.e., about 5% soluble in water) at 20°C as determined visibly using a standard shake bottle method, then the monomer is "hydrophilic". In various examples, the hydrophilic vinyl monomer is N-vinyl-N-methylacetamide (VMA), or N-vinyl pyrrolidone (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 embodiment, the polymerizable composition comprises at least 10 wt%, 15 wt%, 20 wt%, or 25 wt% up to about 45 wt%, 60 wt%, or 75 wt% of the hydrophilic vinyl monomer. As used herein, a given weight percentage of a particular class of components (e.g., hydrophilic vinyl monomers, siloxane monomers, etc.) in the polymerizable composition is equal to the sum of the weight percentages of the components in the composition that fall within the class. Thus, for example, a polymerizable composition comprising 5 wt% BVE and 25 wt% NVP and no other hydrophilic vinyl monomers is considered to comprise 30 wt% hydrophilic vinyl monomers. In one example, the hydrophilic vinyl monomer is a vinyl amide monomer. Exemplary hydrophilic vinylamide monomers are VMA and NVP. In one embodiment, the polymerizable composition comprises at least 25 wt% of the vinylamide monomer. In another embodiment, the polymerizable composition comprises from about 25 wt% up to about 75 wt% of VMA or NVP, or a combination thereof. Additional hydrophilic monomers that may 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.

[0071] Additionally or in place of the hydrophilic monomers, the polymerizable composition may comprise a non-polymerizable hydrophilic polymer, which results in a polymeric lens body comprising an interpenetrating polymer network (IPN), wherein the non-polymerizable hydrophilic polymer interpenetrates the silicone hydrogel polymer matrix. In this example, the non-polymerizable hydrophilic polymer is referred to as the IPN polymer, which serves as an internal wetting agent in the contact lens. In contrast, the polymer chains within the silicone hydrogel network formed by the polymerization of the monomers present in the polymerizable composition are not considered IPN polymers. The IPN polymer can be a high molecular weight hydrophilic polymer, such as from about 50,000 to about 500,000 Daltons. In a specific example, the IPN polymer is polyvinylpyrrolidone (PVP). In other examples, the polymerizable composition is substantially free of polyvinylpyrrolidone or other IPN polymers.

[0072] As an option, one or more non-silicon-containing hydrophobic monomers may be present as part of the polymerizable composition. A hydrophobic monomer can be understood as any monomer that is not visibly 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 acrylate, or 2-hydroxybutyl methacrylate, or vinyl acetate, or vinyl propionate, or vinyl butyrate, or vinyl valerate, styrene, or chloroprene, or vinyl chloride, or vinylidene chloride, or acrylonitrile, or 1-butene, or butadiene, or methacrylonitrile, or vinyltoluene, or vinyl ethyl ether, or perfluorohexylethylthio-carbonylaminoethyl methacrylate, or isobornyl methacrylate (IBM), or trifluoroethyl methacrylate, or hexafluoroisopropyl methacrylate, or tetrafluoropropyl methacrylate, or hexafluorobutyl methacrylate, or any combination thereof.

[0073] The hydrophobic monomer (if used) may be present in the reaction product of the polymerizable composition in an amount of from 1 wt% to about 30 wt%, such as 1 wt% to 25 wt%, 1 wt% to 20 wt%, 1 wt% to 15 wt%, 2 wt% to 20 wt%, 3 wt% to 20 wt%, 5 wt% to 20 wt%, 5 wt% to 15 wt%, 1 wt% to 10 wt% of the total weight of the polymerizable composition.

[0074] The polymerizable composition may additionally comprise at least one crosslinking agent. As used herein, a "crosslinking agent" is a molecule having at least two polymerizable groups. Thus, the crosslinking agent can react with functional groups on two or more polymer chains to bridge one polymer to another. The crosslinking agent may comprise acrylic or vinyl groups, or both acrylic and vinyl groups. In certain instances, the crosslinking agent does not contain a siloxane moiety, i.e., it is a non-siloxane crosslinking agent. A variety of crosslinking agents suitable for use in silicone hydrogel polymerizable compositions are known in the art (see, e.g., U.S. Patent No. 8,231,218, which is incorporated herein by reference). Examples of suitable crosslinking agents include, but are not limited to, lower alkylene glycol di(meth)acrylates such as triethylene glycol dimethacrylate, diethylene glycol dimethacrylate, poly(lower alkylene) glycol di(meth)acrylate, and lower alkylene di(meth)acrylate; 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; methylenebis(meth)acrylamide; triallyl phthalate; 1,3-bis(3-methacryloxypropyl)tetramethyldisiloxane; diallyl phthalate; and combinations thereof.

[0075] As will be appreciated by those skilled in the art, the polymerizable composition may contain one or more 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, a chain transfer agent, and the like. In some instances, the polymerizable composition may contain an amount of an organic diluent that prevents or minimizes phase separation between the hydrophilic and hydrophobic components of the polymerizable composition to yield an optically clear lens. Diluents commonly used in contact lens formulations include hexanol, ethanol, and / or other primary, secondary, or tertiary alcohols. In other instances, the polymerizable composition does not contain or is substantially free of (e.g., less than 500 ppm) an organic diluent. In such instances, the use of a siloxane monomer containing a hydrophilic moiety (such as a poly(ethylene oxide) group, a pendant hydroxyl group, or other hydrophilic group) may obviate 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. Patent No. 8,231,218.

[0076] Non-limiting examples of silicone hydrogels that can be used include Comfilcon A, Fanfilcon A, Stanfilcon 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.

[0077] A specific example of the hydrogel contact lens of the present invention is a contact lens based on a polymerizable composition, the polymerizable composition comprising 25% to 55% by weight of a siloxane monomer or macromonomer, 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. The silicone hydrogel materials made from this specific embodiment of the polymerizable composition include Stanfilcon A, Comfilcon A, Somofilcon A, Fanfilcon A, and Enfilcon A. In another example, the above polymerizable composition contains the siloxane of Stanfilcon A, specifically, a first siloxane having a structure represented by formula (II),

[0078]

[0079] and a second siloxane having a structure represented by formula (III),

[0080]

[0081] The contact lenses of the present invention can be manufactured using conventional methods. As an example, a polymerizable composition for a hydrogel composition is dispensed into a master 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 back surface (i.e., the corneal contact surface) of the contact lens is combined with the master mold member to form a contact lens mold assembly, and the contact lens mold assembly is subjected to curing conditions (e.g., UV or heat curing conditions), under which the curable composition is formed into a polymeric lens body. The master and male mold members can be non-polar molds or polar molds. The mold assembly is disassembled (i.e., demolded) and the polymeric 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 (e.g., water or an aqueous solution) and packaged. An exemplary method for manufacturing silicone hydrogel contact lenses is described in U.S. Patent No. 8,865,789.

[0082] The 2-oleoyl phosphatide is typically loaded into the polymeric lens during the extraction step. Generally, after curing, the polymeric lens body swells in an extraction solvent (e.g., a mixture of ethanol and water) containing the 2-oleoyl phosphatide. When the extracted polymeric lens body is subsequently placed in a hydrating solution (e.g., deionized (DI) water), the extraction solvent is removed, and the 2-oleoyl phosphatide remains associated with the polymeric lens body.

[0083] Examples of extraction solvents and hydrating liquids for the extraction and hydration processes can consist of denatured ethanol, a mixture of denatured ethanol and deionized water, and deionized water. As an example, the extraction and hydration process can involve at least one extraction step in denatured ethanol (EtOH), followed by an extraction step with a mixture of EtOH and water, such as an aqueous solution of about 10% to 95% EtOH, such as an aqueous solution of about 30% to 80% EtOH, followed by at least one hydration step in deionized water, and wherein each extraction and hydration step can be carried out at a temperature of about 20°C to about 30°C for about 15 minutes to about 3 hours. An extraction solvent can contain 2-oleoyl phosphatide to effect the loading of the 2-oleoyl phosphatide onto the polymeric lens body.

[0084] Any extraction solvent used as a loading solution for the 2-oleoyl phosphatide can contain 2-oleoyl phosphatide at a concentration of about 0.01 μg / ml to 10 mg / mL, such as 0.1 μg / ml to 5 mg / mL. The amount of 2-oleoyl phosphatide loaded onto the polymeric lens body can be 10 μg to 1000 μg, such as about 25 μg to 500 μg, or 50 μg to 250 μg.

[0085] As part of the present invention, the contact lens may be sealed within a contact lens package. The packaging solution within which the contact lens is sealed may be any conventional contact lens compatible solution. In one example, the packaging solution comprises, consists of, or consists essentially of an aqueous solution of a buffer and / or a tonicity 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 comprise a polysaccharide (such as 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 thickening agents in ophthalmic solutions and contact lens packaging solutions. In other examples, the packaging solution may comprise an ophthalmic drug. The packaging solution may have a pH in the range of from about 6.8 or 7.0 up to about 7.8 or 8.0. In one example, the packaging solution comprises a phosphate buffer or a borate buffer. In another example, the packaging solution comprises a tonicity agent selected from sodium chloride or sorbitol in an amount such that the osmotic pressure is maintained in the range of from about 200 to 400 mOsm / kg, and typically in the range of from about 270 mOsm / kg up to about 310 mOsm / kg.

[0086] With respect to the contact lens package, the package may include or comprise a plastic base member that includes a cavity configured to hold the contact lens and the packaging solution and a flange region that extends 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 well known in the art and are commonly referred to as “blister packs” (see, for example, U.S. Patent No. 7,426,993).

[0087] It should be understood that conventional manufacturing methods can be used to manufacture sealed contact lens packages. In a method of manufacturing a contact lens package, the method may include the steps of placing an unworn contact lens and a contact lens packaging solution in a container, placing a lid on the container, and sealing the lid on the container. Generally, the container is configured to receive a single contact lens and an amount of packaging solution sufficient to completely cover the contact lens, typically about 0.5 to 1.5 ml. The container can be made of any suitable material (such as glass or plastic). In one example, the container includes a plastic base member that includes a cavity configured to hold the contact lens and the packaging solution and a flange region that extends outwardly around the cavity, and the lid includes a removable foil that is attached to the flange region to provide a sealed contact lens package. The removable foil can be sealed by any conventional means (such as heat sealing or gluing). In another example, the container is in the form of a plastic base member that includes a plurality of threads and the lid includes a plastic cap member that includes a set of compatible threads for engaging the thread teeth of the base member to provide a resealable lid. It should be understood that other types of packaging can also be used to provide a resealable package. For example, a contact lens package can include a plastic lid that includes compatible features that engage with the container to form a tight fit. The method of manufacturing a sealed contact lens package can further include sterilizing the unworn contact lens by heat pressing the sealed contact lens package. Heat pressing generally involves subjecting the sealed contact lens package to a temperature of at least 121 °C for at least 20 minutes.

[0088] The contact lens can be provided in a manner that it is unworn (i.e., a new contact lens that has not been previously used by the patient), immersed in the packaging solution and sealed in the package. The package can be a blister package, a glass vial or other suitable container. The package can include a base member having a cavity for holding the packaging solution, a lid that forms a liquid-tight seal with the base member, and an unworn contact lens. The sealed package can be sterilized by a sterilizing amount of radiation, including heat or steam, such as by heat pressing or by gamma radiation, electron beam radiation, ultraviolet radiation, etc.

[0089] In a specific example, the packaged contact lens is sterilized by heat pressing.

[0090] The final product can be a sterile, packaged contact lens (such as a silicone hydrogel contact lens) having ophthalmically acceptable surface wettability.

[0091] The oleic acid-releasing hydrogel contact lenses described herein can be used to correct the vision of symptomatic contact lens wearers. For example, the oleic acid-releasing hydrogel contact lenses of the present invention can increase the duration of comfortable contact lens wear in symptomatic contact lens wearers. As used herein, "symptomatic contact lens wearer" or "symptomatic individual" refers to a contact lens wearer classified as symptomatic using the CLDEQ-8 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.).

[0092] Compared to control glasses or the habitual glasses of contact lens wearers, the oleic acid-releasing hydrogel contact lenses described herein can be worn by contact lens wearers to reduce lens perception and / or result in fewer "lens perception events" during the day. As used herein, "control glasses" refers to contact lenses that do not contain phospholipids or oleic acid but are otherwise identical to the oleic acid-releasing lenses being compared. A "lens perception recorder" 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) can be used to determine the reduction in lens perception and / or lens perception events during contact lens wear.

[0093] The following examples illustrate certain aspects and advantages of the present invention, which should be understood not to be limiting.

[0094] Example 1. Oleic acid release from Stanfocon A lenses loaded with different 2-oleoylphospholipids.

[0095] 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, sonication (up to 15 minutes), then adding 0.6 mL of DI water and sonication again (up to 15 minutes) to dissolve the phospholipid.

[0096] Table 1.

[0097] Phospholipid Abbreviation Catalog Number 1,2-Dioleoyl-sn-glycero-3-phospho-L-serine (sodium salt) DOPS 840035P 1,2-Dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt) DOPG 840475P 1,2-Dioleoyl-sn-glycero-3-phosphocholine DOPC 850375P 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine DOPE 850725P

[0098] Wash the hydrogel contact lenses made of Stanfikon A three times in 3 mL of pure water for 30 minutes each time. Place each washed lens in 3 mL of a phospholipid-loaded solution and incubate at room temperature with gentle shaking at 75 rpm for 3 hours. Then rinse the loaded lenses and exchange the hydration water several times with DI water. Package the lenses in a buffered saline contact lens packaging solution and perform a heat press treatment.

[0099] Prepare artificial tear fluid (ATF) by adding the first three components listed in Table 2 to a clean vial and then adding 30 mL of the fourth component.

[0100] Table 2.

[0101]

[0102] After the heat press treatment, remove each lens from its package and place it in a 6 mL glass vial containing 5 mL of ATF on an oscillator at 125 rpm at room temperature overnight to elute any free oleic acid that may be present in the lens.

[0103] Before running the digestion assay, rinse each lens in a 6 mL glass vial containing a fresh aliquot of 5 mL of ATF for 30 minutes.

[0104] Prepare a 50 ppm solution of sPLA2 in ATF by adding 200 μL of ATF to a tube containing 10 μg of recombinant human PLA2G2A (Creative BioMart, catalog number PLA2G2A-669H). The solution is designated as ATF + sPLA2. Cut two 4 mm pieces from each lens. Place one piece of each lens in a tube with 100 μL of ATF and the other piece in a tube containing 100 μL of ATF + sPLA2. Incubate the tubes at 35 ± 2 °C for 4 hours without shaking.

[0105] Transfer 50 μL of the release medium from each lens at T = 4 hr to an HPLC vial and add 500 μL of isopropanol (IPA) and mix well. Also prepare T = 0 hr HPLC vials (50 μL of ATF + 500 μL of IPA). All vials are sonicated for 15 minutes and centrifuged. Remove the supernatant for LCMS injection.

[0106] Inject the supernatant onto an LCMS instrument equipped with an ACQUITY UPLC BEH C18 1.7 μg, 2.1 mm x 15 cm column and running 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, and B = 10% acetonitrile in IPA with 10 mM ammonium acetate and 0.2% (v / v) ammonium hydroxide. The mass spectrometer detector is operated in negative electrospray mode. Measure the peak of oleic acid (OA) (m / z trace = 281.24) in the supernatant. Calculate the ratio of the OA peak areas in ATF with and without sPLA2. The results are shown in Table 3.

[0107] Table 3. Oleic acid peak areas in ATF with and without sPLA2.

[0108] Sample ATF ATF + sPLA2 Ratio DOPG 36 9958 279 DOPE 463 2127 4.6 DOPC 102 125 1.2 DOPS 88 1437 16.4

[0109] The results showed that the 2-oleoylphosphatidylcholine-loaded contact lenses were not susceptible to sPLA2-mediated degradation and fatty acid release, while the phosphatidylglycerol-, phosphatidylethanolamine-, and phosphatidylserine-loaded contact lenses were susceptible to sPLA2-mediated fatty acid release.

[0110] Example 2. DOPG-loaded stanfacon A contact lenses.

[0111] Dissolve 1,2-dioleoyl-sn-glycero-3-phosphate-rac-(1-glycerol) sodium salt (DOPG) from Sigma-Aldrich in a 50 volume% ethanol (EtOH) 50 volume% deionized water solution and sonicate until the DOPG is completely dissolved to provide a DOPG-loading solution in the concentration range of 1 mg / ml to 10 mg / ml.

[0112] Prepare silicone hydrogel contact lenses by curing a formulation of stanfacon A in a polypropylene contact lens mold. Remove the cured stanfacon A from the mold and extract each lens in EtOH to remove unreacted monomers. Then place the lenses in the DOPG-loading solution for about 90 minutes and then hydrate with several exchanges of DI water. Package the lenses in plastic blisters with about 1.2 ml of a packaging solution containing phosphate buffered saline (PBS) and perform heat pressing.

[0113] 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 spotted 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 bench top shaker at 300 rpm overnight (about 16 hours) at room temperature. For Stanfacon A, a single 2-hour extraction step was sufficient to extract substantially 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 was removed and replaced with 3 mL of fresh IPA, and then shaken overnight at 300 rpm at room temperature. The amount of DOPG in the IPA extract from each lens was determined by LCMS relative to a DOPG standard solution. The DOPG loading concentration and average DOPG in each lens are shown in Table 4.

[0114] Table 4.

[0115] DOPG Loading Concentration Average Amount of DOPG / Eyeglass 1.0 mg / mL 240 μg 2.5 mg / mL 495 μg 5.0 mg / mL 760 μg 7.5 mg / ml 895 μg 10.0 mg / ml 975 μg

[0116] Example 3. Determination of oleic acid release profile

[0117] To determine the oleic acid release profile of silicone hydrogel contact lenses loaded with 2-oleoylphosphatidylcholine, the lenses were removed from their packaging and placed in 6 mL glass vials containing 5 mL of ATF (described in Example 1) on an oscillator at 125 rpm overnight at room temperature to elute any free oleic acid that may be present in the lenses.

[0118] Then, each lens was transferred to a 6 mL glass vial containing 3 mL of an in vitro release medium containing ATF with 50 ppm recombinant human PLA2G2A at 35°C. As an alternative, phospholipase A2 from bee venom (accession number 9001-84-7) could be used instead of recombinant human PLA2G2A at the same concentration (50 ppm). The vials were placed in an incubator at 35°C on a shaker at 50 rpm, and 2.5 mL of the in vitro release medium was removed from each vial at 2-hour intervals (e.g., 2 hr, 4 hr, 6 hr, 8 hr, and 10 hr) and submitted for analysis. If the release medium was not analyzed immediately at the specific time point, samples were collected and mixed with IPA (1:10 v / v ratio) to stop enzymatic activity. Then, 2.5 mL of fresh in vitro release medium containing ATF with 50 ppm recombinant human PLA2G2A was added back to each vial and the lenses were continued to be incubated. At the end of the release experiment, the amount of OA in the release medium at each time point was analyzed by LCMS using the method described in Example 1.

[0119] The present disclosure refers to certain illustrative examples, and it should be understood that these examples are presented by way of example and not by way of limitation. Although the exemplary examples are discussed, the intention of the foregoing embodiments should be construed to cover all modifications, alternatives, and equivalents of the examples, which may fall within the spirit and scope of the present invention as defined by the additional disclosure.

[0120] As used herein, the phrase "an example" or "a specific example" or "an aspect" or "an embodiment" or similar phrase is intended to introduce one or more features (depending on the context) of the oleic acid-releasing hydrogel contact lens of the present invention or its components, the sealed contact lens package or its components, or the method of manufacturing the oleic acid-releasing hydrogel contact lens of the present invention, which can be combined with any combination of the examples, aspects, embodiments (i.e., features) described previously or subsequently, unless the specific combination of features is mutually exclusive or as otherwise indicated by the context. In addition, as used in this specification, the singular forms "a", "an", and "the" include plural referents (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.

[0121] The entire contents of all references cited in this disclosure are incorporated herein by reference to the extent that they are not inconsistent with this disclosure.

[0122] The present invention may include any combination of the various features or embodiments described above (including the numbered items above) and / or in the claims below, stated in sentences and / or paragraphs. Any combination of the features disclosed herein is considered to be part of the present invention and no intention is made to limit the features that can be combined.

[0123] Those skilled in the art will appreciate other embodiments of the present invention from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered only exemplary, and the true scope and spirit of the present invention be indicated by the following claims and their equivalents.

Claims

1. An unworn silicone hydrogel contact lens sealed in a package, the contact lens comprising a polymeric lens body loaded with at least one 2-oleoyl phospholipid, wherein the contact lens releases at least twice as much oleic acid when contacted with artificial tear serum (ATF) containing 50 ppm of human sPLA2 at 37 °C for four hours as when contacted with ATF without human sPLA2, and wherein the 2-oleoyl phospholipid is phosphatidylserine, phosphatidylethanolamine, or phosphatidylglycerol.

2. The silicone hydrogel contact lens according to claim 1, wherein the 2-oleoyl phospholipid is selected from 1,2-dioleoyl phosphatidylglycerol, 1,2-dioleoyl phosphatidylserine, and 1,2-dioleoyl phosphatidylethanolamine.

3. The silicone hydrogel contact lens according to claim 1, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising 25 wt% to 55 wt% of a siloxane monomer, 30 wt% to 55 wt% of a vinyl monomer selected from N-vinylpyrrolidone, N-vinyl-N-methylacetamide, or a combination thereof, and optionally 1 wt% to 20 wt% of a hydrophilic monomer selected from N,N-dimethylacrylamide, 2-hydroxyethyl methacrylate, ethoxyethyl methacrylamide, or ethylene glycol methyl ether methacrylate, or any combination thereof, and optionally 1 wt% to 20 wt% of a hydrophobic monomer selected from methyl methacrylate, isobornyl methacrylate, or 2-hydroxybutyl methacrylate, or any combination thereof.

4. The silicone hydrogel contact lens according to claim 1, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising a first siloxane having a structure represented by formula (II), and a second siloxane having a structure represented by formula (III).

5. The silicone hydrogel contact lens according to claim 1, which is loaded with 10 μg to 1000 μg of the 2-oleoyl phospholipid.

6. The silicone hydrogel contact lens according to claim 1, which is loaded with 25 μg to 250 μg of the 2-oleoyl phospholipid.

7. The silicone hydrogel contact lens according to claim 1, wherein when immersed in a release medium comprising an artificial tear solution containing 50 ppm sPLA2 at 35 °C, the contact lens continuously releases at least 0.1 μg / hr of oleic acid for at least 4 hours.

8. The silicone hydrogel contact lens according to claim 1, wherein when immersed in a release medium comprising an artificial tear solution containing 50 ppm sPLA2 at 35 °C, the contact lens continuously releases at least 0.1 μg / hr of oleic acid for at least 8 hours.

9. The silicone hydrogel contact lens according to claim 1, wherein when immersed in a release medium comprising an artificial tear solution containing 50 ppm sPLA2 at 35 °C, the contact lens continuously releases at least 0.1 μg / hr of oleic acid for at least 10 hours.

10. An unworn silicone hydrogel contact lens sealed in a package, the contact lens comprising a polymeric lens body loaded with at least 10 μg of 2-oleoyl phosphatide, wherein the 2-oleoyl phosphatide is phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol or phosphatidylglycerol.

11. The silicone hydrogel contact lens according to claim 10, wherein the 2-oleoyl phosphatide is selected from 1,2-dioleoyl phosphatidylglycerol, 1,2-dioleoyl phosphatidylserine and 1,2-dioleoyl phosphatidylethanolamine.

12. The silicone hydrogel contact lens according to claim 10, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising 25 wt% to 55 wt% of a siloxane monomer, 30 wt% to 55 wt% of a vinyl monomer selected from N-vinylpyrrolidone, N-vinyl-N-methylacetamide or a combination thereof, and optionally 1 wt% to 20 wt% of a hydrophilic monomer selected from N,N-dimethylacrylamide, 2-hydroxyethyl methacrylate, ethoxyethyl methacrylate, or ethylene glycol methyl ether methacrylate or any combination thereof, and optionally 1 wt% to 20 wt% of a hydrophobic monomer selected from methyl methacrylate, isobornyl methacrylate or 2-hydroxybutyl methacrylate or any combination thereof.

13. The contact lens according to claim 10, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising a first siloxane having a structure represented by formula (II), and a second siloxane having a structure represented by formula (II).

14. The contact lens according to claim 10, which is loaded with 10 μg to 1000 μg of the 2-oleoyl phosphatide.

15. The contact lens according to claim 10, which is loaded with 25 μg to 250 μg of the 2-oleoyl phosphatide.

16. The contact lens according to claim 10, wherein when immersed in a release medium comprising an artificial tear solution containing 50 ppm sPLA2 at 35 °C, the contact lens continuously releases at least 0.1 μg / hr of oleic acid for at least 4 hours.

17. The contact lens according to claim 10, wherein when immersed in a release medium comprising an artificial tear solution containing 50 ppm sPLA2 at 35 °C, the contact lens continuously releases at least 0.1 μg / hr of oleic acid for at least 8 hours.

18. The contact lens according to claim 10, wherein when immersed in a release medium comprising an artificial tear solution containing 50 ppm sPLA2 at 35 °C, the contact lens continuously releases at least 0.1 μg / hr of oleic acid for at least 10 hours.

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