Sustained release of fatty acids from contact lenses

Abstract

A fatty acid releasing contact lens and a method for making the same are described. The fatty acid releasing contact lens comprises a glycerophospholipid loaded into a polymeric lens body and sustains the release of C12-C26 fatty acids after 1 hour in a release medium comprising an sPLA2 enzyme solution. The fatty acid releasing contact lens can be comfortably worn by a contact lens wearer, can increase comfortable lens wear time, and / or can reduce lens sensation events in a contact lens wearer.

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 over the entire duration of lens wear, thereby increasing the duration over which a contact lens wearer can comfortably wear the contact lens. 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] The feature of the present invention is that fatty acids such as oleic acid, especially C 12 -C 26 The present invention provides a hydrogel contact lens capable of releasing fatty acids. 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 present invention, as embodied and broadly described herein, the present invention provides, in part, a hydrogel contact lens comprising a polymeric lens body loaded with a phospholipid, the phospholipid comprising a C at the sn-2 position. 12 -C 26 The present invention relates to a hydrogel contact lens, which is a glycerophospholipid containing an acyl group. The phospholipid is preferably 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 phospholipid present in the contact lens body is preferably a glycerophospholipid that is susceptible to digestion by sPLA2 enzymes, particularly sPLA2-IIA, found in human tears when present in the polymeric lens body of a hydrogel contact lens, particularly a silicone hydrogel contact lens, such as a stenfilcon A contact lens. 12 -C 26 The glycerophospholipids containing acyl groups were released from stenfilcon A lenses loaded with at least 200 μg of glycerophospholipid in an artificial tear (ATF) release medium containing sPLA2 enzyme after immersion of identical stenfilcon A contact lenses loaded with each of the glycerophospholipids in each release medium at 35° C. for 4 hours. The C 12 -C 26The amount of fatty acid released into an otherwise identical control ATF release medium lacking phospholipase A2 enzyme was 12 -C 26 A glycerophospholipid may be considered susceptible to digestion by sPLA2 enzyme if it is at least three times the amount of fatty acid. An exemplary ATF release medium containing sPLA2 enzyme may be as defined in Table 1 below, further containing 50 ppm recombinant human sPLA2-IIA, and a 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 ATF. For the avoidance of doubt, while the determination of whether a glycerophospholipid is susceptible to digestion by sPLA2 enzyme may be performed by loading the glycerophospholipid into a stenfilcon A lens, the contact lenses of the present invention, including contact lenses containing glycerophospholipids determined to be susceptible to digestion by sPLA2 enzyme, need not be stenfilcon A lenses. In all aspects of the present invention, the contact lenses loaded with glycerophospholipids susceptible to digestion by sPLA2 enzyme may be any contact lens described herein. An example of a phospholipid that, when present in a silicone hydrogel contact lens body, is not susceptible to digestion by the sPLA2 enzyme found in human tears is, for example, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) from the phosphatidylcholine family. The phospholipid present in the contact lens body is advantageously not DMPC. The phospholipid present in the contact lens body may be other than DMPC or DOPC. The phospholipid present in the contact lens body may be other than glycerophosphocholine or other than phosphocholine. The phospholipid may be an anionic glycerophospholipid or a zwitterionic glycerophospholipid. Anionic glycerophospholipids have a phospholipid head group (i.e., R 3 The phospholipid comprises an anionic (negatively charged) substrate group attached at the carboxyl group (position).

[0005] [ka] Formula (I) [wherein X is either -O- or -O(CO)-; R 1 and R 2 are each independently 11-25 is alkyl, 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 - Preferably, R 3 is not a choline, i.e., the glycerophospholipid is other than 1,2-dioleoyl-sn-glycero-3-phosphocholine. The hydrogel contact lenses of the present invention are 12 -C 26 It has been found to sustain the release of fatty acids, 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 provided with 0.01 μg to 50 μg, 0.05 μg to 40 μg, and especially 0.1 to 25 μg of C after 1 hour of immersion in an ATF release medium containing 50 ppm of sPLA2-IIA enzyme solution in phosphate buffered saline (PBS) at 35° C. 12 -C 26 It is possible to release fatty acids.

[0007] The present invention further relates to a method of making the hydrogel contact lenses of the present invention, 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; and c) attaching a C to the polymeric lens body at the sn-2 position.12 -C 26 The method includes the steps of: extracting the glycerophospholipids containing acyl groups into an organic solvent; 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 occur before the extraction step c) in which the phospholipids are loaded into the polymeric lens body. If the hydration step d) occurs before the extraction step c) in which the phospholipids are loaded into the polymeric lens body, a further hydration step may be performed after step c).

[0008] Additionally, the present invention provides a method for the treatment of symptomatic contact lens wearers with a C at the sn-2 position. 12 -C 26 C comprising a polymer lens body filled with glycerophospholipids containing acyl groups 12 -C 26 The present invention relates to a method of correcting vision in a symptomatic contact lens wearer by providing a fatty acid releasing hydrogel contact lens, particularly an oleic acid releasing hydrogel contact lens. Advantageously, the fatty acid releasing hydrogel contact lens has a C 12 -C 26The duration of comfortable contact lens wear is increased and / or lens sensation events are reduced in symptomatic contact lens wearers compared to control lenses that do not contain glycerophospholipids containing acyl groups. The phospholipid, for example, the glycerophospholipid of formula (I), when present in a polymeric lens body, is preferably a glycerophospholipid that is susceptible to digestion by sPLA2 enzymes, particularly sPLA2-IIA, found in human tears. As used herein, a "symptomatic contact lens wearer" is a lens wearer that is 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).

[0009] Furthermore, the present invention provides a C at the sn-2 position. 12 -C 26 The inclusion of C at the sn-2 position by a contact lens wearer to increase the duration of comfortable contact lens wear and / or reduce lens sensation events compared to a control lens that does not contain a glycerophospholipid containing an acyl group. 12 -C 26 C containing glycerophospholipids containing acyl groups 12 -C 26 The present invention relates to the use of fatty acid releasing hydrogel contact lenses. Additionally, the present invention provides a contact lens that includes C at the sn-2 position in an amount that enhances contact lens comfort. 12 -C 26 The present invention relates to the use of a glycerophospholipid containing an acyl group, wherein the glycerophospholipid is associated with a polymeric lens body of a contact lens. The present invention further provides a hydrogel composition for use in reducing the sensation of lens sensation in a contact lens wearer, thereby enhancing contact lens comfort in the contact lens wearer and / or increasing the duration of comfortable contact lens wear in the contact lens wearer, comprising: (b) an amount of C at the sn-2 position; 12 -C 26 The present invention relates to a hydrogel composition comprising a polymeric lens body that is the reaction product of (a) a polymerizable composition loaded with a glycerophospholipid that contains an acyl group.

[0010] In all embodiments of the present invention, a C at the sn-2 position 12 -C 26 Glycerophospholipids containing an acyl group are advantageously susceptible to digestion by sPLA2 enzymes, particularly Group IIA sPLA2s, found in human tears when the glycerophospholipids are present in the polymeric lens body of a hydrogel contact lens, particularly a silicone hydrogel contact lens. 12 -C 26 Contact lenses that include a polymeric lens body loaded with glycerophospholipids containing acyl groups have (a) three times the amount of C when the contact lenses are immersed in human reflex tears for four hours at 35° C. compared to when the lenses are immersed in an ATF release medium lacking phospholipase A2 enzyme for four hours at 35° C. 12 -C 26 and / or (b) when a contact lens is immersed in an ATF release medium containing 50 ppm of recombinant human group IIa phospholipase A2 for 4 hours at 35° C., the amount of C is three times higher than when the lens is immersed in an equivalent ATF release medium lacking the phospholipase A2 enzyme for 4 hours at 35° C. 12 -C 26 It may be characterized in that fatty acid degradation products are detected in reflex tears. The phospholipids are typically glycerophospholipids, such as those of formula (I):

[0011] [ka] Formula (I) [wherein X is either -O- or -O(CO)-; R 1 and R 2 are each independently 11-25 is alkyl, R 3 The group is hydrogen, C 1-10 polyol, ethanolamine (-CH2CH2NH2) and serine (-CH2CH(NH2)COOH)] and salts thereof (e.g., where R 2 is negatively charged, or ethanolamine is -CH2CH2NH3 + (protonated as

[0012] Further aspects of the invention are provided in the following numbered paragraphs. 1. An unworn hydrogel contact lens sealed in packaging, having a C at the sn-2 position. 12 -C 26 An unworn hydrogel contact lens comprising a polymeric lens body loaded with glycerophospholipids containing acyl groups. 2. A contact lens according to paragraph 1, wherein glycerophospholipids, when present in the polymeric lens body, are susceptible to digestion by the secretory phospholipase A2 (sPLA2) enzyme found in human tears. 3. The glycerophospholipid has the formula (I):

[0013] [ka] Formula (I) [wherein X is either -O- or -O(CO)-; R 1 and R 2 are each independently 11-25 is alkyl, R 3 The group is hydrogen, C 1-10 3. The contact lens according to item 1 or 2, wherein the compound is selected from the group consisting of polyols, ethanolamines and serine, and salts thereof. 4. R 1 and R 2 However, each independently, C 13-21A contact lens according to item 3, which is an alkyl group. 5. A contact lens of any preceding claim, wherein the glycerophospholipid is phosphatidylserine, phosphatidylethanolamine, or phosphatidylglycerol. 6. The contact lens of item 5, wherein the glycerophospholipid is a phosphatidylglycerol, in particular, 1,2-dioleoylphosphatidylglycerol, 1-palmitoyl-2-oleoylphosphatidylglycerol, 1-stearoyl-2-oleoyl, or 1,2-didocosahexaenoylphosphatidylglycerol. 7. The contact lens according to any one of items 1 to 4, wherein the glycerophospholipid is other than dimyristoylphosphatidylcholine (DMPC). 8. The contact lens of any one of items 1 to 4, wherein the glycerophospholipid is other than phosphatidylcholine. 9. The contact lens according to any one of items 1 to 8, wherein the contact lens is a silicone hydrogel contact lens. 10. The contact lens according to any one of items 1 to 9, wherein the hydrogel is neutral or cationic. 11. The contact lens of any of items 1 to 10, wherein the polymeric lens body is the reaction product of a polymerizable composition that includes at least one hydrophilic monomer that includes a vinyl group. 12. The polymeric lens body is represented by the formula (II)

[0014] [ka] Formula (II) A first siloxane having a structure represented by: and formula (III)

[0015] [ka] Formula (III) A second siloxane having a structure represented by 12. The contact lens according to any one of items 1 to 11, which is a reaction product of a polymerizable composition comprising: 13. When a hydrogel contact lens comes into contact with a solution containing sPLA2-IIA, C 12 -C 26 Releases fatty acids and their salts, and 12 -C 26 The contact lens of any preceding claim, wherein the fatty acid is a digestion product of a glycerophospholipid. 14. A contact lens of any preceding paragraph, wherein the polymeric lens body is loaded with glycerophospholipid in an amount of 1 μg to 1000 μg, preferably 25 μg to 300 μg. 15. When immersed in a release medium containing artificial tears containing 50 ppm PLA2-IIA at 35°C, the contact lens has a C 12 -C 26 Fatty acids, especially C of at least 0.1 μg / h 12 -C 26 fatty acids, or C at 1 μg / hr 12 -C 26 The contact lens of any preceding claim, wherein the release of fatty acid is sustained for at least 4 hours, such as at least 8 hours, optionally at least 10 hours. 17. A contact lens of any preceding paragraph having an equilibrium water content of at least 40%. 18. Packaging (a) a base member having a cavity for holding a packaging solution; (b) a cover that forms a liquid-tight seal with the base member; A contact lens according to any preceding claim. 19. 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; and c) attaching the polymeric lens body to a C at sn-2 position. 12 -C 26d) extracting the polymeric lens body in an organic solvent containing a glycerophospholipid containing an acyl group; 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, optionally, f) autoclaving the package. 20. A method for correcting vision in a symptomatic contact lens wearer, comprising the step of the symptomatic contact lens wearer wearing a hydrogel contact lens of any of items 1 to 18. 21. The method of paragraph 20, wherein a symptomatic contact lens wearer has an increased duration of comfortable contact lens wear compared to the control lenses. 22. The method of paragraph 20 or paragraph 21, 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. 23. C in sn-2 position in an amount that enhances contact lens comfort 12 -C 26 1. Use of a glycerophospholipid containing an acyl group, wherein the glycerophospholipid is associated with a polymeric lens body of a contact lens. 24. The use according to item 23, wherein the contact lens is a hydrogel contact lens according to any one of items 1 to 16. 25. Use of clause 23 or clause 34, in which the sensation of lens sensation is reduced in a contact lens wearer, thereby enhancing contact lens comfort in a symptomatic contact lens wearer and / or increasing the duration of comfortable contact lens wear in a symptomatic contact lens wearer. 26. A hydrogel composition for use in reducing the sensation of lens sensation in a contact lens wearer, thereby enhancing contact lens comfort in the contact lens wearer and / or increasing the duration of comfortable contact lens wear in the contact lens wearer, comprising: (b) an amount of C at the sn-2 position. 12 -C 26A hydrogel composition comprising a polymeric lens body that is the reaction product of (a) a polymerizable composition loaded with a glycerophospholipid that contains an acyl group. 27. The composition for use according to item 26, which is in the form of a contact lens according to any one of items 1 to 18. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows that dioleylphosphatidylglycerol (DOPG) at the sn-2 ester bond is enzymatically degraded by PLA2 to produce oleic acid and lysophosphatidylglycerol (LOPG). [Diagram 2] FIG. 1 shows the oleic acid release profile of a 5 mg / mL DOPG-loaded silicone hydrogel contact lens (Lens A) in ATF containing 50 ppm PLA2 enzyme solution. [Diagram 3] FIG. 1 shows the oleic acid release profile of a 3 mg / mL DOPG-loaded silicone hydrogel contact lens (Lens B) in ATF containing 50 ppm sPLA2 enzyme solution. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] While wearing C 12 -C 26 Described herein are hydrogel contact lenses that provide sustained release of fatty acids, and methods for their manufacture. The contact lenses are herein 12 -C 26 These can be called fatty acid releasing contact lenses. 12 -C 26 The fatty acids are released from the lenses during wear in amounts that can enhance the comfort of contact lens wear in the contact lens wearer and increase the duration over which the contact lens wearer can comfortably wear the contact lenses. 12 -C 26 Fatty acid releasing lenses may increase end-of-day comfort of lens wear in symptomatic patients. 12 -C 26The fatty acid may be a TRPV1 antagonist, for example, oleic acid.

[0018] The present disclosure advantageously provides a method for treating a hydrogel contact lens comprising the steps of: (a) providing a hydrogel contact lens with a glycerophospholipid, e.g., an oleic acid-containing glycerophospholipid, and (b) providing a hydrogel contact lens with a glycerophospholipid; 12 -C 26 C from hydrogel contact lenses that release fatty acids, especially oleic acid 12 -C 26 Provides sustained release of fatty acids. Effective C 12 -C 26 For fatty acid release rate, C 12 -C 26 The fatty acid group must occupy the sn-2 (middle) position of the glycerophospholipid structure. 12 -C 26 The fatty alcohol or fatty acid group may occupy the sn-1 (end) position of the glycerophospholipid structure. The sn-1 fatty acid may be an alternative fatty acid to that at the sn-2 position, i.e., a fatty acid with a different number of carbon atoms. For example, the fatty acid at the sn-2 position may be oleic acid or docosahexaenoic acid, and the fatty acid at the sn-1 position may be a fatty acid other than oleic acid or docosahexaenoic acid. In one example, the glycerophospholipid is a 2-oleoylglycerophospholipid, in particular a 2-oleoylphosphatidylglycerol, such as 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol), sodium salt (DOPG). In another example, the glycerophospholipid is 2-docosahexaenoylphosphatidylglycerol, e.g., 1,2-di(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoylsn-glycero-3-phospho-rac-(1-glycerol), sodium salt (DHA-PG). In the example of DOPG, oleic acid is the fatty acid at both the sn-1 and sn-2 positions of phosphatidylglycerol. As shown in Figure 1, when a DOPG-loaded lens is placed on the eye, DOPG is degraded by the tear enzyme sPLA2-IIA.

[0019] C at sn-2 position 12 -C26 Glycerophospholipids containing acyl groups can be degraded by the group IIA secretory phospholipase A2 (sPLA2-IIA) enzyme found in human tears. The glycerophospholipid may be, for example, phosphatatidic acid, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, or bisphosphatidylglycerol. Preferably, the glycerophospholipid is other than phosphocholine. It has been found that phosphocholine is less susceptible to degradation by the group IIA sPLA2-IIA enzyme found in human tears other than glycerophospholipids. Advantageously, the glycerophospholipid is selected from phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylglycerol, in particular phosphatidylethanolamine or phosphatidylglycerol. The pKa of the amino group of phosphatidylethanolamine (PE) or phosphatidylserine (PS) is preferably in the range of 8 to 10, preferably in the range of 8.5 to 9.8. Further information regarding the activity of sPLA2 enzymes can be found in Chem Rev. 2011 October 12; 111(10): 6130-6185, "Phospholipase A2 Enzymes: Physical Structure, Biological Function, Disease Implication, Chemical Inhibition, and Therapeutic Intervention", by Dennis et al. By "susceptible to digestion," it is meant that sPLA2s present in human tears hydrolyze the acyl group at the sn2 position of glycerophospholipids to produce free fatty acids and lysophospholipids. Glycerophospholipids are digestible by human tears. Glycerophospholipids are digestible at least from sPLA2 present in human tears. C at sn-2 position 12 -C 26 The fatty acids are advantageously released and eluted from the lens, while the remaining glycerolipids are retained within the lens.12 -C 26 The release rate of fatty acids is C 12 -C 26 In addition to the diffusion rate of the fatty acid itself, this may depend on the kinetics of the enzymatic reaction of the phospholipid. In one embodiment, the hydrogel contact lens comprises a hydrogel having the formula (Ia):

[0020] [ka] Formula (Ia) [wherein X is either -O- or -O(CO)-; R 1 is C 11-25 is alkyl, R 3 The group is hydrogen, C 1-10 2-oleoylglycerophospholipids selected from the group consisting of polyols, ethanolamine (-CH2CH2NH2) and serine (-CH2CH(NH2)COOH), and salts thereof (e.g., R 3 is negatively charged, or ethanolamine is -CH2CH2NH3 + The polymer lens body includes a polymer filled with ruthenium (protonated as in 3 is advantageously selected from -CH2CH2NH2, -CH2CH(NH2)COOH, and -CH2CH(OH)CH2OH, in particular -CH2CH(OH)CH2OH. 1 may be selected from, for example, oleoyl, myristoyl, pentadecanoyl, palmitoyl, or stearoyl.

[0021] C 12 -C 26 Fatty acid-releasing contact lenses, when in contact with tear solution containing sPLA2-IIA, release C 12 -C 26 C at the sn-2 position in amounts that sustain fatty acid release 12 -C 26 The polymeric lens body is loaded with a glycerophospholipid containing an acyl group.The tear solution can be human reflex tear fluid or an in vitro release medium including ATF containing a Group IIA sPLA2 enzyme solution at a concentration of, for example, 50 ppm.

[0022] Optionally, one or more glycerophospholipids as described herein may be used in the preparation of the C 12 -C 26 Fatty acid releasing contact lenses may be present (eg, two different, three different, or more glycerophospholipids, as described herein).

[0023] As an example, contact lenses are non-silicone hydrogels that do not contain or essentially do not contain silicon-containing components that are the reaction product of the polymerizable composition of non-silicone hydrogels. Hydrogels that contain less than 3% by weight, particularly less than 2% by weight, and preferably less than 1% by weight of silicon-containing monomer or macromer derived units are non-silicone hydrogels that essentially do not contain silicon-containing components. Non-silicone hydrogel contact lenses are typically formed from the polymerization of one or more hydrophilic monomers, such as 2-hydroxyethyl methacrylate (HEMA) or vinyl alcohol, which may be combined with other monomers, and do not contain siloxane molecules. The polymer lens body of hydrogel contact lenses may be the reaction product of a polymerizable composition that includes at least one monomer of, for example, N-vinylpyrrolidone, (hydroxyethyl) methacrylate, glycidyl methacrylate, ethylene glycol dimethacrylate, and / or polycarbonate, or any combination thereof, and the composition may not contain siloxane monomers or macromers.

[0024] 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 can be extracted with an extraction solvent containing glycerophospholipids. As a result, a desired amount of glycerophospholipids will be associated with the polymeric lens body. The glycerophospholipids may adhere to the polymeric lens body by electrostatic and / or hydrophobic interactions and / or may be physically encapsulated by the polymer network of the polymeric lens body. Alternatively or in addition, the glycerophospholipids may be added to the polymerizable composition, for example, before curing.

[0025] Advantageously, the hydrogel, i.e., conventional hydrogel or silicone hydrogel, is neutral or positively charged (i.e., cationic), preferably neutral. The term "neutral" refers to units derived from non-ionic or zwitterionic molecules. The presence of an overall negative charge inhibits the activity of the sPLA2 enzyme and thus the C-glycerophospholipid-containing contact lenses. 12 -C 26 It has been found that the release of fatty acids is reduced.Preferably, the contact lenses do not contain anionic units such as those derived from methacrylic acid (MAA) or 2-methacryloxyethyl phosphate (MOEP).

[0026] The polymeric lens body typically has an equilibrium water content (EWC) of at least 40%, for example at least 45%. Advantageously, the hydrogel contact lens is a high water content contact lens with a polymeric lens body having an EWC of at least 50%. The contact lens may be a Food and Drug Administration (FDA) Group II, non-ionic high water content lens, or a cationic FDA Group IV, ionic high water content lens, or a silicone hydrogel contact lens with an EWC of at least 40% or at least 45%. Advantageously, the contact lens is an FDA Group II, non-ionic high water content lens, or a silicone hydrogel contact lens with an EWC of at least 40% or at least 45%. It has been found that an EWC of more than 40% leads to an increase in sPLA2 enzyme activity, which leads to fatty acid release.

[0027] The amount of glycerophospholipid "loaded into" or "associated with" a polymeric lens body refers to the total amount of glycerophospholipid that can be extracted from a contact lens by an isopropyl alcohol (IPA) extraction method as described in Example 2 below. The glycerophospholipid associated with the polymeric lens body may be embedded within the matrix of the polymeric material or may be bound to the polymeric material, for example, via hydrogen bonds or electrostatic interactions. Advantageously, the glycerophospholipid associated with the polymeric lens body is not removed when the lens is immersed in deionized water or a standard contact lens packing solution, for example, phosphate buffered saline or borate buffered saline containing 75 ppm polyvinylpyrrolidone (PVP). Advantageously, 20% by weight or less, especially 10% by weight or less, of the glycerophospholipid is extracted from the polymeric lens body into deionized water upon immersion of the lens in 5 mL of deionized water. In one example, the glycerophospholipid is loaded into the polymeric lens body in a loading solution comprising an alcohol, such as ethanol, and 2-oleoylphospholipid in the range of 1-10 mg / mL. The loading solution may, for example, comprise approximately 60% ethanol and approximately 40% water. In one embodiment, the loading solution comprises 2 mg / mL of glycerophospholipid. The lens may be immersed in the loading solution for 3 hours at 25° C. to load the polymeric lens body with glycerophospholipid. In another example, the amount of 2-oleoylphospholipid associated with the polymeric lens body may be at least about 1 μg, 25 μg, 50 μg, 100 μg, 200 μg, or 300 μg up to about 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, or 1000 μg, for example, about 300 μg to about 1000 μg. Preferably, the amount of glycerophospholipid associated with the polymeric lens body is 100 μg to 1000 μg, more preferably 300 μg to 800 μg.

[0028] Glycerophospholipids have the formula (I): [ka] Formula (I) [wherein X is either -O- or -O(CO)-; R 1 and R2 are each independently 11-25 is alkyl, R 3 is hydrogen, C 1-10 a polyol, ethanolamine (-CH2CH2NH2) and serine (-CH2CH(NH2)COOH)], or a salt of a glycerophospholipid of formula (I) (e.g., 3 is a negative charge, or R 3 is protonated ethanolamine: -CH2CH2NH3 + (wherein

[0029] R 1 and R 2 R is each independently a saturated or unsaturated alkyl group, and as used herein, the term "alkyl," unless otherwise stated, refers to both aliphatic groups having saturated alkyl chains and groups having unsaturated alkenyl chains. 1 and R 2 R may each independently have a straight (i.e., unbranched) or branched alkyl or alkenyl chain. 1 and R 2 each independently represents an unsubstituted or substituted, e.g., hydroxyl-substituted C 1-12 alkyl (e.g., methyl, ethyl, propyl, or butyl), polyethylene glycol (PEG), sugar, epoxy, and any combination thereof, among others, unsubstituted or substituted with hydroxyl or methyl. Optionally, R 1 and R 2 are each independently 11-23 , especially C 13-21 is alkyl, R 1 and R 2 Each independently may be unsaturated and contain at least one unsaturated C=C double bond. 1 and R 2 are each independently -(CH2) 7-11 CH=CH(CH2) 1-9 CH3 or -(CH2) 8-10 CH=CH(CH2) 1-7 CH3, e.g. -(CH2) 10CH=CH(CH2)1CH3, -(CH2)8CH=CH(CH2)7CH3, or -(CH2) 10 CH=CH(CH2)3CH3. Optionally, R 1 and R 2 are each independently oleoyl, oleic acid having the IUPAC name: (9Z)-octadec-9-enoic acid. 1 and R 2 are each independently -(CH2) 1-4 [CH=CH(CH2) 1-2 ] 3-7 CH3, for example -(CH2)2[CH=CH(CH2)]6CH3. Optionally, R 1 and R 2 are each independently docosahexaenoyl, docosahexaenoic acid having the IUPAC name (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid. 2 is C 11-25 Unsaturated alkyl groups, preferably C 11-23 Alkyl groups, for example C 1 -C 2 -C 3 -O 4 -C 1 -O 4 ... 13-21 R is an alkyl group. 2 may have a straight chain (i.e., unbranched) alkyl chain. 2 is -(CH2) 7-11 CH=CH(CH2) 1-9 CH3 or -(CH2) 8-10 CH=CH(CH2) 1-7 CH3, e.g. -(CH2) 10 CH=CH(CH2)1CH3, -(CH2)8CH=CH(CH2)7CH3, or -(CH2) 10 CH=CH(CH2)3CH3. R 2 may be selected from oleoyl, palmitoyl, stearoyl or docosahexaenoyl, for example oleoyl or docosahexaenoyl, especially oleoyl. Advantageously, R 1 is C 11-25 Unsaturated alkyl groups, preferably C 11-23Alkyl groups, for example C 1 -C 2 -C 3 -O 4 -C 1 -O 4 ... 13-21 is an alkyl group. 1 has a straight chain (i.e., unbranched) alkyl chain. Optionally, R 1 is -(CH2) 7-11 CH=CH(CH2) 1-9 CH3 or -(CH2) 8-10 CH=CH(CH2) 1-7 CH3, e.g. -(CH2) 10 CH=CH(CH2)1CH3, -(CH2)8CH=CH(CH2)7CH3, or -(CH2) 10 CH=CH(CH2)3CH3. R 1 may be selected from oleoyl, palmitoyl, stearoyl, or docosahexaenoyl.

[0030] R 3 is hydrogen, C 1-10 Polyols, ethanolamine (-CH2CH2NH2) and serine (-CH2CH(NH2)COOH) and their salts, especially C 1-10 R is a group selected from polyols and ethanolamines (-CH2CH2NH2), and salts thereof. 3is advantageously selected from -CH2CH2NH2 and -CH2CH(OH)CH2OH. A polyol is an organic compound containing multiple hydroxyl groups. Optionally, the glycerophospholipid is a phosphatidylglycerol. Non-limiting examples of suitable glycerophospholipids include 1,2-dioleoylphosphatidylglycerol, 1,2-dimyristoylphosphatidylglycerol, 1,2-dipentadecanoylphosphatidylglycerol, 1-myristoyl-2-oleoylphosphatidylglycerol, 1-pentadecanoyl-2-oleoylphosphatidylglycerol, 1-palmitoyl-2-oleoylphosphatidylglycerol, 1-stearoyl-2-oleoylphosphatidylglycerol, 1,2-didocosahexaenoylphosphatidylglycerol, 1,2-dioleo ... 1-oleoyl-2-docosahexaenoyl phosphatidylglycerol, 1-myristoyl-2-docosahexaenoyl phosphatidylglycerol, 1-pentadecanoyl-2-docosahexaenoyl phosphatidylglycerol, 1-palmitoyl-2-docosahexaenoyl phosphatidylglycerol, 1-stearoyl-2-docosahexaenoyl phosphatidylglycerol, 1-docosahexaenoyl-2-oleoyl phosphatidylglycerol, and 1-oleoyl-2-docosahexaenoyl phosphatidylglycerol. 2-oleoyl phosphatidylglycerol, for example 1,2-dioleoyl phosphatidylglycerol, has been found to be particularly suitable.

[0031] As used herein, unless the context dictates to the contrary, C 12-26 C released from fatty acid releasing contact lenses 12 -C 26 Amount of fatty acid, or C 12 -C 26 The "release profile" of fatty acids is measured using an in vitro release medium (ATF as described in Table 1 below spiked with 50 ppm PLA2-IIA, e.g., recombinant human Group IIA phospholipase 2-acylhydrolase enzyme, or bee venom sPLA2 as described in Example 4 below) to determine the C released from the lens. 12 -C 26The amount of fatty acids released from the contact lens after initial immersion in a release medium at 35°C is at least 0.05 μg / hr or between 0.05 μg / hr and 50 μg / hr. 12-26 Fatty acids, e.g., from the lens at 0.1 μg / h to 25 μg / h, or 0.5 μg / h to 10 μg / h, or 1 μg / h to 5 μg / h C 12 -C 26 In vitro C of fatty acids 12-26 Advantageously, the contact lenses have a fatty acid release profile that is at least 4 hours, such as at least 8 hours, and optionally at least 10 hours. 12 -C 26 Advantageously, the contact lens provides a sustained release of fatty acids from the lens at a C of between 0.05 μg / hr and 50 μg / hr per hour after immersion in the release medium at 35° C. 12-26 Fatty acids, for example, C of 0.01 μg / h to 25 μg / h, or 0.5 μg / h to 10 μg / h, or 1 μg / h to 5 μg / h 12 -C 26 Thus, the contact lenses of the present invention loaded with the phospholipids of formula (I) are prepared by placing the lenses in a 6 mL glass vial containing 3 mL of in vitro release medium (ATF as described in Table 1 spiked with 50 ppm of sPLA2), shaking the vial at 50 rpm in a 35° C. incubator, removing 2.5 mL samples of the release medium from the vial at 2 hour intervals (e.g., 2 hours, 4 hours, 6 hours, 8 hours, and 10 hours), and analyzing the samples by liquid chromatography-mass spectrometry (LCMS). 12 -C 26 The lenses are analyzed for fatty acid content and release of at least 0.05 μg / hr, preferably at least 0.1 μg / hr, e.g., 0.1 μg / hr to 25 μg / hr, e.g., 0.5 μg / hr to 10 μg / hr, or 1 μg / hr to 5 μg / hr, as determined by re-adding 2.5 ml of fresh release medium to the vial and continuing to incubate the lens in the vial on a shaker for an additional 2 hours until the next increment. 12 -C 26In vitro C NMR of fatty acids for at least 4 hours, for example at least 8 hours, optionally at least 10 hours. 12-26 It may have a fatty acid release profile.

[0032] Optionally, the contact lenses of the present invention do not contain any comfort agents, except for the presence of glycerophospholipids as described herein. Optionally, the contact lenses of the present invention may contain one or more comfort agents other than the glycerophospholipids as described herein. The amount of any other comfort agent may be less than the amount of glycerophospholipid 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.

[0033] Optionally, the packaging solutions as described herein do not contain any comfort agents, except for the possible presence of glycerophospholipids and / or fatty acids resulting from the glycerophospholipids originally present in the contact lens. Alternatively, the only phospholipids present in or associated with the contact lenses are glycerophospholipids. Alternatively, the only source of fatty acids released or present with the contact lenses is from the glycerophospholipids present. The present invention has the ability to provide improved controlled release of fatty acids compared to free fatty acids (not derived from glycerophospholipids) associated with contact lenses, for example, the release can be more linear compared to free fatty acids only used / associated with contact lenses. The release of fatty acids from the digestion of glycerophospholipids can be considered a tear-controlled release of fatty acids.

[0034] The polymeric lens body may comprise any hydrogel material suitable for use as a contact lens material. Non-silicone hydrogel materials for contact lenses are typically formed by curing a polymerizable composition (i.e., a monomer mixture) that includes at least one hydrophilic monomer or at least one hydrophilic polymer, or a combination thereof. Polymerizable compositions for forming non-silicone hydrogel lens materials typically contain no or essentially no silicon-containing components, and in particular no or essentially no siloxane monomers or macromers. Polymerizable compositions for forming non-silicone hydrogel lens materials may contain 3% or less by weight of silicone-containing components, in particular 2% or less by weight of silicone-containing components, for example 1% or less by weight of silicon-containing components. Silicone hydrogel materials for 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 having 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, a siloxane macromer contains a siloxane chain having at least five siloxane (-Si-O-) units and / or has a molecular weight of at least 500 Daltons.

[0035] 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 interpenetrating network (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.

[0036] 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.

[0037] 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.

[0038] 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., as determined 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.

[0039] 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.

[0040] 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.

[0041] 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):

[0042] [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.

[0043] 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.

[0044] Glycerophospholipids are typically loaded into the polymeric lens during the extraction step. Generally, after curing, the polymeric lens body is swollen in an extraction solvent, such as ethanol, that contains the glycerophospholipids. When the extracted polymeric lens body is subsequently placed in a hydration solution, such as deionized (DI) water, the extraction solvent is removed and the glycerophospholipids remain associated with the polymeric lens body. Examples of extraction solvents and hydration liquids used in the extraction and hydration process may consist of denatured ethanol, a 50 / 50 (by volume) mixture of denatured ethanol and deionized water, and deionized water. By way of example, the extraction and hydration process may include denatured ethanol followed by at least one extraction step in a 50:50 mixture of ethanol water followed by at least one hydration step in deionized water, each extraction and hydration step lasting 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.

[0045] Any extraction solvent used as a loading solution for glycerophospholipids may contain a concentration of glycerophospholipids of 1 to 50 mg / mL, for example, 2 to 20 mg / mL. This concentration may be at least 1 mg / mL, at least 3 mg / mL, at least 5 mg / mL, or at least 10 mg / mL of glycerophospholipids. In one example, the concentration of glycerophospholipids in the extraction solvent is about 2 to about 20 mg / mL, for example, 3 to 10 mg / mL. The amount of glycerophospholipid loaded into the polymeric lens body may be 1 μg to 1000 μg. The amount of glycerophospholipid loaded into the polymeric lens body may be at least 100 μg, at least 200 μg, or at least 500 μg. Preferably, the amount of glycerophospholipid loaded into the polymeric lens body is at least 300 μg, for example, 300 μg to 1000 μg.

[0046] In some instances, the glycerophospholipids once loaded into the polymeric lens body are stable and do not substantially release from the polymeric lens body or degrade during autoclaving of a sealed contact lens package containing an unworn hydrogel contact lens in the packaging solution or during storage in the packaging solution. Thus, the packaging solution in which the contact lens is immersed prior to or immediately after autoclaving, or after 1 day at 25° C., or after 30 days at 25° C., or after 60 days at 25° C., or after 120 days at 25° C., contains no C at the sn-2 position that has been released from the contact lens into the packaging solution. 12 -C 26 The contact lenses have less than 10 ppm, or less than 5 ppm, or less than 1 ppm, or 0 ppm of glycerophospholipids containing acyl groups released from the contact lenses into the packaging solution. Advantageously, no more than 20% by weight, especially less than 10% by weight, and preferably less than 5% by weight, of the glycerophospholipid associated with the polymeric lens body is released into the packaging solution after at least 1 day of storage at 25° C. Whether glycerophospholipid is released from the contact lenses during autoclaving or storage can be determined by testing for the presence of glycerophospholipid in the packaging solution using LCMS or other suitable analytical methods.

[0047] 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.

[0048] It is recognized that conventional manufacturing methods can be used to manufacture the sealed contact lens packaging. In the method of manufacturing the contact lens packaging, the method includes the steps of placing an unworn contact lens and a contact lens packaging solution into a receptacle, placing a cover into 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 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 is recognized that other types of packaging can also be used to provide a resealable package. For example, the contact lens packaging may include a plastic cover including features that mate with matching features of the receptacle to form an interference fit. The method of manufacturing a sealed contact lens package may further include sterilizing the unworn contact lens by autoclaving the sealed contact lens package, which typically involves subjecting the sealed contact lens package to a temperature of at least 121° C. for at least 20 minutes.

[0049] 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.

[0050] 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. C as described herein 12 -C 26 Fatty acid releasing hydrogel contact lenses can be used to correct vision in symptomatic contact lens wearers. 12 -C 26 Fatty acid releasing hydrogel contact lenses may increase the duration of comfortable contact lens wear in symptomatic contact lens wearers. 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). The fatty acid releasing hydrogel contact lenses described herein may be used to increase the duration of comfortable contact lens wear in symptomatic contact lens wearers. 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). 12 -C 26 The fatty acid releasing hydrogel contact lenses may be worn by a contact lens wearer to reduce lens sensation and / or provide fewer "lens sensation events" throughout the day as compared to control lenses or lenses normally worn by the contact lens wearer. References herein to "control lenses" refer to lenses that contain phospholipid or C 12 -C 26 Contains no fatty acids, but otherwise has the same structure as the C 12 -C 26Refers to contact lenses that are identical to fatty acid releasing lenses. Reduction of 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). EXAMPLES

[0051] 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.

[0052] Example 1 Assay to test the susceptibility of phospholipid digestion by sPLA2-IIA. Each phospholipid-filled lens is removed from its packaging, placed into a 6 mL glass vial containing 5 mL of ATF as described in Example 2 at room temperature, and placed on a shaker at 125 rpm overnight to elute any free fatty acids that may be present in the lens. Each lens is rinsed for 30 minutes in a 6 ml glass vial containing a fresh aliquot of 5 ml of ATF before the digestion assay is performed. A 50 ppm solution of sPLA2 was prepared in ATF by adding 200 μl of ATF to a tube containing 10 μg of recombinant human PLA2G2A (Creative BioMart, Catalog No. PLA2G2A-669H). This solution is called ATF+sPLA2. Optionally, human reflex tear fluid may be used instead of ATF+sPLA2. Two 4 mm pieces are cut from each lens. One piece of each lens is placed in a tube with 100 μL of ATF and the other piece is placed in a tube containing 100 μL of ATF+sPLA2. The tubes are incubated at 35±2° C. for 4 hours without shaking.

[0053] Transfer 50 μl of release medium from each lens at T=4 hours into an HPLC vial and add 500 μl isopropanol (IPA) and mix thoroughly. Also prepare an HPLC vial at T=0 hours (50 μl ATF + 500 μl IPA). Sonicate all vials for 15 minutes and centrifuge. Remove the supernatant for LCMS injection.

[0054] The supernatant is 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, and B = 10% acetonitrile in IPA with 10 mM ammonium acetate and 0.2% (v / v) ammonium hydroxide. The mass spectrometer detector is run in negative electrospray mode. The peaks of specific fatty acids of interest (i.e., fatty acids released from the sn-2 position of phospholipids of contact lenses) in the supernatant are measured. The ratio of fatty acid peak areas in the ATF with and without sPLA2 is calculated.

[0055] Example 2 sPLA2-mediated phospholipid digestion from stenfilcon A lenses loaded with different phospholipids. 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 14 minutes), then adding 0.6 mL of DI water and sonicating again (up to 15 minutes) to dissolve the phospholipid.

[0056] [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.

[0057] [Table 2] After autoclaving, each lens was tested for susceptibility to phospholipid digestion by sPLA2-IIA using the method described in Example 1. The peak of oleic acid (OA) was measured in the supernatant sent for LCMS analysis (m / z trace=281.24). The ratio of OA in the ATF with and without sPLA2 was calculated. The results are shown in Table 3.

[0058] [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.

[0059] Example 3 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.

[0060] 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.

[0061] [Table 4]

[0062] Example 4 Determination of fatty acid release profiles C at sn-2 position 12 -C 26 To determine the fatty acid release profile of silicone hydrogel contact lenses loaded with glycerophospholipids containing acyl groups, the lenses are 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 elute any free fatty acids that may be present in the lenses.

[0063] Each lens is then transferred to a 6 mL glass vial containing 3 mL of ATF+sPLA2 in vitro release medium described in Example 1 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 are placed in a 35° C. incubator at 50 rpm for 2 hour intervals (e.g., 2 hours, 4 hours, 6 hours, 8 hours, and 10 hours). 2.5 ml of in vitro release medium is removed from each vial and sent for analysis. If the release medium is not analyzed immediately at its designated time point, a sample is taken and mixed with IPA (1:10 v / v ratio) to stop the enzyme activity. Following this, 2.5 ml of fresh ATF+sPLA2 in vitro release medium is added back into each vial and the lenses continue to be incubated. At the end of the release experiment, the amount of fatty acids in the release medium at each time point is analyzed by LCMS, using the method described in Example 1.

[0064] Example 5 Oleic acid release from 5 mg / mL DOPG filled contact lenses (Lens A) and 3 mg / mL DOPG filled contact lenses (Lens B). Silicone hydrogel contact lenses were prepared as in Example 2 using a DOPG loading concentration of 5 mg / mL (Lens A) and 3 mg / mL (Lens B). The oleic acid release rates of Lenses A and B were determined using the method of Example 4 with ATF release medium containing 50 ppm bee venom sPLA2 enzyme (CAS number 9001-84-7). Oleic acid release into the in vitro release medium samples was followed every 2 hours as shown in Figures 2 and 3 for Lenses A and B, respectively. The results are shown in Table 5, which shows the cumulative oleic acid release (from T=0) at each time point.

[0065] [Table 5]

[0066] The results show that a constant release of oleic acid was sustained for at least 10 hours for both lenses A and B. The approximate dissolution rates of oleic acid from lenses A and B are shown in Table 6. [Table 6]

[0067] Example 6 Release of DHA from different DHAPG-loaded SiHy lenses. Contact lenses prepared from stenfilcon A and somofilcon A were soaked in 3 mg / mL DHAPG (1,2-didocosahexaenoyl-sn-glycero-3-[phospho-rac-(1-glycerol)](sodium salt) from Avanti Polar Lipids) dissolved in 50% ethanol. DHA release from DHAPG-loaded lenses was tested using the digestion assay of Example 1, except that ATF+sPLA2 reflex tears from a single individual were used. The % DHAPG digested after 4 hours was determined based on the total DHA and DHAPG found in the digested sample by the following formula: Digested DHAPG = (DHA found * MW of DHAPG) / (MW of DHA) Total DHAPG = digested DHAPG + found DHAPG % Digestion = Digested DHAPG / Total DHAPG

[0068] The results are presented in Table 7 and demonstrate that lens material can affect the rate of sPLA2-mediated glycerophospholipid digestion. [Table 7]

[0069] 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. References herein to "examples" or "embodiments" or "aspects" or "embodiments" or similar phrases (where appropriate) refer to the invention. 12 -C 26 A fatty acid releasing hydrogel contact lens or a component thereof, a sealed contact lens package or a component thereof, or a C of the present invention. 12 -C 26 It is intended to introduce a feature or features of a method for making a fatty acid releasing hydrogel contact lens, 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 dictates otherwise. Additionally, 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.

[0070] 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.

Claims

1. An unworn hydrogel contact lens sealed during packaging, comprising a C at the sn-2 position. 12 -C 26 An unworn hydrogel contact lens comprising a polymeric lens body loaded with at least one glycerophospholipid containing an acyl group.

2. When glycerophospholipids are present in the polymer lens body, they act as a lipid transporter, which is a type of lipid transporter that acts as a lipid transporter. 2 2.) The contact lens of claim 1 which is susceptible to enzymatic digestion.

3. The glycerophospholipid has the formula (I): 【Chemistry 1】 Formula (I) [wherein X is either —O— or —O(CO)—; R 1 and R 2 are each independently 11-25 is an alkyl group, R 3 The group is hydrogen, C 1-10 2. The contact lens of claim 1, wherein the compound is selected from the group consisting of polyols, ethanolamines and serine, and salts thereof.

4. The contact lens of claim 1 , wherein the glycerophospholipid is phosphatidylserine, phosphatidylethanolamine, or phosphatidylglycerol.

5. The contact lens of claim 1 , wherein the contact lens is a silicone hydrogel contact lens.

6. The contact lens of claim 1 , wherein the hydrogel is neutral or cationic.

7. 10. The contact lens of claim 1, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising at least one hydrophilic monomer that contains a vinyl group.

8. The polymeric lens body is represented by the formula (II) 【Chemistry 2】 Formula (II) A first siloxane having a structure represented by: and formula (III) 【Chemistry 3】 Formula (III) A second siloxane having a structure represented by The contact lens of claim 1 which is the reaction product of a polymerizable composition comprising:

9. Hydrogel contact lenses are made of sPLA 2 When contacted with a solution containing -IIA, C 12 -C 26 Release fatty acids and their salts, C 12 -C 26 The contact lens of claim 1 , wherein the fatty acid is a digestion product of a glycerophospholipid.

10. 2. The contact lens of claim 1, wherein the glycerophospholipid is 1,2-dioleoylphosphatidylglycerol, 1-palmitoyl-2-oleoylphosphatidylglycerol, 1-stearoyl-2-oleoyl, or 1,2-didocosahexaenoylphosphatidylglycerol.

11. 10. The contact lens of claim 1, wherein the polymeric lens body is loaded with glycerophospholipid in an amount of from 1 μg to 1000 μg, preferably at least 300 μg.

12. 50 ppm sPLA 2 When immersed in a release medium containing artificial tears containing -IIA at 35°C, the contact lens has a C 12 -C 26 Fatty acids, especially C of at least 0.5 μg / hr 12 -C 26 2. A contact lens according to claim 1, which sustains release of fatty acid for at least 4 hours, such as at least 8 hours, optionally at least 10 hours.

13. The glycerophospholipid has the formula (I): 【Chemistry 4】 Formula (I) [wherein X is either —O— or —O(CO)—; R 1 and R 2 are each independently 13-21 alkyl, R 3 The group is hydrogen, C 1-10 2. The contact lens of claim 1, wherein the compound is selected from the group consisting of polyols, ethanolamines and serine, and salts thereof.

14. The packaging, (a) a base member having a cavity for holding a packaging solution; (b) a cover that forms a liquid-tight seal with the base member; The contact lens of claim 1 , comprising:

15. 1. A method of making a hydrogel contact lens comprising a polymeric lens body loaded with glycerophospholipid, the glycerophospholipid containing a C at the sn-2 position. 12 -C 26 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; and c) removing the polymeric lens body from the contact lens mold by dissolving the polymerizable composition in a contact lens mold. 12 -C 26 d) extracting the polymeric lens body in an organic solvent containing a glycerophospholipid containing an acyl group; 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, optionally, f) autoclaving the package.

16. 1. A method for correcting vision in a symptomatic contact lens wearer, comprising: 12 -C 26 The method includes the step of wearing a hydrogel contact lens comprising a polymeric lens body loaded with a glycerophospholipid containing an acyl group.

17. 17. The method of claim 16, wherein a symptomatic contact lens wearer has an increased duration of comfortable contact lens wear compared to the control lenses.

18. 17. The method of claim 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.

19. C at the sn-2 position in an amount that enhances contact lens comfort 12 -C 26 1. The use of a glycerophospholipid containing an acyl group, wherein the phospholipid is associated with a polymeric lens body of a contact lens.

20. The contact lens has a C at the sn-2 position. 12 -C 26 20. The use of claim 19, which is a hydrogel contact lens comprising a polymeric lens body loaded with glycerophospholipids containing acyl groups.

21. 20. The use of claim 19, wherein the sensation of lens sensation is reduced in a contact lens wearer, thereby enhancing contact lens comfort in a symptomatic contact lens wearer and / or increasing the duration of comfortable contact lens wear in a symptomatic contact lens wearer.

22. 1. A hydrogel composition for use in reducing the sensation of lens sensation in a contact lens wearer, thereby enhancing contact lens comfort in the contact lens wearer and / or increasing the duration of comfortable contact lens wear in the contact lens wearer, comprising: (b) an amount of C at the sn-2 position, 12 -C 26 A hydrogel composition comprising a polymeric lens body that is the reaction product of (a) a polymerizable composition loaded with a glycerophospholipid that contains an acyl group.

23. The composition has C at the sn-2 position. 12 -C 26 23. The composition for use according to claim 22 in the form of a contact lens comprising a polymeric lens body loaded with acyl group-containing glycerophospholipid.

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