Contact lenses

Abstract

Contact lenses having an amount of at least one cooling agent and at least one TRPV1 inhibitor releasably attached thereto are described, as well as methods of making the same, which are comfortable to wear for contact lens wearers, can increase the duration of comfortable lens wear time and / or reduce lens consciousness events and / or reduce contact lens dryness in symptomatic contact lens wearers, and can reduce or avoid stinging / burning when the contact lenses are first worn or for a short period thereafter.

Description

[Technical field]

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

[0002] An estimated 50% of all contact lens wearers experience discomfort while wearing their lenses, and approximately 25% of contact lens wearers permanently discontinue lens wear. Dry eye symptoms are the leading reason for dissatisfaction with contact lenses. Despite advances in contact lens materials, there remains a need for improved contact lenses that are comfortable for contact lens wearers who experience dry eye symptoms while wearing currently available contact lenses. Furthermore, lens sensitivity is a major reason for contact lens dissatisfaction among symptomatic contact lens wearers. Despite advances in contact lens materials, there remains a need for improved contact lenses that are comfortable to wear for contact lens wearers who experience lens sensitivity while wearing currently available contact lenses. The cornea is the most densely innervated tissue in the body and is innervated exclusively by A-delta and C primary afferent fibers. C nerve fibers are unmyelinated, while A-delta nerve fibers are slightly myelinated, but they lose their myelin sheath after entering the cornea to maintain corneal transparency. Thus, both types of nerve fibers expose their nerve endings upon reaching the squamous epithelial layer of the cornea. These nerve endings are home to receptors that sense temperature, chemicals, pain, and touch. The pain receptor (nociceptor) that has been shown to be present at these nerve endings is TRPV1. One technical problem that has arisen in the inventors' research in providing a solution for symptomatic contact lens wearers is that, although certain compositions used in contact lenses may ultimately provide a contact lens that is comfortable to wear for the symptomatic contact lens wearer, there may be an initial stinging / burning sensation when the contact lens is first inserted into the eye. Although this stinging / burning sensation is temporary, it may cause the wearer to stop using contact lenses altogether. Thus, there is a need to provide contact lenses, particularly for symptomatic contact lens wearers, which have been treated to allow the symptomatic lens wearer to wear the contact lenses comfortably and to block or reduce any possible stinging / burning sensations. Summary of the Invention

[0003] A feature of the present invention is to provide contact lenses (eg, hydrogel contact lenses) that are comfortable to wear for all contact lens wearers, including symptomatic contact lens wearers. A further feature of the present invention is to provide contact lenses (e.g., hydrogel contact lenses) that can increase the duration of comfortable lens wear time and / or reduce lens consciousness events and / or reduce contact lens dryness in symptomatic contact lens wearers, and further reduce or avoid stinging / burning when the contact lenses are first used or for a short period thereafter.

[0004] A further feature of the present invention is to provide contact lenses capable of releasing two agents, one agent capable of promoting or providing or allowing or contributing to an increased duration of comfortable lens wear time and / or a reduction in lens consciousness events and / or a reduction in contact lens dryness in symptomatic contact lens wearers, and a second agent capable of promoting or providing or allowing or contributing to a reduction or avoidance of stinging / burning when the contact lenses are first used or for a short period thereafter. 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. To achieve these and other advantages, and in accordance with the purposes of the invention as embodied and broadly described herein, the present invention relates, in part, to a contact lens having a certain amount of at least one cooling agent and at least one TRPV1 inhibitor releasably attached thereto.

[0005] The invention further relates to an unworn, sterile hydrogel contact lens immersed in a packaging solution and sealed within a package, the contact lens comprising: a) a polymeric lens body; b) an amount of at least one cooling agent releasably attached to the polymeric lens body; and c) an amount of at least one TRPV1 inhibitor either releasably attached to the polymeric lens body or present in the packaging solution, or both. Additionally, the present invention relates to the use of unworn, sterile hydrogel contact lenses of the present invention to correct vision, particularly the vision of symptomatic contact lens wearers. Additionally, the present invention relates to a method for making the contact lenses of the present invention, the method comprising: polymerizing a polymerizable composition in a contact lens mold to obtain a polymeric lens body; removing the polymeric lens body from the contact lens mold; extracting (in one or more steps) the polymeric lens body in at least a first organic solvent containing a coolant, a TRPV1 inhibitor, or both; hydrating the polymeric lens body in a hydration liquid to obtain a hydrogel contact lens; sealing the hydrogel contact lens in a package with a packaging liquid; and autoclaving the package. The present invention further relates to the use of unworn, sterile hydrogel contact lenses of the present invention for correcting vision, particularly the vision of a symptomatic contact lens wearer, wherein the stinging / burning sensation caused by the cooling agent is blocked or reduced by at least one TRPV1 inhibitor.

[0006] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the invention as claimed. The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate some of the features of the present invention and, together with the description, serve to explain the principles of the invention. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 is a box plot showing preference of symptomatic and asymptomatic contact lens wearers for either WS12 releasing contact lenses or control lenses after 30 days of lens wear. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The cornea is the most densely innervated tissue in the body and is innervated exclusively by A-delta and C primary afferent fibers. While C nerve fibers are unmyelinated, A-delta nerve fibers are slightly myelinated, but they lose their myelin sheath after entering the cornea to maintain corneal transparency. Thus, both types of nerve fibers expose their nerve endings when they reach the squamous epithelial layer of the cornea. These nerve endings are home to receptors that sense temperature, chemicals, pain, and touch. It has been found that embedding a drug (i.e., cooling agent) that interacts with the temperature-sensing receptor (TRPM8) into contact lenses improves end-of-day dryness and reduces CLDEQ-8 scores after 30 days of wear. However, some subjects experience an initial tingling / stinging sensation upon insertion that decreases but does not disappear at the end of the 30-day period. It has been discovered that embedding a drug (i.e., a TRPV1 inhibitor) that interacts with a receptor sensitive to physical and chemical stimuli in contact lenses reduces reports of foreign body sensation upon insertion and reduces or eliminates the tingling / burning sensation.

[0009] One hypothesis is that the tingling / burning sensation associated with the use of cooling agents such as TRPM8 agonists is related to pain sensations relayed to the central nervous system through TRPV1. Incorporating a TRPV1 inhibitor into the lens along with the cooling agent would block or reduce the tingling / burning sensation. By using these two agents together to address both targets and take advantage of their different release characteristics, a TRPVI inhibitor and a cooling agent can be used to address the stinging / burning sensation and improve comfort during contact lens insertion and throughout the day.

[0010] The present invention relates, in part, to contact lenses (e.g., hydrogel contact lenses), uses of contact lenses, and methods for manufacturing contact lenses. One or more coolants are present in and / or on the lens such that they are released from the lens during wear in an amount that improves the comfort of contact lens wear, especially in symptomatic contact lens wearers. One or more TRPV1 inhibitors are additionally present in and / or on the lens (along with the coolant) such that they are released from the lens during wear in an amount that can prevent or reduce the stinging / burning sensation that the wearer may experience when the contact lens is first used or within a short time thereafter. "A short time thereafter" can be, for example, within one hour of use (e.g., within one hour of when the contact lens is first inserted into the eye). This time period may be within the first 30 minutes, or within the first 15 minutes, or within the first 10 minutes, or within the first 5 minutes, or within the first minute, or within the first 30 seconds after the contact lens is first inserted into the eye.

[0011] The present invention relates, in part, to unworn, sterile contact lenses (e.g., hydrogel contact lenses) that have been immersed in a packaging solution and sealed in a package (e.g., a blister package). A preferred contact lens, i.e., a hydrogel contact lens, is described below, although it should be understood that the present invention is applicable to other types of contact lenses. An unworn contact lens may comprise, consist essentially of, consist of, or contain: a) a polymeric lens body; b) an amount of at least one cooling agent releasably attached to the polymeric lens body; and c) an amount of at least one TRPV1 inhibitor that is either releasably attached to the polymeric lens body, present in the packaging solution, or both.

[0012] The term "cooling agent" as used herein refers to a physiological coolant, i.e., a compound that exerts its action at or near the nerve endings associated with the sensation of cooling. The term "a cooling agent" or "the cooling agent" includes one or more cooling agents. The cooling agent may be a mixture of two or more cooling agents that are loaded together in or on the contact lens body. Two or more cooling agents may be loaded separately in or on the contact lens body. As used herein, a cooling agent is an agent that can be releasably attached to a contact lens and has the ability to provide improved comfort to a symptomatic contact lens wearer. As described herein, various methods are described / provided for determining improvement in a symptomatic contact lens wearer (e.g., a reduction in the symptoms of dryness in a contact lens wearer, and / or an increase in the comfortable lens wear time by the contact lens wearer, and / or an increase in the tear meniscus height of a contact lens wearer, and / or a reduction in the CLDEQ-8 score of a contact lens wearer, and / or a reduction in the VAS score of a contact lens wearer). The coolant can be releasably attached to the lens body and loaded into or onto the contact lens body for release during wear. Release can be over a period of time such that a release profile is achieved.

[0013] Examples of cooling agents are icilin, menthol, menthol derivatives, carboxamide, WS-148, WS-30, WS-11, CPS-113, CPS-369, Frescolat ML, Frescolat MGA, Cooling-agent Cooling agents include, but are not limited to, 10, PMD-38, geraniol, linalool, eucalyptol, hydroxycitronellal, AG3-5, 5-methyl-4-(1-pyrrolidinyl)-3[2H]-furanone, 4,5-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, vanillyl butyl ether, peppermint oil, methanecarboxamide ethylpyridine, menthoxypropanediol, menthanediol, cyanomethylphenylmethanecarboxamide, camphor, ethylmethanecarboxamide, menthyldiisopropylpropionamide, menthyl lactate, 4-(butoxymenthyl)-2-methoxyphenol, 3-[[5-methyl-2-(1-methyl)cyclohexyl]oxy]-1,2-propanediol, isopulegol, or mixtures or combinations thereof. Cooling agents are generally commercially available.

[0014] The menthol may be natural menthol or synthetic menthol. Menthol derivatives include racemic menthol derivatives, menthol isomers such as neomenthol, isomenthol, neoisomenthol, corn peppermint oil, or racemates and isomers of synthetic menthol-like coolants which may include monomenthol succinate (MMS), menthol ethylene glycol carbonate, menthol propylene glycol carbonate, menthone glycerol ketal, menthol lactate, 3-(1-menthoxy)propane 1-2 diol (MPD), Cooling-agent 10, TK-10, 3-(1-menthoxy)-2-methylpropane-1-2-diol, 3-(1-menthoxy)ethanol (Coolact 5), 3-(1-menthoxy)propan-1-ol, 3-(1-menthoxy)-butan-1-ol, isopulegol (Coolact P), p-menthane-3,8 diol (Coolact 380, PMD38), menthone glycerol ketal (Frescolat MGA), menthyl lactate (Frescolat ML), (2S)-3-(1-methoxy)-propane-1-2 diol (MPD, TK10), methyl-3-hydroxybutarate (MHB), menthyl pyrrolidin-2-one-5-carboxylate (Questice), 6-isopropyl-9-dimethyl-1-4-dioxaspiro[4,5]decan-2-one, or Cubebol, DL-pyrrolidin-2-one carboxylic acid.

[0015] Carboxamide coolants are alkyloxyamides of the p-menthane carboxamide series of coolant molecules, D-Ala-O-Me and D-Ala-O-Et, N-(R)-2-oxotetrahydrofuran-3-yl (1R,2S5R)-p-menthane-3-carboxamide (D-HSL), N-ethyl-p-menthane-3-carboxamide (WS-3), 2-isopropyltrimethylbutyramide (WS-23), N-([ethoxycarbonyl)methyl]methyl)-p-menthane-3-carboxamide (WS-4), N-methyl-p-menthane-3-carboxamide (WS-5), N-methyl-p-menthane-3-carboxamide (WS-6), N-methyl-p-menthane-3-carboxamide (WS-7), N-methyl-p-menthane-3-carboxamide (WS-8), N-methyl-p-menthane-3-carboxamide (WS-9), N-methyl-p-menthane-3-carboxamide (WS-10), N-methyl-p-menthane-3-carboxamide (WS-11), N-methyl-p-menthane-3-carboxamide (WS-12), N-methyl-p-menthane-3-carboxamide (WS-13), N-methyl-p-menthane-3-carboxamide (WS-14), N-methyl-p-menthane-3-carboxamide (WS-15), N-methyl-p-menthane-3-carboxamide (WS-16), N-methyl-p-menthane-3-carboxamide (WS-17), N-methyl-p-menthane-3-carboxamide (WS-18), N-methyl-p-menthane-3-carboxamide (WS-19), N-methyl-p-menthane-3-carboxamide (WS-20), N-methyl-p-menthane-3-carboxamide (WS-21), N-methyl Examples of such compounds include, but are not limited to, N,N-dimethylmenthyl succinamide, N-(2-ethoxyethyl)-2-isopropyl-2,3-dimethylbutanamide, (1R,2S,5R)N-(4-methoxyphenyl)-p-menthanecarboxamide (also known as N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) (CAS No. 68489-09-8) (WS-12).

[0016] Additional examples of cooling agents include, but are not limited to, vanillyl butyl ether, peppermint oil, methanecarboxamide ethylpyridine, menthoxypropanediol, menthanediol, cyanomethylphenylmenthanecarboxamide, camphor, ethylmenthanecarboxamide, menthyldiisopropylpropionamide, menthyl lactate, 4-(butoxymenthyl)-2-methoxyphenol, 3-[[5-methyl-2-(1-methyl)cyclohexyl]oxy]-1,2-propanediol, isopulegol, or any mixture thereof. In one example, the coolant is WINSENSE Extra 500 manufactured by Lyondell Basell of Rotterdam, The Netherlands, which is a mixture of ethyl menthane carboxamide, menthyl diisopropyl propionamide, and menthyl lactate. The cooling agent may be or contain a TRPM8 agonist.

[0017] The cooling agent may be present in the polymeric lens body in an amount to release 0.01 μg to 10 μg or more of cooling agent in vitro after 1 hour. As used herein, the amount of active agent (e.g., cooling agent or TPV1 inhibitor) released from a polymeric lens body in vitro at a given time point or over a series of time points (i.e., a "release profile") is determined using a release medium consisting of 25% by volume ethanol (EtOH) in phosphate buffered saline (PBS) (hereinafter, the "in vitro release medium") and the method described in Example 3 (hereinafter, the "in vitro release method"). The in vitro release after 1 hour can be 0.01 μg to 10 μg, or 0.02 μg to 10 μg, or 0.05 μg to 10 μg, or 0.075 μg to 10 μg, or 0.1 μg to 10 μg, or 0.5 μg to 10 μg, or 0.75 μg to 10 μg, or 1 μg to 10 μg, or 2 μg to 10 μg, or 3 μg to 10 μg, or 5 μg to 10 μg. Other amounts above or below any one or more of these ranges are also options.

[0018] The amount of cooling agent releasably attached to the polymeric lens body can be from about 0.10 μg to 100 μg or more. As used herein, the amount of active agent "releasably attached" to the polymeric lens body refers to the cumulative amount of active agent released from the polymeric lens body after 16 hours using an in vitro release method. The amount of cooling agent releasably attached to the polymeric lens body can be from 0.10 μg to 100 μg or more, or from about 0.25 μg to 10 μg or more, or from about 0.5 μg to 5 μg, or from 0.10 μg to 9 μg, or from 0.10 μg to 8 μg, or from 0.10 μg to 7 μg, or from 0.10 μg to 6 μg, or from 0.10 μg to 5 μg, or from 0.10 μg to 4 μg, or from 0.10 μg to 3 μg, or from 0.5 μg to 10 μg, or from 0.7 μg to 10 μg, or from 1 μg to 10 μg, or from 2 μg to 10 μg, or from 3 μg to 10 μg, or from 4 μg to 10 μg, or other amounts above or below the ranges set forth herein.

[0019] With respect to the TRPV1 inhibitor, the TRPV1 inhibitor can be one or more TRPV1 inhibitors. The term "a TRPV1 inhibitor" or "the TRPV1 inhibitor" includes one TRPV1 inhibitor or includes more than one TRPV1 inhibitor used together. The TRPV1 inhibitor can be a mixture of two or more TRPV1 inhibitors that are loaded together in or on the contact lens body. Two or more TRPV1 inhibitors can be loaded separately in or on the contact lens body. As an option, the TRPV1 inhibitor can be loaded onto or into the contact lens after the coolant is loaded onto or into the same lens. Thus, the sequential loading procedure can allow for an earlier and / or greater release of the TRPV1 inhibitor when the contact lens is first inserted into the eye.

[0020] As an option, the TRPV1 inhibitor may be loaded onto or into the contact lens simultaneously with the cooling agent. TRPV1 inhibitors may provide inhibition by direct blockade of TRPV1, or indirect inhibition, such as by downregulating expression of TRPV1. As an alternative, the TRPV1 may be a TRPV1 antagonist. The TRPV1 inhibitor can be loaded in or on the contact lens body such that it is releasably attached to the lens body and released during wear. Examples of TRPV1 inhibitors include, but are not limited to, oleic acid, alpha-lipoic acid, L-carnitine, resveratrol (3,5,4'-trihydroxy-trans-stilbene), hyaluronic acid, palmitoylethanolamide petroselinic acid, naringenin, ashibatrep, AMG517 (from Amgen), ABT102 (from Abbott), GRC6211 (from Glenmark), SB-705498 (from GSK), or MK-2295 (from Merck-Neurogen), or any mixture or combination thereof.

[0021] [ka]

[0022] The TRPV1 inhibitor may be present in the lens body in an amount to release from 1 μg to 100 μg (or more) of the TRPV1 inhibitor in vitro after 1 hour. The in vitro release after 1 hour may be from 3 μg to 25 μg, 4 μg to 25 μg, 5 μg to 25 μg, 7 μg to 25 μg, 10 μg to 25 μg, 12 μg to 25 μg, 2 μg to 22 μg, 2 μg to 20 μg, 2 μg to 18 μg, 2 μg to 15 μg, 2 μg to 12 μg, 2 μg to 10 μg, 2 μg to 8 μg, 2 μg to 5 μg. Other amounts above or below any one or more of these ranges are also options. The amount of TRPV1 inhibitor releasably attached to the polymeric lens body can be about 5 μg to 500 μg or more, or about 10 μg to 500 μg, or 20 μg to 500 μg, or 30 μg to 500 μg, or 50 μg to 500 μg, or 75 μg to 500 μg, or 100 μg to 500 μg, or 125 μg to 500 μg, or 150 μg to 500 μg, or 175 μg to 500 μg, or 200 μg to 500 μg, or 5 μg to 450 μg, or 5 μg to 400 μg, or 5 μg to 300 μg, or 5 μg to 200 μg, or 5 μg to 100 μg, or other amounts above or below the ranges set forth herein.

[0023] An example of a specific combination of a cooling agent and a TRPV1 inhibitor can be one in which the cooling agent is or includes a TRPM8 agonist and the TRPV1 inhibitor includes or contains oleic acid. Another example is one in which the cooling agent comprises or contains or is WS12 and the TRPV1 inhibitor comprises or contains or is oleic acid.

[0024] In the present invention, the TRPV1 inhibitor may have a first release profile and the coolant may have a second release profile. The first release profile may be different from the second release profile. The first release profile may be faster than the second release profile based on the percentage of the releasably attached amount of the TRPV1 inhibitor released in the first 1-3 hours (e.g., 1 hour or 30 minutes) and based on the percentage of the releasably attached amount of the coolant released after the same time (e.g., 1 hour or 30 minutes) as determined using an in vitro release method. Thus, for example, if the amount of the TRPV1 inhibitor releasably attached to the polymeric lens body is 40 μg, of which 30 μg (i.e., 75%) is released after 1 hour using the in vitro release method described in Example 3, and the amount of the coolant releasably attached to the polymeric lens body is 400 μg, of which 40 μg (i.e., 10%) is released after 1 hour using the in vitro release method, the TRPV1 inhibitor is said to have a faster release profile than the coolant.

[0025] Thus, as one example, a TRPV1 inhibitor may release 50% to 99% by weight (e.g., 50% to 90% by weight, or 50% to 80% by weight, or 50% to 70% by weight) of the amount of TRPV1 inhibitor releasably attached to a contact lens in the first 1 to 3 hours of release (as determined using the in vitro release method of Example 3), compared to 5% to 50% by weight (e.g., 5% to 45% by weight, or 5% to 40% by weight, or 5% to 30% by weight, or 5% to 20% by weight, or 5% to 10% by weight) of the amount of coolant releasably attached to the same contact lens in the same first 1 to 3 hours of release. Thus, in one example, a first release profile releases a majority (on a mass % basis) of a releasably attached amount of TRPV1 inhibitor in the first 1 to 3 hours (e.g., 1 hour or 30 minutes) of release, and a second release profile releases less than half (on a mass % basis) of a releasably attached amount of cooling agent in the same first 1 to 3 hours (e.g., 1 hour or 30 minutes) of release.

[0026] The first release profile (TRPV1 inhibitor release profile) can be a release of 3 to 20 μg of TRPV1 inhibitor per hour in the release medium for up to at least 9 hours (e.g., 1 hour to 9 hours, or 3 hours to 8 hours). The second release profile (coolant release profile) can be a release of 0.05 μg to 0.5 μg of coolant per hour for up to 6 hours, or the second release profile can be a release of 0.1 μg to 0.3 μg of coolant per hour for up to 6 hours. In one option, the polymeric lens body has a concave and a convex surface, and the TRPV1 inhibitor is present in a higher concentration on the concave or convex surface, or on both, compared to the coolant. For example, the concave surface may have a coating (or layer) that includes the TRPV1 inhibitor, and the coating may allow for an initial release of the TRPV1 inhibitor, but may initially block, inhibit, or reduce or slow the initial release of the coolant (e.g., when the contact lens is first inserted into the eye). With regard to the cooling agent, the cooling agent may be incorporated into the hydrogel contact lens material and remain within the lens material, preferably without decomposition and / or preferably without leaching, during standard contact lens sterilization and storage conditions. Once the contact lens is placed on the eye, the coolant may be continuously released from the lens for a period of time, in one example, the coolant is continuously released from the lens for up to 6 hours, or 8 hours, or 12 hours, or 16 hours or more.

[0027] With respect to TRPV1 inhibitors, the TRPV1 inhibitors can be incorporated into hydrogel contact lens material and remain within the lens material, preferably without decomposition and / or preferably without leaching, during standard contact lens sterilization and storage conditions. Once the contact lens is placed on the eye, the TRPV1 inhibitor may be continuously released from the lens in an amount sufficient to inhibit the TRPV1 receptor for a period of time, such as 30 minutes or more or from 1 to several hours, e.g., 30 minutes to 3 hours or 1 to 2 hours.

[0028] The cooling agent may have the ability to activate the transient receptor potential melastatin-8 (TRPM8) ion channel. In one option, the contact lens has no TRPM8 receptor agonists other than the cooling agent. As an option, contact lenses do not have any other medications present for dry eye. With respect to a polymeric contact lens body having an amount of a cooling agent and an amount of a TRPV1 inhibitor releasably attached to the polymeric lens body, the polymeric lens body can be the reaction product of a polymerizable composition that includes or contains at least one siloxane monomer and at least one hydrophilic monomer or at least one hydrophilic polymer or both at least one hydrophilic monomer and at least one hydrophilic polymer.

[0029] The polymeric lens body can be one of Phanfilcon A, Comfilcon A, Somofilcon A, Lyofilcon A, or Stenfilcon A. As a further example, a contact lens can be the reaction product of a polymerizable composition for a non-silicone hydrogel, which is typically formed by polymerizing one or more hydrophilic monomers, such as 2-hydroxyethyl methacrylate (HEMA) or vinyl alcohol, optionally in combination with other monomers, and which do not contain siloxane molecules.

[0030] The cured polymeric lens body may be extracted in an extraction solvent (or two or more extraction solvents) containing a coolant and / or a TRPV1 inhibitor, which results in a desired amount of the coolant and TRPV1 inhibitor attached to the polymeric lens body. As one example, the extraction solvent may be an organic solvent such as EtOH. The extraction solvent may consist of EtOH (with or without added coolant and / or TRPV1 inhibitor). Alternatively, the extraction solvent may include a mixture of an organic solvent and water, such as a 50 / 50 (by volume) mixture of denatured EtOH and deionized water (with or without added coolant and / or TRPV1 inhibitor). Alternatively, or additionally, the polymeric lens body for the hydrogel can be hydrated in a hydration liquid, such as water or an aqueous solution (or two or more hydration liquids) containing a cooling agent and / or a TRPV1 inhibitor, which results in a desired amount of the cooling agent and TRPV1 inhibitor attached to the polymeric lens body. Alternatively, or additionally, a cooling agent and / or a TRPV1 inhibitor can be added to the polymerizable composition prior to polymerization to form the polymeric lens body. The cooling agent and / or TRPV1 inhibitor can be attached to the polymeric lens body by hydrophobic interactions and / or physically encapsulated by the polymer network of the polymeric lens body.

[0031] A polymeric lens body made of a material and having a certain amount of a cooling agent and / or TRPV1 inhibitor releasably attached thereto may have a different release profile than a polymeric lens body made of a different material and having the same amount of a cooling agent and / or TRPV1 inhibitor releasably attached thereto. Some properties of the polymeric lens body that may affect the release profile of the cooling agent and / or TRPV1 inhibitor include the hydrophobicity of the material, the water content, and the degree of crosslinking of the polymeric lens body. Furthermore, to delay or extend the release of the cooling agent and / or TRPV1 inhibitor from the lens, some or all of the cooling agent and / or TRPV1 inhibitor may be encapsulated using encapsulation techniques such as liposomes or erodible nanoparticles before the cooling agent and / or TRPV1 inhibitor is incorporated into the polymeric lens body. For example, 10% to 80% or more by weight of the cooling agent and / or TRPV1 inhibitor incorporated into the contact lens may have this delayed release characteristic. A contact lens is considered to maintain release of coolant and / or TRPV1 inhibitor for x hours if the amount of coolant and / or TRPV1 inhibitor released after a particular number, x hours, is greater than the amount of coolant and / or TRPV1 inhibitor released after x-1 hours, as measured using the in vitro release method described in Example 3.

[0032] The method of Example 2 can be used to determine the amount of coolant and / or TRPV1 inhibitor released from contact lenses when worn. Briefly, human subjects (n=3) wear the lenses in both eyes for a specified period of time. The amount of coolant and / or TRPV1 inhibitor released from the lenses at a specified time point is the difference between the average amount of coolant and / or TRPV1 inhibitor in unworn lenses (n=3) and the average amount of coolant and / or TRPV1 inhibitor remaining in worn lenses at the time point tested.

[0033] The polymeric lens body may comprise any hydrogel material suitable for use as a contact lens material. Silicone hydrogel materials for contact lenses are typically formed by curing a polymerizable composition (i.e., a monomer mixture) that comprises at least one siloxane monomer 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 that comprises at least one Si-O group and at least one polymerizable group. Siloxane monomers 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 referred to throughout are incorporated by reference in their entirety). In some examples, the polymerizable composition comprises a total amount of siloxane monomers of at least 10%, 20%, or 30% by weight to about 40%, 50%, 60%, or 70% by weight. Unless otherwise specified, as used herein, a given weight percent (wt.%) of a component of a polymerizable composition is relative to the total weight of all polymerizable components and IPN polymer (described further 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 percent calculation.

[0034] In a specific example, the polymerizable composition comprises a hydrophilic vinyl monomer. As used herein, a "hydrophilic vinyl monomer" is a siloxane-free (i.e., Si-O group-free) hydrophilic monomer having a polymerizable carbon-carbon double bond (i.e., vinyl group) present in the molecular structure that is not part of an acrylic group, where the carbon-carbon double bond of the vinyl group is less reactive under free radical polymerization than the carbon-carbon double bond present in the polymerizable methacrylate group. As used herein, the term "acrylic group" refers to a polymerizable group present in acrylates, methacrylates, acrylamides, and the like. Thus, although carbon-carbon double bonds are present in acrylate and methacrylate groups, as used herein, such polymerizable groups are not considered 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., approximately 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 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, siloxane monomer, etc.) in the polymerizable composition is equal to the sum of the weight percentages of each component in the composition that falls into that class. 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 vinyl amide monomer. Exemplary hydrophilic vinylamide monomers are VMA and NVP. In a specific example, the polymerizable composition comprises at least 25% by weight of the vinylamide monomer.In further embodiments, the polymerizable composition comprises from about 25% to about 75% by weight 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.

[0035] In addition, or as an alternative to hydrophilic monomers, 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 and acts as an internal wetting agent for the contact lens. In contrast, the polymer chains within the silicone hydrogel network formed by polymerization of 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, about 50,000 to 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.

[0036] As an option, one or more non-silicone-containing hydrophobic monomers may be present as part of the polymerizable composition. A hydrophobic monomer may be understood as a monomer in which 50 grams of the monomer are not completely soluble in 1 liter of water at 20° C. when visually observed using a 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, or 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.

[0037] When used, the hydrophobic monomer may be present in the reaction product of the polymerizable composition in an amount from 1% to about 30% by weight, such as 1% to 25% by weight, 1% to 20% by weight, 1% to 15% by weight, 2% to 20% by weight, 3% to 20% by weight, 5% to 20% by weight, 5% to 15% by weight, 1% to 10% by weight, etc., based on the total weight of the polymerizable composition.

[0038] 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 polymerization initiators, UV absorbers, colorants, oxygen scavengers, chain transfer agents, etc. 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, such that an optically clear lens is obtained. Diluents commonly used in contact lens formulations include hexanol, ethanol, and / or other 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 that include hydrophilic moieties, such as polyethylene oxide groups, pendant hydroxyl groups, or other hydrophilic groups, 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 described in U.S. Pat. No. 8,231,218.

[0039] Non-limiting examples of silicone hydrogels that can be used include comfilcon A, funfilcon 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 silicone hydrogel contact lenses of the present invention are based on a polymerizable composition comprising 25% to 55% by weight of a siloxane monomer or combination of siloxane monomers, 30% to 55% by weight of a vinyl monomer selected from NVP, VMA, or combinations thereof, and optionally about 1% to about 20% by weight of a hydrophilic monomer selected from N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), ethylene glycol methyl ether methacrylate (EGMA), or any combinations thereof, and optionally about 1% to about 20% by weight of a hydrophobic monomer selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), 2-hydroxybutyl methacrylate (HOB), or any combinations thereof. Silicone hydrogel materials made from the polymerizable composition of this particular embodiment include stenfilcon A, confilcon A, somofilcon A, fanfilcon A, and enfilcon A.

[0040] Conventional methods can be used to manufacture the contact lenses of the present invention. In one example, a polymerizable composition for a silicone 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, is combined with the female mold member to form a contact lens mold assembly, which is subjected to curing conditions, such as UV or thermal curing conditions, under which the curable composition is formed into a polymeric lens body. The female mold member and the male mold member 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. In some examples, the extraction liquid comprises an organic solvent mixed with water. After extraction, the lens body is hydrated with one or more hydration liquids, e.g., water or an aqueous solution, and packaged. In some examples, the extraction and hydration can be accomplished without organic solvents. An exemplary method for making silicone hydrogel contact lenses is described in US Pat. No. 8,865,789.

[0041] As indicated, the coolant and / or TRPV1 inhibitor can be loaded into the polymeric lens during the extraction and / or hydration process. For example, after curing, the polymeric lens body is swollen in an extraction solvent, such as ethanol, that contains the coolant and / or TRPV1 inhibitor. The extracted polymeric lens body is then placed in a hydration liquid, such as deionized water, which removes the extraction solvent and leaves the coolant and / or TRPV1 inhibitor attached to the polymeric lens body. The loading of the cooling agent and / or TRPV1 inhibitor during the extraction process can be done in a number of ways: Both the cooling agent and the TRPV1 inhibitor can be loaded in the same single extraction or hydration step, where both are present together in the same extraction or hydration liquid. Alternatively or additionally, the extraction may include two or more extraction steps. When multiple extraction steps are used, the first extraction step may include a cooling agent in a first extraction solvent, and the second extraction step may include a TRPV1 inhibitor in a second extraction solvent. As an option, the order of extraction may be reversed. The first and second extraction solvents may be the same or different from each other. The extraction solvent can be an organic solvent. The first extraction solvent can be a first organic solvent, and the second extraction solvent can be a second organic solvent (different from the first organic solvent). As an option, the one or more extraction solvents can include a mixture of organic solvent and water, such as a 50 / 50 (by volume) mixture of denatured EtOH and deionized water.

[0042] Alternatively, or additionally, the cooling agent and / or TRPV1 inhibitor may be loaded by being present in a packaging solution (eg, a blister solution) prior to sealing the contact lens with the packaging solution within the base member. Some TRPV1 inhibitors are suitable for loading into or onto contact lenses during extraction with organic solvents (e.g., oleic acid, alpha-lipoic acid, palmitoylethanolamide, petroselinic acid), others are suitable for loading by being present in an aqueous hydration fluid or packaging (i.e., blister) solution (e.g., L-carnitine, hyaluronic acid, naringenin), and still others can be loaded in acceptable amounts using extraction and / or blister loading techniques (e.g., resveratrol). Simple routine experimentation and / or understanding of the solubility of the TRPV1 inhibitor in water can be utilized to determine the suitability of the loading technique.

[0043] Thus, the present invention relates to a method for manufacturing the contact lenses of the present invention. The method may comprise, consist essentially of, or include: polymerizing a polymerizable composition in a contact lens mold to obtain a polymeric lens body, and removing the polymeric lens body from the contact lens mold; then extracting the polymeric lens body (in one or more steps) in at least a first organic solvent containing a coolant, a TRPV1 inhibitor, or both. The method includes hydrating the polymeric lens body in a hydration liquid to obtain a hydrogel contact lens, and sealing the hydrogel contact lens in a package with a packaging solution; and autoclaving the package. The extraction step may include extracting the polymeric lens body in a first organic solvent containing a coolant and a TRPV1 inhibitor. Alternatively, the extraction step may include extracting the polymeric lens body in a first organic solvent containing a coolant and then extracting in a second organic solvent containing a TRPV1 inhibitor (or vice versa). The method may further include, for example, including a TRPV1 inhibitor in the packaging solution before sealing. Alternatively to the extraction and loading steps, or in addition to loading by the extraction steps described above, loading may be achieved by having one or both of a cooling agent and / or a TRPV1 inhibitor present in the packaging solution.

[0044] 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. As one example, the extraction and hydration process may include at least one extraction step in denatured ethanol followed by a 50:50 mixture of ethanol and water, followed by at least one hydration step in deionized water, where each extraction and hydration step may last from about 15 minutes to about 3 hours at a temperature of about 20° C. to about 30° C. For example, the extraction solvent may include WS12 or other coolant to achieve upload of the WS12 or other coolant into the polymer lens body.

[0045] The extraction solvent used as the upload solution of the cooling agent and / or TRPV1 inhibitor may contain a concentration of at least 0.25 μg / ml, or at least 0.5 μg / ml, or at least 1.0 μg / ml of the cooling agent and / or TRPV1 inhibitor. This concentration may be at least 2.5 μg / ml, at least 5.0 μg / ml, or at least 10.0 μg / ml of the cooling agent and / or TRPV1 inhibitor. In one example, the concentration of either (or both) the cooling agent and / or TRPV1 inhibitor in the extraction solvent is about 1.0 μg / ml to about 1.5 mg / ml (i.e., 1 ppm to about 1500 ppm).

[0046] In some instances, the cooling agent and / or TRPV1 inhibitor, once attached to the polymeric lens body, is stable and is not substantially released or degraded from the polymeric lens body during autoclaving of a sealed contact lens package containing an unworn hydrogel contact lens in a packaging solution or during storage in that packaging solution, but is released during lens wear. Thus, the packaging solution in which the contact lens is immersed prior to autoclaving, or immediately after autoclaving, or 1 day thereafter, or 30 days thereafter, or 60 days thereafter, or 120 days thereafter, has a concentration of the cooling agent and / or TRPV1 inhibitor of less than 0.1 μg / ml, or less than 0.05 μg / ml, or has a concentration of the cooling agent and / or TRPV1 inhibitor below the level of detection as determined by HPLC.

[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 agent, and / or a tonicity agent. In another example, the packaging solution includes 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, that are commonly used as comfort polymers or thickeners in ophthalmic solutions 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 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 to 400 mOsm / kg, typically in the range of about 270 mOsm / kg to about 310 mOsm / kg.

[0048] For contact lens packaging, the packaging may include or contain a base member (e.g., a plastic base member) that includes a cavity configured to hold a contact lens and a packaging solution, and a flange region extending outwardly around the cavity. A cover (e.g., a removable foil) that forms a liquid-tight seal with the base member can be attached to the flange region to provide a sealed contact lens package. Such contact lens packages, commonly referred to as "blister packs," are well known in the art (see, e.g., U.S. Pat. No. 7,426,993).

[0049] It will be understood that conventional manufacturing methods may be used to manufacture the sealed contact lens package. In the method of manufacturing the contact lens package, the method may include the steps of placing an unworn contact lens and a contact lens packaging solution into a receptacle, placing a cover over the receptacle, and sealing the cover over 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 embodiment, the receptacle includes a plastic base member including a cavity configured to hold the contact lens and packaging solution and a flange region extending outwardly around the cavity, and the cover includes a removable foil attached to the flange region to provide a sealed contact lens package. The removable foil may be sealed by any conventional means, such as heat sealing or gluing. In another embodiment, 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 set of threads compatible for engagement with the threads of the base member, thereby providing a resealable cover. It will be appreciated that other types of packaging may also be used to provide a resealable package. For example, the contact lens package may include a plastic cover including features that engage compatible features of the receptacle to form an interference fit. The method of manufacturing the sealed contact lens package may further include sterilizing the unworn contact lenses by autoclaving the sealed contact lens package. Autoclaving typically involves subjecting the sealed contact lens package to a temperature of at least 121° C. for at least 20 minutes.

[0050] The contact lenses may be provided unworn (i.e., new contact lenses not previously used by a patient), immersed in the packaging solution, and sealed in a package. The package may be a blister pack, glass vial, or other suitable container. The package includes a base member having a cavity for receiving the packaging solution and the unworn contact lens. The sealed package may be sterilized by autoclaving or by irradiation with a sterilizing amount, including heat or steam, such as by gamma radiation, electron beam radiation, ultraviolet radiation, and the like.

[0051] In a specific example, 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 ophthalmically acceptable surface wettability. The hydrogel contact lenses described herein can be used to correct vision in symptomatic contact lens wearers. For example, the hydrogel contact lenses can extend the comfortable contact lens wear time for symptomatic contact lens wearers. As used herein, "symptomatic contact lens wearer" or "symptomatic subject" refers to a lens wearer who is classified as symptomatic using the method described in Example 5 below, adapted from Young et al. (Young et al. Characterizing contact lens-related dryness symptoms in a cross-section of UK soft lens wearers. Contact Lens & Anterior Eye 34(2011) 64-70). The present contact lenses may reduce symptoms of dryness and / or discomfort in contact lens wearers.

[0052] The hydrogel contact lenses described herein may be worn by a symptomatic contact lens wearer to reduce "dryness" and / or discomfort, particularly at the end of the day, compared to a control lens or the symptomatic wearer's usual lens. As used herein, a "control lens" refers to a contact lens that does not contain a cooling agent and / or a TRPV1 inhibitor, but is otherwise identical to the cooling agent and / or TRPV1 inhibitor lens to which it is compared. The reduction in dryness and / or discomfort in a symptomatic contact lens wearer may be determined in a clinical trial. The overall lens preference of a symptomatic contact lens wearer over a hydrogel contact lens is another way to measure / confirm the beneficial effect on contact lens discomfort and / or dryness.

[0053] The hydrogel contact lenses described herein may provide reduced lens consciousness and / or a reduction in "lens consciousness events" during the day compared to control lenses. Reduction in lens consciousness and / or lens consciousness events during contact lens wear may be determined using a "lens consciousness logger" as described by Read et al. (See Read et al., Monitoring ocular discomfort using a wrist-mounted electronic logger. Contact Lens and Anterior Eye Vol. 43(2020) 476-483). The hydrogel contact lenses described herein may provide increased tear film meniscus height (or tear meniscus height) compared to control lenses after the lenses have been worn for 1 hour, 2 hours, 4 hours or more. Tear film meniscus height may be measured by optical coherence tomography (OCT) or other suitable methods. The hydrogel contact lenses described herein may improve (i.e., reduce) CLDEQ-8 scores in lens wearers, for example, in symptomatic lens wearers (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). Improved CLDEQ-8 scores may be seen after 1 week, 2 weeks, or 4 weeks of wearing the hydrogel contact lenses.

[0054] As mentioned above, some subjects may experience a tingling / burning or cooling sensation early after inserting contact lenses that have a cooling agent present as part of the lens. The presence of a TRPV1 inhibitor as part of the lens may reduce or avoid this potentially early unpleasant sensation. The TRPV1 inhibitor allows the lens wearer to wear the contact lenses without experiencing any discomfort during insertion. Reduction of the initial unpleasant sensation, such as within 30 minutes after lens insertion, may be demonstrated using a validated visual analog scale (VAS) in which the lens wearer records the perceived discomfort on a linear scale with the left end of the scale representing "no discomfort" and the right end of the scale representing "most discomfort" (see Delgado et al. J Am Acad Orthop Surg Glob Res Rev. 2018 Mar; 2(3): e088). A significant reduction in discomfort is indicated by an improvement of at least 1 on a scale of 1 to 10 (i.e., equivalent to 1 cm on a conventional 10 cm paper-based linear scale) when wearing lenses containing both a coolant and a TRPV1 inhibitor compared to wearing otherwise identical lenses without a TRPV1 inhibitor. In some instances, the improvement in VAS score is at least 2, at least 3, or at least 4 or greater. The following examples are intended to illustrate certain aspects and advantages of the present invention, but should not be construed as limiting thereof. EXAMPLES

[0055] Example 1 Preparation of WS12 emissive contact lenses Silicone hydrogel contact lenses were prepared by curing the formulation for Stenfilcon A in a contact lens mold. The cured Stenfilcon A was removed from the mold and extracted by immersion for 215 minutes in ethanol (EtOH) containing WS12 (Tocris Bioscience) at the loading concentration shown in Table 2. The lenses were removed from the EtOH and washed with DI water for approximately 6 minutes, followed by two changes of DI water for approximately 30 minutes each. The lenses were transferred to 6 mL glass vials containing 3 mL of phosphate buffered saline (0.78% by weight NaCl, 0.05% by weight sodium phosphate monobasic, 0.36% by weight sodium phosphate dibasic) at pH 7.5, referred to herein as PBS. The vials were sealed and autoclaved. Each autoclaved lens was transferred to a vial containing 3 mL of EtOH and stored overnight at room temperature on a shaker at 150 rpm to extract WS12 from the lenses. The EtOH extracts and the PBS in which the lenses were autoclaved were subjected to analysis by HPLC (detection wavelength = 250 nm) against calibration standards to determine the average amount of WS12 loaded into each lens (n ​​= 5) and whether WS12 leached from the lenses during autoclaving. The results are shown in Table 1.

[0056] [Table 1] Silicone hydrogel contact lenses were prepared by curing the formulation for Confilcon A in contact lens molds and subjecting the lenses to the same extraction, hydration, and autoclaving procedures described above for lenses made with Stenfilcon A, except that a single WS12 concentration of 15 μg / mL was used in the ethanol extraction step. This lens (Lens D) was subjected to HPLC analysis for WS12 content and showed an average incorporation of 1.04 μg / lens of WS12.

[0057] Example 2 Release of WS12 from contact lenses during lens wear Lenses B of Example 1 were worn by human subjects for 1, 3, and 6 hours (n=2 for each time point). At the end of each lens wear period, the lenses were extracted in EtOH using the method described in Example 1. The extracts were subjected to HPLC analysis to determine the amount of WS12 remaining in the lenses, and the amount of WS12 released during wear was calculated. The average amount and percentage of WS12 released during lens wear are shown in Table 2.

[0058] [Table 2]

[0059] Example 3 In vitro release method For the in vitro release method, contact lenses are removed from the container and excess packaging solution is shaken off from each lens. Each lens (n=3 per time point) is transferred to a 6 mL glass vial containing 3 mL of 25% ethanol by volume in PBS at 35°C (EtOH release medium). The vials are placed on a shaker at 125 rpm in a 35°C incubator. At the 30 min and 1 h time points, 2.5 ml of EtOH release medium is removed (i.e., from the 30 min and 1 h vials, respectively) and submitted for HPLC analysis. At the 1 h time point and at subsequent time points (i.e., 2 h, 3 h, 6 h, 9 h, 12 h, 16 h), 2.5 ml of EtOH release medium is removed from each of the remaining vials and 2.5 ml of fresh EtOH release medium is added back to each vial. The cumulative release of WS12 at each time point is calculated. For example, the 3 hour time point is the sum of the average amount of WS12 detected in the release medium collected at the 1 hour, 2 hour, and 3 hour time points. The above in vitro release method results in an in vitro release of WS12 from contact lenses that corresponds well with the release of WS12 from contact lenses worn on the eye, as shown in Table 3, compared to Table 2.

[0060] [Table 3]

[0061] Example 4 A one-day clinical trial of escalating doses of WS12-releasing contact lenses Two subjects were recruited for a study evaluating all three loading strengths of Example 1. Each subject was exposed to Lenses A, B, and C of Example 1, worn contralaterally in one eye for 30 minutes each. On the first test day, subjects were exposed to Lenses B and C contralaterally, and then on another day, Lenses B and A contralaterally. With Lens C, one subject experienced a tingling sensation, and the other a cooling sensation. With Lens B, both subjects experienced a mild cooling / tingling sensation that lasted for about an hour. Lens A caused the subjects to experience a short-lived cooling / wetting sensation. Lens B was selected for further evaluation.

[0062] Example 5 A 30-day clinical trial of the WS12 releasing contact lens Thirty-three subjects were enrolled in a two-sided, randomized, crossover, double-masked study wearing either Lens B of Example 1 (test product) or MyDay® brand (control) contact lenses for one month each. Subjects were classified as either symptomatic (S) or asymptomatic (A) contact lens wearers using the classification system outlined in Table 4, which was adapted from the classification proposed by Young et al. (supra).

[0063] [Table 4] Sixteen subjects were classified as symptomatic contact lens wearers, reporting a rating of 2 or higher on a 5-point scale for the intensity of contact lens dryness / discomfort and reporting the frequency of contact lens dryness / discomfort as "sometimes, frequently, or all the time." Seventeen subjects were classified as asymptomatic contact lens wearers, reporting a rating of 0 or 1 on a 5-point scale for the intensity of contact lens dryness / discomfort and reporting the frequency of contact lens dryness / discomfort as "rarely or never."

[0064] After a 3-7 day washout period during which subjects wore their usual lenses, the second lens type from the randomization sequence (i.e., Example 1 (test product) or MyDay® brand (control) contact lenses) was worn for one month. Evaluations of comfort, dryness, coolness, niceness, and CLDEQ-8 scores were monitored (see Chalmers et al., supra).

[0065] At 1 week, the test lenses were rated as significantly less comfortable to insert than the control lenses, but this difference diminished after 1 month of wear. This change was likely due to decreased cooling sensation due to sensory adaptation in subjects wearing the test lenses. There were no significant differences in overall comfort ratings between the test and control lenses at 1 week or 1 month. However, after 1 month of wear, twice as many subjects reported increased comfort with the test lenses compared with the control lenses. Overall dryness ratings were significantly better (i.e., less dry) with the test lenses than with the control lenses at both 1 week and 1 month. Tear meniscus height, measured using a Visante OCT (Carl Zeiss Meditec Inc., Dublin, CA), was significantly increased after 1 month of wear with the test lenses compared with the control lenses. CLDEQ-8 scores were significantly lower after 1 month of wear with the test lenses compared with the control lenses. This difference was statistically significant in symptomatic subjects. After 1 month of lens wear, 19 of the 33 subjects (58%) reported a preference for the test lenses, 11 (33%) preferred the control lenses, and 3 (9%) reported no preference. Of the 16 symptomatic subjects, 11 (69%) preferred the test lenses and 5 (31%) preferred the control lenses. The results are shown in Figure 1.

[0066] The present invention includes the following aspects / embodiments / features in any order and / or in any combination: 1. The present invention provides an unworn, sterile hydrogel contact lens immersed in a packaging solution and sealed in a package, comprising: a) a polymeric lens body; b) a quantity of a cooling agent releasably attached to the polymeric lens body; and c) an amount of a TRPV1 inhibitor that is either releasably attached to the polymeric lens body or is present in the packaging solution, or both; The present invention relates to an unworn sterile hydrogel contact lens comprising: 2. The unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the cooling agent is a TRPM8 agonist. 3. The TRPV1 inhibitor is oleic acid, alpha-lipoic acid, L-carnitine, resveratrol, hyaluronic acid, palmitoylethanolamide, petroselinic acid, naringenin, ashibatrep, AMG517, ABT102, GRC6211, SB-705498, or MK-2295; Cooling agents include Icilin, menthol, menthol derivatives, carboxamide, WS-148, WS-30, WS-11, CPS-113, CPS-369, Frescolat ML, Frescolat MGA, Cooling-agent 10, PMD-38, geraniol, linalool, eucalyptol, hydroxycitronellal, AG3-5, 5-methyl-4-(1-pyrrolidinyl)-3[2H]-furanone, 4,5-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, vanillyl butyl ether, peppermint oil, methanecarboxamide ethylpyridine, menthoxypropanediol, menthanediol, cyanomethylphenylmethanecarboxamide 5-(5-methyl-2-(1-methyl)cyclohexyl)oxy]-1,2-propanediol, isopulegol, or a mixture or combination thereof. 4. The unworn, sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the cooling agent comprises a TRPM8 agonist and the TRPV1 inhibitor comprises oleic acid. 5. The unworn, sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the cooling agent comprises WS12 and the TRPV1 inhibitor comprises oleic acid. 6. An unworn, sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein a TRPV1 inhibitor is releasably attached to the polymeric lens body. 7. The unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the TRPV1 inhibitor has a first in vitro release profile and the coolant has a second in vitro release profile, and the first release profile is faster than the second release profile based on the percentage of the total load of TRPV1 inhibitor and coolant released in the first 1-3 hours of release. 8. The unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the first release profile releases a majority of the total payload of the TRPV1 inhibitor in the first 1-3 hours of release and the second release profile releases less than half of the total payload of the coolant in the same first 1-3 hours of release. 9. An unworn, sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the cooling agent has an in vitro release profile of 0.01 μg to 10 μg of cooling agent after 1 hour in a release medium consisting of 25% by volume EtOH in PBS. 10. An unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the amount of cooling agent releasably attached to the polymeric lens body is between about 0.25 μg and 10 μg. 11. An unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the amount of cooling agent releasably attached to the polymeric lens body is between about 0.5 μg and 5 μg. 12. The unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the second release profile comprises release of 0.05 μg to 0.5 μg of coolant per hour for up to 6 hours. 13. The unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the second release profile comprises release of 0.1 μg to 0.3 μg of coolant per hour for up to 6 hours. 14. An unworn, sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the TRPV1 inhibitor has a release profile comprising release of 2 μg to 25 μg of TRPV1 inhibitor in 1 hour in a release medium consisting of 25 vol.% EtOH in PBS. 15. The unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the first release profile comprises release of 3 to 20 μg of TRPV1 inhibitor per hour in the release medium for at least 9 hours. 16. The unworn, sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising at least one siloxane monomer and at least one hydrophilic monomer or at least one hydrophilic polymer, or both at least one hydrophilic monomer and at least one hydrophilic polymer. 17. The unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the polymeric lens body is fanfilcon A, confilcon A, somofilcon A, lyofilcon A, or stenfilcon A. 18. The unworn, sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the polymeric lens body is the reaction product of a polymerizable composition including 25% to 55% by weight of a siloxane monomer or combination of siloxane monomers, 30% to 55% by weight of a vinyl monomer selected from NVP, VMA, or combinations 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), 2-hydroxybutyl methacrylate (HOB), or any combination thereof. 19. The unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the coolant is WS12. 20. An unworn sterile hydrogel contact lens or other embodiment of any preceding or following embodiment / feature / aspect, wherein the packaging is autoclaved. 21. Packaging a) a base member having a cavity for holding a packaging solution; and b) a cover that forms a fluid-tight seal with the base member An unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect. 22. The invention further relates to the use of an unworn, sterile hydrogel contact lens of any preceding or subsequent embodiment / feature / aspect to correct vision in a symptomatic contact lens wearer. 23. Use of any preceding or subsequent embodiment / feature / aspect or other embodiment for reducing symptoms of dryness in a contact lens wearer. 24. Use of any of the preceding or subsequent embodiments / features / aspects or other embodiments to increase comfortable lens wear time by a contact lens wearer. 25. Use of any preceding or subsequent embodiment / feature / aspect or other embodiment for increasing tear meniscus height in a contact lens wearer. 26. Use of any preceding or subsequent embodiment / feature / aspect or other embodiment for reducing CLDEQ-8 scores in a lens wearer. 27. The present invention further relates to a method of manufacturing a contact lens of any preceding or subsequent embodiment / feature / aspect, 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 one or more steps in at least a first organic solvent containing a cooling agent, a TRPV1 inhibitor, or both; (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 together with a packaging solution; and (f) autoclaving said package. The present invention relates to a method comprising the steps of: 28. The method or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein step (c) comprises extracting the polymeric lens body in a first organic solvent comprising a cooling agent and a TRPV1 inhibitor. 29. The method or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein step (c) comprises extracting the polymeric lens body in a first organic solvent containing a coolant, followed by extraction in a second organic solvent containing a TRPV1 inhibitor. 30. The method or any other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the method further comprises including a TRPV1 inhibitor in the packaging solution prior to said sealing. 31. An unworn sterile hydrogel contact lens or other embodiment of any preceding or subsequent embodiment / feature / aspect, wherein the polymeric lens body has a concave and a convex surface, and the TRPV1 inhibitor is present in a higher concentration on the concave surface compared to the coolant. 32. A use or other embodiment of any preceding or following embodiment / feature / aspect for correcting vision in a symptomatic contact lens wearer, wherein the stinging sensation caused by the coolant is blocked or reduced by a TRPV1 inhibitor.

[0067] The present invention may include any combination of the various features or embodiments described above and / or below in the text and / or paragraphs. Any combination of features disclosed herein is considered part of the present invention, and no limitations are intended with respect to features that may be combined. Although the disclosure herein refers to certain illustrated embodiments, it should be understood that these embodiments are presented by way of example and not limitation. The intent of the foregoing detailed description, while discussing exemplary embodiments, is to be construed as covering all modifications, permutations, and equivalents of the embodiments that may fall within the spirit and scope of the invention as defined by the additional disclosure.

[0068] Reference herein to an "example" or "particular example" or "aspect" or "embodiment" or similar phrase is intended to introduce one or more features of a contact lens or components thereof, a sealed contact lens package or components thereof, or a method of making a contact lens (depending on the context) that may be combined with any combination of the examples, aspects, or embodiments (i.e., features) described above or below, unless a particular combination of features is mutually exclusive or the context indicates otherwise. Furthermore, as used herein, the singular forms "a," "an," and "the" include plural referents (e.g., at least one or more) unless the context clearly indicates otherwise. Thus, for example, "contact lens" includes not only a single lens, but also two or more of the same or different lenses.

[0069] The entire contents of all references cited in this disclosure are hereby incorporated by reference, unless inconsistent with this disclosure. The present invention may include any combination of the various features or embodiments described above and / or in the following claims, as defined in the sentences and / or paragraphs. Any combination of features disclosed herein is considered part of the invention, and no limitations are intended with respect to features that may be combined. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims and equivalents thereof. Yet another aspect of the present invention may be as follows. [1] An unworn sterile hydrogel contact lens immersed in a packaging solution and sealed in a package, a) a polymeric lens body; b) a quantity of a cooling agent releasably attached to the polymeric lens body; and c) an amount of a TRPV1 inhibitor that is either releasably attached to the polymeric lens body or is present in the packaging solution, or both; 4. An unworn sterile hydrogel contact lens, comprising: [2] An unworn sterile hydrogel contact lens as described in [1] above, wherein the cooling agent is a TRPM8 agonist. [3] The TRPV1 inhibitor is oleic acid, alpha-lipoic acid, L-carnitine, resveratrol, hyaluronic acid, palmitoylethanolamide, petroselinic acid, naringenin, ashibatrep, AMG517, ABT102, GRC6211, SB-705498, or MK-2295; Cooling agents include Icilin, menthol, menthol derivatives, carboxamide, WS-148, WS-30, WS-11, CPS-113, CPS-369, Frescolat ML, Frescolat MGA, and others. 10, PMD-38, geraniol, linalool, eucalyptol, hydroxycitronellal, AG3-5, 5-methyl-4-(1-pyrrolidinyl)-3[2H]-furanone, 4,5-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, vanillyl butyl ether, peppermint oil, methanecarboxamide ethylpyridine, menthoxypropanediol, menthanediol, cyanomethylphenylmethanecarboxamide, camphor, ethylmethanecarboxamide, menthyldiisopropylpropionamide, menthyl lactate, 4-(butoxymenthyl)-2-methoxyphenol, 3-[[5-methyl-2-(1-methyl)cyclohexyl]oxy]-1,2-propanediol, isopulegol, or mixtures or combinations thereof. An unworn sterile hydrogel contact lens as described in [1] above. [4] The unworn sterile hydrogel contact lens described in [1], wherein the cooling agent comprises a TRPM8 agonist and the TRPV1 inhibitor comprises oleic acid. [5] The unworn sterile hydrogel contact lens described in [1], wherein the cooling agent comprises WS12 and the TRPV1 inhibitor comprises oleic acid. [6] The unworn sterile hydrogel contact lens described in [1] above, wherein a TRPV1 inhibitor is releasably attached to the polymer lens body. [7] The unworn sterile hydrogel contact lens described in [1], wherein the TRPV1 inhibitor has a first in vitro release profile and the cooling agent has a second in vitro release profile, and the first release profile is faster than the second release profile based on the percentage of the total loading of the TRPV1 inhibitor and the cooling agent released in the first 1 to 3 hours of release. [8] The unworn sterile hydrogel contact lens described in [7], wherein the first release profile releases a majority of the total loading of the TRPV1 inhibitor in the first 1 to 3 hours of release, and the second release profile releases less than half of the total loading of the coolant in the same first 1 to 3 hours of release. [9] The unworn sterile hydrogel contact lens described in [1], wherein the cooling agent has an in vitro release profile of 0.01 μg to 10 μg of cooling agent after 1 hour in a release medium consisting of 25 volume% EtOH in PBS.

[10] The unworn sterile hydrogel contact lens described in [1] above, wherein the amount of cooling agent releasably attached to the polymer lens body is about 0.25 μg to 10 μg.

[11] The unworn sterile hydrogel contact lens described in [1] above, wherein the amount of cooling agent releasably attached to the polymer lens body is about 0.5 μg to 5 μg.

[12] The unworn sterile hydrogel contact lens described in [7], wherein the second release profile includes release of 0.05 μg to 0.5 μg of cooling agent per hour for up to 6 hours.

[13] The unworn sterile hydrogel contact lens described in [7], wherein the second release profile includes release of 0.1 μg to 0.3 μg of cooling agent per hour for up to 6 hours.

[14] The unworn sterile hydrogel contact lens described in [1] above, wherein the TRPV1 inhibitor has a release profile including the release of 2 μg to 25 μg of TRPV1 inhibitor per hour in a release medium consisting of 25 volume% EtOH in PBS.

[15] The unworn sterile hydrogel contact lens described in [7], wherein the first release profile comprises release of 3 to 20 μg of TRPV1 inhibitor per hour in the release medium for at least 9 hours.

[16] The unworn sterile hydrogel contact lens described in [1], wherein the polymeric lens body is a reaction product of a polymerizable composition containing at least one siloxane monomer and at least one hydrophilic monomer or at least one hydrophilic polymer, or both at least one hydrophilic monomer and at least one hydrophilic polymer.

[17] The unworn sterile hydrogel contact lens described in [1] above, wherein the polymer lens body is fanfilcon A, confilcon A, somofilcon A, lyofilcon A, or stenfilcon A.

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

[19] The unworn sterile hydrogel contact lens described in

[18] above, wherein the cooling agent is WS12.

[20] The unworn sterile hydrogel contact lens described in [1] above, wherein the packaging is autoclaved.

[21] Packaging, a) a base member having a cavity for holding a packaging solution; and b) a cover that forms a fluid-tight seal with the base member The unworn sterile hydrogel contact lens according to [1] above,

[22] Use of an unworn sterile hydrogel contact lens according to any one of [1] to

[21] above for correcting the vision of a symptomatic contact lens wearer.

[23] The use according to

[22] above for reducing symptoms of dryness in contact lens wearers.

[24] The use according to

[22] above for increasing the comfortable lens wearing time of a contact lens wearer.

[25] The use described in

[22] above for increasing the tear meniscus height in a contact lens wearer.

[26] The use described in

[22] above for reducing a lens wearer's CLDEQ-8 score.

[27] A method for producing a contact lens according to any one of [1] to

[21] above, (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 one or more steps in at least a first organic solvent containing a cooling agent, a TRPV1 inhibitor, or both; (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 together with a packaging solution; and (f) autoclaving said package. A method comprising:

[28] The method according to

[27] , wherein step (c) comprises extracting the polymeric lens body in a first organic solvent containing a cooling agent and a TRPV1 inhibitor.

[29] The method according to

[27] , wherein step (c) comprises extracting the polymeric lens body in a first organic solvent containing a coolant, followed by extraction in a second organic solvent containing a TRPV1 inhibitor.

[30] The method according to any one of

[27] to

[29] , further comprising including a TRPV1 inhibitor in the packaging solution prior to the sealing.

[31] An unworn sterile hydrogel contact lens as described in [1], wherein the polymer lens body has a concave surface and a convex surface, and the TRPV1 inhibitor is present in a higher concentration on the concave surface compared to the coolant.

[32] Use of an unworn sterile hydrogel contact lens according to any one of [1] to

[31] above for correcting the vision of a symptomatic contact lens wearer, wherein the tingling sensation caused by the cooling agent is blocked or reduced by a TRPV1 inhibitor.

Claims

1. 1. An unworn sterile hydrogel contact lens immersed in a packaging solution and sealed within a package, comprising: a) a polymeric lens body; b) 0.25 μg to 10.0 μg of a cooling agent releasably attached to the polymeric lens body; and c) an amount of a TRPV1 inhibitor that is either releasably attached to the polymeric lens body or is present in the packaging solution, or both; 4. An unworn sterile hydrogel contact lens, comprising:

2. The unworn sterile hydrogel contact lens of claim 1 , wherein the cooling agent is a TRPM8 agonist.

3. the TRPV1 inhibitor is oleic acid, alpha-lipoic acid, L-carnitine, resveratrol, hyaluronic acid, palmitoylethanolamide, petroselinic acid, naringenin, ashibatrep, AMG517, ABT102, GRC6211, SB-705498, or MK-2295; Coolants include icilin, menthol, menthol derivatives, carboxamides, di-sec-butyl-n-heptylphosphine oxide (WS-148), 2,3-dihydroxypropyl-p-menthane-3-carboxylate (WS-30), N-(1,1-dimethyl-2-hydroxyethyl)-p-menthane-3-carboxamide (WS-11), N-(3-fluoro-4-methoxyphenyl)-p-menthane-3-carboxamide (CPS-113), N-(p-menthane-3-carbonyl)-D-alanine ethyl ester (CPS-369), 5-methyl-2-(1-methylethyl)cyclohexyl lactate, 6-isopropyl-9-methyl-1,4-dioxaspiro[4.

5. ]decane-2-methanol, menthyl glyceryl ether (Cooling-agent 10), PMD-38, geraniol, linalool, eucalyptol, hydroxycitronellal, 5-methyl-4-(1-pyrrolidinyl)-3[2H]-furanone, 4,5-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, vanillyl butyl ether, peppermint oil, methanecarboxamide ethylpyridine, menthoxypropanediol, menthanediol, cyanomethylphenylmethanecarboxamide, camphor, ethylmethanecarboxamide, menthyldiisopropylpropionamide, menthyl lactate, 4-(butoxymenthyl)-2-methoxyphenol, 3-[[5-methyl-2-(1-methyl)cyclohexyl]oxy]-1,2-propanediol, isopulegol, or mixtures or combinations thereof; 2. The unworn sterile hydrogel contact lens of claim 1.

4. The unworn sterile hydrogel contact lens of claim 1 , wherein the cooling agent comprises a TRPM8 agonist and the TRPV1 inhibitor comprises oleic acid.

5. The unworn sterile hydrogel contact lens of claim 1 , wherein the cooling agent comprises WS12 and the TRPV1 inhibitor comprises oleic acid.

6. The unworn sterile hydrogel contact lens of claim 1 , wherein the TRPV1 inhibitor is releasably attached to the polymeric lens body.

7. 2. The unworn sterile hydrogel contact lens of claim 1, wherein the TRPV1 inhibitor has a first in vitro release profile and the coolant has a second in vitro release profile, the first release profile being faster than the second release profile based on the percentage of the total load of TRPV1 inhibitor and coolant released in the first 1-3 hours of release.

8. 8. The unworn sterile hydrogel contact lens of claim 7, wherein the first release profile releases a majority of the total load of the TRPV1 inhibitor in the first 1 to 3 hours of release, and the second release profile releases less than half of the total load of the coolant in the same first 1 to 3 hours of release.

9. 10. The unworn sterile hydrogel contact lens of claim 1, wherein the cooling agent has an in vitro release profile of 0.01 μg to 10 μg of cooling agent after 1 hour in a release medium consisting of 25% by volume EtOH in PBS.

10. 10. The unworn sterile hydrogel contact lens of claim 1, wherein the amount of cooling agent releasably attached to the polymeric lens body is about 0.5 μg to 5 μg.

11. 8. The unworn sterile hydrogel contact lens of claim 7, wherein the second release profile comprises release of 0.05 μg to 0.5 μg of cooling agent per hour for up to six hours.

12. 8. The unworn sterile hydrogel contact lens of claim 7, wherein the second release profile comprises release of 0.1 μg to 0.3 μg of coolant per hour for up to six hours.

13. 2. The unworn sterile hydrogel contact lens of claim 1, wherein the TRPV1 inhibitor has a release profile comprising release of 2 μg to 25 μg of TRPV1 inhibitor per hour in a release medium consisting of 25% by volume EtOH in PBS.

14. 8. The unworn sterile hydrogel contact lens of claim 7, wherein the first release profile comprises release of 3 to 20 μg of the TRPV1 inhibitor per hour in the release medium for at least 9 hours.

15. The unworn sterile hydrogel contact lens of claim 1, wherein the polymeric lens body is a reaction product of a polymerizable composition comprising at least one siloxane monomer and at least one hydrophilic monomer or at least one hydrophilic polymer, or both at least one hydrophilic monomer and at least one hydrophilic polymer.

16. 2. The unworn sterile hydrogel contact lens of claim 1, wherein the polymeric lens body is fanfilcon A, confilcon A, somofilcon A, lyofilcon A, or stenfilcon A.

17. 2. The unworn sterile hydrogel contact lens of claim 1, wherein the polymeric lens body is the reaction product of a polymerizable composition comprising 25% to 55% by weight of a siloxane monomer or combination of siloxane monomers, 30% to 55% by weight of a vinyl monomer selected from NVP, VMA, or combinations 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), 2-hydroxybutyl methacrylate (HOB), or any combination thereof.

18. 18. The unworn sterile hydrogel contact lens of claim 17, wherein the coolant is WS12.

19. 10. The unworn, sterile hydrogel contact lens of claim 1, wherein the package is autoclaved.

20. The packaging, a) a base member having a cavity for holding a packaging solution; and b) a cover that forms a fluid-tight seal with the base member; The unworn sterile hydrogel contact lens of claim 1 , comprising:

21. 21. Use of an unworn, sterile hydrogel contact lens according to any one of claims 1 to 20 to correct vision in a symptomatic contact lens wearer.

22. 22. Use according to claim 21 for reducing symptoms of dryness in a contact lens wearer.

23. 22. Use according to claim 21 for increasing the comfortable lens wearing time by a contact lens wearer.

24. 22. Use according to claim 21 for increasing the tear meniscus height in a contact lens wearer.

25. 22. The use according to claim 21 for reducing a lens wearer's CLDEQ-8 score.

26. A method for producing a contact lens according to any one of claims 1 to 20, comprising the steps of: (a) polymerizing a polymerizable composition in a contact lens mold to obtain a polymeric lens body; (b) removing the polymeric lens body from the contact lens mold; (c) extracting the polymeric lens body in one or more steps in at least a first organic solvent containing a cooling agent, a TRPV1 inhibitor, or both; (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 together with a packaging liquid; and (f) autoclaving the package. A method comprising:

27. 27. The method of claim 26, wherein step (c) comprises extracting the polymeric lens body in a first organic solvent that contains a cooling agent and a TRPV1 inhibitor.

28. 27. The method of claim 26, wherein step (c) comprises extracting the polymeric lens body in a first organic solvent containing a coolant, followed by extraction in a second organic solvent containing a TRPV1 inhibitor.

29. 27. The method of claim 26, further comprising including a TRPV1 inhibitor in the packaging solution prior to said sealing.

30. The unworn sterile hydrogel contact lens of claim 1 , wherein the polymeric lens body has a concave and a convex surface, and the TRPV1 inhibitor is present in a higher concentration on the concave surface compared to the coolant.

31. 31. Use of an unworn, sterile hydrogel contact lens as described in claim 30 to correct vision in a symptomatic contact lens wearer, wherein the tingling sensation caused by the coolant is blocked or reduced by a TRPV1 inhibitor.

Images