Release the contact lens of WS12

Abstract

Contact lenses that release WS12 and methods of making the same are described. The contact lenses that release WS12 comprise a polymeric lens body and WS12 releasably adhered to the polymeric lens body, and release 0.05 μg to 0.5 μg of WS12 in a release medium or after 1 hour when worn by a human subject. The contact lenses that release WS12 can be worn comfortably by symptomatic contact lens wearers, and in symptomatic contact lens wearers, can extend the comfortable lens wearing time, and / or reduce lens awareness events, and / or reduce contact lens drying.

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 Art

[0002] An estimated 50% of all contact lens wearers experience discomfort while wearing their lenses, and approximately 25% of contact lens wearers permanently stop wearing their lenses. Symptoms of dry eyes are a major cause of dissatisfaction with contact lenses. Despite advances in contact lens materials, there remains a need for improved contact lenses that can be comfortably worn by contact lens wearers who otherwise experience symptoms of dry eyes while wearing currently commercially available contact lenses.

[0003] N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide (CAS No. 68489-09-8), known as WS12, is a synthetic menthol derivative that has been used as a cooling agent and flavoring agent in chewing gum and candy. It selectively activates the transient receptor potential melanostatin-8 (TRPM8) ion channel. A therapeutic composition comprising a TRPM8 receptor agonist has been proposed for the treatment of dry eye (Belmonte et al., U.S. Pat. No. 10,028,920). Summary of the invention

[0004] A feature of the present invention is to provide a hydrogel contact lens that releases WS12 during lens wear.

[0005] It is an additional feature of the present invention to provide a contact lens that can be comfortably worn by symptomatic contact lens wearers.

[0006] An additional feature of the present invention is to prolong comfortable lens wear time and / or reduce contact lens dryness in symptomatic contact lens wearers.

[0007] Additional features and advantages of the present invention will be described in part in the following description, and in part will be obvious from the description, or can be learned through practice of the present invention. The objects and other advantages of the present invention will be realized and obtained by means of the elements and combinations particularly pointed out in the description and appended claims.

[0008] To achieve these and other advantages, and in accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention relates in part to a hydrogel contact lens containing an amount of WS12 releasably adhered to the lens that can enhance contact lens comfort in symptomatic lens wearers and / or reduce contact lens dryness in symptomatic contact lens wearers. In one example, the hydrogel contact lens is a silicone hydrogel contact lens.

[0009] In one example, a silicone hydrogel contact lens is capable of releasing 0.05 μg to 0.5 μg of WS12 after 1 hour in an in vitro release medium consisting of 25 vol.% ethanol / phosphate buffered saline.

[0010] In addition, the present invention relates to a method for making the silicone hydrogel contact lens of the present invention. The method comprises the steps of: a) polymerizing a polymerizable composition (as described herein) in a contact lens mold to obtain a polymerized lens body; b) removing the polymerized lens body from the contact lens mold; c) extracting the polymerized lens body in an organic solvent, the organic solvent comprising about 5 ppm to about 50 ppm WS12; d) hydrating the polymerized lens body in a hydrating liquid to obtain a silicone hydrogel contact lens; e) sealing the silicone hydrogel contact lens in a package together with a packaging solution; and f) autoclaving the package.

[0011] In addition, the present invention relates to a method for correcting the vision of a symptomatic contact lens wearer by providing a symptomatic contact lens wearer with a hydrogel contact lens that releases WS12, wherein the hydrogel contact lens that releases WS12 prolongs the comfortable lens wearing time and / or reduces the dryness of the contact lens in the symptomatic contact lens wearer compared to a control lens that does not contain WS12. The present invention further relates to a method for prolonging the comfortable contact lens wearing time and / or reducing the symptoms of dry eyes in a contact lens wearer by releasably adhering a certain amount of WS12 to the polymer lens body of the contact lens and / or by providing the contact lens wearer with a hydrogel contact lens that releases WS12 of the present invention. Compared with a control lens that does not contain WS12, the hydrogel contact lens that releases WS12 advantageously prolongs the comfortable contact lens wearing time and / or reduces the dryness of the contact lens in a symptomatic contact lens wearer. The contact lens wearer is advantageously a symptomatic contact lens wearer. The present invention also relates to the use of a certain amount of WS12 releasably adhered to the polymeric lens body of a hydrogel contact lens, which is used to relieve the symptoms of dry eyes of a contact lens wearer; to extend the comfortable lens wearing time of the contact lens wearer; to increase the tear meniscus height of the contact lens wearer; and / or to reduce the CLDEQ-8 score of the contact lens wearer, wherein the contact lens wearer is advantageously a symptomatic contact lens wearer and / or wherein the hydrogel contact lens is advantageously a contact lens of the present invention as described herein. The present invention also relates to a method of selecting a contact lens for correcting the vision of a symptomatic contact lens wearer, for relieving the symptoms of dry eyes of a contact lens wearer; for extending the comfortable lens wearing time of the contact lens wearer; for increasing the tear meniscus height of the contact lens wearer; and / or for reducing the CLDEQ-8 score of the contact lens wearer, the method comprising selecting a hydrogel contact lens that can release WS12 during the wearing of the lens of the present invention, and providing the contact lens to a symptomatic contact lens wearer. The present invention also relates to a composition comprising a hydrogel releasably adhered to WS12, which is used to correct the vision of symptomatic contact lens wearers; to alleviate the symptoms of dry eyes in contact lens wearers; to extend the comfortable lens wearing time of contact lens wearers; to increase the tear meniscus height of contact lens wearers; and / or to reduce the CLDEQ-8 score of contact lens wearers, wherein the composition is advantageously in the form of a contact lens of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Box plots showing the preference of symptomatic and asymptomatic contact lens wearers for WS12-releasing contact lenses or control lenses after 30 days of lens wear. DETAILED DESCRIPTION

[0013] Through extensive experiments, the inventors have found that, unlike other TRPM8 receptor agonists evaluated, the menthol derivative WS12 (CAS No. 68489-09-8) can be incorporated into hydrogel contact lens materials and maintained in the lens material under standard contact lens sterilization and storage conditions without degradation or leaching. Once the contact lens is placed on the eyeball, WS12 is continuously released from the lens for several hours to provide improved comfort in symptomatic contact lens wearers. Therefore, a hydrogel contact lens and a method for making the same are described herein that releases WS12 during wear. The contact lens may be referred to herein as a contact lens that releases WS12. WS12 is released from the lens during wear in an amount that improves the comfort of contact lens wear in symptomatic contact lens wearers.

[0014] Alternatively, the contact lenses are free of other TRPM8 receptor agonists.

[0015] As an alternative, contact lenses do not have other medicaments for dry eyes.

[0016] The contact lens releasing WS12 comprises a polymeric lens body and a certain amount of WS12 releasably adhered to the polymeric lens body. As an example, the contact lens is a reaction product of a polymerizable composition for a non-silicone hydrogel. Non-silicone hydrogel contact lenses are generally formed by the polymerization reaction of one or more hydrophilic monomers (such as 2-hydroxyethyl methacrylate (HEMA) or vinyl alcohol, optionally in combination with other monomers), and do not contain siloxane molecules.

[0017] As an example, a contact lens comprises a polymeric lens body that is the reaction product of a polymerizable composition comprising at least one siloxane monomer and at least one hydrophilic monomer and / or at least one hydrophilic polymer. Suitably, as described in more detail below, the cured polymeric lens body for the silicone hydrogel can be extracted in an extraction solvent containing WS12, thereby causing the desired amount of WS12 to adhere to the polymeric lens body. Alternatively or additionally, WS12 can be added to the polymerizable composition. WS12 can adhere to the polymeric lens body through hydrophobic interactions and / or can be physically encapsulated by the polymer network of the polymeric lens body.

[0018] The amount of WS12 "releasably adhered" to the polymeric lens body refers to the total amount of WS12 that can be extracted from the contact lens by an ethanol (EtOH) extraction method as described in Example 1 below. In one example, the amount of WS12 releasably adhered to the polymeric lens body can be at least about 0.25 μg or 0.50 μg, up to about 2.5 μg, 5.0 μg or 10.0 μg, such as about 0.30 μg to about 3.0 μg.

[0019] As used herein, and unless the context dictates otherwise, reference to an in vitro release profile of a contact lens that releases WS12 refers to the amount of WS12 released from the lens over a period of time, as measured using an in vitro release medium (PBS containing 25 vol% EtOH) and the method described in Example 4 below. An in vitro release method employing a protein-free release medium comprising EtOH provides a release profile that is less variable than when an artificial tear film composition (ATF) is used as a release medium, and is suitable for determining the effect of a particular lens material on WS12 release. For example, a polymeric lens body made of one material and having a certain amount of WS12 releasably adhered to the polymeric lens body may have a different WS12 release profile than a polymeric lens body made of a different material but having the same amount of WS12 releasably adhered thereto. Some properties of the polymeric lens body that may affect the WS12 release profile include the hydrophobicity of the material, the water content, and the degree of cross-linking of the polymeric lens body. In addition, encapsulation techniques, such as liposomes or erodible nanoparticles, can be used to encapsulate a portion or all of the WS12, which is then incorporated into a polymeric lens body to delay or prolong the release of WS12 from the lens. For example, 10 wt% to 80 wt% or more of WS12 incorporated into a contact lens may have this delayed release property. When the amount of WS12 released after x hours is greater than the amount of WS12 released after x-1 hours when measured using the in vitro release method of Example 4 using PBS containing 25 vol% EtOH as the release medium, the contact lens releasing WS12 is considered to be able to maintain the release of WS12 for a certain number of hours x. In one example, the contact lens releasing WS12 maintains the release of WS12 for at least 6 hours. In one example, the contact lens releasing WS12 may have an in vitro release profile, wherein 0.05 μg to 0.5 μg WS12 is released per hour for at least 6 hours, or 0.1 μg to 0.4 μg WS12 is released per hour for at least 6 hours, or 0.1 μg to 0.3 μg WS12 is released per hour for at least 6 hours when measured using the in vitro release method of Example 4. In some examples, the contact lens maintains the release of WS12 for at least 8 hours or at least 10 hours.

[0020] To determine the amount of WS12 released from a WS12-releasing contact lens when worn, human individuals (n=3) wore a WS12-releasing contact lens in both eyes for a specified period of time. The amount of WS12 released from the glasses at a specified time point is the difference between the average amount of WS12 in the unworn WS12-releasing contact lens (n=3) and the average amount of WS12 remaining in the glasses worn at the tested time point. In one example, after one hour of wear, the WS12-releasing contact lens releases 0.05 μg to 0.75 μg WS12, or 0.05 μg to 0.50 μg WS12. In another example, after three hours of wear, the WS12-releasing contact lens releases 0.10 μg to 1.5 μg WS12, or 0.25 μg to 1.0 μg WS12. In yet another example, the WS12 releasing contact lens releases 0.25 μg to 2.0 μg WS12, or 0.5 μg to 1.5 μg WS12 after six hours of wear.

[0021] The polymerized lens body may include 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 includes 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" is a molecule containing at least one Si-O group and at least one polymerizable group. The siloxane monomers used in contact lens compositions are well known in the art (see, for example, U.S. Pat. No. 8,658,747 and U.S. Pat. No. 6,867,245). (All patents and publications mentioned herein and throughout are incorporated herein by reference in their entirety.) In some examples, the polymerizable composition includes at least 10 wt%, 20 wt%, or 30 wt% to about 40 wt%, 50 wt%, 60 wt%, or 70 wt% of the total amount of siloxane monomers. Unless otherwise specified, as used herein, a given weight percentage (wt%) of a component of a polymerizable composition is related to the total weight of all polymerizable ingredients and IPN polymers (as further described below) in the polymerizable composition. The weight of the polymerizable composition contributed by components (such as diluents) that are not incorporated into the final contact lens product is not included in the wt% calculation.

[0022] In a particular example, the polymerizable composition includes a hydrophilic vinyl monomer. As used herein, a "hydrophilic vinyl monomer" is any hydrophilic monomer that does not contain siloxane (i.e., does not contain Si-O groups), which has a polymerizable carbon-carbon double bond (i.e., vinyl) that is not part of an propylene group in its molecular structure, wherein the carbon-carbon double bond of the vinyl group is less reactive than the carbon-carbon double bond present in a polymerizable methacrylate group under free radical polymerization. As used herein, the term "propylene group" refers to a polymerizable group present in acrylates, methacrylates, acrylamides, and the like. Therefore, as used herein, although there are carbon-carbon double bonds in acrylate and methacrylate groups, such polymerizable groups are not considered vinyl. In addition, as used herein, if at least 50 grams of the monomer is completely soluble in 1 liter of water (i.e., about 5% soluble in water) at 20°C, as determined using a standard shake bottle method, the monomer is "hydrophilic". In various examples, the hydrophilic vinyl monomer is N-vinyl-N-methylacetamide (VMA) or N-vinyl pyrrolidone (NVP) or 1,4-butanediol vinyl ether (BVE) or ethylene glycol vinyl ether (EGVE) or diethylene glycol vinyl ether (DEGVE) or any combination thereof. In one example, the polymerizable composition comprises at least 10 wt%, 15 wt%, 20 wt%, or 25 wt% to about 45 wt%, 60 wt%, or 75 wt% of the hydrophilic vinyl monomer. As used herein, a given weight percentage of a particular class of components (e.g., hydrophilic vinyl monomers, siloxane monomers, etc.) in a polymerizable composition is equal to the sum of the weight percentages of each ingredient in the composition that falls within that class. Thus, for example, a polymerizable composition comprising 5 wt% BVE and 25 wt% NVP and no other hydrophilic vinyl monomers is said to comprise 30 wt% hydrophilic vinyl monomers. In one example, the hydrophilic vinyl monomer is a vinyl amide monomer. Exemplary hydrophilic vinyl amide monomers are VMA and NVP. In one specific example, the polymerizable composition comprises at least 25 wt% of vinylamide monomer. In another specific example, the polymerizable composition comprises about 25 wt% to about 75 wt% of VMA or NVP or a combination thereof. Additional hydrophilic monomers that may be included in the polymerizable composition are N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), ethylene glycol methyl ether methacrylate (EGMA), and combinations thereof.

[0023] In addition, or as an alternative to a hydrophilic monomer, the polymerizable composition may include a non-polymerizable hydrophilic polymer, which produces a polymerized lens body comprising an interpenetrating polymer network (IPN), wherein the non-polymerizable hydrophilic polymer and the silicone hydrogel polymer matrix interpenetrate. In this example, the non-polymerizable hydrophilic polymer is referred to as an IPN polymer, which acts as an internal wetting agent in a contact lens. In contrast, the polymer chains in the silicone hydrogel network formed by polymerizing 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, such as about 50,000 to about 500,000 daltons. In a particular example, the IPN polymer is polyvinyl pyrrolidone (PVP). In other examples, the polymerizable composition is substantially free of polyvinyl pyrrolidone or other IPN polymers.

[0024] Alternatively, one or more non-silicon containing hydrophobic monomers may be present as part of the polymerizable composition.A hydrophobic monomer is understood to be any monomer for which 50 grams of monomer will not be appreciably completely soluble in 1 liter of water at 20°C 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.

[0025] If used, the hydrophobic monomer can be present in the reaction product of the polymerizable composition in an amount from 1 wt % to about 30 wt %, such as 1 wt % to 25 wt %, 1 wt % to 20 wt %, 1 wt % to 15 wt %, 2 wt % to 20 wt %, 3 wt % to 20 wt %, 5 wt % to 20 wt %, 5 wt % to 15 wt %, 1 wt % to 10 wt %, based on the total weight of the polymerizable composition.

[0026] As will be appreciated by those skilled in the art, the polymerizable composition may include additional polymerizable or non-polymerizable ingredients conventionally used in contact lens formulations, such as one or more of polymerization initiators, UV absorbers, colorants, deoxidizers, chain transfer agents, etc. In some examples, the polymerizable composition may include an amount of organic diluent to prevent or minimize phase separation between the hydrophilic and hydrophobic components of the polymerizable composition, thereby obtaining optically clear lenses. Commonly used diluents in contact lens formulations include hexanol, ethanol, and / or other alcohols. In other examples, the polymerizable composition is free of or substantially free of (e.g., less than 500ppm) organic diluents. In such examples, the use of siloxane monomers containing hydrophilic portions such as polyethylene oxide groups, pendant hydroxyl groups, or other hydrophilic groups may make it unnecessary to include diluents in the polymerizable composition. Non-limiting examples of these and other ingredients that may be included in the polymerizable composition are provided in U.S. Patent No. 8,231,218.

[0027] 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.

[0028] A specific example of the silicone hydrogel contact lens of the present invention is a silicone hydrogel contact lens based on a polymerizable composition comprising 25 wt% to 55 wt% of a siloxane monomer, 30 wt% to 55 wt% of a vinyl monomer selected from NVP, VMA, or a combination thereof, and optionally about 1 wt% to about 20 wt% of a hydrophilic monomer selected from N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), or ethylene glycol methyl ether methacrylate (EGMA), or any combination thereof, and optionally about 1 wt% to about 20 wt% of a hydrophobic monomer selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), or 2-hydroxybutyl methacrylate (HOB), or any combination thereof. The silicone hydrogel materials prepared from this specific embodiment of the polymerizable composition include Stanfilcon A, Conofilcon A, Somofilcon A, Fanfilcon A, and Enfilcon A.

[0029] Conventional methods can be used to make the contact lenses of the present invention. For example, a polymerizable composition for a silicone hydrogel composition is dispensed into a concave mold part having a concave surface defining the front surface of the contact lens. A male mold part having a convex surface defining the back of the contact lens, i.e., the cornea contact surface, is combined with a female mold part 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 polymerized lens body. The female mold part and the male mold part can be non-polar molds or polar molds. The mold assembly is disassembled (i.e., demolded), and the polymerized lens body is removed from the mold and contacted with a solvent (e.g., an organic solvent, such as ethanol) to extract unreacted components from the lens body. After extraction, the lens body is hydrated in one or more hydrating liquids (e.g., water or an aqueous solution) and packaged. An exemplary method for making a silicone hydrogel contact lens is described in U.S. Pat. No. 8,865,789.

[0030] WS12 can be loaded into the polymerized lens during the extraction step. Typically, after curing, the polymerized lens body is swollen in an extraction solvent (such as ethanol) containing WS12. When the extracted polymerized lens body is subsequently placed in a hydration solution, such as deionized water, the extraction solvent is removed and the WS12 remains adhered to the polymerized lens body.

[0031] 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. For example, the extraction and hydration process may involve at least one extraction step with denatured ethanol, followed by a 50:50 mixture of ethanol water, followed by at least one hydration step with deionized water, and wherein each extraction and hydration step may last for about 15 minutes to about 3 hours at a temperature of about 20° C. to about 30° C. The extraction solvent may contain WS12 to enable uploading of WS12 to the polymerized lens body.

[0032] Any extraction solvent used as a loading solution for WS12 may contain a concentration of at least 1.0 μg / ml of WS12. This concentration may be at least 2.5 μg / ml, at least 5.0 μg / ml, or at least 10.0 μg / ml of WS12. In one example, the concentration of WS12 in the extraction solvent is about 5.0 μg / ml to about 50.0 μg / ml (i.e., 5 ppm to about 50 ppm).

[0033] In some examples, once adhered to the polymeric lens body, WS12 is stable and does not release or degrade 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 its packaging solution, but is released during wearing of the lens. Thus, the packaging solution in which the contact lens is immersed has a WS12 concentration of less than 0.1 μg / ml or less than 0.05 μg / ml, or has a WS12 concentration less than the detection level as determined by HPLC before autoclaving, or immediately after autoclaving, or after 1 day thereafter, or after 30 days thereafter, or after 60 days thereafter, or after 120 days thereafter.

[0034] As part of the present invention, contact lenses can be sealed in contact lens packaging. The packaging solution sealed in the contact lens packaging can be any conventional contact lens compatible solution. In one example, the packaging solution comprises an aqueous solution of a buffer and / or a tension agent, is composed of it or is substantially composed of it. 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 can include polysaccharides (e.g., hyaluronic acid, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, etc.) or other high molecular weight polymers, such as polyvinyl pyrrolidone, which is commonly used as a comfortable polymer or thickener in ophthalmic solutions and contact lens packaging solutions. In other examples, the packaging solution can include ophthalmic drugs. The pH of the packaging solution can be in the range of 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 comprises a tonicity agent selected from sodium chloride or sorbitol in an amount to maintain osmolarity in the range of about 200 to 400 mOsm / kg, and typically about 270 mOsm / kg to about 310 mOsm / kg.

[0035] Regarding contact lens packaging, this packaging may include or comprise a plastic base member comprising a cavity configured to accommodate a contact lens and a packaging solution and a flange area extending outwardly around the cavity. A removable foil is adhered to the flange area to provide a sealed contact lens package. Such contact lens packaging is commonly referred to as a "blister package" and is well known in the art (see, e.g., U.S. Patent No. 7,426,993).

[0036] It should be understood that a sealed contact lens package can be manufactured using conventional manufacturing methods. In the method for manufacturing a contact lens package, the method may include the following steps: placing unworn contact lenses and contact lens packaging solution in a receptacle, placing a cover on the receptacle, and sealing the cover on the receptacle. Generally speaking, the receptacle is configured to receive a single pair of contact lenses and a packaging solution sufficient to completely cover the contact lenses, typically about 0.5 to 1.5 ml. The receptacle may be made of any suitable material, such as glass or plastic. In one example, the receptacle includes a plastic base member, the plastic base member including: a cavity, which is configured to accommodate contact lenses and packaging solution; and a flange area, which extends outwardly around the cavity, and the cover includes a removable foil adhered to the flange area to provide a sealed contact lens package. The removable foil can be sealed by any conventional means such as heat sealing or gluing. In another example, the 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 threaded engagement with the base member, thereby providing a compatible set of threads for a resealable cover. It should be appreciated that other types of packaging may also be used to provide a resealable package. For example, a contact lens package may include a plastic cover including features that engage with compatible features of the receptacle to form a tight fit. The method of manufacturing a sealed contact lens package may further include sterilizing unworn contact lenses by autoclaving the sealed contact lens package. Autoclaving generally involves subjecting the sealed contact lens package to a temperature of at least 121° C. for at least 20 minutes.

[0037] A contact lens can be provided, which has not been worn (i.e., a new contact lens, not previously used by a patient), immersed in a packaging solution and sealed in a package. The package can be a blister package, a glass vial, or other suitable container. The package comprises a base member having a cavity for containing the packaging solution and the unworn contact lens. The sealed package can be sterilized by a sterilizing amount of radiation (including heat or steam), such as by autoclaving or by gamma radiation, electron beam radiation, ultraviolet radiation, etc.

[0038] In certain examples, the packaged contact lenses are sterilized by autoclaving.

[0039] The final product can be a sterile packaged contact lens (eg, a silicone hydrogel contact lens) having an ophthalmically acceptable surface wettability.

[0040] The hydrogel contact lenses releasing WS12 described herein can be used to correct the vision of symptomatic contact lens wearers. For example, the hydrogel contact lenses releasing WS12 can prolong the comfortable contact lens wearing time of symptomatic contact lens wearers. References to "symptomatic contact lens wearers" or "symptomatic individuals" herein refer to symptomatic lens wearers classified as symptomatic lens wearers using the method adapted from Young et al. described in Example 6 below (Young et al., Characterizing contact lens-related dryness symptoms in a cross-section of UK soft lens wearers in a typical population of UK soft lens wearers. Contact Lens & Anterior Eye 34 (2011) 64-70).

[0041] The hydrogel contact lenses releasing WS12 described herein can be worn by symptomatic contact lens wearers to reduce the feeling of "dryness" compared to control lenses or the usual lenses of symptomatic wearers, especially at the end of the day. The "control lenses" mentioned herein refer to contact lenses that do not contain WS12 but are the same as contact lenses releasing WS12 in other compared aspects. The reduction of lens dryness during contact lens wear can be determined using the characterization method described in Example 6. The overall lens preference for hydrogel contact lenses releasing WS12 in symptomatic contact lens wearers is another way to measure / determine its beneficial effects on contact lens discomfort / dryness.

[0042] The WS12-releasing hydrogel contact lenses described herein can result in reduced eyeglass awareness and / or fewer "eyeglass awareness events" during the day compared to control lenses. Reductions in eyeglass awareness and / or eyeglass awareness events during contact lens wear can be determined using a "eyeglass awareness logger" as described by Read et al. (see Read et al., Monitoring ocular discomfort using a wrist-mounted electronic logger. Contact Lenses & Anterior Eyes Vol. 43 (2020) 476-483).

[0043] After wearing the glasses for 1 hour, 2 hours, 4 hours or more, the hydrogel contact lenses releasing WS12 described herein can increase the height of the tear film meniscus compared to the control glasses. The tear film meniscus height can be measured by optical coherence tomography (OCT) or other suitable methods.

[0044] The WS12-releasing hydrogel contact lenses described herein can improve (i.e., reduce) CLDEQ-8 scores in symptomatic lens wearers (see Chalmers et al., Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) and opinion of contactlens performance. Optom Vis Sci 2012; 89(10): 1435-1442.). Improvements in CLDEQ-8 scores can be seen after wearing WS12-releasing hydrogel contact lenses for 1 week, or after 2 weeks, or after 4 weeks.

[0045] Some individuals may experience an initial stinging or cooling sensation after inserting a WS12-releasing lens, which subsides after a period of daily wearing of the lens, indicating that they have adapted to WS12. The initial discomfort can be reduced or avoided by starting the patient with a WS12-releasing contact lens with a lower WS12 release rate. After wearing a low-dose WS12-releasing contact lens for several days, the patient adapts to WS12 and can switch to a contact lens with a higher WS12 release rate without experiencing any initial insertion discomfort. A low-dose WS12-releasing contact lens can be considered a "starting" WS12-releasing lens. In some instances, a patient can wear a starting WS12-releasing lens daily, such as for 3, 5, 7, or 10 days, and then switch to a WS12-releasing contact lens with a higher WS12 release rate to improve the contact lens wearing comfort of symptomatic contact lens wearers. According to the method of Example 4, after being in an in vitro release medium for 1 hour, the starting WS12-releasing lens can release about 0.05 to about 0.2 μg WS12.

[0046] A "starter test package" or kit may be provided that includes at least two WS12-releasing contact lenses, wherein a first contact lens includes a first polymeric lens body and a first amount of WS12 releasably adhered to the first polymeric lens body, and a second contact lens includes a second polymeric lens body and a second amount of WS12 releasably adhered to the second polymeric lens body, wherein the second amount is greater than the first amount, and wherein the first polymeric lens body and the second polymeric lens body include the same material. In some examples, the starter test package may include a third WS12-releasing contact lens that includes a third polymeric lens body and a third amount of WS12 releasably adhered to the third polymeric lens body, wherein the third amount is greater than the second amount, and wherein the first, second, and third polymeric lens bodies include the same material. Each individual WS12-releasing contact lens of the starter test package may be immersed in a packaging solution, and sealed in a package such as a blister package, sterilized, and packaged in a secondary package such as a carton. A drug instruction sheet may be included in the secondary package that instructs the lens wearer to wear a lens containing a lower amount of WS12 before wearing a lens containing a higher amount of WS12. The primary packaging of the lens with the initial release of WS12 may differ in appearance (eg, color) from the lens with the higher WS12 release rate.

[0047] The following examples illustrate certain aspects and advantages of the present invention and should be construed as not limiting.

[0048] Example 1: Preparation of WS12-releasing contact lenses

[0049] Silicone hydrogel contact lenses were prepared by curing the Steinfikon A formulation in a contact lens mold. The cured Steinfikon A was removed from the mold and extracted by immersing it in ethanol (EtOH) containing WS12 (Tocris Bioscience) for 215 minutes at the loading concentration shown in Table 1. The lenses were removed from the EtOH and washed in deionized water for about 6 minutes, followed by two exchanges of deionized water for about 30 minutes each. The lenses were transferred to a 6 mL glass vial containing 3 mL of phosphate buffered saline (0.78 wt % NaCl, 0.05 wt % sodium dihydrogen phosphate, and 0.36 wt % sodium dihydrogen phosphate) at a pH of 7.5 (referred to herein as PBS). The vial was sealed and autoclaved.

[0050] Each autoclaved lens was transferred to a vial containing 3 ml of EtOH and stored overnight at room temperature on a 150 rpm shaker to extract WS12 from the lens. The EtOH extract and PBS (in which the lenses were autoclaved) were analyzed by HPLC (detection wavelength = 250 nm) against calibration standards to determine the average loading of WS12 in each lens (n ​​= 5), and whether WS12 leached from the lenses during autoclaving. The results are shown in Table 1.

[0051] Table 1

[0052] Glasses ID WS12 loading concentration WS12 / Average value of glasses WS12 concentration in PBS packaging solution A 5 μg / mL 0.42 μg Not Detected B 15 μg / mL 1.28 μg Not Detected C 50 μg / mL 4.30 μg 0.05 μg / mL

[0053] Silicone hydrogel contact lenses were prepared by curing the ConocoPhillips A formulation in a contact lens mold and subjecting the lenses to the same extraction, hydration, and autoclaving procedures as lenses made with ConocoPhillips A, except that a single WS12 concentration, 15 μg / mL, was used in the ethanol extraction step. The lenses (lenses D) were subjected to HPLC analysis for WS12 content and were shown to have an average WS12 absorption of 1.04 μg / lens.

[0054] Example 2: In vitro release of WS12-releasing contact lenses in 5 Vol.% EtOH

[0055] Lens B and Lens D from Example 1 were removed from their vials and excess packaging solution was shaken out of each lens. Each lens (n=3 for each time point) was transferred to a 6 ml glass vial containing 3 ml of 5 vol.% ethanol / PBS at 35°C. The vials were placed on a shaker at 125 rpm in a 35°C incubator. At the 30 minute and 1 hour time points, 2.5 ml of EtOH release medium (i.e., from the vials at the 30 minute and 1 hour time points, respectively) were removed and provided for HPLC analysis. At the 1 hour time point and subsequent time points (i.e., 2 hours, 3 hours, and 4 hours), 2.5 ml of EtOH release medium was removed from each of the remaining vials and 2.5 ml of fresh EtOH release medium was added back to each vial. Table 2 below shows the cumulative WS12 release for each lens material. For example, the 3 hour time point is the sum of the amount of WS12 detected in the release medium taken at the 1 hour, 2 hours, and 3 hour time points.

[0056] Table 2

[0057]

[0058] Example 3: WS12 released from contact lenses during lens wear

[0059] Human subjects wore glasses B for 1, 3 and 6 hours (n=2 for each time point). At the end of each glasses wearing duration, the lenses were extracted in EtOH using the method described in Example 1. The extracts were subjected to HPLC analysis to determine the residual amount of WS12 remaining in the glasses and to calculate the amount of WS12 released during the wearing period. The average amount and percentage of WS12 released during the wearing of the glasses are shown in Table 3.

[0060] Table 3

[0061] Time point (hour) Average amount of WS12 released per eyeglass Average percentage of WS12 released per glasses 1 0.22 μg / mL 17％ 3 0.51 μg / mL 40％ 6 0.69 μg / mL 54％

[0062] Example 4: In vitro release of WS12-releasing contact lenses in 25 Vol.% EtOH

[0063] To achieve an in vitro release method that more closely approximates the release of WS12 during the wearing of the glasses, the release of WS12 from the glasses B was tested using the method of Example 2, except that EtOH at a higher concentration of 15%, 20%, 25%, or 30% was used in the release medium. The release medium composed of 25 vol.% EtOH / 75 vol.% PBS most closely approximated the release of WS12 from the glasses when the glasses were worn for 6 hours; the results are shown in Table 4.

[0064] Table 4

[0065]

[0066] Example 5: Dose escalation, one-day clinical study of contact lenses releasing WS12

[0067] Two individuals were recruited into the study in which all three loading concentrations from Example 1 were evaluated. Each individual was exposed to lenses A, B, and C of Example 1 in one eye for 30 minutes, worn contralaterally. On the first study day, the individuals were exposed to contralateral wear of lenses B and C, followed by contralateral wear of lenses B and A on a separate day. With lenses C, one individual experienced a stinging sensation, while the other experienced a cooling sensation. With lenses B, both individuals experienced a mild cooling / tingling sensation that lasted approximately one hour. Lenses A induced a brief cooling / wet sensation in the individual. Lenses B were selected for further evaluation.

[0068] Example 6: Thirty-day clinical study of contact lenses releasing WS12

[0069] Thirty-three subjects participated in a 1-month, bilateral, randomized, crossover double-masked study in which the subjects wore two glasses B or brand (control) contact lenses, each for 1 month. Individuals were classified as symptomatic (S) or asymptomatic (A) contact lens wearers using the classification system outlined in Table 5, which was adapted from the classification proposed by Young et al. (supra).

[0070] Table 5

[0071]

[0072] Sixteen individuals were classified as symptomatic contact lens wearers, reporting an intensity of contact lens dryness / discomfort of 2 or more (out of 5), and reporting a frequency of contact lens dryness / discomfort of "sometimes, frequently, or constantly." Seventeen individuals were classified as asymptomatic contact lens wearers, reporting an intensity of contact lens dryness / discomfort of 0 or 1 (out of 5), and reporting a frequency of contact lens dryness / discomfort of "rarely or never."

[0073] After a 3 to 7 day washout period in which the individual wore their usual eyeglasses, the second eyeglass type from the randomization order (i.e., Example 1 (Test) or Brand (control) contact lenses) were worn for 1 month. Comfort, dryness, cooling, pleasantness, and CLDEQ-8 scores were monitored (see Chalmers et al., supra).

[0074] At the time point of 1 week, the test glasses were evaluated as being significantly more uncomfortable than the control lenses when inserted, however, this difference decreased after wearing for 1 month. This change may be attributed to a reduction in cooling sensation, possibly due to sensory adaptation of the individual wearing the test glasses. There was no significant difference in the overall comfort rating between the test and control lenses at the time point of 1 week or 1 month. However, after 1 month of wearing, up to twice as many individuals reported an increase in the comfort of the test glasses compared to the control glasses. Compared to the control glasses, with the use of the test lenses, there was a significantly better (i.e., lower) overall dryness rating at 1 week and 1 month. The tear meniscus height was measured using Visante OCT (Carl Zeiss Meditec Inc., Dublin, Calif.), and the height increased significantly after wearing the test glasses for one month compared to the control glasses. Compared to the control glasses, after wearing the test glasses for 1 month, the CLDEQ-8 score was significantly reduced. The differences between symptomatic individuals were statistically significant. After wearing the glasses for 1 month, 19 of the 33 individuals (58%) preferred the test glasses, 11 (33%) preferred the control glasses and 3 (9%) reported no preference. Of the 16 symptomatic individuals, 11 (69%) preferred the test glasses and 5 (31%) preferred the control glasses. The results are depicted in Figure 1 middle.

[0075] The disclosure herein relates to certain illustrated examples, which should be understood to be provided by way of example and not limitation. Although exemplary examples are discussed, the foregoing detailed description is intended to be interpreted as covering all modifications, substitutions, and equivalents of the examples that may fall within the spirit and scope of the invention as defined by the additional disclosure.

[0076] Unless specific combinations of features are mutually exclusive, or the context indicates otherwise, the "examples" or "specific examples" or "aspects" or "embodiments" or similar phrases mentioned herein are intended to introduce one or more features of a hydrogel contact lens or a component thereof that releases WS12, a sealed contact lens package or a component thereof, or a method of making a hydrogel contact lens that releases WS12 (depending on the context), which can be combined with any combination of previously or subsequently described examples, aspects, embodiments (i.e., features). In addition, as used in this specification, "a / an" and "the" include multiple references (e.g., at least one or more references) unless the context clearly indicates otherwise. Thus, for example, reference to a "contact lens" includes a single lens as well as two or more identical or different lenses.

[0077] All references cited in this disclosure are hereby incorporated by reference in their entirety to the extent they are not inconsistent with this disclosure.

[0078] The present invention may include any combination of the various features or embodiments set forth in sentences and / or paragraphs of the above and / or following claims.Any combination of features disclosed herein is considered part of the present invention and no limitation is intended in terms of combinable features.

[0079] 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 exemplary only, with the true scope and spirit of the invention being indicated by the appended claims and their equivalents.

Claims

1. A sterile, unworn hydrogel contact lens immersed in a packaging solution and sealed in a package, the contact lens comprising: (a) a polymeric lens; and (b) an amount of N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide WS12, which is releasably adhered to the polymeric mirror body, wherein the WS12 concentration of the packaging solution is less than 0.1 μg / ml, and The amount of WS12 releasably attached to the polymeric lens body is 0.25 μg to 10.0 μg.

2. The contact lens of claim 1, wherein the WS12 concentration of the packaging solution is less than 0.05 μg / ml.

3. The contact lens of claim 1, wherein the WS12 concentration of the packaging solution is less than the detection level as determined by HLPC.

4. A contact lens according to any one of the preceding claims, having an in vitro release profile of 0.05 μg to 0.5 μg WS12 after 1 hour in a release medium consisting of phosphate buffered saline containing 25 vol.% ethanol.

5. The contact lens of any one of claims 1-3, wherein the polymeric lens body comprises a silicone hydrogel material.

6. The contact lens of any one of claims 1-3, wherein the amount of WS12 releasably adhered to the polymeric lens body is 0.50 μg to 5.0 μg.

7. The contact lens of claim 4, wherein the contact lens maintains WS12 release in the release medium for at least 6 hours.

8. The contact lens of claim 4, wherein the release profile comprises releasing 0.05 μg to 0.5 μg WS12 per hour for up to 6 hours.

9. The contact lens of claim 4, wherein the release profile comprises releasing 0.1 μg to 0.3 μg WS12 per hour for up to 6 hours.

10. The contact lens of any one of claims 1-3, wherein the package is autoclaved.

11. The contact lens of any one of claims 1-3, wherein the packaging comprises: (a) a base member having a cavity for containing the packaging solution; and (b) A cover that forms a fluid-tight seal with the base member.

12. A contact lens immersed in a packaging solution and sealed in a package, the contact lens being an unworn sterile silicone hydrogel contact lens, and comprising: (a) a polymeric lens; and (b) an amount of N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide WS12 releasably adhered to the polymeric lens body, wherein the contact lens releases 0.05 μg to 0.50 μg WS12 after being worn by a human subject for one hour; and (c) the WS12 concentration of the packaging solution is less than 0.1 μg / ml, The amount of WS12 releasably attached to the polymeric lens body is 0.25 μg to 10.0 μg.

13. The contact lens of claim 12, which releases 0.10 μg to 1.5 μg WS12 after being worn for three hours by a human subject.

14. A contact lens according to claim 12 or claim 13 which releases 0.25 μg to 2.0 μg WS12 after six hours of wear by a human subject.

15. A composition for correcting vision in symptomatic contact lens wearers; for alleviating symptoms of dry eyes in contact lens wearers; for extending the comfortable lens wearing time of contact lens wearers; for increasing the tear meniscus height of contact lens wearers; and / or for reducing the CLDEQ-8 score of contact lens wearers, wherein the composition comprises an amount of N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide WS12 releasably adhered to a polymerized silicone hydrogel contact lens body; wherein the composition is in the form of an unworn sterile hydrogel contact lens immersed in a packaging solution as claimed in any one of claims 1 to 12.

16. A method of manufacturing a contact lens according to any one of claims 1 to 14, the method comprising: (a) polymerizing a polymerizable composition in a contact lens mold to obtain said polymerized lens body; (b) removing the polymerized lens body from the contact lens mold; (c) extracting the polymeric Spiegelmer in an extraction solvent comprising at least 1.0 μg / ml WS12; (d) hydrating the polymeric lens body in a hydrating liquid to obtain a hydrogel contact lens; (e) sealing the hydrogel contact lens together with a packaging solution in a package; and (f) autoclaving the package.

17. A kit comprising at least two contact lenses releasing N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide WS12, each of which is immersed in a packaging solution and sealed in a package, sterilized and packaged in a secondary package, wherein a first contact lens comprises a first polymeric lens and a first amount of WS12 releasably adhered to the first polymeric lens, and a second contact lens comprises a second polymeric lens and a second amount of WS12 releasably adhered to the second polymeric lens, wherein the second amount is greater than the first amount, and wherein the first polymeric lens and the second polymeric lens comprise the same material; wherein the WS12 concentration of the packaging solution is less than 0.1 μg / ml; and The amount of WS12 releasably attached to the polymeric lens body is 0.25 μg to 10.0 μg.

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