Compositions and methods for treatment of contact lens discomfort

Abstract

SOLUTION: Described herein are compositions and methods for the treatment of contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE). Such compositions comprise keratolytic agents, such as a salicylic acid and selenium disulfide. Topical administration of the compositions to the inner surface of the eyelid provides therapeutic benefit to patients suffering from contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE).SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 833,281, filed Apr. 12, 2019, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Contact lens discomfort (CLD) is a condition characterized by sudden or persistent adverse eye sensations resulting from a decrease in the compatibility between a contact lens and the ocular environment in relation to lens wear, with or without visual impairment, and may cause a shortening of the contact lens wearing period or discontinuation of wear. CLD patients present symptoms of eye discomfort (e.g., dryness, irritation, discomfort, fatigue, etc.), and these symptoms may increase in severity over the course of a day during which the patient wears the contact lens. The symptoms of dryness and discomfort are highly prevalent among contact lens wearers (up to 50%) and are the most commonly cited reasons for contact lens discontinuation, and the contact lens discontinuation rate remains consistently high (16% - 34% per year) despite decades of research into contact lens design, materials, rewetting products, and behavior improvement during use. CLD is mainly diagnosed by symptomatology as opposed to observable signs. For this reason, the use of symptoms is often used as an evaluation item because it is directly related to the patient's contact lens use experience and the motivation to seek treatment.

[0003] Common treatments for CLD include the regular use of rewetting eye drops, re - fitting of contact lenses (using different designs or materials, or changing the replacement schedule), and in addition to contact lens care solutions or regimens, less commonly used techniques including topical or systemic drug therapy, dietary improvement, and punctal plugs. Ultimately, CLD is considered a major factor associated with permanent discontinuation of contact lens wear.

Summary of the Invention

[0004] Among more than 1.4 million contact lens wearers worldwide, the high prevalence of contact lens discontinuation represents an important problem that results from tissue changes in the eye due to the destructive presence of contact lenses in some cases. Lid wiper epitheliopathy (LWE) and lid parallel conjunctival folds (LIPCOF) are examples of tissue changes in the eye that have been reported to be strongly correlated with contact lens wear. LWE is seen in 67 - 80% of symptomatic CL wearers, but only in 13 - 32% of asymptomatic subjects. In CLD patients, an increase in the number of cells with atypical keratinization has been histologically verified, extending from the physiologically occurring Marx's natural stainable line to the surface of the lid wiper epithelium.

[0005] Many lens - related factors, including lens material, design, and surface properties, are also associated with CLD. Changes related to the surface properties of the lens include biofilm accumulation, which can modify mechanical properties (such as lubricity and wettability), and the interaction between surface deposits and their biological role in maintaining eye health. It has been shown that protein accumulation on the lens surface, particularly the modification of protein activity that loses its natural activity upon denaturation, is associated with CLD. For this reason, in some cases, by providing therapeutic agents for the eye that can treat CLD and / or LWE or one or more of their symptoms, it is possible to prevent the accumulation of some proteins, lipids, and / or mucins and prevent protein denaturation. In particular, it has been confirmed that keratin accumulates on contact lenses during wear, which is strongly correlated with dryness symptoms (Negar Babaei Omali et al. Mol Vis. 2013;19:390 - 399).

[0006] The present disclosure provides a method of treating contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE) by administering a keratolytic agent to an individual's eye (or surrounding tissues such as the eyelid (e.g., eyelid margin)). In some embodiments, the treatment of the contact lens discomfort comprises treating one or more symptoms associated with contact lens discomfort (such as described herein). In certain embodiments, the symptoms associated with contact lens discomfort are symptoms that are distinguishable by an individual and / or a clinician.

[0007] In one embodiment, the methods provided herein are related to treating any symptoms associated with contact lens discomfort, such as, by way of non-limiting example, inflammation, dryness, pain, or combinations thereof.

[0008] In certain embodiments, the compositions used in the methods provided herein include keratolytics selected from the group consisting of benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, alpha-hydroxy acids, urea, lactic acid, boric acid, retinoic acid, sodium thioglycolate, allantoin, zinc pyrithione, zinc L-pyrrolidone carboxylate, selenocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, glutathione, dithiothreitol, tiolurfan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octothiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, lenthionine, ajoene, allicin, gemopatrilat, thioethanol, thio phospholipids, thiocolesterol, 12-mercaptododecanoic acid, 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosanoic acid, and sulfanegen. In certain embodiments, the compositions used in the methods provided herein include keratolytics selected from the group consisting of benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, alpha-hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and zinc L-pyrrolidone carboxylate.

[0009] In some embodiments, provided herein are methods for treating an individual's contact lens discomfort (CLD) and its symptoms (e.g., signs associated with such symptoms). In certain embodiments, the method comprises topically administering to the eye (or surrounding tissues such as the eyelid (e.g., the eyelid margin)) of the individual a pharmaceutically acceptable composition comprising a therapeutically effective amount of at least one keratolytic agent (such as described herein). In particular embodiments, the pharmaceutically acceptable composition further comprises an eye-acceptable carrier (e.g., comprising an eye-acceptable solvent and / or an eye-acceptable excipient). In certain particular embodiments, the pharmaceutically acceptable composition consists essentially of at least one keratolytic agent and an eye-acceptable carrier. In certain particular embodiments, the pharmaceutically acceptable composition consists of at least one keratolytic agent and an eye-acceptable carrier.

[0010] In certain embodiments, administration (e.g., topical administration) to an individual's eye (e.g., by the methods described herein) includes topical ocular administration, (e.g., topical) palpebral (eyelid) administration (e.g., to the inner and / or outer side of the eyelid), or combinations thereof. In some embodiments, administration (e.g., topical administration) to an individual's eye (e.g., by the methods described herein) includes administration to the eyelid margin of the eye. In certain preferred embodiments, the (e.g., direct) administration is (e.g., topical) administration to the inner lid surface. In a more preferred embodiment, the administration is (e.g., direct) administration to, or includes, the lid wiper area of the inner lid surface. In certain embodiments, the administration is (e.g., direct) administration to, or includes, the lid wiper area and the stratified squamous epithelial area and / or the sub-eyelid fold area. In some embodiments, the administration is (e.g., direct) administration to, or includes, the lid wiper area, the stratified squamous epithelial area, and the sub-eyelid fold area of the eyelid. In certain embodiments, the administration is (e.g., direct) administration to, or includes, the lid wiper, stratified squamous epithelium, sub-eyelid fold, and stratified columnar epithelial areas of the eyelid. In certain particular embodiments, topical administration to the individual's eye includes direct topical administration to at least a portion of the palpebral conjunctiva (or inner surface of the eyelid) of the eye. In some embodiments, the topical administration to the eye includes topical administration that results in delivery (after administration) of at least a portion of the composition or the keratolytic agent to at least a portion of the palpebral conjunctiva (or inner surface of the eyelid) of the eye. In some embodiments, the composition is administered (e.g., by the methods described herein) to one eye of an individual. In other embodiments, the composition is administered (e.g., by the methods described herein) to both eyes of an individual (e.g., at the same or different times, by the same or different persons, and at the same or different concentrations or amounts).

[0011] In some embodiments, contact lens discomfort and / or lid wiper epitheliopathy described herein and / or treated according to the methods described herein is associated with a modification (e.g., clinically identified or suspected) to a part of the eye such as one or more eyelids (e.g., its inner surface such as the tarsal conjunctiva, or other parts such as the lid wiper area and / or lid parallel conjunctival folds). In certain embodiments, the modification to the inner surface of the eyelid (or tarsal conjunctiva) is a modification to the leading edge of the tarsal conjunctiva (e.g., the "lid wiper" area of the eyelid). In some embodiments, the processes provided herein identify a modification at the inner surface (e.g., the lid wiper area or tarsal conjunctiva) or the leading edge of the eyelid of the individual (e.g., in a clinical setting such as prior to administration of a pharmaceutical composition), or administer the composition to an individual in whom a modification at the inner surface of the eyelid (e.g., the lid wiper area or tarsal conjunctiva) has been identified. In various examples, there is and / or is targeted a modification (e.g., a problematic modification, i.e., a modification corresponding to contact lens discomfort (CLD)) at the inner surface of the eyelid (e.g., the lid wiper area or tarsal conjunctiva), or a trauma to, or a modification causing a trauma to, the inner surface of the eyelid (wherein the trauma in this case is related to friction between the inner surface of the eyelid (e.g., the tarsal conjunctiva) and the lens). In some embodiments, the modification is or includes (e.g., an atypical) keratinization (e.g., para-keratinization (pk)) of a part of the inner surface of the eyelid (e.g., a part of the lid wiper area or tarsal conjunctiva).

[0012] In certain embodiments, contact lens discomfort and / or lens wiper epitheliopathy treated according to the methods described herein and / or described herein are associated with a (e.g., clinically identified or suspected) modification in the inner surface of the eyelid of the upper eyelid (e.g., the lid wiper area or tarsal conjunctiva). In other certain embodiments, contact lens discomfort treated according to the methods described herein is associated with a (e.g., clinically identified or suspected) modification in the inner surface of the eyelid of the lower eyelid (e.g., the lid wiper area or tarsal conjunctiva).

[0013] Furthermore, in certain embodiments herein, a method for treating lid wiper epithelial keratopathy (LWE) is provided, such as by administering a keratolytic agent to the eye or surrounding tissue, such as the eyelid or a part thereof (e.g., the eyelid margin) of an individual. In some embodiments, the treatment of the lid wiper epithelial keratopathy (LWE) includes treating symptoms associated with lid wiper epithelial keratopathy (LWE). In certain embodiments, the symptoms associated with lid wiper epithelial keratopathy (LWE) are symptoms distinguishable by an individual and / or a clinician. In one embodiment, the methods provided herein relate to treating any symptoms associated with lid wiper epithelial keratopathy (LWE), such as, by way of non-limiting example, inflammation, dryness, pain, or combinations thereof. In certain embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, alpha-hydroxy acids, urea, lactic acid, boric acid, retinoic acid, sodium thioglycolate, allantoin, zinc pyrithione, zinc L-pyrrolidone carboxylate, selenocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, glutathione, dithiothreitol, tiolafane, cysteamine, buserelin, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fluthiamine, octothiamine, sulbutiamine, prosultiamine, thiam, lipoic acid, lenthionine, ajoene, allicin, gemopatrilat, thioethanol, thio lipids, thiocolesterol, 12-mercaptododecanoic acid, 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosanoic acid, and sulfanegen. In certain embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, alpha-hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and zinc L-pyrrolidone carboxylate.

[0014] In some embodiments, provided herein are methods for treating lid wiper epitheliopathy (LWE) and its symptoms (e.g., signs associated with the symptoms) in an individual. In certain embodiments, the method includes topically administering to the eye of the individual (or its surrounding tissues such as the eyelid or a part thereof (e.g., the eyelid margin)) a pharmaceutically acceptable composition comprising a therapeutically effective amount of at least one keratolytic agent. In particular embodiments, the pharmaceutically acceptable composition further comprises an ophthalmologically acceptable carrier (e.g., including an ophthalmic solvent and an isotonic agent). In some embodiments, the topical administration to the eye of the individual includes topical ocular administration, topical palpebral (eyelid) administration (e.g., to the inner and / or outer side of the eyelid), or a combination thereof. In some embodiments, the topical administration to the eye or eyelid of the individual includes administration to the eyelid margin of the eye of the individual. In certain embodiments, the topical administration to the eye of the individual includes direct topical administration to at least a part of the lid wiper area of one or more eyelids of the eye. In some embodiments, the topical administration to the eye includes topical administration resulting from delivery (after administration) of at least a part of the composition or the keratolytic agent to at least a part of the palpebral conjunctiva (or lid wiper area) of the eye.

[0015] In certain preferred embodiments, the administration (e.g., direct) is topical administration to the inner lid surface. In a more preferred embodiment, the administration is or includes (e.g., direct) administration to the lid wiper area of the inner lid surface. In some embodiments, the administration is or includes (e.g., direct) administration to the lid wiper area and the stratified squamous epithelial area and / or the subpalpebral fold area. In some embodiments, the administration is or includes (e.g., direct) administration to the lid wiper area, the stratified squamous epithelial area, and the plantar fold area of the lid. In some embodiments, the administration is or includes (e.g., direct) administration to the lid wiper, the stratified squamous epithelium, the subpalpebral fold, and the stratified columnar epithelial area of the eyelid.

[0016] In certain embodiments, the lid wiper epithelial erosion (LWE) is superior lid wiper epithelial erosion (LWE). However, in some embodiments, the lid wiper epithelial erosion (LWE) is inferior lid wiper epithelial erosion (LWE).

[0017] In some embodiments, an individual (e.g., a patient) being treated according to the methods described herein wears one or more contact lenses (e.g., regularly, such as for at least one hour per day or on at least one day per week). In some embodiments, an individual being treated according to the methods described herein wears one or more contact lenses on two or more days per week, such as three, four, five, or six days per week. In some embodiments, an individual being treated according to the methods described herein wears one or more contact lenses over a treatment period (e.g., as described herein). In other embodiments, an individual being treated according to the methods described herein does not wear one or more contact lenses over a treatment period (e.g., regular wear is resumed after a given treatment period). In certain embodiments, the lid wiper epithelial erosion is associated with contact lens discomfort (CLD) and / or the individual has, is diagnosed with, or is suspected of having contact lens discomfort (CLD). In some examples, contact lens discomfort is primarily associated with the upper eyelid because the interaction between the upper lid wiper and the contact lens is greater than the interaction between the lower lid wiper and the contact lens (e.g., due to longer movement of the upper eyelid during a blink).

[0018] In certain embodiments of the methods provided herein (e.g., in the treatment of contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE)), the individual has, is diagnosed with, or is suspected of having lid wiper epitheliopathy (LWE) of any severity. For example, in some embodiments, the lid wiper epitheliopathy is clinically graded with a severity level of 1 (e.g., based on a discrete 0-3 scale or a 0-3 subjective scale, where 3 is the most severe and 0 is no impairment). In some embodiments, the lid wiper epitheliopathy is clinically graded with a severity level of at least 1, such as at least 2 (e.g., based on a discrete 0-3 scale or a 0-3 subjective scale, where 3 is the most severe and 0 is no impairment). In certain embodiments, the lid wiper epitheliopathy is clinically graded with a severity level of 2. In certain embodiments, the lid wiper epitheliopathy is clinically graded with a severity level of 3.

[0019] In some embodiments, the lid wiper epitheliopathy may be present in any form, such as a clinically significant form. In one embodiment, the lid wiper epitheliopathy includes and / or is an indication of the presence of trauma to and / or around the lid wiper area of the eyelid (e.g., the upper eyelid). In some embodiments, treatment is continued until a reduction in said trauma is observed. In one embodiment, the lid wiper epitheliopathy includes and / or is an indication of the presence of (e.g., atypical) keratinization (e.g., parakeratosis (pk)) in and / or around the lid wiper area of the eyelid (e.g., the upper eyelid). In some embodiments, treatment is continued until a reduction in said (e.g., atypical) keratinization (e.g., parakeratosis (pk)) is observed. In one embodiment, the lid wiper epitheliopathy includes and / or is an indication of the presence of inflammation in and / or around the lid wiper area of the eyelid (e.g., the upper eyelid). In some embodiments, treatment is continued until a reduction in said inflammation is observed. In one embodiment, the lid wiper epitheliopathy includes and / or is an indication of the presence of dry eye. In some embodiments, treatment is continued until a reduction in said dryness is observed. In one example, such a condition is considered to be present when it is present in all or a part of the adaptation area of the eye.

[0020] In certain embodiments herein, a method of treating dry eye is provided, such as by administering a keratolytic agent to an individual's eye. In some embodiments, said dryness is associated with contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE). In various embodiments herein, such treatment is as described herein for any method that includes the treatment of contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE).

[0021] In certain embodiments herein, methods of treating eye pain are provided, such as by administering a keratolytic agent to an individual's eye. In some embodiments, the pain is associated with contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE). In various embodiments herein, such treatment is as described herein for any method that includes treatment of contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE).

[0022] In certain embodiments herein, methods of treating eye inflammation are provided, such as by administering a keratolytic agent to an individual's eye. In some embodiments, the inflammation is associated with contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE). In various embodiments herein, such treatment is as described herein for any method that includes treatment of contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE).

[0023] In certain embodiments herein, methods are provided for inhibiting the modification of a contact lens or its surface in an individual's eye. In certain embodiments, such methods include administering a pharmaceutically acceptable composition (e.g., topically) to the eye or eyelid associated with the contact lens, or to the contact lens in contact with the eye. In certain embodiments, the pharmaceutically acceptable composition includes a therapeutically effective amount of at least one keratolytic agent and an eye-acceptable carrier. In certain specific embodiments, the method is a method for maintaining (e.g., preventing modification) of one or more surface properties of a contact lens (e.g., smoothness, absence of biofilm, etc.) (e.g., in an individual's eye). In some embodiments, the individual suffers from contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE). In some examples, by inhibiting the modification of the contact lens in an individual wearing such a contact lens, the method inhibits the onset of contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE) in the individual and / or reduces the severity thereof. In some embodiments, the method for maintaining (e.g., preventing modification) or modifying one or more surface properties (e.g., smoothness, absence of biofilm, etc.) includes administering a composition (e.g., as described herein) to the contact lens. In other embodiments, the method for maintaining (e.g., preventing modification) or modifying one or more surface properties (e.g., smoothness, absence of biofilm, etc.) includes administering a composition (e.g., as described herein) to the eye or surrounding tissue associated with the contact lens (e.g., the eyelid or a part thereof (e.g., the eyelid margin)).

[0024] In certain embodiments herein, a method of inhibiting bioform formation on a contact lens in an individual's eye is provided, the method comprising administering to the eye or surrounding tissue associated with the contact lens (e.g., the eyelid (e.g., the eyelid margin)), or the contact lens in contact with the eye, a pharmaceutically acceptable composition. In some embodiments, the pharmaceutically acceptable composition comprises a therapeutically effective amount of at least one keratolytic agent (e.g., as described herein) and an eye-acceptable carrier.

[0025] In certain embodiments, an individual being treated according to the methods provided herein is evaluated using symptom scoring techniques such as contact lens discomfort (CLD), lid wiper epitheliopathy (LWE), dry eye pain in the eye, eye inflammation, or other symptom scoring techniques suitable for diagnosing the indications described herein. In certain embodiments, the individual has been diagnosed using a contact lens dry eye questionnaire (CLDEQ) measurement tool, such as the Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) and opinion of contact lens performance (described in Chalmers et al, Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) and opinion of contact lens performance. Optom Vis Sci. 2012;89:1435-1442, which is incorporated herein by reference in its entirety, or as copyrighted by the University of Indiana), or any portion thereof, such as described in Nichols et al. The Performance of the Contact Lens Dry Eye Questionnaire as a Screening Survey for Contact Lens-related Dry Eye, Cornea 2002;21(5):469-475, which is incorporated herein by reference. In certain embodiments, the individual's CLDEQ-8 score is at least 5. In some specific embodiments, the individual's CLDEQ-8 score is at least 10. In more specific embodiments, the individual's CLDEQ-8 score is at least 12. In even more specific embodiments, the individual's CLDEQ-8 score is at least 15. In yet more specific embodiments, the individual's CLDEQ-8 score is at least 18. In some embodiments, the method results in an improvement in the CLDEQ-8 measurement tool. In certain embodiments, an individual being treated according to the methods provided herein has had, or is having, pre-administration comfortable wearing time and / or subjective vision evaluated (e.g., using VAS as an outcome variable). In some embodiments, the method results in an improvement in comfortable wearing time and / or subjective vision assessment.In various embodiments, other suitable symptom scoring processes (e.g., scoring the negative effects of the disorder and / or signs of the symptoms of the disorder) are optionally utilized (e.g., any or a combination of the symptoms (e.g., syndromes) described in Siddireddy, et al, Predictive Potential of Eyelids and Tear Film in Determining Symptoms in Contact Lens Wearers. Optom Vis Sci 2018;95(11):1035-1045, which is incorporated herein by reference thereto) to diagnose an individual in need of the treatment described herein (e.g., thereby diagnosing that the individual suffers from LWE or CLD).

[0026] In some embodiments, the individual being treated according to the methods provided herein is not diagnosed with meibomian gland dysfunction (MGD). In some embodiments, the individual being treated for CLD as provided herein is not diagnosed with MGD. In some embodiments, the individual being treated for CLD as provided herein does not suffer from MGD. According to Foulks et al., The TFOS International Workshop on Contact Lens Discomfort: Report of the Subcommittee on Clinical Trial Design and Outcomes. Invest Ophthalmol Vis Sci. 2013;54:TFOS157-TFOS182, combining the results of tests primarily aimed at predicting CLD, the clinical outcome variables of tear film stability, tear meniscus height / area, “lid wiper epitheliopathy” (LWE), and lid parallel conjunctival folds (LIPCOF) are most likely to predict CLD. Notably lacking from this finding are conventional MGD measurements such as gland grading (e.g., meibomian gland score (MGS)). Indeed, Young et al., Soft contact lens-related dryness with and without clinical signs. Optom. Vis. Sci. 2012;89:1125-32 reported that no signs of disease were found in 23% of symptomatic soft contact lens wearers who reported significant dryness related to soft contact lenses using the CLDEQ.

[0027] In some embodiments, treating an individual according to the methods provided herein results in a decrease in a composite scale related to symptoms (e.g., dryness, grittiness, scratchiness, soreness, irritation, burning, watering, or a combination of two or more thereof), or is continued until the method results in such a decrease. In certain embodiments, the method results in an improvement in the horizontal (width) and / or sagittal (height) direction of a lesion (e.g., of a lid wiper). In one embodiment, the method results in an improvement in the lid parallel conjunctival fold (LIPCOF). In one embodiment, the method results in an improvement in the lid signs of contact lens discomfort (CLD). In one embodiment, the method results in an improvement in the tear film signs of contact lens discomfort (CLD). In some embodiments, the method results in an improvement in meibomian gland secretion (MGS) and / or meibomian glands that secrete lipids (MGYLS).

[0028] Accordingly, this specification describes methods and formulations for treating various eye disorders (e.g., contact lens discomfort (CLD) and / or lid wiper epitheliopathy (LWE)) using keratolytic agents. In certain embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, α-hydroxy acids, urea, lactic acid, boric acid, retinoic acid, sodium thioglycolate, allantoin, zinc pyrithione, zinc L-pyrrolidone carboxylate, selenocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, glutathione, dithiothreitol, tiolfan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octothiamine, sulbutiamine, prosultiamine, thiam, lipoic acid, lenthionine, ajoene, allicin, gemopatrilat, thioethanol, thio lipid, thiocolesterol, 12-mercaptododecanoic acid, 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosanoic acid, and sulfanegen. In some embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, α-hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and zinc L-pyrrolidone carboxylate. In some embodiments, the keratolytic agent is salicylic acid or selenium disulfide. In some embodiments, the keratolytic agent is selenium disulfide. In some embodiments, the concentration of selenium disulfide in the composition is from about 0.01% to about 30% (e.g., from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 2.5%, from about 0.01% to about 1%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 2.5%, from about 0.1% to about 1%, or a useful range therein).In some embodiments, the concentration of selenium disulfide in the composition is at least about 0.01%, such as at least about 0.05%, about 0.1%, about 1%, about 2%, about 2.5%, about 5%, or about 10% or more. In some embodiments, the concentration of selenium disulfide in the composition is about 10% or less, such as about 5% or less, about 2.5% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.1% or less. In some embodiments, the keratolytic agent is salicylic acid. In some embodiments, the concentration of salicylic acid in the composition is from about 0.01% to about 30% (e.g., from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 2.5%, from about 0.01% to about 1%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 2.5%, from about 0.1% to about 1%, or a useful range therein). In some embodiments, the concentration of salicylic acid in the composition is at least about 0.01%, such as at least about 0.05%, about 0.1%, about 1%, about 2%, about 2.5%, about 5%, or about 10% or more. In some embodiments, the concentration of salicylic acid in the composition is about 10% or less, such as about 5% or less, about 2.5% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.1% or less. In some embodiments, the composition is topically administered to the individual until the targeted disorder and / or associated symptoms (e.g., signs of the symptoms) are (e.g., partially or completely) alleviated. In some embodiments, the composition is topically administered to the patient regularly even after alleviation is achieved. In some embodiments, the topical administration is a single administration (e.g., the composition is administered in a single dose). In some embodiments, the topical administration is a regular administration (e.g., the composition is administered regularly, such as once a day, twice a day, once a week, twice a week, every other week, etc.). In some embodiments, the regular administration is once a day (e.g., the composition is administered once a day). In some embodiments, the regular administration is twice a day (e.g., the composition is administered at least twice a day). In some embodiments, the regular administration is twice a week (e.g., the composition is administered at least twice a week). In some embodiments, the composition for topical administration is a semi-solid composition. In some embodiments, the composition for topical administration is homogeneous.In some embodiments, the composition for topical administration is a dispersion or a suspension. In some embodiments, the composition for topical administration is hydrophilic. In some embodiments, the composition for topical administration is hydrophobic. In some embodiments, the composition for topical administration comprises an oily base. In some embodiments, the ophthalmologically acceptable carrier comprises at least one ophthalmologically acceptable excipient. In one embodiment, the composition for topical administration is a gel such as a non-aqueous gel. In other embodiments, the composition is a suspension, a dispersion, a hydrophobic oil, a foam, a liposome, an emulsion, a lotion, microparticles, or other suitable formulation.

[0029] In one embodiment, the topical administration of the composition provided herein to an individual is an administration such that the composition reaches the eyelid margin of the patient. In certain embodiments, the composition comprises a therapeutically effective amount of a keratolytic agent in an ophthalmologically acceptable carrier. In some embodiments, the keratolytic agent is salicylic acid or selenium disulfide. In some embodiments, the keratolytic agent is selenium disulfide. In some embodiments, the concentration of selenium disulfide in the composition is from about 0.01% to about 30% (for example, from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 2.5%, from about 0.01% to about 1%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 2.5%, from about 0.1% to about 1%, or a useful range therein). In some embodiments, the concentration of selenium disulfide in the composition is at least about 0.01%, such as at least about 0.05%, about 0.1%, about 1%, about 2%, about 2.5%, about 5%, or about 10% or more. In some embodiments, the concentration of selenium disulfide in the composition is about 10% or less, such as about 5% or less, about 2.5% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.1% or less. In some embodiments, the composition for topical administration is homogeneous. In some embodiments, the composition for topical administration is a dispersion or suspension. In some embodiments, the composition for topical administration is hydrophilic. In some embodiments, the composition for topical administration comprises an oily base. In some embodiments, the ophthalmologically acceptable carrier comprises at least one ophthalmologically acceptable excipient. In one embodiment, the composition for topical administration is a gel such as a non-aqueous gel. In other embodiments, the composition is a suspension, dispersion, hydrophobic oil, foam, liposome, emulsion, lotion, microparticle, or other suitable formulation.

[0030] In one aspect, the methods and formulations described herein include (e.g., additional) pharmacological agents useful for treating eye disorders such as dry eye, eye pain, eye inflammation, contact lens discomfort (CLD), and / or lid wiper epitheliopathy (LWE) in a subject. In some embodiments, the formulations described herein are applied to a patient's eye. In some embodiments, the formulations described herein are applied to a patient's eyelid (e.g., the eyelid margin). In some embodiments, the formulations described herein are applied to a patient's bulbar conjunctiva. In some embodiments, the formulations described herein are applied to one eye of a patient or the surrounding tissue thereof (e.g., the eyelid (e.g., the eyelid margin or the bulbar conjunctiva)). In some embodiments, the formulations described herein are applied to both eyes of a patient or the surrounding tissue thereof (e.g., the eyelid (e.g., the eyelid margin or the bulbar conjunctiva)). In some embodiments, multiple applications of the formulation are required (e.g., regular applications such as daily, twice a day, weekly, twice a week, or biweekly).

[0031] In some embodiments, in any of the methods provided herein, the method further comprises performing a physical intervention such as the application of a warm compress, debridement, therapeutic assistance, or a combination thereof (e.g., a combination of debridement and therapeutic assistance) to the eye of the individual. In one embodiment, debridement is performed on one eye and a combination of debridement and therapeutic assistance is performed on the other eye. In some embodiments, the physical intervention is performed after administration of the composition provided herein. For example, in some embodiments, the physical intervention is performed at least about 5 minutes, at least about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, or more after administration of the composition provided herein. In some embodiments, the composition is administered regularly and the physical intervention is performed at a single time such as about 1 month after the first administration of the composition.

[0032] In some embodiments, during administration, the eyeball (the "eyeball") is at least partially shielded to prevent or inhibit the drug from contacting the individual's eyeball. Further, kits are described that include a device for protecting the eye from contact with the formulation, along with the formulations described herein.

[0033] The methods and formulations described herein include an active agent at a therapeutic level that acts, either alone or in combination with other components, to provide a therapeutic benefit such as the treatment of the disorders or symptoms associated therewith described herein. Further, in some embodiments, the active agent is formulated or applied to be acceptable on the surface of the eye (e.g., so as not to cause excessive irritation or disruption to the epithelial surface of the eye). In certain embodiments, the active agent is formulated and / or applied so as not to impair lipid-producing cells (e.g., upon contact with the formulation).

[0034] In some embodiments, the formulation is applied at a period and frequency that is acceptable and practical for the physician or patient administering the drug. For example, a physician applies the formulations described herein once a week or twice a week over several weeks to (at least partially) induce the opening of the occlusion, and a patient applies different formulations daily or uses a more potent formulation daily over several weeks and then a less potent formulation daily thereafter.

[0035] In some embodiments, the method of application varies according to the concentration of the active agent and / or the severity of the eye disorder or condition being treated, and includes, but is not limited to, shielding of the ocular surface. In other embodiments, the method of application or formulation (with or without preservatives such as, for example, benzalkonium chloride (BAK)) is varied to enhance the penetration time or residence time in the target tissue to enhance the therapeutic effect. In other embodiments, the method of application or formulation is varied to enhance the penetration time or residence time in the target tissue to minimize the time required. In other embodiments, the method of application or formulation is formulated (e.g., with viscosity enhancers and / or skin adhesives) to increase contact with the target tissue while minimizing contact with non-target tissue, including the eye, thereby limiting or reducing unwanted collateral activity.

[0036] In certain aspects of the methods and formulations described herein, the concentration of the active agent, and the components of the co-formulation, are optimized to deliver the minimum effective concentration of the active agent while minimizing irritation or disruption to the eye or to the surrounding tissues of the eye to achieve a therapeutic benefit.

[0037] In some embodiments, the active drug is a keratolytic agent and / or a keratoplastic agent selected from benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, inorganic selenium compounds such as selenium disulfide, SeCl4, Na2SeO3, organic selenium compounds such as ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) or analogs thereof, α-hydroxy acids, urea, lactic acid, or sodium thioglycolate. In some embodiments, the active drug is benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, α-hydroxy acids, urea, lactic acid, boric acid, retinoic acid, sodium thioglycolate, allantoin, zinc pyrithione, zinc L-pyrrolidone carboxylate, selenocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, glutathione, dithiothreitol, tiolfan, cysteamine, buserelin, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, lenatilpril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octothiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, lenitionine, ajoene, allicin, gemopatrilat, thioethanol, thiophospholipids, thiocolesterol, 12-mercaptododecanoic acid, 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosanoic acid, and sulfanegen. In some embodiments, the keratolytic agent and / or keratoplastic agent is selected from benzoyl peroxide, coal tar, disranol, salicylic acid, or selenium disulfide. In some embodiments, the keratolytic agent and / or keratoplastic agent is salicylic acid or selenium disulfide. In some embodiments, the keratolytic agent and / or keratoplastic agent is salicylic acid. In some embodiments, the keratolytic agent and / or keratoplastic agent is selenium disulfide.In some embodiments, at least one of the keratolytic agent and / or keratinogenic agent is salicylic acid. In some embodiments, at least one of the keratolytic agent and / or keratinogenic agent is selenium disulfide. In some embodiments, the concentration of salicylic acid in the composition is from about 0.01% to about 30% (such as from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 2.5%, from about 0.01% to about 1%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 2.5%, from about 0.1% to about 1%, or a useful range therein). In some embodiments, the concentration of salicylic acid in the composition is at least about 0.01%, such as at least about 0.05%, about 0.1%, about 1%, about 2%, about 2.5%, about 5%, or about 10% or more. In some embodiments, the concentration of salicylic acid in the composition is about 10% or less, such as about 5% or less, about 2.5% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.1% or less. In some embodiments, the concentration of selenium disulfide in the composition is from about 0.01% to about 30% (such as from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 2.5%, from about 0.01% to about 1%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 2.5%, from about 0.1% to about 1%, or a useful range therein). In some embodiments, the concentration of selenium disulfide in the composition is at least about 0.01%, such as at least about 0.05%, about 0.1%, about 1%, about 2%, about 2.5%, about 5%, or about 10% or more. In some embodiments, the concentration of selenium disulfide in the composition is about 10% or less, such as about 5% or less, about 2.5% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.1% or less.

[0038] In certain embodiments, the symptoms associated with CLD or LWE treated according to the methods provided herein include symptoms (e.g., a deviation from normal function or sensation that is apparent to an individual or patient, which reflects the presence of an unnatural condition of a disease or disorder. Symptoms can be either objective or subjective). In certain embodiments, the symptoms associated with CLD or LWE described herein include any one or more of dryness, shakiness, roughness, scratching, irritation, burning, and / or tearing in the eye or surrounding tissues (e.g., of an individual or patient wearing or having worn at least one contact lens and / or suffering from or suspected of having CLD or LWE). In certain embodiments, such symptoms result in a shortened contact lens wearing period. In some embodiments, the presence of one or more such symptoms is utilized to diagnose that an individual or patient is suffering from CLD or LWE.

[0039] In some embodiments, other symptoms or signs are present in an individual suffering from CLD and / or LWE or are utilized to diagnose that an individual is suffering from CLD and / or LWE. In some embodiments, such symptoms or signs include abnormal eyelid conjunctival folds, meibomian foam, tear evaporation rate (regardless of the presence of contact lenses), lid roughness, lid staining, lid hyperemia, or a combination of one or more such symptoms or signs.

Brief Description of the Drawings

[0040]

Figure 1

Figure 2

Figure 3

Figure 4

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In various embodiments herein, methods for treating eye disorders and their symptoms are provided by administering a therapeutically effective amount of a pharmaceutically active agent provided herein to an individual's eye (e.g., the eyeball or eyelid). In certain embodiments, the method includes treating contact lens discomfort (CLD) or its symptoms. In certain specific embodiments, the method includes treating lid wiper epitheliopathy (LWE) or its symptoms. In some embodiments, the method includes treating dry eye, eye pain, eye inflammation, or other disorders or symptoms described herein, such disorders or symptoms being related to contact lens discomfort (CLD) or lid wiper epitheliopathy (LWE). In certain embodiments, the method includes administering a composition to a contact lens configured to be used on an individual's (e.g., a patient's) eye (e.g., to prevent modification to the contact lens surface [e.g., to maintain smoothness and / or to reduce bioform formation] and / or to regulate the accumulation of proteins [e.g., keratin] and / or lipids, mucin, and denatured proteins associated with CLD on the contact lens).

[0042] In certain embodiments herein, a method of treating contact lens discomfort (CLD) is provided, such as by administering a keratolytic agent to an individual's eye or surrounding tissue (e.g., eyelid (e.g., eyelid margin)). In some embodiments, the treatment of the contact lens discomfort includes treating one or more symptoms associated with contact lens discomfort. In certain embodiments, the symptoms associated with contact lens discomfort are symptoms that can be identified by an individual and / or a clinician. In one embodiment, the methods provided herein relate to treating any symptoms associated with contact lens discomfort, such as, by way of non-limiting example, inflammation, dryness, pain, or combinations thereof. In certain embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, alpha-hydroxy acids, urea, lactic acid, boric acid, retinoic acid, sodium thioglycolate, allantoin, zinc pyrithione, zinc L-pyrrolidone carboxylate, selenocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, glutathione, dithiothreitol, tiolurfan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, lenatilpril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octothiamine, sulbutiamine, prosultiamine, thiam, lipoic acid, lenitionine, ajoene, allicin, gemopatrilat, thioethanol, thionolipids, thiocolesterol, 12-mercaptododecanoic acid, 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosanoic acid, and sulfanegen. In certain embodiments, the keratolytic agent is benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, alpha-hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylate.

[0043] Furthermore, in certain embodiments herein, a method of treating lid wiper epithelial keratopathy (LWE) is provided, such as by administering a keratolytic agent to an individual's eye or surrounding tissue (e.g., eyelid (e.g., eyelid margin) or bulbar conjunctiva). In some embodiments, the treatment of lid wiper epithelial keratopathy (LWE) includes treating symptoms associated with lid wiper epithelial keratopathy (LWE). In certain embodiments, the symptoms associated with lid wiper epithelial keratopathy (LWE) are symptoms that can be identified by an individual and / or a clinician. In one embodiment, the methods provided herein are related to treating any symptoms associated with lid wiper epithelial keratopathy (LWE), such as, by way of non-limiting example, inflammation, dryness, pain, or combinations thereof. In certain embodiments, the keratolytic agent is benzoyl peroxide, coal tar, disulanol, salicylic acid, selenium disulfide, alpha hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylate.

[0044] In various embodiments, the treatments provided herein include administering a composition to an individual's eye or surrounding tissue (e.g., eyelid (e.g., eyelid margin)). Generally, for the purposes of the embodiments described herein, an individual's eye comprises an ocular component (eyeball or "eyeball") and an eyelid component (e.g., upper eyelid and lower eyelid). In one example, the upper eyelid and the lower eyelid each typically comprise a bulbar conjunctiva, which is the tissue that covers the inside (or at least a portion thereof) of the lid. In some embodiments, the treatments provided herein include administering a composition to an individual's eyelid margin. In some embodiments, the treatment methods provided herein include administering a composition to one eye of an individual. In other embodiments, the treatments provided herein include administering a composition to both eyes of an individual.

[0045] In some examples, the lid wiper area is a thickened epithelial "lip" having a conjunctival mucosal form that extends from the tarsal conjunctiva to the ridge of the posterior eyelid border and aids in distributing the precorneal tear film. In one example, since the lid wiper is the main part of the eyelid that interacts with the CL surface, it is subject to mechanical friction during blinking, indicating its importance during lens wear. Thus, the lid wiper has obvious importance during lens wear. Usually, the Marx line extends from the ridge of the posterior eyelid border and is seen at the bottom of the lacrimal meniscus. A thin band of stainable epithelial cells just behind the mucocutaneous junction is the base of the Marx line. Conventionally, the Marx line was considered to be the area in contact with the eyeball and represented the wiping surface of the eyelid border.

[0046] In various embodiments discussed herein, administration of the active agent or composition described herein is achieved by administration to surrounding tissues such as the eye or eyelid of an individual. In certain embodiments, topical administration to the eye of an individual includes topical ocular administration, (e.g., topical) palpebral (eyelid) administration (e.g., to the inner and / or outer sides of the eyelid), or combinations thereof. In certain preferred embodiments, the administration (e.g., direct) is topical administration to the inner lid surface. In a more preferred embodiment, the administration is (e.g., direct) administration to the lid wiper area of the inner lid surface or includes such administration. In certain embodiments, the administration is (e.g., direct) administration to the lid wiper area and the stratified squamous epithelial area and / or the subpalpebral fold area or includes such administration. In some embodiments, the administration is (e.g., direct) administration to the lid wiper area, the stratified squamous epithelial area, and the plantar fold area of the lid or includes the same. In certain embodiments, the administration is (e.g., direct) administration to the lid wiper, the stratified squamous epithelium, the subpalpebral fold, and the stratified columnar epithelial area of the eyelid or includes such administration. In various other embodiments, administration to the meibomian gland openings of the eyelid is not performed.

[0047] FIG. 1 illustrates a schematic view of an exemplary ocular surface and a portion of an eyelid. As illustrated in the figure, eyelashes can be observed at the ends of the eyelids. The inner surface of the eyelid moves inward from the eyelashes and includes a stratified squamous epithelial region located proximal to the eyelashes. Further, along the inner surface of the eyelid, the stratified squamous epithelium continues into a lid wiper region, which is the inner surface region that contacts the ocular surface (or contact lens) (e.g., in a normally functioning eyelid). In some examples, when an individual suffers from contact lens discomfort (CLD) or lid wiper epitheliopathy (LWE), other inner surface portions of the eyelid may also contact the ocular surface. The inner surface of the eyelid moves away from the lid wiper region (e.g., moving distally from the eyelashes along the inner surface of the eyelid) and includes a sub-eyelid fold region and a stratified columnar epithelial region. In some examples, the palpebral conjunctiva extends over all or a portion of the inner surface of the eyelid, such as having a leading edge within the lid wiper region.

[0048] The keratolytic and keratinogenic agents described herein are useful for either acute treatment (e.g., by a trained professional or physician) or chronic treatment (e.g., by the patient or caregiver's hand, or alternatively by a trained professional or physician). In certain embodiments, these agents are tested using the assays and methods described herein (e.g., as described in the examples).

[0049] One embodiment provides a method for treating CLD or LWE in a patient, including topical administration of a composition comprising a keratolytic or a keratinogenic agent. In some embodiments, the keratolytic agent is selected from allantoin, benzoyl peroxide, inorganic selenium compounds such as selenium disulfide, SeCl4, Na2SeO3, organic selenium compounds such as ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) or analogs thereof, coal tar, disranol, salicylic acid, selenium disulfide, α-hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylate. In some embodiments, the keratolytic agent is selected from benzoyl peroxide, coal tar, disranol, salicylic acid, selenium disulfide, α-hydroxy acids, urea, lactic acid, boric acid, retinoic acid, sodium thioglycolate, allantoin, zinc pyrithione, zinc L-pyrrolidone carboxylate, selenocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, glutathione, dithiothreitol, tiolafane, cysteamine, buserelin, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, lenatilpril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octothiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, lenitionine, ajoene, allicin, gemopatrilat, thioethanol, thio phospholipids, thiocolesterol, 12-mercaptododecanoic acid, 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosanoic acid, and sulfanegen. In some embodiments, the keratolytic agent is selenium disulfide. In some embodiments, the keratolytic agent is salicylic acid. In some embodiments, the keratolytic agent is not retinoic acid.

[0050] In certain embodiments, it is desirable that the agent have minimal undesirable side effects, such as causing inflammation or other adverse eye conditions.

[0051] In certain embodiments, mild or weak keratolytic agents and / or keratinizing agents are used in the methods and formulations described herein for subjects that produce, for example, low amounts of keratin. Such mild or weak keratolytic and / or keratinizing agents are optionally used in maintenance therapy settings. Mild or weak keratolytic agents and / or keratinizing agents include low concentrations of active keratolytic agents and / or keratinizing agents, as well as keratolytic agents and / or keratinizing agents having low intrinsic activity (as determined, for example, by the methods described herein). In certain embodiments, the mild or weak keratolytic agent and / or keratinizing agent is not boric acid.

[0052] In certain embodiments, the composition comprises a therapeutically effective amount of at least one keratolytic agent (such as described herein) and an ophthalmologically acceptable carrier. In one embodiment, the keratolytic agent is benzoyl peroxide. In another embodiment, the keratolytic agent is coal tar. In another embodiment, the keratolytic agent is disulanol. In another embodiment, the keratolytic agent is salicylic acid. In another embodiment, the keratolytic agent is selenium sulfide (such as selenium disulfide). As used herein, the terms "selenium sulfide" and "selenium disulfide" are used interchangeably to refer to a chemical compound having the formula SeS2, wherein the ratio of selenium to sulfur in the formula is about 1:2. In another embodiment, the keratolytic agent is zinc pyrithione. In another embodiment, the keratolytic agent is zinc L-pyrrolidone carboxylate.

[0053] In some embodiments, more than one keratolytic agent is used.

[0054] In some embodiments, administration of a keratolytic agent to keratin plugs results in proteolysis of desmosome proteins that form tight junctions between keratinocytes. In some embodiments, administration of the keratolytic agent results in lysis, including hydrolysis of disulfide bonds. In some embodiments, administration of the keratolytic agent reduces keratin production.

[0055] In certain embodiments, the keratolytic agent is benzoyl peroxide. In some embodiments, the composition comprises about 2.5%, about 5%, or about 10% benzoyl peroxide (e.g., weight / weight percent of the total composition). In some embodiments, the composition comprises at least about 2.5%, about 5%, about 10%, or more benzoyl peroxide. In some embodiments, the composition comprising benzoyl peroxide is a suspension, emulsion, cream, lotion, gel (e.g., aqueous or non-aqueous), or ointment. In some embodiments, the composition comprising benzoyl peroxide is initially applied as a thin layer once daily every other day for skin cleansing and then gradually increased up to twice daily when tolerance is observed.

[0056] In one embodiment, the keratolytic agent is coal tar. In some embodiments, the composition comprises a coal tar solution of about 5% to about 10%. In some embodiments, the composition comprising coal tar is a coal tar solution of at least about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or more. In one embodiment, the composition comprising coal tar is a crude coal tar ointment of about 1%. In some embodiments, the coal tar inhibits hyperplasia of epidermal cells by reducing DNA synthesis and mitotic activity to normal levels.

[0057] In some embodiments, the keratolytic agent is disranol. In some embodiments, the composition comprises from about 0.1% to about 2.0% disranol ointment. In some embodiments, the composition comprising disranol is at least about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, or more disranol. In some embodiments, the composition comprising disranol is initiated as about 0.1% ointment. After more than 1 day, such as 7 days later, the concentration is increased to about 0.25%, and subsequently, it may be increased (e.g., doubled) to maximum strength (e.g., about 2%) at regular intervals (e.g., weekly intervals) as needed. In some embodiments, a thin layer of the ointment is applied once daily to the affected area over a period of more than 1 week, such as 2 to 4 weeks. In some embodiments, the ointment is left in place for about 10 to about 20 minutes before thoroughly rinsing the affected area. In some embodiments, the disranol slows epidermal cell division and inhibits the excessive proliferation and keratinization of the patient's epidermal cells.

[0058] In one embodiment, the keratolytic agent is salicylic acid. In some embodiments, the composition comprises from about 0.01% to about 30% (such as from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 2.5%, from about 0.01% to about 1%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 2.5%, from about 0.1% to about 1%, or a useful range therein) of salicylic acid. In some embodiments, the composition comprises from about 0.1% to about 6% of salicylic acid. In some embodiments, the composition comprises at least about 0.1%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, or more of salicylic acid. In some embodiments, the concentration of salicylic acid in the composition is at least about 0.01%, such as at least about 0.05%, about 0.1%, about 1%, about 2%, about 2.5%, about 5%, or about 10% or more. In some embodiments, the concentration of salicylic acid in the composition is about 10% or less, such as about 5% or less, about 2.5% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.1% or less. In some embodiments, the composition comprises from about 0.01% to about 30% of salicylic acid, such as from about 0.01% to about 10%, from about 0.1% to about 10%, or from about 0.1% to about 30%. In some embodiments, the composition containing salicylic acid is an ointment or a paste. In some embodiments, the composition containing salicylic acid is initially applied as a thin layer consisting of about 2% ointment or paste and is applied daily. In some embodiments, the concentration is gradually increased to a maximum of about 5% concentration and the treatment is continued as long as necessary.

[0059] In some specific embodiments, the keratolytic agent is selenium disulfide. In some embodiments, the composition comprises from about 0.01% to about 30% (such as from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 2.5%, from about 0.01% to about 1%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 2.5%, from about 0.1% to about 1%, or useful ranges therein) of selenium disulfide. In some embodiments, the composition comprises from about 0.01% to about 10% of selenium disulfide. In some embodiments, the composition comprises at least about 0.01%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, or more of selenium disulfide. In some embodiments, the concentration of selenium disulfide in the composition is at least about 0.01%, such as at least about 0.05%, about 0.1%, about 1%, about 2%, about 2.5%, about 5%, or about 10% or more. In some embodiments, the concentration of selenium disulfide in the composition is about 10% or less, such as about 5% or less, about 2.5% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.1% or less. In some embodiments, the composition comprises from about 0.01% to about 30% of selenium disulfide, such as from about 0.01% to about 10%, from about 0.1% to about 10%, or from about 0.1% to about 30%. In some embodiments, the composition containing selenium disulfide is a suspension, emulsion, cream, lotion, gel (e.g., aqueous or non-aqueous), or ointment. In some embodiments, the composition containing selenium disulfide is a semi-solid composition. In some embodiments, the composition containing selenium disulfide is a lotion. In some embodiments, the composition containing selenium disulfide is a cream. In some embodiments, the composition containing selenium disulfide is an ointment. In some embodiments, the composition containing selenium disulfide is a suspension.In some embodiments, the composition comprising selenium disulfide is a dispersion. In some embodiments, the composition comprising selenium disulfide is a solution. In other embodiments, the composition is a suspension, a hydrophobic oil, a foam, a liposome, an emulsion, a lotion, microparticles, or other suitable formulation.

[0060] In some embodiments, the composition comprises an inorganic selenium compound that is an inhibitor of prostaglandin synthase, an enzyme involved in the production of prostaglandins. Selenium mixtures that exhibit this inhibitory effect include SeCl4 and Na2SeO3. Since the pro-inflammatory action of prostaglandins is known to promote keratinization, these water-soluble inorganic selenium compounds that prevent prostaglandin production may be useful for reducing keratinization.

[0061] In some embodiments, the composition comprises an organic selenium compound. Organic selenium compounds such as ebselen inhibit cyclooxygenase and lipoxygenase enzymes and act as antioxidants and anti-inflammatory agents that scavenge hydroperoxides including hydrogen peroxide as well as membrane-bound phospholipids and cholesteryl ester hydroperoxides. Since anti-inflammatory agents are known to inhibit keratinization, ebselen and other organic selenium analogs may act as keratolytics due to this antioxidant / anti-inflammatory activity.

[0062] In some embodiments, the formulation comprising the keratolytic and / or keratinizing agent further comprises an additional therapeutic agent that is not a meibomian gland opening drug. In some embodiments, the formulation does not contain jojoba wax or jojoba extract. In some embodiments, the formulation does not contain boric acid. In some embodiments, the formulation does not contain retinoic acid. Alternatively, in some embodiments, the formulation comprising the keratolytic and / or keratinizing agent excludes additional therapeutic agents other than optionally added meibomian gland opening drugs.

[0063] In certain embodiments, the composition (e.g., further) comprises a local anesthetic. In some embodiments, the local anesthetic is selected from an aminoamide local anesthetic or an aminoester local anesthetic.

[0064] As used herein, the term "local anesthetic" refers to an agent that reversibly abolishes the sense of pain. In some embodiments, the local anesthetic can further induce temporary muscle paralysis in addition to reversibly abolishing the sense of pain.

[0065] The local anesthetics described herein are primarily useful as acute therapies, for example, under the guidance of a physician or other trained professional. In certain embodiments, these local anesthetics are tested using the assays and methods described herein.

[0066] In some embodiments, the local anesthetic is an aminoamide. In some embodiments, the local anesthetic is an aminoester. In some embodiments, the local anesthetic comprises a combination of two or more local anesthetics. In some embodiments, the combination comprises an aminoamide local anesthetic and an aminoester local anesthetic.

[0067] In some embodiments, the local anesthetic is an aminoester selected from the group consisting of benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, propalacaine, tetracaine, and amethocaine.

[0068] In some embodiments, the local anesthetic is an aminoamide selected from the group consisting of articaine, bupivacaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine.

[0069] In some embodiments, the local anesthetic is a combination of lidocaine and prilocaine, or a combination of lidocaine and tetracaine.

[0070] In some embodiments, the local anesthetic is a naturally derived local anesthetic. In some embodiments, this naturally derived local anesthetic is selected from the group consisting of saxitoxin, neosaxitoxin, tetrodotoxin, menthol, eugenol, and cocaine.

[0071] In some embodiments, the local anesthetic is mixed with a vasoconstrictor to increase the duration of local anesthesia by constricting blood vessels. In some embodiments, prilocaine hydrochloride is mixed with epinephrine. In some embodiments, lidocaine and bupivacaine are mixed with epinephrine. In some embodiments, iontocaine is mixed with lidocaine and epinephrine. In some embodiments, septocaine is mixed with a combination of articaine and epinephrine. In some embodiments, the local anesthetic, bupivacaine, or lidocaine is mixed in combination with a steroid.

[0072] In some embodiments, the compositions described herein (e.g., for topical use) are combined with a pharmaceutically suitable or acceptable carrier (e.g., a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier). Exemplary excipients are described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)). Other additives such as preservatives are provided optionally.

[0073] In certain embodiments, the compositions provided herein include any suitable additional agent or additive. In specific embodiments, additives are included, such as for improving the performance and / or effectiveness of the compositions or formulations provided herein. In some examples, for instance, the compositions provided herein include penetration enhancers and / or surfactants (e.g., ionic, anionic, cationic, nonionic, lipids (e.g., oleic or caprylic), BNZ, etc.). In some embodiments, the compositions provided herein include excipients that function to improve drug penetration, and / or solubilize plaque or keratinization present in the eyelids or lens, etc., according to methods described herein, etc.

[0074] In certain specific embodiments, the pharmaceutically acceptable composition consists essentially of at least one keratolytic agent (such as described herein) and an ophthalmologically acceptable carrier. In certain specific embodiments, the pharmaceutically acceptable composition consists of at least one keratolytic agent (such as described herein) and an ophthalmologically acceptable carrier.

[0075] This specification describes methods for treating various eye disorders (such as LWE and / or CLD) in an individual (e.g., a patient), including topically administering the compositions described herein to the individual (e.g., a patient) (e.g., the inner surface of one or more eyelids). In some embodiments, the individual is a patient, such as a patient receiving medical care (e.g., with respect to an eye disease and / or other disease). In some examples, some embodiments constitute acute treatment in which more potent drugs (in terms of either the concentration or the intrinsic activity of the agent) are utilized. In one embodiment, maintenance therapy enables the use of a lower concentration of the agent or an agent with less intrinsic activity. In one embodiment, maintenance use requires the patient to make routine visits to a healthcare provider. Both acute use and maintenance use optionally require the use of a device or apparatus for protecting the eye. In one embodiment, acute use is performed by a healthcare provider and maintenance use is performed by a non-healthcare provider such as the patient or a caregiver. In some embodiments, the patient applies a drug (e.g., a composition comprising a keratolytic) to themselves (e.g., the inner surface of one or more eyelids). In one embodiment, such administration is carried out over a long period of time. Such a mode of multiple administrations performed by the patient is, in short, chronic use. Usually, a different or second formulation of the drug is recommended for chronic use or for use by the patient themselves. In one embodiment, the different or second formulation utilizes a lower concentration of the drug. In another embodiment, the different or second formulation utilizes a drug that is less active than the first formulation.

[0076] In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is performed until keratinization (e.g., parakeratosis (pk)), which is abnormal for example, is reduced. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is performed periodically even after achieving a reduction in keratinization. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is a single administration. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is a periodic administration. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is performed once a day. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is performed twice a day. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is performed twice a week.

[0077] In some embodiments, the composition for topical administration comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is a semi-solid composition. In some embodiments, the composition for topical administration comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is homogeneous. In some embodiments, the composition for topical administration comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is a dispersion. In some embodiments, the composition for topical administration comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier is hydrophilic. In some embodiments, the composition for topical administration comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier has an oily base. In some embodiments, the composition for topical administration comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmologically acceptable carrier has at least one ophthalmologically acceptable excipient. In one embodiment, the composition for topical administration is a gel such as a non-aqueous gel.

[0078] In certain preferred embodiments, semi-solid or other viscous formulations are utilized (e.g., gels (e.g., gel-like emulsion suspension foams), creams or ointments, or other formulations such as suspensions, hydrophobic oils, foams, liposomes, emulsions, lotions, microparticles). In some instances, such formulations facilitate maintenance of the pharmacologically active formulation at or near the site being treated (e.g., a dysfunctional site such as a trauma or abnormal keratinization). In some instances, the semi-solid or other viscous formulations do not move substantially from the site of administration.

[0079] In some embodiments, topical administration of the composition comprising the drug is performed once a week. In some embodiments, topical administration of the composition comprising the drug is performed twice a week. In some embodiments, topical administration of the composition comprising the drug is performed every other day. In some embodiments, topical administration of the composition comprising the drug is performed daily. In some embodiments, topical administration of the composition comprising the drug is performed several times a day.

[0080] In some embodiments, the method includes treatment in an acute treatment scenario. In another embodiment, the method includes treatment for a patient who has not received treatment. In another embodiment, the method includes treatment in a chronic treatment scenario. In another embodiment, the method includes treatment in a maintenance therapy scenario. The dosage of the drug in the acute treatment scenario may be higher than the dosage of the drug used in the chronic treatment scenario or the maintenance therapy scenario. The pharmacological agent in the acute treatment scenario may be different from the drug used in the chronic treatment scenario. In some embodiments, the treatment period begins with an initial stage of treatment as an acute treatment scenario and then transitions to a chronic treatment scenario or a maintenance therapy scenario. In some embodiments, the drug administered in this acute treatment scenario is a local anesthetic, and the drugs administered in the chronic treatment scenario or the maintenance therapy scenario are keratolytic agents and / or keratinizing agents. In some embodiments, the drug administered in the acute treatment scenario is a keratolytic agent and / or keratinizing agent, and the drugs administered in the chronic treatment scenario or the maintenance therapy scenario are also keratolytic agents and / or keratinizing agents.

[0081] In certain clinical situations, the patient may require an initial treatment administered by a physician or healthcare professional in a formulation that is a more highly concentrated form of one of the therapeutic agents described herein. If a higher concentration formulation is required, this application may require eye shielding or other actions to minimize the effects of irritation or disruption of the ocular surface or surrounding tissues. Following this procedure, the patient may be administered an active agent of a different formulation for regular application to the inner surface of the eyelid at home. This application can be performed twice a day, once a day, weekly, twice a week, every other week, or monthly, depending on the formulation activity and the desired product profile of the therapeutic agent.

[0082] In some embodiments, the methods provided herein result in the improvement of one or more symptoms of CLD and / or LWE, such as dryness, roughness, granularity, stinging, irritation, burning, or tearing. In some embodiments, the improvement of such symptoms can be evaluated according to subjective vision assessment (e.g., VAS) or another subjective scoring system (e.g., CLDEQ-8). In some embodiments, the methods provided herein result in the improvement of the eyelid signs of CLD. In some embodiments, the methods provided herein result in the improvement of the tear film signs of CLD. In some embodiments, the method results in the improvement of the CLDEQ-8 measurement tool. In some embodiments, the method results in the improvement of the comfortable wearing time (e.g., of contact lenses). In some embodiments, the method results in the improvement of subjective vision assessment (e.g., as evaluated by visual analog scale, i.e., VAS). In some embodiments, the improvement of one or more symptoms of CLD and / or LWE, including comfortable wearing time, is observed within about 1 month, such as within about 4 weeks, 3 weeks, 2 weeks, 1 week, 3 days, or earlier, (e.g., according to the methods provided herein). In some embodiments, the improvement of one or more symptoms of CLD and / or LWE, including comfortable wearing time, is observed within about 2 months (e.g., according to the methods provided herein). In some embodiments, the improvement of the symptoms of CLD and / or LWE persists over the administration period, e.g., for 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, or longer.

[0083] In some embodiments, an individual (e.g., a patient) being treated according to the methods described herein wears one or more contact lenses regularly (e.g., for one hour or more per day, or for one day or more per week). In some embodiments, an individual being treated according to the methods described herein wears one or more contact lenses for two or more days per week, such as three, four, five, or six days per week. In some embodiments, an individual being treated according to the methods described herein wears one or more contact lenses over a treatment period (e.g., as described herein). In other embodiments, an individual being treated according to the methods described herein does not wear one or more contact lenses over a treatment period (e.g., regular wearing is resumed after a given treatment period). In some embodiments, the individual wears soft contact lenses. In some embodiments, the individual wears hard contact lenses (e.g., gas permeable rigid contact lenses). In some embodiments, the individual wears disposable contact lenses (e.g., contact lenses configured to be worn once over the course of a day) or extended wear contact lenses (e.g., contact lenses configured to be worn for longer than one day, such as longer than one week, longer than two weeks, longer than three weeks, or longer than four weeks). In some embodiments, the individual wears orthokeratology (ortho-K) lenses. In some embodiments, the individual wears decorative or cosmetic contact lenses, such as colored contact lenses.

[0084] In some embodiments, improvement of one or more symptoms of CLD and / or LWE can be evaluated according to the 8-item Contact Lens Dry Eye Questionnaire (CLDEQ-8). This CLDEQ-8 is an 8-point questionnaire that checks for discomfort, dryness, vision changes, frequency and recent intensity of blurriness, and frequency of closing the eyes for relief during contact lens wear and during earlier-than-scheduled lens removal for symptom relief. The CLDEQ-8 is optionally self-administered. A CLDEQ-8 score of 12 or more can identify contact lens (e.g., soft contact lens) wearers who may benefit from clinical management of their contact lens-related symptoms. Clinically important differences in the CLDEQ-8 are defined as ±3 points (see Chalmers et al. Cont. Lens. Anterior Eye. 2016 Oct.;39(5):342-52).

[0085] In some embodiments, the methods provided herein further include one or more additional therapeutic interventions such as the application of warm compresses, debridement, and / or therapeutic assistance (e.g., manual or physical assistance using an instrument such as LipiFlow). In some embodiments, the methods provided herein further include the step of performing debridement alone or in combination with therapeutic assistance to the individual's eye. In some embodiments, debridement is performed on one eye and the combination of debridement and therapeutic assistance is performed on the other eye. In some embodiments, the therapeutic intervention (also referred to herein as physical intervention) is performed after administration of the composition provided herein. For example, in some embodiments, the physical intervention is performed at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 4 hours, at least about 8 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, or more after administration of the composition. In some embodiments, the composition is administered periodically and the physical intervention is performed at a single time such as about 1 month after the first administration of the composition.

[0086] One aspect of the treatment method described herein is the location of local administration of the composition. In one embodiment, the composition containing the drug is administered so that little or no irritation occurs to the eye or the surrounding tissues. In one embodiment, the composition containing a drug (e.g., a keratolytic agent) is administered to the inner surface of the eyelid (e.g., one or both upper eyelids and / or one or both lower eyelids) of the individual in need.

[0087] A further embodiment of the treatment method described herein is the use of a protective element provided to the eye to avoid irritation to the eye. The formulations described herein are generally non-irritating, but in some embodiments (e.g., when using a high concentration of the drug or for use in sensitive eyes), the protective element provides an additional layer for the safety and comfort of the patient. In one embodiment, the composition containing the drug is administered while placing an eye shield on the eye to reduce contact between the drug and the cornea and / or conjunctiva and thereby reduce irritation to the eye. In some embodiments, the eye shield is a contact lens or an eye cover. In some embodiments, the eye cover has self-adhesiveness. In one embodiment, the composition containing the drug is administered while pulling the eyelid away from the eyeball to reduce contact between the drug and the cornea and / or conjunctiva and thereby reduce irritation to the eye.

[0088] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to "an agent" refers to a plurality of such agents, and reference to "the cell" refers to one or more cells (or plural cells) known to those skilled in the art and their equivalents, among others. When ranges are used with respect to physical properties such as molecular weight or chemical properties such as chemical formula, all combinations and sub-combinations in the range and in its particular embodiments are intended to be included. The term "about" when referring to a number or numerical range means that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the recited number or numerical range can vary between 1% and 5% of the recited number or numerical range. The term "comprising" (and related terms such as "comprise", "comprises", "having", or "including") is intended not to exclude the possibility that in other particular embodiments, for example, embodiments of the compositions, compositions, methods, or processes described herein may "consist of" or "consist essentially of" the features recited.

[0089] The terms "treat", "treating", or "treatment" as used herein, as construed herein, include a reduction, decrease, attenuation, alleviation, amelioration, mitigation, or decline of a disorder described herein, such as CLD and / or LWE, in either a chronic or acute treatment scenario. In one embodiment, treatment includes a reduction in terminal duct occlusion.

[0090] The terms "recurrence" or "reduce recurrence" with respect to the symptoms of a disorder described herein, such as CLD and / or LWE, are in the context of a chronic treatment scenario.

[0091] The terms "keratolytic agent" and / or "keratoplastic agent", as used herein, refer to agents that soften, disrupt, dissolve, solubilize, or relieve keratin plugs or prevent the formation of keratin plugs. Specifically, the term "keratolytic agent" refers to an agent used to promote the softening and dissolution of keratin, and the term "keratoplastic agent" refers to an agent used to reduce keratin production.

[0092] The term "lotion" represents an emulsion liquid dosage form. This dosage form is usually related to external application to the skin (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0093] The term "cream" represents an emulsion semi-solid dosage form that usually contains more than 20% water and volatile substances and / or less than 50% hydrocarbons, waxes, or polyols as solvents. Creams are more viscous than lotions. This dosage form is usually related to external application to the skin (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0094] The term "ointment" represents a semi-solid dosage form that usually contains less than 20% water and volatile substances and / or more than 50% hydrocarbons, waxes, or polyols as solvents. This dosage form is usually related to external application to the skin or mucosa (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0095] The term "solution" represents a clear and homogeneous liquid dosage form that contains one or more chemical substances dissolved in a solvent or a mixture of mutually miscible solvents (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0096] The term "suspension" refers to a heterogeneous mixture containing solid particles that are not dissolved but are suspended over at least a portion of the majority of the solvent.

[0097] The concentrations of the agents provided herein are based on appropriate measurements such as wt.%, w / w%, or w / v%.

[0098] The term "about" means any acceptable amount, such as an amount suitable to achieve the stated purpose. In some examples, "about" refers to, for example, plus or minus 20%, plus or minus 10%, or plus or minus 5%.

[0099] The term "comprising", as used herein, includes the explicit disclosure of "consisting of" and "consisting essentially of".

Examples

[0100] Example 1: Pharmacologically Active Formulations

[0101] Prepare high-viscosity formulations such as those for administration according to the disclosure provided herein. Optionally utilize appropriate formulations such as creams, ointments, emulsions, suspensions, microspheres, etc. In various embodiments, an exemplary ophthalmic ointment formulation is prepared according to the following formulation.

[0102]

Table 1

[0103] Other formulations such as ointments / semi-solids, surfactant formulations, etc. are contemplated and provided herein.

[0104] Induce abnormal keratitis in the eyes of rabbits using a 0.5% benzalkonium chloride solution. Assign to each rabbit the administration of the ointment provided herein to one eye and the administration of a control ointment to the other eye. Evaluate the inner surface of the eyelids such as the lid wiper and / or conjunctival fold.

[0105] Example 2: Diagnosis and Treatment

[0106] After wearing soft contact lenses for at least six months before admission, the subject (individual) is admitted to the clinical site. The subject is asked to rate the overall comfort of their contact lenses and their satisfaction with the contact lens wearing time. Further, the subject is evaluated based on one or more symptom scoring metrics. In some examples, the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire is provided to the subject (e.g., scored on a scale of 28 points). In one example, the Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) is also provided to the subject and scored (e.g., on a scale of 35 points) (e.g., Chalmers et al. Invest. Ophth. & Visual Science, Apr. 2009, 50:6337). In one example, the subject further evaluates themselves using symptoms commonly seen with contact lens discomfort such as dryness, blurriness, grittiness, or burning.

[0107] The appearance of the subject's eyes is evaluated. The appearance of the eyelashes (e.g., symptoms) is also evaluated, such as checking for eyelash loss, blepharitis, seborrheic pruritus, or collarettes. The fluorescein tear break-up time of both eyes is analyzed, such as by measuring using Amcon's Dry Eye Test (DET) strips.

[0108] In some examples, a direct assessment of the lid wiper area is performed. For example, in some examples, 40 μl drops of 2% fluorescein diluted with raw saline (Astrazeneca) from ophthalmic strips (Fluor-I-strip A.T. ophthalmic strips 1 mg, Wyeth-Ayerst Laboratories, Rouses Point, NY) are instilled into the inferior conjunctival sacs of both eyes by immersing for 1 minute. One minute later, 40 μl drops of resazurin green dye are prepared by immersing one (OpGreen 1.5 mg, Ophtechnics Unlimited, Haryana, India) in raw saline for 1 minute, and this is also instilled into both eyes. Finally, 1 minute after instilling the dye into the eyes, changes in the lid wiper area are examined. The lid wiper area is evaluated for an increase in the sagittal direction width and horizontal direction length of the resazurin green staining, and / or an increase in the eyelid parallel conjunctival folds. Changes in Meibomian gland dysfunction (changes) may also be evaluated, but this dysfunction is not necessary for the discrimination of CLD or LWE.

[0109] In one example, pre-symptomatic CLD or LWE is determined according to the scoring and / or analysis of the LWE symptom score questionnaire. In other examples, mild CLD or LWE is determined according to the scoring and / or analysis of the LWE symptom score questionnaire. In still other examples, mild CLD or LWE is determined according to the scoring and / or analysis of the LWE symptom score questionnaire.

[0110] For example, in a case where a subject scored 4 out of 28 on the SPEED questionnaire and 6 out of 35 on the CLDEQ-8 questionnaire, there are no specific problems with the symptoms commonly seen in contact lens discomfort such as dryness, shakiness, scratching, or burning. The appearance of the eyes is white and there is no disturbance. The eyelashes are normal without eyelash loss, blepharitis, seborrheic pruritus, or collarettes. The fluorescein tear secretion time is 4 - 6 s as measured using the Amcon dry eye test (DET) strip. There are no signs of meibomian gland abnormalities, the sagittal width and horizontal length of Lissamine Green staining are increased, and the eyelid parallel conjunctival folds are increased. These are diagnosed as pre-symptomatic contact lens discomfort (CLD). Therefore, although there are no "symptoms" of CLD, this patient is diagnosed with (pre-symptomatic) CLD mainly based on the signs of CLD.

[0111] However, in a case where a subject scored 11 out of 28 on the SPEED questionnaire and 15 out of 35 on the CLDEQ-8 questionnaire, stabbing pain, foreign body sensation, tearing, and dry eye were observed. The appearance of the eyes is white and there is no disturbance. The eyelashes are normal without eyelash loss, blepharitis, seborrheic pruritus, or collarettes. The fluorescein tear secretion time is 11 - 12 s as measured using the Amcon dry eye test (DET) strip. There are no signs of meibomian gland abnormalities and no signs of conjunctival staining. These are diagnosed as symptomatic contact lens discomfort (CLD). Therefore, although there are no "signs" of CLD, this patient is diagnosed with CLD based only on the symptoms.

[0112] The composition described in this specification as in Example 1 is administered to the inner surface of the eyelid identified as having pre-symptomatic or symptomatic CLD (or LWE). After administration (e.g., single administration and / or multiple administrations), the evaluations (e.g., symptoms and signs) described in this specification are performed again to determine the improvement in the condition.

[0113] Example 3: Clinical Evaluation of CLD Treatment

[0114] Six patients with CLD were treated with a pharmaceutical formulation containing 1% selenium disulfide. The treatment consisted of twice-weekly administration of the pharmaceutical product to the lower eyelids of both eyes. The patients were followed up at the 14th day and the 4th week, and the level of discomfort was evaluated using a Visual Analogue Scale (VAS) and a Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) (only for 4 weeks). Figures 2 to 4 are diagrams explaining the mechanism for evaluating the efficacy of the treatment, including VAS, CLDEQ-8, and the Berkeley Dry Eye Flow Chart (DEFC).

[0115]

Table 2

[0116] As shown in this Table 1, on average, the patients improved by 24 points 14 days after the treatment and by 34 points 4 weeks after the treatment.

[0117]

Table 3

[0118] As shown in this Table 2, among the 5 patients, for the data at baseline and at the 1st month, 80% (4 / 5) improved in the CLDEQ-8 questionnaire, and 40% (2 / 5) achieved a change exceeding the clinically important difference in CLDEQ-8 from baseline after treatment with the pharmaceutical formulation. Among the 4 patients with abnormal baseline CLDEQ-8 scores, 100% (4 / 4) improved in CLDEQ-8, and 50% (2 / 4) achieved a change exceeding the clinically important difference in CLDEQ-8 from baseline after treatment with the pharmaceutical formulation. The average change from baseline to the 1st month achieved the clinically important difference in CLDEQ-8 of ±3 points.

[0119] The baseline scores of the CLDEQ-8 for patients (202) and (208) were 21, indicating patients who could benefit from the clinical management of contact lens-related symptoms. One month after treatment with the pharmaceutical formulation, patient (208) presented with a CLDEQ-8 score of 13. This indicates a patient in whom contact lens-related symptoms were significantly improved. Similarly, one month after treatment with the pharmaceutical formulation, patient (202) presented with a CLDEQ-8 score of 16. This indicates a patient in whom contact lens-related symptoms were significantly improved. The improvement in patient (202) was derived from a significant reduction in haze or blurring of vision at the end of contact lens wear time, and a decrease in the frequency of feeling concerned about the eyes and having to interrupt work to remove the contact lenses during contact lens wear in the past two weeks. The improvement in patient (208) was derived from a decrease in the frequency and severity of dryness and discomfort in the eyes at the end of contact lens wear.

[0120] Therefore, patients reported improvement in the main CLD symptoms (such as dryness and discomfort) across the means (e.g., CLDEQ-8 and VAS) during use of the pharmaceutical formulation, as well as a significant reduction in haze or blurring of vision at the end of contact lens wear time.

[0121] Preferred embodiments of the present invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. It is intended that the invention not be limited by the specific examples provided within this specification. The invention is described with reference to the foregoing specification, but the description and illustration of the embodiments herein are not intended to be construed in a limiting sense. Numerous variations, modifications, and substitutions are presently contemplated by those skilled in the art without departing from the invention. Further, it is to be understood that all aspects of the invention are not limited to the specific depictions, configurations, or relative ratios described herein, which depend on various conditions and variables. It is to be understood that various alternatives to the embodiments of the invention described herein are available for use in practicing the invention. Therefore, the invention is considered to extend to any such alternatives, modifications, variations, or equivalents. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be thereby encompassed.

Claims

1. 1. A method for treating contact lens discomfort (CLD) or a symptom thereof (e.g., a symptom associated with the symptom) in an individual, comprising topically administering to the eye or eyelid of the individual a pharma- ceutical acceptable composition comprising a therapeutically effective amount of at least one keratolytic agent and an ophthalmically acceptable carrier.

2. The method of claim 1 , wherein the composition is administered to at least a portion of the tarsal conjunctiva of the individual's eye.

3. 3. The method of claim 1 or 2, wherein the contact lens discomfort is associated with alterations to the lid conjunctiva or a portion thereof.

4. The method of claim 3 , wherein the alteration to the ocular conjunctiva comprises trauma or keratinization of the ocular conjunctiva or a portion thereof.

5. The method of claim 1 , wherein the composition is administered to the eyelid margin of the individual's eye.

6. 6. The method of claim 1, wherein the composition is administered to both eyes of the individual.

7. 7. The method of claim 1, further comprising treating inflammation, dryness, or pain associated with contact lens discomfort.

8. 8. The method of claim 1, which results in improvement of eyelid or tear film symptoms of contact lens discomfort (CLD).

9. 9. The method of any one of claims 1 to 8, wherein the individual is afflicted with Lidwiper's keratoepitheliopathy (LWE).

10. 10. The method of claim 9, wherein the eye of the individual includes a lid wiper area and the pharmaceutical composition is administered directly to and / or reaches at least a portion of the lid wiper area after administration.

11. 11. The method of claim 9 or 10, wherein the lidwiper keratoepitheliopathy is clinically graded with a severity level of at least 1 (e.g., based on a separate 0 to 3 scale or a subjective scale of 0 to 3, where 3 is most severe and 0 is no damage).

12. 12. The method of any one of claims 9 to 11, wherein the lid wiper keratoepitheliopathy comprises trauma to the lid wiper area of ​​the eyelid.

13. 13. The method of any one of claims 1 to 12, wherein the individual has been assessed as having a score of at least 12 according to the CLDEQ-8 measurement tool.

14. 14. The method of any one of claims 1 to 13, resulting in an improvement of the CLDEQ-8 measurement tool.

15. 15. The method of any one of claims 1 to 14, wherein the individual is or has been assessed for comfortable wear time and / or subjective visual acuity prior to administration.

16. 16. The method of claim 15, which results in improved comfortable wearing time and / or subjective visual acuity assessment.

17. 17. The method of any one of claims 1 to 16, which results in a reduction in a composite measure of one or more symptoms selected from the group consisting of dryness, roughness, coarseness, stinging, irritation, burning, and tearing.

18. 18. The method of any one of claims 1 to 17, which results in improvement in the horizontal (width) and / or sagittal (height) of the lesion and / or the palpebral conjunctival fold (LIPCOF).

19. 19. The method of any one of claims 1 to 18, wherein the at least one keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and L-pyrrolidone carboxylate.

20. 20. The method of claim 19, wherein the at least one keratolytic agent is salicylic acid.

21. 20. The method of claim 19, wherein the at least one keratolytic agent is selenium disulfide.

22. 22. The method of any one of claims 19 to 21, wherein the concentration of the at least one keratolytic agent in the composition is between about 0.01% and about 10% by weight.

23. 23. The method of any one of claims 1 to 22, wherein the composition is administered in a single dose.

24. 23. The method of any one of claims 1 to 22, wherein the composition is administered periodically.

25. 23. The method of any one of claims 1 to 22, wherein the composition is administered at least twice a week.

26. 26. The method of any one of claims 1 to 25, wherein the composition is homogenous.

27. 27. The method of any one of claims 1 to 26, wherein the composition is a dispersion or suspension.

28. 28. The method of any one of claims 1 to 27, wherein the composition is hydrophilic.

29. 29. The method of any one of claims 1 to 28, wherein the composition comprises an oily base.

30. 30. The method of any one of claims 1 to 29, wherein the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable solvent and at least one ophthalmically acceptable excipient.

31. 1. A method for treating lid wiper keratoepitheliopathy (LWE) or a symptom thereof in an individual, comprising topically administering to the eye or eyelid (e.g., the lid margin) of the individual a pharma- ceutical acceptable composition comprising a therapeutically effective amount of at least one keratolytic agent and an ophthalmically acceptable carrier.

32. 32. The method of claim 31, wherein the eye of the individual includes a lid wiper area and the pharmaceutical composition is administered directly to and / or reaches at least a portion of the lid wiper area after administration.

33. 33. The method of claim 31 or 32, wherein the Lidwiper Epitheliopathy (LWE) is Upper Lidwiper Epitheliopathy (LWE).

34. 33. The method of claim 31 or 32, wherein the Lidwiper Epitheliopathy (LWE) is Lower Lidwiper Epitheliopathy (LWE).

35. 35. The method of any one of claims 31 to 34, wherein the lid wiper keratopathy is associated with contact lens discomfort (CLD).

36. 36. The method of claim 35, wherein the individual is suffering from contact lens discomfort.

37. 37. The method of claim 35 or 36, wherein the individual wears contact lenses.

38. 38. The method of any one of claims 31 to 37, wherein the lidwiper keratoepitheliopathy is clinically graded with a severity level of at least 1 (e.g., based on a separate 0 to 3 scale or a subjective scale of 0 to 3, where 3 is most severe and 0 is no damage).

39. 39. The method of any one of claims 31 to 38, wherein the lid wiper keratoepitheliopathy comprises trauma to the lid wiper area of ​​the eyelid.

40. 40. The method of any one of claims 31 to 39, comprising treating inflammation, dryness, or pain associated with lidwiper keratoepitheliopathy (LWE).

41. 41. The method of any one of claims 31 to 40, wherein the individual has been assessed according to the CLDEQ-8 measurement tool as having a score of at least 12.

42. 42. The method of any one of claims 31 to 41, resulting in an improvement of the CLDEQ-8 measurement tool.

43. 43. The method of any one of claims 31 to 42, wherein the individual is or has been assessed for comfortable wear time and / or subjective visual acuity prior to administration.

44. 44. The method of claim 43, which results in improved comfortable wearing time and / or subjective visual acuity assessment.

45. 45. The method of any one of claims 31 to 44, which results in a reduction in a composite measure of one or more symptoms selected from the group consisting of dryness, roughness, coarseness, stinging, irritation, burning, and tearing.

46. 46. ​​The method of any one of claims 31 to 45, which results in improvement in the horizontal (width) and / or sagittal (height) of the lesion and / or the palpebral conjunctival fold (LIPCOF).

47. 47. The method of any one of claims 31 to 46, which results in improvement of eyelid or tear film symptoms of contact lens discomfort (CLD).

48. 48. The method of any one of claims 31 to 47, wherein the at least one keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and L-pyrrolidone carboxylate.

49. 49. The method of claim 48, wherein the at least one keratolytic agent is selenium disulfide.

50. 49. The method of claim 48, wherein the at least one keratolytic agent is salicylic acid.

51. 51. The method of any one of claims 48 to 50, wherein the concentration of the at least one keratolytic agent in the composition is between about 0.01% and about 10%.

52. 52. The method of any one of claims 31 to 51, wherein the composition is administered in a single dose.

53. 52. The method of any one of claims 31 to 51, wherein the composition is administered periodically.

54. 52. The method of any one of claims 31-51, wherein the composition is administered at least twice a week.

55. 55. The method of any one of claims 31 to 54, wherein the composition is homogenous.

56. 56. The method of any one of claims 31 to 55, wherein the composition is a dispersion or suspension.

57. 57. The method of any one of claims 31 to 56, wherein the composition is hydrophilic.

58. 58. The method of any one of claims 31 to 57, wherein the composition comprises an oily base.

59. 59. The method of any one of claims 31 to 58, wherein the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable solvent and at least one ophthalmically acceptable excipient.

60. A method for inhibiting biofilm formation on a contact lens of an individual, comprising the step of topically administering to the contact lens in contact with the individual's eye, or to the eye or eyelid associated with the contact lens, a pharma- ceutically acceptable composition comprising a therapeutically effective amount of at least one keratolytic agent and an ophthalmically acceptable carrier.

61. 61. The method of claim 60, wherein the composition is administered to the individual's eye or eyelid in association with the contact lens.

62. 62. The method of claim 61, wherein the composition is administered to the individual's eyelid margin in association with the contact lens.

63. 61. The method of claim 60, wherein the composition is administered to the contact lens in contact with the eye.

64. 64. The method of any one of claims 60 to 63, wherein the contact lens is a gas permeable hard contact lens.

65. 64. The method of any one of claims 60 to 63, wherein the contact lenses are soft contact lenses.

66. 66. The method of any one of claims 60 to 65, wherein the individual suffers from contact lens discomfort (CLD).

67. 67. The method of any one of claims 60 to 66, wherein the individual is affected by Lidwiper's keratoepitheliopathy (LWE).

68. 68. The method of any one of claims 60 to 67, wherein the individual has been assessed according to the CLDEQ-8 measurement tool as having a score of at least 12.

69. 69. The method of any one of claims 60 to 68, resulting in an improvement of the CLDEQ-8 measurement tool.

70. 70. The method of any one of claims 60 to 69, wherein the individual is or has been assessed for comfortable wear time and / or subjective visual acuity prior to administration.

71. 71. The method of claim 70, which results in improved comfortable wearing time and / or subjective visual acuity assessment.

72. 72. The method of any one of claims 60 to 71, which results in a reduction in a composite measure of one or more symptoms selected from the group consisting of dryness, roughness, roughness, stinging, irritation, burning, and tearing.

73. 73. The method of any one of claims 60 to 72, which results in improvement in the horizontal (width) and / or sagittal (height) of the lesion and / or the palpebral conjunctival fold (LIPCOF).

74. 74. The method of any one of claims 60 to 73, wherein the at least one keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and L-pyrrolidone carboxylate.

75. 75. The method of claim 74, wherein the at least one keratolytic agent is salicylic acid.

76. 75. The method of claim 74, wherein the at least one keratolytic agent is selenium disulfide.

77. 77. The method of any one of claims 74 to 76, wherein the concentration of the at least one keratolytic agent in the composition is between about 0.01% and about 10% by weight.

78. 78. The method of any one of claims 60 to 77, wherein the composition is administered in a single dose.

79. 78. The method of any one of claims 60 to 77, wherein the composition is administered periodically.

80. 78. The method of any one of claims 60 to 77, wherein the composition is administered at least twice a week.

81. 81. The method of any one of claims 60 to 80, wherein the composition is homogenous.

82. 82. The method of any one of claims 60 to 81, wherein the composition is a dispersion or suspension.

83. 83. The method of any one of claims 60 to 82, wherein the composition is hydrophilic.

84. 84. The method of any one of claims 60 to 83, wherein the composition comprises an oily base.

85. 85. The method of any one of claims 60 to 84, wherein the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable solvent and at least one ophthalmically acceptable excipient.

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