Compositions and methods for treating contact lens discomfort

Abstract

Described herein are compositions and methods for treating contact lens discomfort (CLD) and / or lid wiper keratoepitheliopathy (LWE). These compositions contain a keratolytic agent, such as salicylic acid or 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 keratoepitheliopathy (LWE).

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 April 12, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Contact lens discomfort (CLD) is a condition characterized by sudden or persistent adverse ocular sensations associated with lens wear, with or without visual impairment, resulting from incompatibility between the contact lens and the ocular environment, potentially leading to a shortened contact lens wear period or cessation. Patients with CLD experience symptoms of ocular discomfort (e.g., dryness, irritation, discomfort, fatigue, etc.), which may increase in severity over the course of a day while the patient is wearing contact lenses. Symptoms of dryness and discomfort are highly prevalent among contact lens wearers (up to 50%) and are the most commonly cited reason for discontinuing contact lens wear. Contact lens discontinuation rates are consistently high (16%–34% per year) despite decades of research into contact lens design, materials, rewetting products, and behavioral modifications during wear. CLD is primarily diagnosed by symptomatology as opposed to observational signs. For this reason, symptom use is often used as an endpoint because it directly relates to the patient's contact lens experience and motivations for seeking treatment.

[0003] Common treatments for CLD include the regular use of rewetting eye drops, contact lens refitting (using a different design or material or replacement schedule), and contact lens care solutions or regimens, as well as other less commonly used techniques including topical or systemic medications, dietary modifications, and punctal plugs. Ultimately, CLD is considered a major factor associated with permanent cessation of contact lens wear. Summary of the Invention

[0004] The high prevalence of contact lens discontinuation, occurring in over 1.4 million contact lens wearers worldwide, represents a significant problem resulting in ocular tissue changes that, in some cases, result from the destructive presence of contact lenses on the eye. Lid-wiper keratoepitheliopathy (LWE) and palpebral parallel conjunctival folds (LIPCOF) are examples of ocular tissue changes that have been reported to be strongly correlated with contact lens wear. LWE is found in 67–80% of symptomatic contact lens wearers but only 13–32% of asymptomatic subjects. Histology has demonstrated that in patients with CLD, an increased number of cells with atypical keratinization extend beyond the physiologically occurring natural stainable line of Marx across the surface of the lid-wiper corneal epithelium.

[0005] Many lens-related factors, including lens material, design, and surface properties, are also associated with CLD. Changes related to lens surface properties include biofilm accumulation, which can alter mechanical properties (e.g., lubricity and wettability), and the interaction of surface deposits with their biological role in maintaining ocular health. Protein accumulation on the lens surface, particularly altered protein activity that loses its native activity upon denaturation, has been shown to be associated with CLD. Therefore, in some instances, providing ocular therapeutics capable of treating CLD and / or LWE or one or more of their symptoms can prevent the accumulation of certain proteins, lipids, and / or mucins and prevent protein denaturation. In particular, evidence has shown that keratin accumulates on contact lenses during wear, which is strongly correlated with dry eye symptoms (Negar Babaei Omali et al. Mol Vis. 2013;19:390-399).

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

[0007] In certain embodiments, the methods provided herein relate to treating any symptoms associated with contact lens discomfort, such as, but not limited to, inflammation, dryness, pain, or a combination thereof.

[0008] In certain embodiments, the compositions used in the methods provided herein may contain any of the following: benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acid, urea, lactic acid, boric acid, retinoic acid, sodium thioglycolate, allantoin, zinc pyrithione, zinc L-pyrrolidone carboxylate, seleocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, glutathione, dithiothreitol, thiorphan, 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, octotiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, lenthionine, ajoene, allicin, gemopatrilat, thioethanol, thiophospholipids, thiocholesterol, 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 comprise a keratolytic agent selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and zinc L-pyrrolidone carboxylate.

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

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

[0011] In some embodiments, the contact lens discomfort and / or lens wiper epitheliopathy described herein and / or treated according to the methods described herein is associated with a (e.g., clinically identified or suspected) modification to a portion of the eye, such as one or more eyelids (e.g., an inner surface thereof, such as the tarsal conjunctiva, or other portions thereof, such as the lid wiper region and / or palpebral conjunctival fold). In certain embodiments, the modification to the inner surface of the eyelid (or tarsal conjunctiva) is a modification to the anterior edge of the tarsal conjunctiva (e.g., the "lid wiper" region of the eyelid). In certain embodiments, the processes provided herein comprise identifying (e.g., in a clinical setting, such as prior to administration of a pharmaceutical composition) a modification in the inner surface of the individual's eyelid (e.g., the lid wiper region or tarsal conjunctiva) or its anterior edge, or administering the composition to an individual in whom a modification in the inner surface of the eyelid (e.g., the lid wiper region or tarsal conjunctiva) has been identified. In various examples, a modification (e.g., a problematic modification, i.e., a modification corresponding to contact lens discomfort (CLD)) of the inner surface of the eyelid (e.g., the lid wiper region or the lid conjunctiva) is present and / or targeted, resulting in trauma to the inner surface of the eyelid (e.g., the lid wiper region or the lid conjunctiva) or a modification resulting in trauma (where the trauma is associated with friction between the inner surface of the eyelid (e.g., the lid conjunctiva) and the lens). In some embodiments, the modification is or includes (e.g., atypical) keratinization (e.g., parakeratinization (PK)) of a modification in a portion of the inner surface of the eyelid (e.g., a portion of the lid wiper region or the lid conjunctiva).

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

[0013] Additionally, certain embodiments herein provide methods for treating lidwiper keratoepitheliopathy (LWE), such as by administering a keratolytic agent to an individual's eye or surrounding tissue, such as the eyelid or a portion thereof (e.g., the eyelid margin). In some embodiments, treating the lidwiper keratoepitheliopathy (LWE) comprises treating a symptom associated with the lidwiper keratoepitheliopathy (LWE). In certain embodiments, the symptom associated with the lidwiper keratoepitheliopathy (LWE) is a symptom identifiable by an individual and / or a clinician. In certain embodiments, the methods provided herein relate to treating any symptom associated with the lidwiper keratoepitheliopathy (LWE), such as, but not limited to, inflammation, dryness, pain, or a combination thereof. In certain embodiments, the keratolytic agent is benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acid, 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, thiorphan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omadextrin, methylparaben ... Selected from the group consisting of patrilat, ovothiol A, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octotiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, lenthionine, ajoene, allicin, gemopatrilat, thioethanol, thiophospholipids, thiocholesterol, 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, dithranol, 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 keratoepitheliopathy (LWE), its symptoms (e.g., symptoms associated with the condition). In certain embodiments, the method comprises topically administering to the eye (or surrounding tissues thereof, such as the eyelid or a portion thereof (e.g., the lid margin)) of the individual a pharmaceutically acceptable composition comprising a therapeutically effective amount of at least one keratolytic agent. In certain embodiments, the pharmaceutically acceptable composition further comprises an ophthalmically acceptable carrier (e.g., comprising an ophthalmic solvent and an isotonic agent). In certain embodiments, topical administration to the eye of the individual comprises topical ocular administration, topical eyelid (eyelid) administration (e.g., to the inside and / or outside of the eyelid), or a combination thereof. In some embodiments, topical administration to the eye or eyelid of the individual comprises administration to the lid margin of the eye of the individual. In certain embodiments, topical administration to the eye of the individual comprises topical administration directly to (at least a portion of) the lid wiper region of one or more eyelids (of the eye). In some embodiments, topical administration to the eye comprises topical administration resulting in delivery (after administration) of at least a portion of the composition or keratolytic agent to (at least a portion of) the lid conjunctiva (or lid wiper region) of the eye.

[0015] In certain preferred embodiments, administration (e.g., directly) is administration (e.g., topical) to the inner lid surface. In more preferred embodiments, administration is or includes administration (e.g., directly) to the lid wiper region of the inner lid surface. In certain embodiments, administration is or includes administration (e.g., directly) to the lid wiper region and the stratified squamous epithelium region and / or the sub-lid fold region. In some embodiments, administration is or includes administration (e.g., directly) to the lid wiper region, the stratified squamous epithelium region and the plantar fold region of the lid. In certain embodiments, administration is or includes administration (e.g., directly) to the lid wiper, stratified squamous epithelium, sub-lid fold, and stratified columnar epithelium region of the eyelid.

[0016] In certain embodiments, the lid-wiper keratoepitheliopathy (LWE) is upper lid-wiper keratoepitheliopathy (LWE), however, in some embodiments, the lid-wiper keratoepitheliopathy (LWE) is lower lid-wiper keratoepitheliopathy (LWE).

[0017] In some embodiments, an individual (e.g., a patient) being treated in accordance with the methods described herein wears one or more contact lenses (e.g., regularly, such as at least one hour per day or at least one day per week). In some embodiments, an individual being treated in accordance with the methods described herein wears one or more contact lenses two or more days per week, such as three, four, five, or five days per week. In some embodiments, an individual being treated in accordance with the methods described herein wears one or more contact lenses throughout the treatment period (e.g., as described herein). In other embodiments, an individual being treated in accordance with the methods described herein does not wear one or more contact lenses throughout the treatment period (e.g., regular wear is resumed after a given treatment period). In some embodiments, the lid wiper keratoepitheliopathy is associated with contact lens discomfort (CLD) and / or the individual is suffering from, has been diagnosed with, or is suspected of suffering from contact lens discomfort (CLD). In some instances, contact lens discomfort is primarily associated with the upper eyelid due to greater interaction between the upper lid wiper and the contact lens compared to interaction between the lower lid wiper and the contact lens (e.g., due to longer upper eyelid movement during blinking).

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

[0019] In some embodiments, the lid wiper keratoepitheliopathy is present in any form, including clinically significant forms. In some embodiments, the lid wiper keratoepitheliopathy includes and / or is indicated by the presence of trauma to and / or around the lid wiper region of the eyelid (e.g., the upper eyelid). In some embodiments, treatment is continued until a decrease in the trauma is observed. In some embodiments, the lid wiper keratoepitheliopathy includes and / or is indicated by the presence of (e.g., atypical) keratinization (e.g., subkeratinization (PK)) in and / or around the lid wiper region of the eyelid (e.g., the upper eyelid). In some embodiments, treatment is continued until a decrease in (e.g., atypical) keratinization (e.g., subkeratinization (PK)) is observed. In some embodiments, the lid wiper keratoepitheliopathy includes and / or is indicated by the presence of inflammation in and / or around the lid wiper region of the eyelid (e.g., the upper eyelid). In some embodiments, treatment is continued until a decrease in the inflammation is observed. In some embodiments, the lid wiper keratoepitheliopathy comprises the presence of, and / or is indicated by, dry eye. In some embodiments, treatment is continued until a decrease in the dryness is observed. In some instances, such a condition is considered to be present when it is present in all or part of the indicated area of the eye.

[0020] In certain embodiments herein, methods are provided for treating ocular dryness, such as by administering a keratolytic agent to the eye of an individual. In some embodiments, the dryness is associated with contact lens discomfort (CLD) and / or lid wiper keratoepitheliopathy (LWE). In various embodiments herein, such treatment is as described herein for any method involving the treatment of contact lens discomfort (CLD) and / or lid wiper keratoepitheliopathy (LWE).

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

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

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

[0024] In certain embodiments herein, there is provided a method of inhibiting biofilm formation on a contact lens in the eye of an individual, the method comprising administering a pharmaceutically acceptable composition to an ocular or surrounding tissue associated with the contact lens, such as the eyelid (e.g., the eyelid margin), or to a contact lens in contact with the eye. 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 ophthalmically acceptable carrier.

[0025] In some embodiments, individuals treated according to the methods provided herein have been evaluated using a symptom scoring technique, such as a symptom scoring technique suitable for diagnosing contact lens discomfort (CLD), lid wiper keratoepitheliopathy (LWE), dry eye pain, ocular inflammation, or any other indication described herein. In certain embodiments, the individual has been diagnosed using a Contact Lens Dry Eye Questionnaire (CLDEQ) measurement tool, such as a CLDEQ-8 measurement tool (e.g., as 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, or copyrighted by Indiana University, the disclosures of which are both incorporated herein by reference), or any portion thereof (e.g., 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, the disclosures of which are 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 has a CLDEQ-8 score of at least 12. In even more specific embodiments, the individual has a CLDEQ-8 score of at least 15. In even more specific embodiments, the individual has a CLDEQ-8 score of at least 18. In some embodiments, the method results in an improvement in a CLDEQ-8 measurement tool. In certain embodiments, an individual treated in accordance with the methods provided herein is or has been assessed for comfortable wear time and / or subjective visual acuity prior to administration (e.g., using a VAS as the outcome variable). In some embodiments, the method results in an improvement in comfortable wear time and / or subjective visual acuity assessment.In various embodiments, other suitable symptom scoring processes (e.g., scoring the negative effects of the disorder and / or symptomatic signs of the disorder) are optionally utilized to diagnose an individual in need of a treatment described herein (e.g., thereby diagnosing the individual as suffering from LWE or CLD) (e.g., any or a combination of the symptoms (e.g., signs) 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, the disclosure of which is incorporated herein by reference).

[0026] In some embodiments, an individual treated according to the methods provided herein has not been diagnosed with meibomian gland dysfunction (MGD). In some embodiments, an individual treated for CLD as provided herein has not been diagnosed with MGD. In some embodiments, an individual 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, combined results from trials primarily aimed at predicting CLD suggest that the clinical outcome variables of tear stability, tear meniscus height / area, "lid wiper keratoepitheliopathy" (LWE), and lid parallel conjunctival folds (LIPCOF) are most likely to predict CLD. Notably absent from this finding are traditional MGD measures, such as gland grading (e.g., meibomian gland score (MGS)). In fact, Young et al., Soft contact lens-related dryness with and without clinical signs. Optom. Vis. Sci. 2012;89:1125-32, reported that 23% of symptomatic soft contact lens wearers who reported significant soft contact lens-related dryness using the CLDEQ had no signs of disease.

[0027] In some embodiments, treating an individual according to the methods provided herein results in a decrease in a composite measure of symptoms (e.g., dryness, grittiness, scratchiness, soreness, irritation, burning, watering, or a combination of two or more thereof), or the method is continued until such decrease occurs. In certain embodiments, the method results in an improvement in the horizontal (width) and / or sagittal (height) of the lesion (e.g., of the lid wiper). In some embodiments, the method results in an improvement in palpebral conjunctival folds (LIPCOF). In some embodiments, the method results in an improvement in the eyelid symptoms of contact lens discomfort (CLD). In some embodiments, the method results in an improvement in the tear film symptoms of contact lens discomfort (CLD). In some embodiments, the method results in an improvement in meibomian gland secretions (MGS) and / or lipid-secreting meibomian glands (MGYLS).

[0028] Thus, described herein are methods and formulations for treating various ocular disorders (e.g., contact lens discomfort (CLD) and / or lid wiper keratoepitheliopathy (LWE)) using keratolytic agents. In certain embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, 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, thiorphan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omalidomide, methylparaben ... Selected from the group consisting of patrilat, ovothiol A, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octotiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, lenthionine, ajoene, allicin, gemopatrilat, thioethanol, thiophospholipids, thiocholesterol, 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, dithranol, salicylic acid, selenium disulfide, alpha 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 about 0.01% to about 30% (e.g., about 0.01% to about 10%, about 0.01% to about 5%, about 0.01% to about 2.5%, about 0.01% to about 1%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 2.5%, 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%, about 2.5%, about 2%, about 1%, about 0.5%, 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 about 0.01% to about 30% (e.g., about 0.01% to about 10%, about 0.01% to about 5%, about 0.01% to about 2.5%, about 0.01% to about 1%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 2.5%, 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 administered topically to the individual until the targeted disorder and / or symptoms associated therewith (e.g., symptoms of the condition) are alleviated (e.g., partially or completely). In some embodiments, the composition is administered topically to the patient periodically after alleviation is achieved. In some embodiments, the topical administration is a single administration (e.g., the composition is administered a single time). In some embodiments, the topical administration is regular administration (e.g., the composition is administered regularly, such as once daily, twice daily, once weekly, twice weekly, every other week, etc.). In some embodiments, the regular administration is once daily (e.g., the composition is administered once daily). In some embodiments, the regular administration is twice daily (e.g., the composition is administered at least twice daily). In some embodiments, the regular administration is twice weekly (e.g., the composition is administered at least twice weekly). In some embodiments, the composition for topical administration is a semi-solid composition. In some embodiments, the composition for topical administration is homogenous.In some embodiments, the topical composition is a dispersion or suspension. In some embodiments, the topical composition is hydrophilic. In some embodiments, the topical composition is hydrophobic. In some embodiments, the topical composition comprises an oily base. In some embodiments, the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable excipient. In some embodiments, the topical composition 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.

[0029] In one embodiment, a composition provided herein is topically administered to an individual such that the composition reaches the patient's eyelid margin. In certain embodiments, the composition comprises a therapeutically effective amount of a keratolytic agent in an ophthalmically 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 about 0.01% to about 30% (e.g., about 0.01% to about 10%, about 0.01% to about 5%, about 0.01% to about 2.5%, about 0.01% to about 1%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 2.5%, 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 topical composition is homogeneous. In some embodiments, the topical composition is a dispersion or suspension. In some embodiments, the topical composition is hydrophilic. In some embodiments, the topical composition comprises an oily base. In some embodiments, the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable excipient. In some embodiments, the topical composition is a gel, such as a non-aqueous gel. In another embodiment, 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 comprise (e.g., additional) pharmacological agents useful for treating an ocular disorder, such as dry eye, eye pain, eye inflammation, contact lens discomfort (CLD), and / or lid wiper keratoepitheliopathy (LWE), in a subject. In some embodiments, the formulations described herein are applied to the patient's eye. In some embodiments, the formulations described herein are applied to the patient's eyelid (e.g., the eyelid margin). In some embodiments, the formulations described herein are applied to the patient's lid conjunctiva. In some embodiments, the formulations described herein are applied to one of the patient's eyes or surrounding tissues (e.g., the eyelid (e.g., the eyelid margin or the lid conjunctiva)). In some embodiments, the formulations described herein are applied to both of the patient's eyes or surrounding tissues (e.g., the eyelid (e.g., the lid margin or the lid conjunctiva)). In some embodiments, multiple applications of the formulation are required (e.g., periodically, such as daily, twice daily, weekly, twice weekly, or every other week).

[0031] In some embodiments, in any of the methods provided herein, the method further comprises performing a physical intervention, such as applying a warm compress, debridement, therapeutic intervention, or a combination thereof (e.g., a combination of debridement and therapeutic intervention), to the individual's eye. In some embodiments, debridement is performed on one eye and a combination of debridement and therapeutic intervention is performed on the other eye. In some embodiments, the physical intervention occurs after administration of a composition provided herein. For example, in some embodiments, the physical intervention occurs at least about 5 minutes after administration of a composition provided herein, such as 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 a composition provided herein. In some embodiments, the composition is administered periodically and the physical intervention occurs at a single time, such as about 1 month after the initial administration of the composition.

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

[0033] The methods and formulations described herein include therapeutic levels of an active agent that acts alone or in combination with other components to provide a therapeutic benefit, such as treating a disorder or associated symptoms described herein. Furthermore, in some embodiments, the active agent is formulated or applied to be tolerable to the ocular surface (e.g., so as not to cause excessive irritation or disruption to the epithelial surface of the eye). In some embodiments, the active agent is formulated and / or applied to avoid damaging lipid-producing cells (e.g., upon contact with the formulation).

[0034] In some embodiments, the formulations are applied for a duration and frequency that is acceptable and practical to the physician or patient administering the drug, for example, a physician may apply a formulation described herein weekly or twice weekly for several weeks to induce (at least partial) opening of the obstruction, and the patient may apply a different formulation daily, or may use a stronger formulation daily for several weeks, followed by a weaker formulation daily.

[0035] In some embodiments, the application method varies depending on the concentration of the active agent and / or the severity of the ocular disorder or condition being treated, including, but not limited to, occlusion of the ocular surface. In other embodiments, the application method or formulation (e.g., with or without a preservative such as benzalkonium chloride (BAK)) is altered to enhance penetration or residence time in the target tissue to enhance therapeutic efficacy. In other embodiments, the application method or formulation is altered to enhance penetration or residence time in the target tissue to minimize the time required. In other embodiments, the application method or formulation is formulated (e.g., with a viscosity enhancer and / or skin adhesive) to increase contact with the target tissue while minimizing contact with non-target tissues, including the eye, thereby limiting or reducing undesired 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 to achieve therapeutic benefit while minimizing irritation or disruption to the eye or tissues surrounding the eye.

[0037] In some embodiments, the active agent is a keratolytic and / or keratoplastic agent selected from benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, inorganic selenium compounds such as selenium disulfide, SeCl, NaSeO, organic selenium compounds such as ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) or an analog thereof, alpha hydroxy acid, urea, lactic acid, or sodium thioglycolate. In some embodiments, the active agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acid, urea, lactic acid, boric acid, retinoic acid, sodium thioglycolate, allantoin, zinc pyrithione, zinc L-pyrrolidone carboxylate, seleocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, glutathione, dithiothreitol, thiorphan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, and o- The keratolytic and / or keratinogenic agent is selected from bothiol A, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octotiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, lenthionine, ajoene, allicin, gemopatrilate, thioethanol, thiophospholipids, thiocholesterol, 12-mercaptododecanoic acid, 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosanoic acid, and sulfanegen. In some embodiments, the keratolytic and / or keratinogenic agent is selected from benzoyl peroxide, coal tar, dithranol, salicylic acid, or selenium disulfide. In some embodiments, the keratolytic and / or keratinogenic agent is salicylic acid or selenium disulfide. In some embodiments, the keratolytic and / or keratinogenic agent is salicylic acid. In some embodiments, the keratolytic and / or keratinogenic agent is selenium disulfide.In some embodiments, at least one of the keratolytic and / or keratinogenic agents is salicylic acid. In some embodiments, at least one of the keratolytic and / or keratinogenic agents is selenium disulfide. In some embodiments, the concentration of salicylic acid in the composition is about 0.01% to about 30% (e.g., about 0.01% to about 10%, about 0.01% to about 5%, about 0.01% to about 2.5%, about 0.01% to about 1%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 2.5%, 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 about 0.01% to about 30% (e.g., about 0.01% to about 10%, about 0.01% to about 5%, about 0.01% to about 2.5%, about 0.01% to about 1%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 2.5%, 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%, about 2.5%, about 2%, about 1%, about 0.5%, or about 0.1% or less.

[0038] In some embodiments, the symptoms associated with CLD or LWE treated in accordance with the methods provided herein include symptoms (e.g., a deviation from normal function or sensation that is evident to an individual or patient and reflects the presence of an unnatural state of disease or disorder; symptoms can be objective or subjective). In some embodiments, the symptoms associated with CLD or LWE described herein include any one or more of dryness, grittiness, roughness, stinging, irritation, burning, and / or tearing in the eye or surrounding tissues (e.g., in an individual or patient who wears or is wearing at least one contact lens and / or who has or is suspected of having CLD or LWE). In some embodiments, such symptoms result in a reduced duration of contact lens wear. In some embodiments, the presence of one or more such symptoms is used to diagnose an individual or patient as having CLD or LWE.

[0039] In some embodiments, other symptoms or signs are present in an individual with CLD and / or LWE or are utilized to diagnose an individual as having CLD and / or LWE, hi some embodiments, such symptoms or signs include abnormal lid juxtaposition conjunctival folds, meibomian foam, tear evaporation rate (with or without contact lenses), eyelid roughness, eyelid staining, eyelid hyperemia, or a combination of one or more such symptoms or signs. [Brief explanation of the drawings]

[0040] [Figure 1] 1 illustrates a cross-sectional schematic of a typical eyelid functioning normally in relation to the ocular surface. [Figure 2] FIG. 1 shows a visual analogue scale (VAS) sensitive to CLD. [Figure 3] FIG. 1 shows the Contact Lens Dry Eye Questionnaire 8 (CLDEQ-8). [Figure 4] FIG. 1 shows the Berkeley Dry Eye Flow Chart (DEFC). DETAILED DESCRIPTION OF THE INVENTION

[0041] Various embodiments herein provide methods for treating ocular disorders and their symptoms by administering a therapeutically effective amount of a pharmaceutically active agent provided herein to the eye (e.g., the eyeball or eyelid) of an individual. In certain embodiments, the method comprises treating contact lens discomfort (CLD) or a symptom thereof. In certain embodiments, the method comprises treating lid wiper keratoepitheliopathy (LWE) or a symptom thereof. In certain embodiments, the method comprises treating dry eye, eye pain, eye inflammation, or other disorders or symptoms described herein, where such disorders or symptoms are associated with contact lens discomfort (CLD) or lid wiper keratoepitheliopathy (LWE). In certain embodiments, the method comprises administering the composition to a contact lens configured for use in the eye of an individual (e.g., a patient) (e.g., to prevent modifications to the contact lens surface [e.g., to maintain lubricity and / or reduce biofilm formation] and / or to modulate the accumulation of proteins [e.g., keratin] and / or lipids, mucins, and modified proteins associated with CLD on the contact lens).

[0042] In certain embodiments, provided herein are methods for treating contact lens discomfort (CLD), such as by administering a keratolytic agent to an individual's eye or surrounding tissues, such as the eyelid (e.g., the eyelid margin). In some embodiments, treating 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 identifiable by an individual and / or a clinician. In certain embodiments, the methods provided herein relate to treating any symptom associated with contact lens discomfort, such as, but not limited to, inflammation, dryness, pain, or a combination thereof. In certain embodiments, the keratolytic agent is benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acid, 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, thiorphan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omadextrin, methylparaben ... Selected from the group consisting of patrilat, ovothiol A, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octotiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, lenthionine, ajoene, allicin, gemopatrilat, thioethanol, thiophospholipids, thiocholesterol, 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, dithranol, salicylic acid, selenium disulfide, an alpha hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylate.

[0043] Further provided herein in certain embodiments are methods for treating lidwiper keratoepitheliopathy (LWE), such as by administering a keratolytic agent to an individual's eye or surrounding tissues (e.g., the eyelid (e.g., the lid margin) or the tarsal conjunctiva). In some embodiments, treating the lidwiper keratoepitheliopathy (LWE) comprises treating a symptom associated with the lidwiper keratoepitheliopathy (LWE). In certain embodiments, the symptom associated with the lidwiper keratoepitheliopathy (LWE) is a symptom identifiable by an individual and / or a clinician. In certain embodiments, the methods provided herein relate to treating any symptom associated with the lidwiper keratoepitheliopathy (LWE), such as, but not limited to, inflammation, dryness, pain, or a combination thereof. In certain embodiments, the keratolytic agent is benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, an alpha hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylate.

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

[0045] In some instances, the lid wiper region is a thickened epithelial "lip" that extends from the tarsal conjunctiva to the ridge of the posterior eyelid border and has a conjunctival mucosal morphology that helps distribute the precorneal tear film. In some instances, the lid wiper is the primary portion of the eyelid that interacts with the CL surface and therefore experiences mechanical friction during blinking, demonstrating its importance during lens wear. Therefore, the lid wiper is of clear importance during lens wear. Typically, the Marx line extends from the ridge of the posterior eyelid border and is found at the base of the lacrimal meniscus. A thin band of stainable epithelial cells directly behind the mucocutaneous junction is the base of the Marx line. Traditionally, the Marx line was thought to be the area that contacts the eyeball and represents the wiping surface of the eyelid border.

[0046] In various embodiments discussed herein, administration of an active agent or composition described herein is achieved by administration to an individual's eye or surrounding tissues, such as the eyelid. In some embodiments, topical administration to an individual's eye includes topical ocular administration, (e.g., topical) eyelid (eyelid) administration (e.g., to the inside and / or outside of the eyelid), or a combination thereof. In some preferred embodiments, (e.g., direct) administration is (e.g., topical) administration to the inner lid surface. In more preferred embodiments, administration is or includes (e.g., direct) administration to the lid wiper region of the inner lid surface. In some embodiments, administration is or includes (e.g., direct) administration to the lid wiper region and stratified squamous epithelium region and / or the sub-lid fold region. In some embodiments, administration is or includes (e.g., direct) administration to the lid wiper region, stratified squamous epithelium region, and plantar fold region of the lid. In certain embodiments, administration is or includes administration to (e.g., directly) the lid wiper, stratified squamous epithelium, sub-lid fold, and stratified columnar epithelium regions of the eyelid, while in various other embodiments, administration is not to the meibomian gland orifices of the eyelid.

[0047] FIG. 1 illustrates a schematic diagram of an exemplary ocular surface and a portion of an eyelid. As illustrated, eyelashes can be observed at the edge of the eyelid. The inner surface of the eyelid extends inward from the eyelashes and includes a stratified squamous epithelium region located proximal to the eyelashes. Further along the inner surface of the eyelid, the stratified squamous epithelium continues to the 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 instances, when an individual suffers from contact lens discomfort (CLD) or lid wiper keratoepitheliopathy (LWE), other portions of the inner surface of the eyelid may also contact the ocular surface. The inner surface of the eyelid extends from the lid wiper region (e.g., moving distal to the eyelashes along the inner surface of the eyelid) and includes a subpalpebral fold region and a stratified columnar epithelium region. In some instances, the lid conjunctiva extends over all or part of the inner surface of the eyelid, such as with a leading edge in 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., in the hands of the patient or caregiver, or alternatively, by a trained professional or physician). In some 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, comprising topically administering a composition comprising a keratolytic or keratinogenic agent. In some embodiments, the keratolytic agent is selected from allantoin, benzoyl peroxide, an inorganic selenium compound such as selenium disulfide, SeCl, NaSeO, an organic selenium compound such as ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) or an analog thereof, coal tar, dithranol, salicylic acid, selenium disulfide, an alpha hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolodione carboxylate. In some embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acid, 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, thiorphan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, ointment, hydroxybenzoates ... The keratolytic agent is selected from the group consisting of mapatrilat, ovothiol A, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octotiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, lenthionine, ajoene, allicin, gemopatrilate, thioethanol, thiophospholipids, thiocholesterol, 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 unwanted side effects, such as causing irritation or other adverse ocular symptoms.

[0051] In some embodiments, mild or weak keratolytics and / or keratinizing agents are used in the methods and formulations described herein, for example, for subjects who produce low amounts of keratin. Such mild or weak keratolytics and / or keratinizing agents are optionally used in a maintenance therapy setting. Mild or weak keratolytics and / or keratinizing agents include low concentrations of active keratolytics and / or keratinizing agents, as well as keratolytics and / or keratinizing agents with low intrinsic activity (e.g., as determined by the methods described herein). In some embodiments, the mild or weak keratolytics and / or keratinizing agents are not boric acid.

[0052] In one embodiment, the composition comprises a therapeutically effective amount of at least one keratolytic agent (e.g., as described herein) and an ophthalmically 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 dithranol. In another embodiment, the keratolytic agent is salicylic acid. In another embodiment, the keratolytic agent is selenium sulfide (e.g., 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, in which the ratio of selenium to sulfur is approximately 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 occlusions results in proteolysis of desmosomes, which form tight junctions between keratinocytes. In some embodiments, administration of a keratolytic agent results in dissolution, including hydrolysis of disulfide bonds. In some embodiments, administration of a 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 benzoyl peroxide-containing composition is a suspension, emulsion, cream, lotion, gel (e.g., aqueous or non-aqueous), or ointment. In some embodiments, the benzoyl peroxide-containing composition is applied as a thin layer once daily every other day to cleanse the skin, and then gradually increased to twice daily as tolerated.

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

[0057] In some embodiments, the keratolytic agent is dithranol. In some embodiments, the composition comprises about 0.1% to about 2.0% dithranol ointment. In some embodiments, the composition comprising dithranol 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 dithranol. In some embodiments, the dithranol-containing composition is started as an about 0.1% ointment. After one or more days, such as seven days, the concentration is increased to about 0.25%, and then may be increased (e.g., doubled) at regular intervals (e.g., weekly intervals) as needed to a maximum strength (e.g., about 2%). In some embodiments, a thin layer of ointment is applied to the affected area once daily for one or more weeks, such as two to four weeks. In some embodiments, the ointment is left in place for about 10 to about 20 minutes before thoroughly rinsing the area. In some embodiments, the dithranol slows epidermal cell division and inhibits hyperproliferation and keratinization of epidermal cells in patients.

[0058] In some embodiments, the keratolytic agent is salicylic acid. In some embodiments, the composition comprises about 0.01% to about 30% salicylic acid (e.g., about 0.01% to about 10%, about 0.01% to about 5%, about 0.01% to about 2.5%, about 0.01% to about 1%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 2.5%, about 0.1% to about 1%, or any useful range therein). In some embodiments, the composition comprises about 0.1% to about 6% 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 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%, about 2.5%, about 2%, about 1%, about 0.5%, or about 0.1% or less. In some embodiments, the composition contains about 0.01% to about 30%, such as about 0.01% to about 10%, about 0.1% to about 10%, or about 0.1% to about 30% salicylic acid. In some embodiments, the salicylic acid-containing composition is an ointment or paste. In some embodiments, the salicylic acid-containing composition is initially applied as a thin layer of about 2% ointment or paste and applied daily. In some embodiments, the concentration is gradually increased to a maximum concentration of about 5%, and treatment is continued for as long as necessary.

[0059] In some specific embodiments, the keratolytic agent is selenium disulfide. In some embodiments, the composition comprises about 0.01% to about 30% selenium disulfide (e.g., about 0.01% to about 10%, about 0.01% to about 5%, about 0.01% to about 2.5%, about 0.01% to about 1%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 2.5%, about 0.1% to about 1%, or any useful range therein). In some embodiments, the composition comprises about 0.01% to about 10% 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 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%, about 2.5%, about 2%, about 1%, about 0.5%, or about 0.1% or less. In some embodiments, the composition contains about 0.01% to about 30%, such as about 0.01% to about 10%, about 0.1% to about 10%, or about 0.1% to about 30% selenium disulfide. 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 comprising selenium disulfide is a lotion. In some embodiments, the composition comprising selenium disulfide is a cream. In some embodiments, the composition comprising selenium disulfide is an ointment. In some embodiments, the composition comprising 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, hydrophobic oil, foam, liposome, emulsion, lotion, microparticle, or other suitable formulation.

[0060] In some embodiments, the compositions include inorganic selenium compounds that are inhibitors of prostaglandin synthase, an enzyme involved in the production of prostaglandins. Selenium compounds that exhibit this inhibitory effect include SeCl4 and Na2SeO3. Because the pro-inflammatory effects of prostaglandins are known to promote keratinization, water-soluble inorganic selenium compounds that interfere with the production of these prostaglandins may be useful in reducing keratinization.

[0061] In some embodiments, the composition includes an organoselenium compound. Organoselenium compounds, such as ebselen, are antioxidants and anti-inflammatory agents that inhibit cyclooxygenase and lipoxygenase enzymes and act as scavengers of hydrogen peroxide and hydroperoxides, including membrane-bound phospholipid and cholesteryl ester hydroperoxides. Because anti-inflammatory agents are known to inhibit keratinization, ebselen and other organoselenium analogs may act as keratolytic agents due to their antioxidant / anti-inflammatory activity.

[0062] In some embodiments, the keratolytic and / or keratinizing agent-containing formulation further comprises an additional therapeutic agent that is not a meibomian gland opening agent. 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 keratolytic and / or keratinizing agent-containing formulation excludes additional therapeutic agents, except for an optionally added meibomian gland opening agent.

[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] The term "local anesthetic," as used herein, refers to an agent that causes a reversible lack of pain sensation. In some embodiments, the local anesthetic is further capable of inducing temporary muscle paralysis in addition to causing a reversible lack of pain sensation.

[0065] The local anesthetics described herein are primarily useful as acute therapy, e.g., under the guidance of a physician or other trained professional, and in certain embodiments, 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 amino ester selected from the group consisting of benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, 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 occurring local anesthetic, hi some embodiments, the naturally occurring 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 constrict blood vessels and thereby increase the duration of local anesthesia. In some embodiments, prilocaine hydrochloride is mixed with epinephrine. In some embodiments, lidocaine, 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 (e.g., topical) compositions described herein 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, 2001). st Ed. Mack Pub. Co., Easton, PA (2005). Other additives, such as preservatives, are optionally provided.

[0073] In certain embodiments, the compositions provided herein include any suitable additional agent or additive. In certain embodiments, additives are included to, for example, improve the performance and / or efficacy of the compositions or formulations provided herein. In some examples, for example, the compositions provided herein include a penetration enhancer and / or surfactant (e.g., ionic, anionic, cationic, nonionic, lipid (e.g., oleic or caprylic), BNZ, etc.). In some embodiments, the compositions provided herein include an excipient that would normally function to improve drug penetration and / or solubilize plaque or keratinization present, for example, on the eyelid or lens, such as in accordance with the methods described herein.

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

[0075] Described herein are methods for treating various ocular disorders (e.g., LWE and / or CLD) in an individual (e.g., a patient), comprising topically administering a composition described herein to the individual (e.g., a patient) (e.g., to the inner surface of one or more of their eyelids). In some embodiments, the individual is a patient, such as a patient receiving medical care (e.g., for ocular and / or other illnesses). In some instances, this constitutes acute treatment, in which, in some embodiments, a more potent drug (either in terms of concentration or intrinsic activity of the drug) is utilized. In one embodiment, maintenance therapy allows for the use of a lower concentration of drug or a drug with less intrinsic activity. In one embodiment, maintenance use requires the patient to visit a healthcare professional on a regular basis. Both acute and maintenance use optionally require the use of an eye protection device or apparatus. In one embodiment, acute use is administered by a healthcare provider, while maintenance use is administered by a non-healthcare provider, such as the patient or a caregiver. In some embodiments, the patient applies the drug (e.g., a composition comprising a keratolytic agent) to themselves (e.g., to the inner surface of one or more of their eyelids). In one embodiment, such administration is over an extended period of time. This type of multiple-dose regimen for patients is simply called chronic use. Usually, a different or second formulation of the drug is recommended for chronic use or for patient self-use. 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 ophthalmically acceptable carrier is performed until a decrease in (e.g., abnormal) keratinization (e.g., subkeratinization (PK)) is achieved. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed periodically after a decrease in keratinization is achieved. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed as a single administration. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed periodically. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed once daily. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed twice daily. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier occurs twice weekly.

[0077] In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is a semi-solid composition. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is homogeneous. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is a dispersion. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is hydrophilic. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier has an oily base. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier has at least one ophthalmically acceptable excipient. In some embodiments, the topical composition 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, etc.). In some instances, such formulations facilitate maintenance of the pharmacologically active formulation at or near the site to be treated (e.g., site of dysfunction such as trauma or dyskeratosis). In some instances, semi-solid or other viscous formulations exhibit little migration from the site of administration.

[0079] In some embodiments, the topical administration of the drug-containing composition is performed once a week. In some embodiments, the topical administration of the drug-containing composition is performed twice a week. In some embodiments, the topical administration of the drug-containing composition is performed every other day. In some embodiments, the topical administration of the drug-containing composition is performed daily. In some embodiments, the topical administration of the drug-containing composition 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 of a treatment-naive patient. 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 drug dosage in the acute treatment scenario may be higher than the drug dosage used in a chronic treatment scenario or a 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 as an acute treatment scenario at an early stage of treatment and then transitions to a chronic treatment scenario or a maintenance therapy scenario. In some embodiments, the drug administered in the acute treatment scenario is a local anesthetic, and the drug administered in the chronic treatment scenario or a maintenance therapy scenario is a keratolytic and / or keratinogenic agent. In some embodiments, the drug administered in the acute treatment scenario is a keratolytic and / or keratinogenic agent, and the drug administered in the chronic treatment scenario or a maintenance therapy scenario is also a keratolytic and / or keratinogenic agent.

[0081] In some clinical conditions, patients may require initial treatment by a doctor or medical professional administering a more highly concentrated formulation of one of the therapeutic agents described herein.If a more concentrated formulation is required, this application may require eye shielding or other measures to minimize the effects of irritation or destruction of the ocular surface or surrounding tissue.Following this procedure, patients may be administered a different formulation of the active agent to be applied regularly to the inner surface of the eyelid at home.This application may 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 an improvement in one or more symptoms of CLD and / or LWE, such as dryness, roughness, stinging, irritation, burning, or tearing. In some embodiments, such symptom improvement can be assessed according to a subjective visual acuity assessment (e.g., a VAS) or another subjective scoring system (e.g., the CLDEQ-8). In some embodiments, the methods provided herein result in an improvement in eyelid symptoms of CLD. In some embodiments, the methods provided herein result in an improvement in tear film symptoms of CLD. In some embodiments, the methods result in an improvement in the CLDEQ-8 measurement tool. In some embodiments, the methods result in an improvement in comfortable wear time (e.g., of contact lenses). In some embodiments, the methods result in an improvement in subjective visual acuity assessment (e.g., as assessed by a visual analog scale, or VAS). In some embodiments, an improvement in one or more symptoms of CLD and / or LWE, including comfortable wear time, is observed within about one month, such as within about four weeks, three weeks, two weeks, one week, three days, or sooner, of administration of a composition (e.g., according to the methods provided herein). In some embodiments, improvement in one or more symptoms of CLD and / or LWE, including comfortable wear time, is observed within about two months of administration of the composition (e.g., according to the methods provided herein). In some embodiments, improvement in 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 in accordance with the methods described herein wears one or more contact lenses (e.g., regularly, such as at least one hour per day or at least one day per week). In some embodiments, an individual being treated in accordance with the methods described herein wears one or more contact lenses two or more days per week, such as three, four, five, or five days per week. In some embodiments, an individual being treated in accordance with the methods described herein wears one or more contact lenses throughout the treatment period (e.g., as described herein). In other embodiments, an individual being treated in accordance with the methods described herein does not wear one or more contact lenses throughout the treatment period (e.g., regular wear is resumed after a predetermined treatment period). In some embodiments, the individual wears soft contact lenses. In some embodiments, the individual wears hard contact lenses (e.g., rigid gas-permeable contact lenses). In some embodiments, the individual wears disposable contact lenses (e.g., contact lenses configured for single wear, such as for one day) or continuous wear contact lenses (e.g., contact lenses configured for wear for more than one day, such as contact lenses configured for wear for more than one week, more than two weeks, more than three weeks, or more 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 in one or more symptoms of CLD and / or LWE can be assessed according to the 8-item Contact Lens Dry Eye Questionnaire (CLDEQ-8). The CLDEQ-8 is an 8-point questionnaire that assesses the frequency and recent intensity of discomfort, dryness, vision changes, blurred vision, and frequency of eye closure for relief while wearing contact lenses and during premature lens removal for symptom relief. The CLDEQ-8 is optionally self-administered. A CLDEQ-8 score of 12 or greater can identify contact lens (e.g., soft contact lens) wearers who may benefit from clinical management of their contact lens-related symptoms. A clinically important CLDEQ-8 difference has been 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 comprise one or more additional interventions, such as the application of a warm compress, debridement, and / or therapeutic intervention (e.g., manual or physical intervention using an instrument such as LipiFlow). In some embodiments, the methods provided herein further comprise performing debridement alone or in combination with therapeutic intervention on the individual's eye. In some embodiments, debridement is performed on one eye and the combined debridement and therapeutic intervention is performed on the other eye. In some embodiments, the therapeutic intervention (also referred to herein as physical intervention) is performed after administration of a composition provided herein. For example, in some embodiments, the physical intervention occurs at least about 5 minutes after administration of a composition provided herein, such as 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. In some embodiments, the composition is administered periodically and the physical intervention occurs at a single time, such as about 1 month after the initial administration of the composition.

[0086] One aspect of the treatment methods described herein is the location of topical administration of the composition. In one embodiment, the drug-containing composition is administered so as to cause little or no irritation to the eye or surrounding tissues. In one embodiment, the drug (e.g., keratolytic)-containing composition is administered to the inner surface of the eyelids (e.g., one or both upper eyelids and / or one or both lower eyelids) of an individual in need thereof.

[0087] A further embodiment of the treatment methods described herein is the use of a protective element provided to the eye to avoid eye irritation. While the formulations described herein are typically non-irritating, in some embodiments (e.g., when used with high drug concentrations or sensitive eyes), the protective element provides an additional layer of patient safety and comfort. In one embodiment, the drug-containing composition is administered while an eye shield is placed on the eye to reduce contact of the drug with the cornea and / or conjunctiva, thereby reducing eye irritation. In some embodiments, the eye shield is a contact lens or an eye cover. In some embodiments, the eye cover is self-adhesive. In one embodiment, the drug-containing composition is administered while the eyelid is pulled away from the eyeball to reduce contact of the drug with the cornea and / or conjunctiva, thereby reducing eye irritation.

[0088] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" is intended to include a plurality of such agents, and a reference to "the cell" is intended to include one or more cells (or cells), and equivalents thereof, known to those of skill in the art. When ranges are used for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is an approximation within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 5% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise," "comprises," "having," or "including") is not intended to exclude that in other particular embodiments, embodiments such as, for example, compositions, methods, or processes described herein, may "consist of" or "consist essentially of" the recited features.

[0089] The terms "treat," "treating," or "treatment," as used herein, include the reduction, lessening, attenuation, alleviation, improvement, amelioration, or decline of disorders described herein, such as CLD and / or LWE, in either chronic or acute treatment scenarios. In one embodiment, treatment includes the reduction of end duct obstruction.

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

[0091] The terms "keratolytic agent" and / or "keratinogenic agent," as used herein, refer to agents that soften, disrupt, dissolve, solubilize, or loosen keratinized occlusions or prevent their formation. Specifically, the term "keratolytic agent" refers to agents used to promote the softening and dissolution of keratin, and the term "keratogenic agent" refers to agents used to reduce keratin production.

[0092] The term "lotion" refers to an emulsion liquid dosage form, typically intended for external application to the skin (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

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

[0094] The term "ointment" refers to a semi-solid dosage form, usually containing less than 20% water and volatile materials and / or more than 50% hydrocarbons, waxes, or polyols as solvents, which is usually intended for external application to the skin or mucous membranes (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0095] The term "solution" refers to a clear, homogeneous liquid dosage form containing one or more chemicals dissolved in a solvent or 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 may be suspended throughout at least a portion of a bulk solvent.

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

[0098] The term "about" means any acceptable amount, such as that appropriate to achieve the stated purpose. In some instances, "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, also includes the express disclosure of "consisting of" and "consisting essentially of." [Example]

[0100] Example 1: Pharmacologically active formulations

[0101] High viscosity formulations, such as those for administration in accordance with the disclosures provided herein, are prepared. Suitable formulations, such as creams, ointments, emulsions, suspensions, microspheres, and the like, are optionally utilized. In various embodiments, an exemplary ophthalmic ointment formulation is prepared according to the following formulation:

[0102] [Table 1]

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

[0104] Abnormal keratitis is induced in rabbit eyes using 0.5% benzalkonium chloride solution. Each rabbit is assigned to receive the ointment provided herein in one eye and a control ointment in the other eye. The inner surface of the eyelid, including the lid wiper and / or conjunctival fold, is evaluated.

[0105] Example 2: Diagnosis and Treatment

[0106] Individuals are admitted to the clinical setting after wearing soft contact lenses for at least six months prior to the visit. Individuals are asked to rate their overall contact lens comfort and satisfaction with contact lens wear time. Additionally, individuals are assessed based on one or more symptom scoring measures. In some instances, the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire is administered to the individual (e.g., scored on a 28-point scale). In some instances, the Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) is also administered to the individual (e.g., scored on a 35-point scale) (e.g., Chalmers et al. Invest. Ophth. & Visual Science, Apr. 2009, 50:6337). In some instances, individuals are (e.g., further) assessed using symptoms commonly associated with contact lens discomfort, such as dryness, irritation, stinging, or burning.

[0107] Evaluate the subject's ocular appearance. Also evaluate eyelash appearance (e.g., symptoms), such as checking for lash loss, blepharitis, seborrheic pruritus, or collarettes. Analyze fluorescein tear break-up time in both eyes, such as measured using Amcon Dry Eye Test (DET) strips.

[0108] In some instances, a direct assessment of the lid wiper area is performed. For example, in some instances, a 40 μl drop of 2% fluorescein diluted in plain saline (Astrazeneca) is instilled into the lower conjunctival sac of each eye by soaking for 1 minute from an ophthalmic strip (Fluor-I-strip Atophthalmic strips 1 mg, Wyeth-Ayerst Laboratories, Rouses Point, NY). One minute later, a 40 μl drop of Lissamine Green dye is prepared by soaking a strip (OpGreen 1.5 mg, Ophtechnics Unlimited, Haryana, India) in plain saline and instilled into each eye. One minute after the final dye instillation into the eye, the lid wiper area is examined for changes. The lid wiper area is evaluated for an increase in the sagittal width and horizontal length of the Lissamine Green stain and / or an increase in the palpebral conjunctival fold. Changes in meibomian gland dysfunction may also be assessed, but this dysfunction is not required to distinguish between CLD or LWE.

[0109] In some instances, pre-symptomatic CLD or LWE is determined depending on the scoring and / or analysis of an LWE symptom score questionnaire. In other instances, mild CLD or LWE is determined depending on the scoring and / or analysis of an LWE symptom score questionnaire. In yet other instances, mild CLD or LWE is determined depending on the scoring and / or analysis of an LWE symptom score questionnaire.

[0110] For example, if a subject scores 4 out of 28 on the SPEED questionnaire and 6 out of 35 on the CLDEQ-8 questionnaire, but has no specific problems with symptoms commonly associated with contact lens discomfort such as dryness, roughness, irritation, or burning, the eyes appear white and undisturbed, the eyelashes are normal without cilia, blepharitis, seborrheic pruritus, or collaterals, the fluorescein tear secretion time is 4–6 s as measured using Amcon dry eye test (DET) strips, there is no sign of meibomian gland abnormalities, the sagittal width and horizontal length of Lissamine Green staining are increased, and there are increased palpebral conjunctival folds, then the patient is diagnosed with presymptomatic contact lens discomfort (CLD). Therefore, despite the absence of CLD "symptoms," this patient is diagnosed with CLD (presymptomatic) primarily based on the signs of CLD.

[0111] However, in the example where a subject scores 11 out of 28 on the SPEED questionnaire and 15 out of 35 on the CLDEQ-8 questionnaire, experiences stinging, foreign body sensation, tearing, and dry eyes, the eyes appear white and undisturbed, the eyelashes are normal without iris defects, blepharitis, seborrheic pruritus, or collaterals, the fluorescein tear secretion time is 11-12 seconds as measured using Amcon's Dry Eye Test (DET) strips, there is no sign of meibomian gland abnormalities, and there is no sign of conjunctival staining, this would be diagnosed as symptomatic contact lens discomfort (CLD). Therefore, despite the absence of "signs" of CLD, this patient would be diagnosed with CLD based on symptoms alone.

[0112] A composition described herein, such as in Example 1, is administered to the inner surface of the eyelid of an eye in which CLD (or LWE) has been identified as pre-symptomatic or symptomatic. After administration (e.g., single and / or multiple administrations), assessments (e.g., symptoms and signs) as described herein are again performed to determine improvement in the condition.

[0113] Example 3: Clinical evaluation of CLD treatment

[0114] Six patients with CLD were treated with a drug formulation containing 1% selenium disulfide. Treatment consisted of twice-weekly administration of the drug product to the lower eyelids of both eyes. Patients returned for follow-up visits at 14 days and 4 weeks, and their level of discomfort was assessed using a visual analog scale (VAS) and the Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) questionnaire (4 weeks only). Figures 2–4 illustrate the mechanisms for assessing treatment effectiveness, including the VAS, CLDEQ-8, and Berkeley Dry Eye Flow Chart (DEFC).

[0115] [Table 2]

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

[0117] [Table 3]

[0118] As shown in Table 2, of the five patients with baseline and 1-month data, 80% (4 / 5) improved on the CLDEQ-8 questionnaire, and 40% (2 / 5) achieved a change of more than a clinically important difference (e.g., a change of more than 3 points) on the CLDEQ-8 from baseline after treatment with the drug formulation. Of the four patients with abnormal baseline CLDEQ-8 scores, 100% (4 / 4) improved on the CLDEQ-8, and 50% (2 / 4) achieved a change of more than a clinically important difference on the CLDEQ-8 from baseline after treatment with the drug formulation. The mean change from baseline to 1 month achieved a clinically important difference on the CLDEQ-8 of ±3 points.

[0119] Patients (202) and (208) had a baseline CLDEQ-8 score of 21, indicating patients who could benefit from clinical management of their contact lens-related symptoms. One month after treatment with the drug formulation, patient (208) returned to the clinic with a CLDEQ-8 score of 13, indicating a patient with significant improvement in their contact lens-related symptoms. Similarly, one month after treatment with the drug formulation, patient (202) returned to the clinic with a CLDEQ-8 score of 16, indicating a patient with significant improvement in their contact lens-related symptoms. Patient (202)'s improvement was indicated by a significant decrease in blurred or fuzzy vision at the end of contact lens wear and a decrease in the frequency of eye discomfort during the past two weeks, requiring interruption of work to remove the contact lenses. Patient (208)'s improvement was indicated by a decrease in the frequency and severity of eye dryness and discomfort at the end of contact lens wear.

[0120] Thus, patients report improvement in key CLD symptoms (e.g., dryness and discomfort) across measures (e.g., CLDEQ-8 and VAS) when using the drug formulation, as well as a significant reduction in blurred or blurred vision at the end of the contact lens wear period.

[0121] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the present invention be limited by the specific examples provided herein. While the present invention has been described with reference to the foregoing specification, the description and illustration of the embodiments herein are not intended to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it is to be understood that all aspects of the present invention are not limited to the specific depictions, configurations, or relative proportions set forth herein, which depend upon a variety of conditions and variables. It is to be understood that various alternatives to the embodiments of the present invention described herein are available for practicing the invention. It is therefore contemplated that the present invention shall cover any such alternatives, modifications, variations, or equivalents. The following claims define the scope of the present invention, and methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.

Claims

1. 1. A pharmaceutically acceptable composition for use in a method for treating contact lens discomfort (CLD) or a symptom thereof in an individual, comprising: (a) a therapeutically effective amount of selenium disulfide; (b) an ophthalmically acceptable carrier; and Including, The method comprises topically administering the pharmaceutically acceptable composition to the eye or eyelid of the individual.

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

3. the contact lens discomfort is associated with alterations to the lid conjunctiva or a portion thereof; 3. The pharmaceutically acceptable composition of claim 1 or 2, wherein the alteration to the ophthalmic conjunctiva optionally comprises trauma or keratinization of the ophthalmic conjunctiva or a portion thereof.

4. (a) the method comprises treating inflammation, dryness, or pain associated with contact lens discomfort; and / or (b) The pharmaceutically acceptable composition of any one of claims 1 to 3, wherein the method results in improvement of eyelid or tear film symptoms of contact lens discomfort (CLD).

5. 5. The pharmaceutically acceptable composition of claim 1, wherein the individual is suffering from Lidwiper's keratoepitheliopathy (LWE).

6. 6. The pharmaceutically acceptable composition of claim 1, wherein the individual is or has been evaluated for comfortable wear time and / or subjective visual acuity assessment prior to administration.

7. 7. A pharmaceutically acceptable composition according to any one of claims 1 to 6, wherein the method results in improved comfortable wear time and / or subjective visual acuity assessment.

8. 8. A pharmaceutically acceptable composition according to any one of claims 1 to 7, wherein the method results in improved wearing comfort time.

9. 9. The pharmaceutically acceptable composition of claim 1, wherein the composition is administered to the eyelid margin of the eye of the individual.

10. 10. A pharmaceutically acceptable composition according to any one of claims 1 to 9, which is administered periodically.

11. 11. A pharmaceutically acceptable composition according to any one of claims 1 to 10, which is homogeneous.

12. 12. A pharmaceutically acceptable composition according to any one of claims 1 to 11, comprising an oily base.

13. 13. The pharmaceutically acceptable composition of any one of claims 1 to 12, wherein the method comprises treating symptoms associated with a condition of CLD or LWE.

14. 1. A pharmaceutically acceptable composition for use in a method for improving contact lens wear comfort in an individual, comprising: (a) a therapeutically effective amount of selenium disulfide; (b) an ophthalmically acceptable carrier; and Including, The method comprises topically administering the pharmaceutically acceptable composition to the eye or eyelid of the individual.

15. 15. The pharmaceutically acceptable composition of claim 14, wherein the composition is administered to at least a portion of the tarsal conjunctiva of the eye of the individual.

16. 15. The pharmaceutically acceptable composition of claim 14, wherein the composition is administered to the eyelid margin of the individual's eye.

17. 15. The pharmaceutically acceptable composition of claim 14, wherein the method comprises treating inflammation, dryness, or pain associated with contact lens discomfort.

18. 15. The pharmaceutically acceptable composition of claim 14, wherein the method results in improvement of eyelid or tear film symptoms of contact lens discomfort (CLD).

19. 15. The pharmaceutically acceptable composition of claim 14, wherein the individual is suffering from lidwiper's keratoepitheliopathy.

20. 20. The pharmaceutically acceptable composition of claim 19, wherein the individual's eye includes a lid wiper area and the pharmaceutically acceptable composition is administered directly to at least a portion of the lid wiper area and / or reaches the lid wiper area after administration.

21. 21. The pharmaceutically acceptable composition of claim 20, wherein the lid wiper keratoepitheliopathy comprises trauma to the lid wiper area of the eyelid.

22. 15. The pharmaceutically acceptable composition of claim 14, wherein the method results in improvement of horizontal (width) and / or sagittal (height) lesions and / or palpebral juxtaconjunctival folds (LIPCOF).

23. 15. The pharmaceutically acceptable composition of claim 14, wherein the concentration of selenium disulfide in the composition is between about 0.01% and about 10% by weight.

24. 15. The pharmaceutically acceptable composition of claim 14, wherein the individual has contact lens discomfort (CLD) or symptoms thereof.

25. 25. The pharmaceutically acceptable composition of claim 24, wherein the method further comprises assessing the symptom using a symptom scoring technique.

26. 26. The pharmaceutically acceptable composition of claim 25, wherein the symptom scoring technique is suitable for diagnosing contact lens discomfort (CLD), lid wiper keratoepitheliopathy (LWE), eye dryness, eye pain, or eye inflammation.

27. 27. The pharmaceutically acceptable composition of claim 26, wherein the individual has been diagnosed with the ocular disorder using the Contact Lens Dry Eye Questionnaire (CLDEQ) measurement tool.

28. 28. The pharmaceutically acceptable composition of claim 27, wherein the individual has a CLDEQ-8 score of at least 5.

29. 1. A pharmaceutically acceptable composition for use in a method for treating contact lens discomfort (CLD) or a symptom thereof in an individual, comprising: (a) selenium disulfide at a concentration of about 0.01% to about 10% by weight; (b) an ophthalmically acceptable carrier; and Including, The method comprises topically administering the pharmaceutically acceptable composition to the eye or eyelid of the individual.

30. 30. The pharmaceutically acceptable composition of claim 29, comprising an oily base.

31. 31. The pharmaceutically acceptable composition of claim 30, comprising about 0.5% by weight of selenium disulfide.

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