Compositions and methods for improving vision

Abstract

Described herein is a composition and method for treating vision loss and / or dry eye syndrome. Such compositions include keratolytic agents such as salicylic acid, selenium disulfide, etc. Topical administration of such compositions to the inner surface of the eyelid provides treatment to patients suffering from vision loss and / or dry eye syndrome.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 214,690, filed June 24, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] When the corneal tissue or other parts of the ocular surface become inflamed and prevent the tissue from functioning properly, vision can be adversely affected. Common causes of inflammation include medications (e.g., antihistamines, beta-blockers, diuretics, etc.), exposure to dry or smoky environments, medical conditions (e.g., diabetes, autoimmune diseases such as rheumatoid arthritis, etc.), herpes, and eye surgery.

[0003] In many cases, inflammation of eye tissues causes symptoms that indicate dry eye syndrome. Dry eye syndrome is a common condition with various symptoms, such as poor night vision, burning, itching, or stinging sensation in the eyes, photosensitivity, watery eyes, redness and / or pain of the eyelids, and mucus secretion from the eyes. The main cause of dry eye syndrome is the dysfunction of one or more oil glands and / or tear ducts in an individual, which causes inflammation of the corneal tissue.

[0004] Current treatments for dry eye syndrome include treatments that increase, maintain, or induce tear production and heal inflammation. Summary of the Invention

[0005] Disclosed herein is a composition comprising keratolytic agent.In some embodiments, provided herein is a composition that is used in a method for treating vision loss by administering the composition ophthalmologically to the ocular surface or surrounding tissue of the subject, for example, to eyelid margin and / or palpebral conjunctiva.

[0006] Disclosed herein is a method of improving vision in an individual in need thereof, the method comprising providing to the individual a composition comprising a keratolytic agent in an ophthalmically or pharma- ceutically acceptable vehicle or carrier, the composition being administered to the individual's eyelid or eye in a manner suitable for delivering the keratolytic agent to the lid margin or ocular surface of the individual's eyelid.

[0007] The composition may be provided to the individual periodically. The composition may be administered to the individual periodically for a period of at least two weeks. The composition may be administered to the individual periodically for a period of at least one month. The periodic administration may include administering the composition at least once a week. The periodic administration may include administering the composition at least twice a week.

[0008] In some embodiments, the individual has not been diagnosed with meibomian gland dysfunction (MGD) or lid wiper epitheliopathy (LWE).

[0009] In some embodiments, the individual has not been diagnosed with MGD.

[0010] In some embodiments, the individual has not been diagnosed with LWE.

[0011] In some embodiments, the individual has been diagnosed with meibomian gland disorder (MGD) or lid wiper epithelium disorder (LWE).

[0012] In some embodiments, the individual has been diagnosed with MGD.

[0013] In some embodiments, the individual has been diagnosed with LWE.

[0014] In some embodiments, the individual does not wear contact lenses.

[0015] In some embodiments, the individual wears contact lenses.

[0016] The concentration of the keratolytic agent in the composition may be between about 0.01% and about 10% by weight.

[0017] The keratolytic agent may be selenium disulfide. The composition may include 0.1% by weight of selenium disulfide in an ophthalmically acceptable carrier.

[0018] An ophthalmically acceptable carrier can include at least one ophthalmically acceptable vehicle and at least one ophthalmically acceptable excipient.

[0019] The composition can be administered to at least a portion of the palpebral conjunctiva of the eye of the individual.

[0020] The composition may be a dispersion or a suspension. The composition may be hydrophilic. The composition may include an oleaginous base. The composition may be homogeneous.

[0021] The composition can be administered by an applicator, which can be the individual's finger.

[0022] Vision may be improved either by questioning the patient about their visual function or by improvement measured using a subjective scale or improvement measured using an objective scale.

[0023] Visual function can be assessed using questionnaires. Questionnaires can be OSDI (see, for example, www.supereyecare.com / resources / OSDI.pdf), VAS, Berkeley Dry Eye Flow Chart (DEFC, see, for example, www.researchgate.net / figure / The-Berkeley-Dry-Eye-Flow-Chart-DEFC-https-doiorg-101371-journalpone0190752g001_fig1_322688369), or CLDEQ-8 (see, for example, cdn-links.lww.com / permalink / icl / a / icl_2016_04_08_hicksoncurran_15-146_sdc1.pdf).

[0024] Visual function can be improved by at least 2 points as measured by the OSDI visual function scale after one month of regular administration. Visual function can be improved by at least 5 points as measured by the OSDI visual function scale after two months of regular administration. Visual function can be improved in aspects including reading, driving at night, working with a computer, watching television, etc.

[0025] The subjective measure may be any one or combination of visual acuity, hyperacuity, contrast sensitivity, glare acuity, visual acuity using PAM, visual acuity under photopic conditions, and visual acuity under scotopic conditions. The objective measure may be any one or combination of visual quality aberrometer, objective scatter image, and double pass system. In certain embodiments, the subjective measure is visual acuity. [Brief description of the drawings]

[0026] [Figure 1] 1 illustrates a cross-sectional schematic diagram of an exemplary eyelid functioning normally with respect to the ocular surface. [Figure 2A] 1 shows the change in visual acuity seen in subjects at 2 weeks, 1 month, 1.5 months, and 3 months after treatment as measured by the Ocular Surface Disease Index (OSDI) visual function subscale. [Figure 2B] 1 shows the change in visual acuity seen in subjects at 2 weeks, 1 month, 1.5 months, and 3 months after treatment as measured by the Ocular Surface Disease Index (OSDI) visual function subscale. [Figure 2C] 1 shows the change in visual acuity seen in subjects at 2 weeks, 1 month, 1.5 months, and 3 months after treatment as measured by the Ocular Surface Disease Index (OSDI) visual function subscale. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] In various embodiments herein, methods are provided for treating ocular disorders and symptoms thereof by administering a therapeutically effective amount of a pharmacologically active agent provided herein to the eye (e.g., the eyeball or eyelid) of an individual in need of such treatment (e.g., an individual who does not wear contact lenses and / or an individual who has not been diagnosed with meibomian gland dysfunction (MGD)). In certain embodiments, the method includes improving vision, treating dry eye syndrome or a symptom thereof. In certain embodiments, the method includes treating dry eye syndrome or a symptom thereof. In certain embodiments, the method includes treating eye dryness, eye pain, eye inflammation, or any other disorder or symptom described herein, for example, such disorder or symptom is associated with reduced vision or dry eye syndrome.

[0028] In certain embodiments herein, methods are provided for treating vision loss, such as by administering a keratolytic agent to the eye or surrounding tissues (e.g., palpebral conjunctiva, eyelid (e.g., eyelid margin)) of an individual in need of such treatment (e.g., an individual who does not wear contact lenses and / or an individual who has not been diagnosed with meibomian gland dysfunction (MGD)). In some embodiments, treating the vision loss includes treating one or more symptoms associated with the vision loss. In certain embodiments, the symptoms associated with the vision loss are symptoms identifiable by the individual and / or the clinician. In certain embodiments, the methods provided herein relate to treating any symptoms associated with vision loss, such as, by way of non-limiting example, inflammation, dryness, pain, or combinations thereof.

[0029] 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, seleocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, glutathione, dithiothreitol, thiorphan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapidine, ketone ... The keratolytic agent is selected from the group consisting of trilat, ovothiol A, lentiapril, thiosalicylic acid, thixocortol, mycothiol, coenzyme A, coenzyme B, disulfiram, sammaprin 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, alpha-hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylate. In some embodiments, the keratolytic agent is selenium disulfide.

[0030] Also provided herein in certain embodiments are methods of treating reduced vision and / or dry eye syndrome, such as by administering a keratolytic agent to the eye or surrounding tissues (e.g., palpebral conjunctiva, eyelid (e.g., lid margin) or palpebral conjunctiva) of an individual in need of such treatment (e.g., an individual who does not wear contact lenses and / or an individual who has not been diagnosed with meibomian gland dysfunction (MGD)). In some embodiments, treating dry eye syndrome and / or reduced vision includes treating symptoms associated with dry eye syndrome and / or reduced vision. In certain embodiments, symptoms associated with dry eye syndrome and / or reduced vision are symptoms identifiable by an individual and / or a clinician. In certain embodiments, the methods provided herein relate to treating any symptoms associated with dry eye syndrome and / or reduced vision, such as, by way of non-limiting example, inflammation, dryness, pain, or combinations thereof. In certain embodiments, the keratolytic agent is benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, alpha-hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylate. In some embodiments, the keratolytic agent is selenium disulfide.

[0031] In some embodiments, the individual does not wear contact lenses.

[0032] In some embodiments, the individual has not been diagnosed with contact lens discomfort.

[0033] In some embodiments, the individual wears contact lenses.

[0034] In some embodiments, the individual has not been diagnosed with meibomian gland dysfunction (MGD).

[0035] In some embodiments, the individual has not been diagnosed with lid-wiper epitheliopathy (LWE).

[0036] In some embodiments, the individual has been diagnosed with meibomian gland dysfunction (MGD).

[0037] In some embodiments, the individual has been diagnosed with lidwiper epitheliopathy (LWE).

[0038] In some embodiments, the individual (eg, the individual in need of treatment) has blurred vision.

[0039] In various embodiments, the therapy provided herein comprises administering a composition to the eye of an individual (e.g., an individual who does not wear contact lenses and / or an individual who has not been diagnosed with meibomian gland dysfunction (MGD)) or to the surrounding tissues thereof (e.g., palpebral conjunctiva, eyelid (e.g., lid margin)). Typically, for purposes of the embodiments described herein, the eye of an individual comprises an ocular component (i.e., eye globe or "eyeball") and an eyelid component (e.g., upper eyelid and lower eyelid). In certain instances, the upper eyelid and lower eyelid each generally comprise the palpebral conjunctiva, which is the tissue that covers the inside (or at least a portion thereof) of the eyelid. In some embodiments, the therapy provided herein comprises administering a composition to at least a portion of the palpebral conjunctiva and / or lid margin of an individual. In some embodiments, the therapy provided herein comprises administering a composition to one eye of an individual. In other embodiments, the methods of therapy provided herein comprise administering a composition to both eyes of an individual.

[0040] In some instances, the lid wiper area is a thickened epithelial "lip" with a conjunctival mucosa morphology that extends from the tarsal conjunctiva to the apex of the posterior lid margin, aiding in the distribution of the precorneal tear film.

[0041] In various embodiments described herein, administration of the active agent or composition described herein is achieved by administering the active agent or composition to the eye or surrounding tissues, such as the eyelid, of an individual in need thereof. In some embodiments, topical use to the eye of an individual includes topical ocular administration, (e.g., topical) palpebra (lid) administration (e.g., inside and / or outside the lid), or a combination thereof. In some preferred embodiments, (e.g., direct) administration is (e.g., topical) administration to the inner surface of the eyelid. In more preferred embodiments, administration is (e.g., directly) administration to the lid wiper region of the inner surface of the eyelid. In some embodiments, administration is (e.g., directly) administration to the lid wiper region and stratified squamous epithelium region and / or subtarsal fold region of the eyelid. In some embodiments, administration is to or includes (e.g., directly) administration to the lid wiper region, stratified squamous epithelium region, and subpalpebral fold region of the eyelid. In certain embodiments, administration is to or includes (e.g., directly) administration to the lid wiper region, stratified squamous epithelium region, subpalpebral fold region, and stratified columnar epithelium region of the eyelid. In various other embodiments, administration is not even to the meibomian gland orifices of the eyelid.

[0042] FIG. 1 shows a schematic diagram of an exemplary ocular surface and a portion of an eyelid. As shown in the figure, eyelashes can be observed at the edge of the eyelid. Moving inward from the eyelashes, the inner surface of the eyelid includes a stratified squamous epithelium region located proximal to the eyelashes. Further along the inner surface of the eyelid, the stratified squamous epithelium leads to a lid wiper region, which is the region of the inner surface that contacts the ocular surface (e.g., in a normally functioning eyelid). In some instances, if an individual suffers from a disease that affects the ocular surface, resulting in reduced vision, other portions of the inner surface of the eyelid may also contact the ocular surface. Moving from the lid wiper region (e.g., along the inner surface of the eyelid distal to the eyelashes), the inner surface of the eyelid includes a subtarsal fold region and a stratified columnar epithelium region. In some instances, the palpebral conjunctiva extends over all or part of the inner surface of the eyelid, for example with a leading edge in the lid wiper region.

[0043] The keratolytic and keratinogenic agents described herein are useful as either acute therapies (e.g., by a trained professional or physician) or chronic therapies (e.g., in the hands of the patient or caregiver, or by a trained professional or physician). Agents are, in some embodiments, tested using the assays and methods described herein (e.g., those described in the Examples).

[0044] In one embodiment, a method of treating vision loss in a patient in need thereof (e.g., an individual who does not wear contact lenses and / or an individual who has not been diagnosed with meibomian gland dysfunction (MGD)) is provided, comprising topically administering a composition comprising a keratolytic or keratinogenic agent. In some embodiments, the keratolytic agent is allantoin, benzoyl peroxide, selenium disulfide, SeCl 4 , Na 2 SeO 3 and the like, organic selenium compounds such as ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) or analogs thereof, coal tar, dithranol, salicylic acid, selenium disulfide, alpha-hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidinone carboxylate. In some embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, and selenium disulfide. 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.

[0045] In certain embodiments, it is desirable for the drug to minimize undesirable side effects, such as causing irritation or other adverse ocular conditions.

[0046] In some embodiments, for example for subjects with low keratin production levels, weak or weak keratolytic and / or keratinizing agents are used in the methods and formulations described herein. Such weak or weak keratolytic and / or keratinizing agents are optionally used in the setting of maintenance therapy. The weak or weak keratolytic and / or keratinizing agents include keratolytic and / or keratinizing agents with lower concentrations of active keratolytic and / or active keratinizing agents, as well as keratolytic and / or keratinizing agents with low inherent activity (e.g., as determined by the methods described herein). In some embodiments, the weak or weak keratolytic and / or keratinizing agent is not boric acid.

[0047] In certain embodiments, the composition comprises a therapeutically effective amount of at least one keratolytic agent (e.g., as described herein) in 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 and refer to SeS, which has a selenium to sulfur ratio of about 1:2. 2 In another embodiment, the keratolytic agent is zinc pyrithione. In another embodiment, the keratolytic agent is zinc L-pyrrolidone carboxylate.

[0048] In some embodiments, multiple keratolytic agents are used.

[0049] In some embodiments, administration of a keratolytic agent to a keratinocyte obstruction results in proteolysis of desmosomes, which form the 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.

[0050] In some embodiments, the therapeutically effective amount of keratolytic agent is about 0.01% or more. In some embodiments, the therapeutically effective amount of keratolytic agent 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 any range therein). In some embodiments, the therapeutically effective amount of keratolytic agent is about 0.01% to about 10%. In some embodiments, the therapeutically effective amount of keratolytic agent is 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 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, or more. In some embodiments, the therapeutically effective amount of keratolytic agent 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%, about 10%, or more. In some embodiments, the therapeutically effective amount of keratolytic agent is about 10% or less, e.g., about 5% or less, about 2.5% or less, about 2% or less, about 1% or less, about 0.5% or less, about 0.1% or less, or less. In some embodiments, the therapeutically effective amount of keratolytic agent is about 0.01% to about 30%, e.g., about 0.01% to about 10%, about 0.1% to about 10%, or about 0.1% to about 30%.

[0051] In a particular embodiment, the keratolytic agent is selenium disulfide.

[0052] 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 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, or more of selenium disulfide. In some embodiments, the concentration of selenium disulfide in the composition is at least about 0.01%, such as at least about 0.05%, about 0.1%, about 1%, about 2%, about 2.5%, about 5%, about 10%, or more. In some embodiments, the concentration of selenium disulfide in the composition is about 10% or less, e.g., about 5% or less, about 2.5% or less, about 2% or less, about 1% or less, about 0.5% or less, about 0.1% or less, or less. In some embodiments, the composition comprises about 0.01% to about 30% selenium disulfide, e.g., about 0.01% to about 10%, about 0.1% to about 10%, or about 0.1% to about 30% selenium disulfide.

[0053] In some embodiments, the composition comprising selenium disulfide is a suspension, emulsion, cream, lotion, gel (e.g., aqueous or non-aqueous), or ointment. In some embodiments, the composition comprising 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.

[0054] In some embodiments, the composition comprises an inorganic selenium compound that is an inhibitor of prostaglandin synthase, an enzyme involved in the production of prostaglandins. A selenium compound that exhibits this inhibitory effect is SeCl 4 and Na 2 SeO 3 It is known that the proinflammatory effects of prostaglandins promote keratinization, therefore, these water-soluble inorganic selenium compounds that interfere with the production of prostaglandins may be useful in reducing keratinization.

[0055] In some embodiments, the composition comprises an organic selenium compound.Organic selenium 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 phospholipids and cholesteryl ester hydroperoxides.Anti-inflammatory agents are known to inhibit keratinization, and thus ebselen and other organic selenium analogs may function as keratolytic agents through this antioxidant / anti-inflammatory activity.

[0056] In some embodiments, the formulation comprising a keratolytic and / or keratinizing agent further comprises an additional agent that is not a meibomian gland opening pharmacological 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 formulation comprising a keratolytic and / or keratinizing agent excludes any additional agent other than any additional meibomian gland opening pharmacological agent.

[0057] In certain embodiments, the composition comprises (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.

[0058] As used herein, the term "local anesthetic" refers to an agent that induces a reversible absence of pain sensation. In some embodiments, the local anesthetic may also induce temporary muscle paralysis in addition to inducing a reversible absence of pain sensation.

[0059] The local anesthetic agents described herein are primarily useful as acute therapies, e.g., under the guidance of a physician or other trained professional. The agents are, in certain embodiments, tested using the assays and methods described herein.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] In some embodiments, the local anesthetic is a combination of lidocaine and prilocaine, or a combination of lidocaine and tetracaine.

[0064] 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.

[0065] In some embodiments, the local anesthetic is mixed with a vasoconstrictor to constrict blood vessels and thereby extend 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 are mixed in combination with a steroid.

[0066] In some embodiments, the (e.g., topical) compositions described herein are combined with a pharma- ceutically suitable or acceptable carrier (e.g., a pharma- ceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier. Exemplary excipients are described, for example, in "Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)). Other additives, such as preservatives, are optionally provided.

[0067] In certain embodiments, the compositions provided herein include any suitable additional agent or additive. In certain embodiments, additives are included, for example, to 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 a surfactant (e.g., ionic, anionic, cationic, non-ionic, lipid (e.g., oleic or caprylic acid), BNZ, etc.). In some examples, the compositions provided herein include an excipient that otherwise improves drug penetration, for example, according to the processes described herein, and / or functions to solubilize plaque or keratinization present, for example, on the eyelid or lens.

[0068] In certain embodiments, the pharma- ceutically acceptable composition consists essentially of at least one keratolytic agent (e.g., as described herein) and an ophthalmically acceptable carrier. In certain embodiments, the pharma- ceutically acceptable composition consists essentially of at least one keratolytic agent (e.g., as described herein) and an ophthalmically acceptable carrier.

[0069] Described herein are methods for treating various ocular disorders (e.g., dry eye syndrome) in an individual (e.g., patient) in need thereof, comprising topically administering a composition described herein to the individual (e.g., patient) in need thereof (e.g., administering to one or more inner eyelids of the individual). In some embodiments, the individual is a patient undergoing medical treatment (e.g., for an ocular condition and / or another condition). In some examples, such therapy is an acute therapy, such that in some embodiments, a more potent pharmacological agent is utilized (either in terms of concentration of the agent or intrinsic activity of the agent). In one embodiment, maintenance use allows for the use of a lower concentration of the agent, or an agent with a lower intrinsic activity. Maintenance use, in one embodiment, involves the patient visiting a healthcare provider on a daily basis. Both acute and maintenance use are optionally accompanied by the use of an eye-protecting device or appliance. In one embodiment, acute use is performed by a healthcare provider, and maintenance use is performed by a non-healthcare provider, such as the patient or a caregiver. In some embodiments, the patient applies the pharmacological agent (e.g., a composition including a keratolytic agent) to themselves (e.g., to the inner surface of one or more of their eyelids). In one embodiment, such administration occurs over an extended period of time, and one way to describe this multiple dose mode of patient administration is chronic use. Generally, for chronic or patient administration use, a separate or second formulation of the pharmacological agent is recommended. In one embodiment, the separate or second formulation utilizes a lower concentration of the pharmacological agent. In another embodiment, the second or separate formulation utilizes a pharmacological agent that is less active than the first formulation.

[0070] 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 (e.g., abnormal) keratinization (e.g., parakeratinization (pk)) is reduced. 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 reduced 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 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 a periodic 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 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 is performed twice weekly. 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 at night or in the evening. 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 after a period of not exposing the eye to light.

[0071] 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 oleaginous 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.

[0072] In certain preferred embodiments, a semi-solid or other viscous formulation (e.g., a gel (e.g., a gel-emulsion suspended foam), cream or ointment, or other formulation such as a suspension, hydrophobic oil, foam, liposome, emulsion, lotion, microparticle, etc.) is utilized. In some instances, such a formulation facilitates maintaining the pharmacologically active formulation at or near the site to be treated (e.g., site of dysfunction such as trauma, abnormal keratinization, etc.). In some instances, the semi-solid or other viscous formulation migrates little or nothing from the site of administration.

[0073] In some embodiments, the topical administration of the composition comprising the pharmacological agent is performed once a week. In some embodiments, the topical administration of the composition comprising the pharmacological agent is performed twice a week. In some embodiments, the topical administration of the composition comprising the pharmacological agent is performed every other day. In some embodiments, the topical administration of the composition comprising the pharmacological agent is performed daily. In some embodiments, the topical administration of the composition comprising the pharmacological agent is performed several times a day.

[0074] 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. In an acute treatment scenario, the dosage of the pharmacological agent may be greater than the dosage of the pharmacological agent used in a chronic treatment scenario or a maintenance therapy scenario. In an acute treatment scenario, the pharmacological agent may be different from the pharmacological agent used in a chronic treatment scenario. In some embodiments, the treatment course 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 pharmacological agent administered in the acute treatment scenario is a local anesthetic agent and the pharmacological agent administered in the chronic treatment scenario or the maintenance therapy scenario is a keratolytic and / or keratinizing agent. In some embodiments, the pharmacological agent administered in the acute treatment scenario is a keratolytic and / or keratinizing agent and the pharmacological agent administered in the chronic treatment scenario or the maintenance therapy scenario is a keratolytic and / or keratinizing agent.

[0075] In some clinical conditions, patients may require initial treatment by a physician or medical professional by administering a more concentrated formulation of any of the therapeutic agents described herein. If a more concentrated formulation is required, its application may require eye protection or other procedures to minimize the effects of irritation or destruction of the ocular surface or surrounding tissue. Following such procedures, patients may be given a different formulation of the active agent to take home and apply periodically to the inner surface of the eyelid. Such application may be performed twice daily, once daily, weekly, twice weekly, biweekly, or monthly, depending on the formulation activity and the desired product profile of the treatment.

[0076] In some embodiments, the methods provided herein provide for an improvement in one or more symptoms of dry eye syndrome, such as dryness, grittiness, stinging, pain, irritation, burning, or discharge. In some embodiments, such improvement in symptoms can be assessed by Ocular Surface Disease Index (OSDI), subjective visual acuity assessment (e.g., VAS), or another subjective scoring system (e.g., CLDEQ-8). In some embodiments, the methods provided herein provide for an improvement in reduced visual acuity and / or eyelid symptoms associated with dry eye syndrome. In some embodiments, the methods provide for an improvement in reduced visual acuity and / or tear film symptoms associated with dry eye syndrome. In some embodiments, the methods provide for an improvement in the CLDEQ-8 measurement tool. In some embodiments, the methods provide for an improvement in visual acuity. In some embodiments, the methods provide for an improvement in subjective visual acuity assessment (e.g., assessed by Ocular Surface Disease Index (OSDI) or visual analog scale, VAS). In some embodiments, the improvement of one or more symptoms of vision loss and / or dry eye syndrome is observed within about 1 month, e.g., within 3 months, within 2 months, within 6 weeks, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 3 days, within 2 days, or sooner, of administration of the composition (e.g., by the methods provided herein). In some embodiments, the improvement of one or more symptoms of vision loss and / or dry eye syndrome is observed within about 3 months of administration of the composition (e.g., by the methods provided herein). In some embodiments, the improvement of vision loss and / or dry eye syndrome symptoms continues for, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or longer, of administration.

[0077] In some embodiments, the methods provided herein further comprise one or more additional therapeutic interventions, such as application of a hot compress, debridement, and / or therapeutic expression (e.g., manual expression or physical expression using an instrument such as LipiFlow). In some embodiments, the methods provided herein further comprise performing debridement or debridement combined with therapeutic expression in the individual's eye. In some embodiments, debridement is performed in one eye and debridement combined with therapeutic expression is performed in the other eye. In some embodiments, the therapeutic intervention (also referred to herein as physical intervention) is performed after administration of the compositions provided herein. For example, in some embodiments, the physical intervention is performed at least about 5 minutes after administration of the compositions provided herein, e.g., 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, 6 weeks, 3 months, or longer after administration of the compositions provided herein. In some embodiments, the compositions are administered periodically and the physical intervention is performed once, such as about 1 month after the initial administration of the composition.

[0078] One aspect of the treatment method described herein is the location of topical administration of the composition.In one embodiment, the composition containing the pharmacological agent is administered so as to cause little or no irritation to the eye or the surrounding tissue.In one embodiment, the composition containing the pharmacological agent (e.g., keratolytic agent) is administered to the inner eyelid surface (e.g., one or both upper eyelids and / or one or both lower eyelids) of an individual in need thereof.

[0079] A further embodiment of the treatment methods described herein is the use of a protective element provided to the eye to avoid eye irritation. The formulations described herein are generally non-irritating, but in some embodiments (e.g., when used with high concentrations of drugs or sensitive eyes), the protective element provides an additional layer of safety and comfort to the patient. In one embodiment, the composition comprising the pharmacological agent is administered with an eye shield on the eye to reduce contact of the pharmacological agent 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 composition comprising the pharmacological agent is administered with the eyelids pulled away from the eyeball, thereby reducing contact of the pharmacological agent with the cornea and / or conjunctiva, thereby reducing eye irritation.

[0080] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "cells" includes a reference to one or more cells (or cells), and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, it is intended to include all combinations and subcombinations of the ranges and specific embodiments within the ranges. The term "about" when referring to a numerical value or numerical range means that the numerical value or numerical range referred to is an approximation within the range of experimental variation (or within the range of statistical error), and thus the numerical value or numerical range may vary between 1% and 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as embodiments of any substance, composition, method, or process described herein, from "consisting of" or "consist essentially of" the recited features.

[0081] As used herein, the terms "treat," "treating," or "treatment" include reducing, alleviating, reducing, eliminating, alleviating, or attenuating symptoms of the disorders described herein, such as vision loss and / or in either a chronic or acute treatment scenario. In one embodiment, treatment includes reduction of terminal duct obstruction.

[0082] The term "recurrence" or "reducing relapse" of symptoms of the disorders described herein, such as vision loss and / or symptoms in a chronic treatment scenario.

[0083] As used herein, the terms "keratolytic agent" and / or "keratoplastic agent" refer to agents that soften, break down, dissolve, solubilize, or loosen keratinized obstructions, or that prevent the formation of keratinized obstructions. Specifically, the term "keratolytic agent" refers to agents used to promote the softening and dissolution of keratin, and the term "keratinizing agent" refers to agents used to reduce the production of keratin.

[0084] The term "lotion" refers to an emulsion liquid dosage form, generally intended for external application to the skin (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0085] The term "cream" refers to an emulsion semisolid dosage form that typically contains more than 20% water and volatile materials and / or less than 50% hydrocarbons, waxes or polyols as a vehicle. Creams are more viscous than lotions. This dosage form is generally intended for external application to the skin (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0086] The term "ointment" refers to a semi-solid dosage form that typically contains less than 20% water and volatile materials and / or more than 50% hydrocarbons, waxes or polyols as a vehicle, generally intended for external application to the skin or mucous membranes (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0087] The term "solution" refers to a clear, homogeneous liquid dosage form containing one or more chemical substances dissolved in a solvent or mixture of mutually miscible solvents (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0088] 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 the bulk of the solvent.

[0089] The concentration of the agents provided herein may be determined by any suitable measure, such as wt%, w / w%, or w / v%, etc. In certain instances, the concentration is a wt% (e.g., w / w% or w / v%).

[0090] The term "about" means, for example, any acceptable amount suitable for achieving a stated purpose. In some examples, "about" refers to, for example, ±20%, or ±10%, or ±5%.

[0091] As used herein, "comprising" also includes the explicit disclosure of "consisting of" and "consisting essentially of." EXAMPLES

[0092] Example 1. Pharmacologically active formulations

[0093] High viscosity formulations are prepared, for example, for administration according to the disclosure provided herein. Any suitable formulation is optionally utilized, such as creams, ointments, emulsions, suspensions, granules, etc. In various embodiments, an exemplary eye ointment formulation is prepared according to the following formula:

[0094] [Table 1-1]

[0095] [Table 1-2]

[0096] Other formulations, such as ointment / semi-solid formulations, surfactant formulations, etc., are contemplated and provided herein.

[0097] Abnormal keratitis is induced in the eyes of rabbits 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 wipers and / or within the conjunctival folds, is evaluated.

[0098] Example 2: Clinical evaluation of visual acuity improvement

[0099] Patients with vision loss were treated with a control (N=26) or a drug formulation containing 0.1% selenium disulfide (n=9), 0.5% selenium disulfide (n=26), or 1% selenium disulfide (n=34). Treatment consisted of applying the drug to the lower eyelids of both eyes twice weekly. Patients were followed up and had visual acuity assessments performed using the Ocular Surface Disease Index (OSDI) after 2 weeks, 1 month, 6 weeks, and 3 months. Figures 2A-2C show patients' change from baseline as assessed by OSDI visual acuity assessment (e.g., based on the OSDI ocular symptoms subscale, change from baseline (Figure 2A), the OSDI visual function subscale, change from baseline (Figure 2B), and the OSDI environmental triggers subscale, change from baseline (Figure 2C)). As can be seen in Figures 2A-2C, visual acuity in patients treated with 0.5% and 1% selenium disulfide not only improved, but also showed sustained improvement over the course of 2 weeks to 3 months. † denotes significant difference from control (p<0.10), ° denotes significant difference from control (p<0.05), ~ denotes significant difference from baseline (p<0.10), * denotes significant difference from baseline (p<0.05).

[0100] 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. Although 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, modifications, and substitutions will occur to those skilled in the art without departing from the present invention. Furthermore, it should be understood that all aspects of the present invention are not limited to the specific depictions, configurations, or relative proportions described herein, which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in carrying out the present invention. It is therefore contemplated that the present invention will cover such alternatives, modifications, variations, or equivalents. The following claims are intended to define the scope of the present invention, and methods and structures within the scope of the claims and their equivalents are intended to be covered thereby.

Claims

1. A composition comprising selenium disulfide in an ophthalmically or pharmaceutically acceptable vehicle or carrier for use in a method of improving vision in an individual in need thereof, wherein the method comprises, providing the composition to the individual, and the composition is administered to the eyelid or eye of the individual in a manner suitable for delivering the selenium disulfide to the eyelid margin or ocular surface of the eyelid of the individual, wherein the improvement in vision is, measured using a questionnaire regarding visual function, a subjective scale, or an objective scale, Composition.

2. The composition according to claim 1, wherein the composition is provided to the individual on a regular basis.

3. The composition according to claim 2, wherein the composition is administered to the individual on a regular basis over a period of at least two weeks.

4. The composition according to claim 2, wherein the composition is administered to the individual on a regular basis over a period of at least one month.

5. The composition according to claim 2, wherein regular administration comprises administering the composition at least once a week.

6. The composition according to claim 2, wherein regular administration comprises administering the composition at least twice a week.

7. The composition according to claim 1, wherein the individual is not diagnosed with meibomian gland dysfunction (MGD) or lid wiper epithelial disorder (LWED).

8. The composition according to claim 1, wherein the individual is not wearing contact lenses.

9. The composition according to claim 1, wherein the concentration of selenium disulfide in the composition is between about 0.01% by weight and about 10% by weight.

10. The composition according to claim 9, wherein the composition comprises 0.5% by weight of selenium disulfide in an ophthalmically acceptable carrier.

11. The composition according to claim 1, wherein the composition is administered to at least a part of the palpebral conjunctiva of the eye of the individual.

12. The composition according to claim 1, which is a dispersion or suspension.

13. The composition according to claim 1, which is hydrophilic.

14. The composition according to claim 1, which comprises an oily base.

15. The composition according to claim 1, which is homogeneous.

16. The composition according to claim 1, wherein the questionnaire is OSDI, VAS, or CLDEQ-8.

17. The composition according to claim 16, wherein the questionnaire is OSDI.

18. The composition according to claim 16, wherein when the visual function is measured by the OSDI visual function scale after regular administration for 1 month, it is improved by at least 2 points.

19. The composition according to claim 16, wherein when the visual function is measured by the OSDI visual function scale after regular administration for 2 months, it is improved by at least 5 points.

20. The composition according to claim 1, wherein the visual function is improved in reading, night driving, computer work, and watching TV.

21. The composition according to claim 1, wherein the subjective scale is visual acuity, hyperacuity, contrast sensitivity, glare vision, visual acuity using PAM, visual acuity under photopic conditions, visual acuity under scotopic conditions, or a combination thereof.

22. The composition according to any one of claims 1 to 21, wherein the objective scale is an aberrometer, an objective scatter image, a double-pass system, or a combination thereof.

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