EP4739293A2 - Compositions and methods for the treatment of autoimmune disorders - Google Patents

Abstract

Described herein are compositions and methods for the treatment of an inflammatory or autoimmune disease or disorder associated with conditions in or around an eye of an individual in need thereof. Said compositions and methods comprises providing a pharmaceutically (e.g., ophthalmically acceptable) composition comprising a keratolytic agent to an ocular or periocular surface of the individual in need thereof.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF AUTOIMMUNE DISORDERS

CROSS REFERENCE

[0001] The present application claims the benefit of U.S. Provisional Application No. 63/525,548, filed July 7, 2023, which is entirely incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Expression of keratinization of the Conjunctiva, posterior surface of the eyelid and meibomian glands are major contributing factors to ocular signs and symptoms of inflammatory and autoimmune eye disease and is often characterized by production of a keratinized material, which is uncommon in healthy eye.

[0003] Keratolytic agents are highly irritable to the eye and cannot be applied without substantial precaution to avoid mucosal and corneal touch. Selenium sulfide (SeS?) is indicated for the treatment of dermatological condition such as seborrheic dermatitis, tinea versicolor and dandruff. It is typically used as shampoo, foam or lotion at commercially available concentrations of 1% and 2.5% and is applied for several minutes, then rinsed off. The use of SeS? can be associated with known side effects that are listed in the drug insert and which may include irritation, burning, and on rare occasion, loss and discoloration of hair. Contact of a significant amount of preparations containing high-concentration SeS? with mucous membranes of the eye may cause irritation (e.g., stinging) and prolonged contact (e.g., overnight application) of preparations containing SeS2 with the skin may cause local irritation.

[0004] Adverse events reported following topical ocular use of SeS? containing products include: superficial punctate keratitis and conjunctivitis which resolved upon cessation of treatment. When SeS? is applied topically for the treatment of tinea versicolor, skin irritation may occur in the genital areas and/or folds of the skin. SeS? lotions can also cause rebound oiliness of the scalp. AHFS Drug Information 2010.

SUMMARY OF THE INVENTION

[0005] Patients with an inflammatory or autoimmune disease or disorder (e.g., Stevens- Johnson syndrome (SJS)) sometimes manifest conditions and/or disease in or around an eye (e.g., keratinization of an eyelid margin or posterior surface of an eyelid of an individual). For example, Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) is a dermatologic emergency, characterized by the presence of epidermal and mucosal bullous lesions. Severe damage to the skin and mucous membranes of certain inflammatory or autoimmune disease or disorder associated with keratinization of an eyelid margin or posterior surface of an eyelid or an ocular surface of an individual can make such inflammatory or autoimmune conditions have substantially negative life experience and/or even be life-threatening. Because the skin normally acts as a protective barrier, extensive skin damage can lead to a dangerous loss of fluids and allow infections to develop. In some instances, such conditions can affect the eyes as well, causing irritation and redness of the conjunctiva (e.g., the mucous membrane that line the eyelids and eye surface). Lid margin keratinization (LMK) is a chronic ocular sequela of SJS, which causes lid wiper epitheliopathy and progressive ocular surface damage. Prior to the methods described herein, there were no pharmacological agents useful for the treatment of disease or disorder associated with conditions in or around an eye.

[0006] Provided in certain embodiments herein is a method for treating a disease or disorder associated with conditions in or around an eye. In some embodiments, a method comprises providing or administering a pharmaceutical (e.g., ophthalmically acceptable) composition to an ocular and/or periocular surface of an individual in need thereof (e.g., having a disease or disorder associated with conditions in or around an eye). In some embodiments, a pharmaceutical composition comprises one or more keratolytic agents (e.g., SeS?). In some embodiments, a disease or disorder comprises an inflammatory and/or autoimmune disease (e.g., SJS). In some embodiments, an inflammatory and/or autoimmune disease is associated with conditions in or around an eye (e.g., keratinization of an ocular and/or periocular surface, such as an eyelid, eyelid margin and/or posterior eyelid surface). In some embodiments, an individual in need thereof has a disease or disorder associated with conditions in or around an eye (e.g., keratinization of an eyelid margin or posterior surface of an eyelid).

[0007] Provided in certain embodiment herein is a method for treating an inflammatory or autoimmune disease or disorder associated with keratinization of an eyelid margin or posterior surface of an eyelid of an individual in need thereof, the method comprising providing to a periocular surface of the individual a pharmaceutical composition comprising a keratolytic agent and an ophthalmically or pharmaceutically acceptable vehicle or carrier.

[0008] Provided in certain embodiment herein is a method for treating an inflammatory or autoimmune disease or disorder associated with keratinization of an eyelid margin or posterior surface of an eyelid of an individual in need thereof, the method comprising providing to a periocular surface of the individual a pharmaceutical composition comprising a keratolytic agent in an ophthalmically or pharmaceutically acceptable vehicle or carrier.

[0009] In some embodiments, the inflammatory or autoimmune disease or disorder affects mucous membrane(s) of the individual.

[0010] In some embodiments, the inflammatory or autoimmune disease or disorder affects skin of the individual. [0011] In some embodiments, the inflammatory or autoimmune disease or disorder affects both the mucous membrane(s) and skin areas of the individual.

[0012] In some embodiments, the inflammatory or autoimmune disease or disorder is associated with ocular manifestations.

[0013] In some embodiments, the individual has Sjogren's Syndrome, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Behget's disease, Sarcoidosis, Graft-versus-host disease (GvHD), Stevens- Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), psoriasis, ichthyosis, Lichen planus, atopic dermatitis, Ocular cicatricial pemphigoid (OCP), Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), exposure keratopathy (EK), or post chemical burns (e.g., exposure to strong acids or alkalis that causes severe damage to the ocular surface).

[0014] In some embodiments, the inflammatory or autoimmune disease or disorder associated with keratinization of an eyelid margin or posterior surface of an eyelid comprises Sjogren's Syndrome, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Behget's disease, Sarcoidosis, Graft-versus-host disease (GvHD), Stevens- Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), psoriasis, ichthyosis, Lichen planus, atopic dermatitis, Ocular cicatricial pemphigoid (OCP), Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), exposure keratopathy (EK), or post chemical bums (e.g., exposure to strong acids or alkalis that causes severe damage to the ocular surface).

[0015] In some embodiments, the individual has SJS.

[0016] Provided in certain embodiment herein is a method for treating SJS in an individual, the method comprising providing to a periocular surface of the individual a pharmaceutical composition comprising a keratolytic agent and an ophthalmically or pharmaceutically acceptable vehicle or carrier.

[0017] In some embodiments, the method comprises providing to a periocular surface of the individual a pharmaceutical composition comprising a keratolytic agent and an ophthalmically or pharmaceutically acceptable vehicle or carrier.

[0018] In some embodiments, the method comprises providing to a periocular surface of the individual a pharmaceutical composition comprising a keratolytic agent in an ophthalmically or pharmaceutically acceptable vehicle or carrier.

[0019] In some embodiments, skin of the individual is affected by SJS.

[0020] In some embodiments, periocular surface of the individual is affected by SJS.

[0021] In some embodiments, mucous membrane of the individual is affected by SJS. [0022] In some embodiments, the pharmaceutical composition is administered to the periocular surface of the individual in a manner suitable to deliver the keratolytic agent to the affected skin and/or mucous membrane of the individual.

[0023] In some embodiments, SJS is characterized by (e.g., severe) burning, conjunctival ulcerations, membrane formation, and/or sloughing of surface epithelium, such as at the lid margin.

[0024] In some embodiments, SJS is characterized by chronic and/or long-term sequelae (e.g., of the skin, ocular, and/or periocular surface).

[0025] In some embodiments, SJS is characterized by dry eye, conjunctival scarring/deficiency, loss of limbal epithelial stem cells, and/or (e.g., heavy) keratinization, such as over the lid wiper zone and/or conjunctiva of the individual.

[0026] In some embodiments, SJS is characterized by lid margin keratinization (LMK).

[0027] In some embodiments, SJS is ocular SJS.

[0028] In some embodiments, the pharmaceutical composition is provided to or around the eye of the individual. In some embodiments, the pharmaceutical composition is provided to the eye of the individual. In some embodiments, the pharmaceutical composition is provided to the surface of the eye of the individual.

[0029] In some embodiments, the pharmaceutical composition is administered to the eyelid of the individual.

[0030] In some embodiments, the pharmaceutical composition is administered to the eyelid of the individual in a manner suitable to deliver the keratolytic agent to an eyelid margin of the individual.

[0031] In some embodiments, the pharmaceutical composition is administered to an eyelid margin of the individual.

[0032] In some embodiments, the pharmaceutical composition is administered to the individual monthly, bi-weekly, weekly, or daily. In some embodiments, the pharmaceutical composition is administered to the individual at least once weekly. In some embodiments, the pharmaceutical composition is administered to the individual at least twice weekly. In some embodiments, the pharmaceutical composition is administered to the individual at least once daily. In some embodiments, the pharmaceutical composition is administered to the individual at least twice daily.

[0033] In some embodiments, the pharmaceutical composition is self-administered.

[0034] In some embodiments, the pharmaceutical composition is administered by a healthcare professional or physician. [0035] In some embodiments, the individual has or has developed meibomian gland dysfunction (MGD).

[0036] In some embodiments, the method further comprises improving lipid secretion of one or more (e.g., meibomian) gland.

[0037] In some embodiments, the method further comprises opening or clearing a (e.g., meibomian) gland obstruction in the individual.

[0038] In some embodiments, the method further comprises opening or clearing the (e.g., meibomian) gland obstruction in the individual comprises reducing an amount of particulate matter (e.g., keratinized material), such as in meibum.

[0039] In some embodiments, the (e.g., meibomian) gland comprises altered (e.g., meibum) secretions and keratinized material.

[0040] In some embodiments, the (e.g., meibomian) gland obstruction comprises one or more of chronic ocular discomfort, anatomic abnormalities around a (e.g., meibomian) gland orifice, obstruction of a meibomian gland, or decreased meibum production.

[0041] In some embodiments, the anatomic abnormalities around the (e.g., meibomian) gland orifice comprise one or more of vascular engorgement, anterior or posterior displacement of the mucocutaneous junction, or irregularity of the eyelid margin.

[0042] In some embodiments, the pharmaceutical composition comprises an oleaginous base.

[0043] 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, seleocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, N-acetyl cysteine (NAC), gluthatione, dithiothreitol, thiorphan, cysteamine, bucillamine, dimercaprol, 1,1 -ethanedi thiol, dimercaptosuccinic acid, furan-2- ylmethanethiol, omapatrilat, ovothiol A, rentiapril, 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, thiophospholipid, thiocholesterol, 12-mercaptododecanoic acid, 23-(9- mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosanoic acid, and sulfanegen.

[0044] In some embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, N-acetyl cysteine (NAC), bucillamine, captopril, alpha-hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and zinc L-pyrrolidone carboxylate.

[0045] In some embodiments, the keratolytic agent is selenium disulfide. [0046] In some embodiments, a combination of keratolytic agents are provided to the individual (e.g., wherein a first keratolytic agent is provided for a first period of time and a second keratolytic agent is provided for a second period of time).

[0047] In some embodiments, the keratolytic agent is provided in a concentration greater than or equal to about 0.01% by weight (wt. %). In some embodiments, the keratolytic agent is provided in a concentration greater than or equal to about 0.1% by weight (wt. %).

[0048] In some embodiments, the keratolytic agent is provided to the individual at a concentration of about 0.1 wt. % to about 10 wt. %.

[0049] In some embodiments, the keratolytic agent is provided to the individual at concentration of about 0.1 wt. % to about 2 wt. % of selenium disulfide.

[0050] In some embodiments, the keratolytic agent is provided to the individual at concentration of less than or equal to about 1 wt. %. In some embodiments, the keratolytic agent is provided to the individual at concentration of less than 0.5 wt. %. In some embodiments, the keratolytic agent is provided to the individual at concentration of less than 0.4 wt. %. In some embodiments, the keratolytic agent is provided to the individual at concentration of less than 0.2 wt. %.

DETAILED DESCRIPTION OF THE INVENTION

Certain Definitions

[0051] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range.

[0052] As used herein, the term “comprise” or variations thereof such as “comprises” or “comprising” are to be read to indicate the inclusion of any recited feature but not the exclusion of any other features. Thus, as used herein, the term “comprising” is inclusive and does not exclude additional, unrecited features. Any disclosure of “comprising” provided herein is understood to separately include a disclosure of “consisting of’ and a disclosure of “consisting essentially of.” In some embodiments of any of the pharmaceutical compositions and methods provided herein, “comprising” may be replaced with “consisting essentially of’ or “consisting of.” The phrase “consisting essentially of’ is used herein to require the specified feature(s) as well as those which do not materially affect the character or function of the claimed disclosure. As used herein, the term “consisting" is used to indicate the presence of the recited feature alone.

[0053] The terms “treat,” “treating,” or “treatment” as used herein, include reducing, alleviating, abating, ameliorating, managing, relieving, or lessening the symptoms associated with a disease, disease state, condition, or indication (e.g., provided herein) in either a chronic or acute therapeutic scenario. Also, treatment of a disease or disease state described herein includes the disclosure of use of such compound or composition for the treatment of such disease, disease state, disorder, or indication.

[0054] The terms “individual,” “patient,” or “subj ect” are used interchangeably. None of the terms require or are limited to situation characterized by the supervision (e.g., constant or intermittent) of a health care worker (e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly, or a hospice worker).

[0055] The term “keratolytic agent” as used herein refers to an agent that softens, disrupts, dissolves, solubilizes, or loosens a keratinized obstruction, or prevents the formation of a keratinized obstruction. In some instances, keratolytic agents are used to promote softening and dissolution of keratin.

[0056] Concentrations of agents provided herein are based on any suitable measurement, such as wt. %, w/w %, or w/v%. In specific instances, the concentration is wt. % (e.g., w/w % or w/v%). [0057] The term, “meibomian gland dysfunction,” as used herein, refers to chronic, diffuse abnormality of the meibomian glands, that is characterized by terminal duct obstruction or qualitative or quantitative changes in the glandular secretion, or both. MGD may result in alteration of the tear film, eye irritation symptoms, inflammation, or ocular surface disease. The most prominent aspects of MGD are obstruction of the meibomian gland orifices and terminal ducts and changes in the meibomian gland secretions.

[0058] “Lid margin keratinization” is a chronic ocular sequela of SJS and other mucosal surface diseases, which causes lid wiper epitheliopathy and sometimes to a progressive ocular surface damage.

[0059] The term, “Stevens- Johnson syndrome (SJS)”, as used herein, refers to a dermatologic emergency, characterized by the presence of epidermal and mucosal bullous lesions. SJS typically manifests a flu-like symptom, which precedes or occurs concurrently with the development of a macular rash involving the trunk and face. As the disease progresses, the macular rash coalesces and the affected areas develop bullae. Eventually the epidermal layer sloughs off. Serious complications can include pneumonia, overwhelming bacterial infections (sepsis), shock, multiple organ failure, and death. About 10 percent of patients with SJS die from the disease. Among patients who survive, long-term effects of SJS can include changes in skin coloring (pigmentation), dryness of the skin and mucous membranes (xerosis), excess sweating (hyperhidrosis), impaired taste, difficulty urinating, and genital abnormalities. A small percentage of patients develop chronic dryness or inflammation of the eyes, which can lead to increased sensitivity to light (photophobia) and vision impairment.

[0060] Provided in certain embodiments herein is a method for treating a disease or disorder associated with conditions in or around an eye. In some embodiments, a method comprises providing or administering a (e.g., pharmaceutical and/or ophthalmically acceptable) composition to an ocular and/or periocular surface of an individual in need thereof (e.g., having a disease or disorder associated with conditions in or around an eye). In some embodiments, a pharmaceutical composition comprises one or more keratolytic agents (e.g., SeS?). In some embodiments, a disease or disorder comprises an inflammatory and/or autoimmune disease (e.g., SJS). In some embodiments, an inflammatory and/or autoimmune disease is associated with conditions in or around an eye (e.g., keratinization of an ocular and/or periocular surface, such as an eyelid, eyelid margin and/or posterior eyelid surface). In some embodiments, an individual in need thereof has a disease or disorder associated with conditions in or around an eye (e.g., keratinization of an eyelid margin or posterior surface of an eyelid).

[0061] In some embodiments, provided herein are methods for treating an inflammatory or autoimmune disease or disorder associated with keratinization of an eyelid margin or posterior surface of an eyelid or an ocular surface of an individual, the method comprising providing to a periocular surface of the individual a pharmaceutical composition comprising a keratolytic agent and an ophthalmically or pharmaceutically acceptable vehicle or carrier.

[0062] In some embodiments, provided herein are methods for treating SJS in an individual, the method comprising providing to a periocular surface of the individual a pharmaceutical composition comprising a keratolytic agent and an ophthalmically or pharmaceutically acceptable vehicle or carrier.

[0063] In certain embodiments, any methods provided herein comprises treating a disease or disorder associated with conditions in or around an eye.

[0064] In some embodiments, conditions in or around an eye comprises a disease or disorder in or around the eye. In certain embodiments, a disease or disorder in or around the eye comprises one or more conditions selected from the group comprising meibomian gland dysfunction (MGD), blepharitis, seborrheic blepharitis, Demodex infestation, dry eye disease (DED) or dry eye syndrome (DES), hyperkeratosis, dermatitis, keratitis, contact lens discomfort, lid wiper epitheliopathy (LWE), Keratoconjunctivitis Sicca, Sjogren's Syndrome, or ocular rosacea. In some embodiments, the disease or disorder in or around the eye is Blepharitis or Seborrheic Blepharitis. In some embodiments, the disease or disorder in or around the eye is meibomian gland dysfunction (MGD). In some embodiments, the disease or disorder in or around the eye is DED. In some embodiments, the disease or disorder in or around the eye is dry eye syndrome. In some embodiments, the disease or disorder in or around the eye is keratitis or hyperkeratosis. In some embodiments, the disease or disorder in or around the eye is contact lens discomfort. In some embodiments, the disease or disorder in or around the eye is LWE. In some embodiments, the disease or disorder in or around the eye is a condition characterized by insufficient secretion of lipids.

[0065] In some embodiments, a disease or disorder in or around an eye is a condition characterized by keratinization in the eye (e.g., a formation of whitish keratin deposits over the lip wiper zone and/or palpebral conjunctiva). In certain embodiments, a disease or disorder in or around an eye is a condition characterized by keratinization of an ocular surface of an individual. In certain embodiments, a disease or disorder in or around an eye is a condition characterized by keratinization of an eyelid margin or posterior surface of an eyelid. In some embodiments, a disease or disorder in or around an eye is a condition characterized by keratinization of an eyelid margin. In certain embodiments, a disease or disorder in or around an eye is a condition characterized by keratinization of posterior surface of an eyelid.

[0066] In some embodiments, a disease or disorder in or around an eye is a meibomian gland dysfunction (MGD). In some embodiments, a MGD comprises altered (e.g., meibum) secretions and keratinized material in a (e.g., meibomian) gland. In some embodiments, a MGD comprises a (e.g., meibomian) gland obstruction. In specific embodiments, the (e.g., meibomian) gland obstruction comprises one or more of chronic ocular discomfort, anatomic abnormalities around a (e.g., meibomian) gland orifice, obstruction of a meibomian gland, or decreased meibum production. In some embodiments, a MGD comprises anatomic abnormalities around a (e.g., meibomian) gland orifice. In specific embodiments, the anatomic abnormalities around a (e.g., meibomian) gland orifice comprise one or more of vascular engorgement, anterior or posterior displacement of the mucocutaneous junction, or irregularity of the eyelid margin.

[0067] In certain embodiments, a disease or disorder associated with conditions in or around an eye described herein comprises an inflammatory or autoimmune disease or disorder. In certain embodiments, a disease or disorder associated with conditions in or around an eye described herein affects mucous membrane(s) of an individual in need thereof (e.g., having the disease or disorder described herein). In certain embodiments, a disease or disorder associated with conditions in or around an eye described herein is associated with ocular manifestations in an individual in need thereof (e.g., having the disease or disorder described herein). In certain embodiments, a disease or disorder associated with conditions in or around an eye described herein is associated with periocular manifestations in an individual in need thereof (e.g., having the disease or disorder described herein).

[0068] In some embodiments, an inflammatory or autoimmune disease or disorder affects mucous membrane(s) of an individual. For instance, the mucous membrane(s) is the moist, inner lining of some organs and body cavities (e.g., nose, mouth, lungs, and stomach). In further or alternative some embodiments, the inflammatory or autoimmune disease or disorder is associated with ocular or periocular manifestations of an individual. In some embodiments, an inflammatory or autoimmune disease or disorder is associated with ocular manifestations of an individual. In some embodiments, an inflammatory or autoimmune disease or disorder is associated with periocular manifestations of an individual.

[0069] In some embodiments, an inflammatory or autoimmune disease or disorder affects skin area (e.g., eyelid) of an individual. In some embodiments, an inflammatory or autoimmune disease or disorder affects an eyelid of an individual. In some embodiments, an inflammatory or autoimmune disease or disorder affects both the mucous membrane(s) and skin areas of the individual.

[0070] In some embodiments, periocular manifestation of an individual comprises keratinization of an eye. In specific embodiments, periocular manifestation of an individual comprises keratinization of an eyelid margin or posterior surface of an eyelid. In specific embodiments, periocular manifestation of an individual comprises keratinization of an ocular surface. In some embodiments, periocular manifestations of an individual comprise keratinization of an eyelid margin. In some embodiments, periocular manifestations of an individual comprise keratinization of posterior surface of an eyelid.

[0071] In some embodiments, ocular manifestation of an individual comprises development of bulbar and conjunctival ulcerations with subsequent pseudomembrane formation, epithelial sloughing, anterior uveitis, panophthalmitis, corneal ulceration, and corneal perforation.

[0072] In some embodiments, an inflammatory or autoimmune disease or disorder associated with conditions in or around an eye comprises Sjogren's Syndrome, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Behget's disease, Sarcoidosis, Graft-versus-host disease (GvHD), Stevens- Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), psoriasis, ichthyosis, Lichen planus, atopic dermatitis, Ocular cicatricial pemphigoid (OCP), Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), exposure keratopathy (EK), or post chemical bums (e.g., exposure to strong acids or alkalis that causes severe damage to the ocular surface). [0073] In some embodiments, an inflammatory or autoimmune disease or disorder associated with keratinization of an eyelid margin comprises Sjogren's Syndrome, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Behget's disease, Sarcoidosis, Graft-versus-host disease (GvHD), Stevens- Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), psoriasis, ichthyosis, Lichen planus, atopic dermatitis, Ocular cicatricial pemphigoid (OCP), Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), exposure keratopathy (EK), or post chemical bums (e.g., exposure to strong acids or alkalis that causes severe damage to the ocular surface).

[0074] In some embodiments, an inflammatory or autoimmune disease or disorder associated with keratinization of posterior surface of an eyelid comprises Sjogren's Syndrome, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Behcet's disease, Sarcoidosis, Graft-versus-host disease (GvHD), Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), psoriasis, ichthyosis, Lichen planus, atopic dermatitis, Ocular cicatricial pemphigoid (OCP), Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), exposure keratopathy (EK), or post chemical burns (e.g., exposure to strong acids or alkalis that causes severe damage to the ocular surface).

[0075] In some embodiments, an inflammatory or autoimmune disease or disorder associated with keratinization of an ocular surface comprises Sjogren's Syndrome, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Behget's disease, Sarcoidosis, Graft-versus-host disease (GvHD), Stevens- Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), psoriasis, ichthyosis, Lichen planus, atopic dermatitis, Ocular cicatricial pemphigoid (OCP), Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), exposure keratopathy (EK), or post chemical bums (e.g., exposure to strong acids or alkalis that causes severe damage to the ocular surface).

[0076] In some embodiments, an inflammatory or autoimmune disease or disorder associated with conditions in or around an eye comprises SJS.

[0077] In some embodiments, SJS affects skin (e.g., eyelid) of an individual in need thereof as described herein. In some embodiments, SJS affects periocular surface (e.g., eyelid margin) of an individual in need thereof as described herein. In some embodiments, SJS affects ocular surface (e.g., by development of bulbar and conjunctival ulceration) of an individual in need thereof as described herein. In some embodiments, SJS affects mucous membrane of an individual in need thereof as described herein.

[0078] In some embodiments, SJS is characterized by (e.g., severe) burning, conjunctival ulcerations, membrane formation, and/or sloughing of surface epithelium, such as at the lid margin. In some embodiments, SJS is characterized by chronic and/or long-term sequelae (e.g., of the skin, ocular, and/or periocular surface). In some embodiments, SJS is characterized by dry eye, conjunctival scarring/deficiency, loss of limbal epithelial stem cells, and/or (e.g., heavy) keratinization, such as over the lid wiper zone and/or conjunctiva of the individual. In some embodiments, SJS is characterized by lid margin keratinization (LMK). In some embodiments, LMK comprises keratinization of an eyelid margin or posterior surface of an eyelid. In some embodiments, LMK comprises keratinization of an eyelid margin. In some embodiments, LMK comprises keratinization of posterior surface of an eyelid. In some embodiments, SJS is ocular SJS.

[0079] In some embodiments, an individual in need thereof has conditions in or around an eye as described herein. In some embodiments, an individual in need thereof has meibomian gland dysfunction (MGD), blepharitis, seborrheic blepharitis, Demodex infestation, dry eye disease (DED) or dry eye syndrome (DES), hyperkeratosis, dermatitis, keratitis, contact lens discomfort, lid wiper epitheliopathy (LWE), Keratoconjunctivitis Sicca, Sjogren's Syndrome, or ocular rosacea. In specific embodiments, an individual in need thereof has meibomian gland dysfunction (MGD) as described herein. In some embodiments, an individual has developed meibomian gland dysfunction (MGD) as described herein.

[0080] In some embodiments, an individual in need thereof has keratinization of an eye. In some embodiments, an individual in need thereof has keratinization of an eyelid margin or posterior surface of an eyelid, or conjunctiva. In some embodiments, an individual in need thereof has keratinization of an eyelid margin. In some embodiments, an individual in need thereof has keratinization of posterior surface of an eyelid. In some embodiments, an individual in need thereof has keratinization of conjunctiva.

[0081] In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein. In specific embodiments, an individual in need thereof has Sjogren's Syndrome, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Behcet's disease, Sarcoidosis, Graft-versus-host disease (GvHD), Stevens- Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), psoriasis, ichthyosis, Lichen planus, atopic dermatitis, Ocular cicatricial pemphigoid (OCP), Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), exposure keratopathy (EK), or post chemical bums (e.g., exposure to strong acids or alkalis that causes severe damage to the ocular surface). In some embodiments, an individual in need thereof has SJS as described herein.

[0082] In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein that is associated with conditions in or around the eye described herein. In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein that is associated with ocular or periocular manifestations as described herein. In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein that is associated with keratinization of an eyelid margin or posterior surface of an eyelid of an individual. In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein that is associated with keratinization of an eyelid margin. In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein that is associated with keratinization of posterior surface of an eyelid of an individual.

[0083] In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein and conditions in or around the eye described herein. In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein and ocular or periocular manifestations as described herein. In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein and keratinization of an eyelid margin or posterior surface of an eyelid of an individual. In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein and keratinization of an eyelid margin of an individual. In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein and keratinization of posterior surface of an eyelid of an individual. In some embodiments, an individual in need thereof has an inflammatory or autoimmune disease or disorder as described herein and keratinization of an ocular surface of an individual.

[0084] In some embodiments, any method provided herein comprises administering a pharmaceutical (e.g., ophthalmically acceptable) composition provided herein to an ocular and/or periocular surface of the individual in any manner suitable to deliver the pharmaceutical composition (e.g., one or more of the keratolytic agents, such as SeS?) to any suitable area (e.g., skin and/or mucous membrane affected by the disease or disorder as described herein) of an individual in need thereof as described herein. In some embodiments, the method comprises administering a pharmaceutical (e.g., ophthalmically acceptable) composition provided herein to a periocular surface of the individual in any manner suitable to deliver the pharmaceutical composition (e.g., one or more of the keratolytic agents, such as SeS?) to any suitable area (e.g., skin and/or mucous membrane affected by the disease or disorder as described herein) of an individual in need thereof as described herein. In some embodiments, the method comprises administering a pharmaceutical (e.g., ophthalmically acceptable) composition provided herein to an ocular surface of the individual in any manner suitable to deliver the pharmaceutical composition (e.g., one or more of the keratolytic agents, such as SeS?) to any suitable area (e.g., skin and/or mucous membrane affected by the disease or disorder as described herein) of an individual in need thereof as described herein. In specific embodiments, the pharmaceutical composition is delivered to the affected skin (e.g., eyelid) of an individual in need thereof as described herein. In alternative or further embodiments, the pharmaceutical composition is delivered to the mucous membrane (e.g., posterior surface of an eyelid) of an individual in need thereof as described herein.

[0085] In some embodiments, administration of a pharmaceutical composition provided herein is in any suitable manner. For example, in some instances, administration of a pharmaceutical composition provided herein is via a finger (e.g., a forefinger or a ring finger rubbing on an eye lid or any eyelid margin such that the pharmaceutical composition is delivered and/or reached to an affected ocular and/or periocular surface affected by the disease or disorder provided herein). In some instances, administration of a pharmaceutical composition provided herein is via a forefinger. In some instances, administration of a pharmaceutical composition provided herein is via a swab.

[0086] In certain embodiments, any method provided herein comprises delivering a pharmaceutical (e.g., ophthalmically acceptable) composition provided herein to any suitable area. In some embodiments, a suitable area is in or around an area affected by a disease or disorder described herein and/or an area wherein administration of a pharmaceutical composition provided herein would provide efficacious treatment of a disease or disorder described herein, such as according to a method provided herein. In some embodiments, a suitable area is in or around an area affected by a disease or disorder associated with keratinization of an eyelid margin or posterior surface of an eyelid as described herein.

[0087] In some embodiments, any method provided herein comprises administering a pharmaceutical composition provided herein to an ocular area (e.g., surface) and/or a periocular area (e.g., surface) of an individual (e.g., having a disease or condition affecting the periocular area and/or ocular area associated with the periocular area to which the pharmaceutical composition is administered). In some embodiments, a method provided herein comprises administering the pharmaceutical composition to a periocular area of an individual (e.g., having a disease or condition affecting the periocular area and/or ocular area associated with the periocular area to which the pharmaceutical composition is administered). In some embodiments, a method provided herein comprises administering the pharmaceutical composition to an ocular area of an individual (e.g., having a disease or condition affecting the periocular area and/or ocular area associated with the periocular area to which the pharmaceutical composition is administered).

[0088] In some embodiments, a method provided herein comprises administering a pharmaceutical composition provided herein to or around the eye of an individual described herein. In some embodiments, a method provided herein comprises administering the pharmaceutical composition to the eye of an individual described herein. In some embodiments, a method provided herein comprises administering the pharmaceutical composition to the surface of the eye of an individual described herein. In some instances, when administering the composition to the eye or the surface of the eye, such as in a treatment of SJS, it is desirable to use a lower concentration of keratolytic agent in a pharmaceutical composition. In some instances, particularly when lower concentrations of keratolytic agent is used in a pharmaceutical composition, it is desirable to increase frequency of administration in order to achieve improved therapeutic outcomes.

[0089] In certain embodiments, any method provided herein comprises administering a pharmaceutical composition provided herein to an ocular surface, surrounding ocular tissues, eyelid, eyelid margin, lid wiper, meibomian gland, mucocutaneous margin, eyelashes, lash line, lash follicle, tarsal glands, palpebral border, medial angle, lacrimal papilla and punctum, dermal or epidermal tissue within 1 cm of the ocular surface, dermal or epidermal tissue within 2 cm of the ocular surface, or any combination thereof. In some embodiments, a pharmaceutical composition provided herein is administered to or around an affected eye of an individual in need thereof as described herein.

[0090] In certain embodiments, any method provided herein comprises administering a pharmaceutical composition provided herein to an eyelid (e.g., upper and/or lower eyelid) of an individual in need thereof as described herein. In some embodiments, a pharmaceutical composition provided herein is administered to a lower eyelid of an individual in need thereof as described herein. In some embodiment, a pharmaceutical composition provided herein is administered to the eyelid of an individual in need thereof as described herein in any manner suitable to deliver the keratolytic agent to an eyelid margin of the individual. In some embodiments, a pharmaceutical composition provided herein is administered to an eyelid margin (e.g., upper and/or lower eyelid margin). In specific embodiments, a pharmaceutical composition provided herein is administered to a lower eyelid margin. In specific embodiments, a pharmaceutical composition provided herein is administered to an upper eyelid margin.

[0091] In some embodiments, administration of a pharmaceutical composition provided herein to an eyelid comprises administration to an ocular or periocular area, such that the pharmaceutical composition is delivered to the eyelid. In some embodiments, administration of a pharmaceutical composition provided herein to an eyelid comprises administration to an ocular or periocular area, such that the pharmaceutical composition is delivered to a posterior surface of the eyelid. In some embodiments, administration of a pharmaceutical composition provided herein to an eyelid margin comprises administration to an ocular or periocular area (e.g., eyelid), such that the pharmaceutical composition is delivered to the eyelid margin.

[0092] In some embodiments, a pharmaceutical composition provided herein is administered to an individual in need thereof as described herein monthly, bi-weekly, weekly, or daily. In specific embodiments, a pharmaceutical composition provided herein is administered to an individual in need thereof as described herein at least once a week. In more specific embodiment, a pharmaceutical composition provided herein is administered to an individual in need thereof as described herein at least twice a week. In still more specific embodiments, a pharmaceutical composition provided herein is administered to an individual in need thereof as described herein at least once a day. In some embodiments, the pharmaceutical composition is administered to the individual at least once weekly. In some embodiments, the pharmaceutical composition is administered to the individual at least twice weekly. In some embodiments, the pharmaceutical composition is administered to the individual at least once daily. In some embodiments, the pharmaceutical composition is administered to the individual at least twice daily. In some instances, when low concentration of keratolytic agents are used (e.g., when administrated to the surface of the eye, such as in the treatment of SJS), it is desirable to administered the composition more frequently, such as at least once daily or at least twice daily.

[0093] In certain embodiments, any method provided herein comprises self-administering a (e.g., pharmaceutically or ophthalmically acceptable) composition provided herein to an individual (one’s self) in need thereof (e.g., having a disease or condition associated with conditions in or around the periocular area and/or ocular area associated with the periocular area to which the pharmaceutical composition is administered). In some embodiments, any method provided herein comprises self-administering the pharmaceutical composition at home. In further or alternative embodiments, any method provided herein comprises administering the pharmaceutical composition to the individual by a medical practitioner (e.g., a doctor, a nurse, a skilled medical technician, etc.). In some embodiments, the pharmaceutical composition is administered by a healthcare professional or physician. In some embodiments, the pharmaceutical composition is administered to the individual by another individual or by a machine.

[0094] In some embodiments, any method provided herein further comprises improving lipid secretion of one or more (e.g., meibomian) glands.

[0095] In some embodiments, any method provided herein further comprises opening or clearing a (e.g., meibomian) gland obstruction in an individual in need thereof as described herein. For example, in some embodiments, opening or clearing the (e.g., meibomian) gland obstruction in an individual comprises reducing an amount of particulate matter (e.g., keratinized material), such as in meibum. [0096] In certain embodiments, a pharmaceutical (e.g., ophthalmically acceptable) composition provided herein is formulated in any suitable manner. In some embodiments, a pharmaceutical composition comprises a keratolytic agent (e.g., SeS?) and an (e.g., ophthalmically or pharmaceutically acceptable) vehicle or carrier. In some embodiments, a pharmaceutical composition comprises a keratolytic agent (e.g., SeS?) in an (e.g., ophthalmically or pharmaceutically acceptable) vehicle or carrier. In some embodiments, a pharmaceutical composition provided herein comprises an oleaginous base.

[0097] In some embodiments, a (e.g., pharmaceutically or ophthalmically acceptable) composition provided herein comprises a keratolytic agent. In specific 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, seleocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, N-acetyl cysteine (NAC), gluthatione, dithiothreitol, thi orphan, cysteamine, bucillamine, dimercaprol, 1,1- ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, rentiapril, 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, thiophospholipid, 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, N-acetyl cysteine (NAC), bucillamine, captopril, alpha-hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylate.

[0098] In some embodiments, the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, N-acetyl cysteine (NAC), bucillamine, captopril, alpha-hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and zinc L-pyrrolidone carboxylate. In some embodiments, the keratolytic agent is selenium disulfide.

[0099] In some embodiments, a combination of keratolytic agents is provided to an individual in need thereof as described herein (e.g., wherein a first keratolytic agent is provided for a first period of time and a second keratolytic agent is provided for a second period of time).

[0100] In some embodiments, a pharmaceutical (e.g., ophthalmically acceptable) composition provided herein comprises a keratolytic agent (e.g., SeS?) described herein with a therapeutically effective concentration. In some embodiments, a pharmaceutical composition provided herein comprises SeS? in a therapeutically effective concentration. In some embodiments, a pharmaceutical composition provided herein comprises SeS? in less than a therapeutically effective concentration. In some embodiments, a pharmaceutical composition provided herein comprises SeS? in a homeopathic concentration. In some embodiments, a pharmaceutical composition provided herein comprises SeS? in greater than a therapeutically effective concentration.

[0101] In some embodiments, the therapeutically effective concentration comprises about 0.01 wt. %, about 0.05 wt. %, about 0.1 wt. %, about 0.15 wt. %, about 0.2 wt. %, about 0.25 wt. %, about 0.3 wt. %, about 0.35 wt. %, about 0.4 wt. %, about 0.45 wt. %, about 0.5 wt. %, about 0.55 wt. %, about 0.6 wt. %, about 0.65 wt. %, about 0.7 wt. %, about 0.75 wt. %, about 0.8 wt. %, about 0.85 wt. %, about 0.9 wt. %, about 0.95 wt. %, about 1.0 wt. %, about 1.25 wt. %, about 1.5 wt. %, about 1.75 wt. %, about 2.0 wt. %, about 2.5 wt. %, about 3.0 wt. %, about 4.0 wt. %, about

4.5 wt. %, about 5.0 wt. %, about 5.5 wt. %, about 6.0 wt. %, about 6.5 wt. %, about 7.0 wt. %, about 7.5 wt. %, about 8.0 wt. %, about 8.5 wt. %, about 9.0 wt. %, about 9.5 wt. %, about 10.0 wt. %, about 10.5 wt. %, about 11.0 wt. %, about 11.5 wt. %, about 12.0 wt. %, about 15.0 wt. % or more of the keratolytic agent (e.g., SeS?) described herein.

[0102] In some embodiments, the therapeutically effective concentration comprises at least about 0.01 wt. %, about 0.05 wt. %, about 0.1 wt. %, about 0.15 wt. %, about 0.2 wt. %, about 0.25 wt. %, about 0.3 wt. %, about 0.35 wt. %, about 0.4 wt. %, about 0.45 wt. %, about 0.5 wt. %, about 0.55 wt. %, about 0.6 wt. %, about 0.65 wt. %, about 0.7 wt. %, about 0.75 wt. %, about 0.8 wt. %, about 0.85 wt. %, about 0.9 wt. %, about 0.95 wt. %, about 1.0 wt. %, about 1.25 wt. %, about

1.5 wt. %, about 1.75 wt. %, about 2.0 wt. %, about 2.5 wt. %, about 3.0 wt. %, about 4.0 wt. %, about 4.5 wt. %, about 5.0 wt. %, about 5.5 wt. %, about 6.0 wt. %, about 6.5 wt. %, about 7.0 wt. %, about 7.5 wt. %, about 8.0 wt. %, about 8.5 wt. %, about 9.0 wt. %, about 9.5 wt. %, about 10.0 wt. %, about 10.5 wt. %, about 11.0 wt. %, about 11.5 wt. %, about 12.0 wt. %, about 15.0 wt. % or more of the keratolytic agent (e.g., SeS?) described herein. In some embodiments, the keratolytic agent is provided in a concentration greater than or equal to about 0.1% wt. %.

[0103] In some embodiments, the therapeutically effective concentration comprises at most about 15.0 wt. %, about 14.0 wt. %, about 13.0 wt. %, about 12.0 wt. %, about 11.0 wt. %, about 10.0 wt. %, about 9.0 wt. %, , about 8.0 wt. %, about 7.0 wt. %, about 6.0 wt. %, about 5.0 wt. %, about 4.0 wt. %, about 3.0 wt. %, about 2.5 wt. %, about 2.0 wt. %, about 1.75 wt. %, about 1.5 wt. %, about 1.25 wt. %, about 1.0 wt. %, about 0.95 wt. %, about 0.9 wt. %, about 0.85 wt. %, about 0.8 wt. %, about 0.75 wt. %, about 0.70 wt. %, about 0.65 wt. %, about 0.60 wt. %, about 0.55 wt. %, about 0.5 wt. %, about 0.45 wt. %, about 0.4 wt. %, about 0.35 wt. %, about 0.3 wt. %, about 0.25 wt. %, or less of the keratolytic agent (e.g., SeS?) described herein. In some embodiments, the keratolytic agent is provided to the individual at concentration of less than or equal to about 1 wt. %.

[0104] In some embodiments, the therapeutically effective concentration comprises about 0.01 wt. % to about 15.0 wt. %, about 0.01 wt. % to about 10.0 wt. %, about 0.01 wt. % to about 9.0 wt. %, about 0.01 wt. % to about 8.0 wt. %, about 0.01 wt. % to about 7.0 wt. %, about 0.01 wt. % to about 6.0 wt. %, about 0.01 wt. % to about 5.0 wt. %, about 0.01 wt. % to about 4.0 wt. %, about 0.01 wt. % to about 3.0 wt. %, about 0.01 wt. % to about 2.0 wt. %, about 0.01 wt. % to about 1.5 wt. %, about 0.01 wt. % to about 1.0 wt. %, about 0.01 wt. % to about 0.5 wt. %, about 0.01 wt. % to about 0.1 wt. %, about 0.01 wt. % to about 0.05 wt. %, about 0.05 wt. % to about 4.0 wt. %, about 0.05 wt. % to about 3.0 wt. %, about 0.05 wt. % to about 2.0 wt. %, about 0.05 wt. % to about 1.5 wt. %, about 0.05 wt. % to about 1.0 wt. %, about 0.05 wt. % to about 0.5 wt. %, about 0.05 wt. % to about 0.1 wt. %, about 0.1 wt. % to about 4.0 wt. %, about 0.1 wt. % to about 3.0 wt. %, about 0.1 wt. % to about 2.0 wt. %, about 0.1 wt. % to about 1.5 wt. %, about 0.1 wt. % to about 1.0 wt. %, about 0.1 wt. % to about 0.5 wt. %, about 0.5 wt. % to about 4.0 wt. %, about 0.5 wt. % to about 3.0 wt. %, about 0.5 wt. % to about 2.0 wt. %, about 0.5 wt. % to about 1.5 wt. %, about 0.5 wt. % to about 1.0 wt. %, about 1.0 wt. % to about 4.0 wt. %, about 1.0 wt. % to about 3.0 wt. %, about 1.0 wt. % to about 2.5 wt. %, about 1.0 wt. % to about 2.0 wt. %, about 1.0 wt. % to about 1.5 wt. %, or any combination thereof of the keratolytic agent (e.g., SeS?) described herein. In some embodiments, the keratolytic agent is provided to the individual at a concentration of about 0.1 wt. % to about 10 wt. %. In some embodiments, the keratolytic agent is provided to the individual at concentration of about 0.1 wt. % to about 2 wt. % of selenium disulfide.

[0105] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

EXAMPLES

Example 1. Treatment of SJS with a compound comprising SeSi

[0106] In a clinical study, three different concentrations of SeS? are used; 0.1 wt. %, 0.5 wt. %, and 1 wt. %. Patients with SJS that manifest keratinization of an eyelid margin or posterior surface of an eyelid participate in the study. One of the three concentrations of SeS? (0.1 wt. %, 0.5 wt. %, and 1 wt. %) is applied to a patient to determine safety and efficacy. The applications are done bi-weekly in a clinic for three months. Adverse events are recorded. Patients stop participating in the study if a significant adverse event occurs. Fluorescein staining is used to assess for epithelial defects on the cornea, conjunctiva, and eyelid margins. Lid margin keratinization (e.g., keratin deposits over the lid wiper zone and palpebral conjunctiva) is also assessed.

[0107] After application of SeS2, fluorescein staining and lid margin keratinization are assessed in patients with SJS after the treatment during each visit and compared to assessment made before the treatment and prior visits.

[0108] Following determination of a suitable concentration of SeS2, in a clinical study three different dose frequencies are used: twice weekly, once daily, and twice daily. Patients with SJS that manifest keratinization of an eyelid margin or posterior surface of an eyelid participate in the study. Patients are treated with one of the dose frequencies to determine efficacy. Adverse events are recorded. Patients stop participating in the study if a significant adverse event occurs. Fluorescein staining is used to assess for epithelial defects on the cornea, conjunctiva, and eyelid margins. Lid margin keratinization (e.g., keratin deposits over the lid wiper zone and palpebral conjunctiva) is also assessed. After application of SeS2, fluorescein staining and lid margin keratinization are assessed in patients with SJS after the treatment during each visit and compared to assessment made before the treatment and prior visits.

Claims

CLAIMS We claim:

1. A method for treating an inflammatory or autoimmune disease or disorder associated with keratinization of an eyelid margin or posterior surface of an eyelid or an ocular surface of an individual, the method comprising providing to a periocular surface of the individual a pharmaceutical composition comprising a keratolytic agent and an ophthalmically or pharmaceutically acceptable vehicle or carrier.

2. The method of claim 1, wherein the inflammatory or autoimmune disease or disorder affects mucous membrane(s) of the individual.

3. The method of claim 1, wherein the inflammatory or autoimmune disease or disorder affects skin of the individual.

4. The method of claim 1, wherein the inflammatory or autoimmune disease or disorder affects both the mucous membrane(s) and skin areas of the individual.

5. The method according to claim 1 or 2, wherein the inflammatory or autoimmune disease or disorder is associated with ocular manifestations.

6. The method of any one of the preceding claims, wherein the individual has Sjogren's Syndrome, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Behget's disease, Sarcoidosis, Graft-versus-host disease (GvHD), Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), psoriasis, ichthyosis, Lichen planus, atopic dermatitis, Ocular cicatricial pemphigoid (OCP), Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), exposure keratopathy (EK), or post chemical bums (e.g., exposure to strong acids or alkalis that causes severe damage to the ocular surface).

7. The method of any one of the preceding claims, wherein the inflammatory or autoimmune disease or disorder associated with keratinization of an eyelid margin or posterior surface of an eyelid comprises Sjogren's Syndrome, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Behget's disease, Sarcoidosis, Graft-versus-host disease (GvHD), Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), psoriasis, ichthyosis, Lichen planus, atopic dermatitis, Ocular cicatricial pemphigoid (OCP), Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), exposure keratopathy (EK), or post chemical bums (e.g., exposure to strong acids or alkalis that causes severe damage to the ocular surface).

8. The method of any one of the preceding claims, wherein the individual has SJS.

9. A method for treating SJS in an individual, the method comprising providing to a periocular surface of the individual a pharmaceutical composition comprising a keratolytic agent and an ophthalmically or pharmaceutically acceptable vehicle or carrier.

10. The method of any one of the preceding claims, wherein skin of the individual is affected by

SJS.

11. The method of any one of the preceding claims, wherein periocular surface of the individual is affected by SJS.

12. The method of any one of the preceding claims, wherein mucous membrane of the individual is affected by SJS.

13. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the periocular surface of the individual in a manner suitable to deliver the keratolytic agent to the affected skin and/or mucous membrane of the individual.

14. The method of any one of the preceding claims, wherein SJS is characterized by (e.g., severe) burning, conjunctival ulcerations, membrane formation, and/or sloughing of surface epithelium, such as at the lid margin.

15. The method of any one of the preceding claims, wherein SJS is characterized by chronic and/or long-term sequelae (e.g., of the skin, ocular, and/or periocular surface).

16. The method of any one of the preceding claims, wherein SJS is characterized by dry eye, conjunctival scarring/deficiency, loss of limbal epithelial stem cells, and/or (e.g., heavy) keratinization, such as over the lid wiper zone and/or conjunctiva of the individual.

17. The method of any one of the preceding claims, wherein SJS is characterized by lid margin keratinization (LMK).

18. The method of any one of the preceding claims, wherein SJS is ocular SJS.

19. The method of any one of the preceding claims, wherein the pharmaceutical composition is provided to or around the eye of the individual.

20. The method of any one of the preceding claims, wherein the pharmaceutical composition is provided to the eye of the individual.

21. The method of any one of the preceding claims, wherein the pharmaceutical composition is provided to the surface of the eye of the individual.

22. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the eyelid of the individual.

23. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the eyelid of the individual in a manner suitable to deliver the keratolytic agent to an eyelid margin of the individual.

24. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to an eyelid margin of the individual.

25. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual monthly, bi-weekly, weekly, or daily.

26. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual at least once weekly.

27. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual at least twice weekly.

28. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual at least once daily.

29. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual at least twice daily.

30. The method of any one of the preceding claims, wherein the pharmaceutical composition is self-administered.

31. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered by a healthcare professional or physician.

32. The method of any one of the preceding claims, wherein the individual has or has developed meibomian gland dysfunction (MGD).

33. The method of any one of the preceding claims, further comprising improving lipid secretion of one or more (e.g., meibomian) gland.

34. The method of any one of the preceding claims, further comprising opening or clearing a (e.g., meibomian) gland obstruction in the individual.

35. The method of any one of the preceding claims, wherein opening or clearing the (e.g., meibomian) gland obstruction in the individual comprises reducing an amount of particulate matter (e.g., keratinized material), such as in meibum.

36. The method of any one of the preceding claims, wherein the (e.g., meibomian) gland comprises altered (e.g., meibum) secretions and keratinized material.

37. The method of any one of the preceding claims, wherein the (e.g., meibomian) gland obstruction comprises one or more of chronic ocular discomfort, anatomic abnormalities around a (e.g., meibomian) gland orifice, obstruction of a meibomian gland, or decreased meibum production.

38. The method of any one of the preceding claims, wherein the anatomic abnormalities around the (e.g., meibomian) gland orifice comprise one or more of vascular engorgement, anterior or posterior displacement of the mucocutaneous junction, or irregularity of the eyelid margin.

39. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises an oleaginous base.

40. The method of any one of the preceding claims, wherein 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, seleocysteine, selenomethionine, captopril, zofenopril, tiopronin, penicillamine, L-cysteine, N-acetyl cysteine (NAC), gluthatione, dithiothreitol, thi orphan, cysteamine, bucillamine, dimercaprol, 1,1 -ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, rentiapril, 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, thiophospholipid, thiocholesterol, 12-mercaptododecanoic acid, 23-(9-mercaptononyl)-3,6,9,12,15,18,21- heptaoxatricosanoic acid, and sulfanegen.

41. The method of any one of the preceding claims, wherein the keratolytic agent is selected from the group consisting of benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, N-acetyl cysteine (NAC), bucillamine, captopril, alpha-hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, and zinc L-pyrrolidone carboxylate.

42. The method of any one of the preceding claims, wherein the keratolytic agent is selenium disulfide.

43. The method of any one of the preceding claims, wherein a combination of keratolytic agents are provided to the individual (e.g., wherein a first keratolytic agent is provided for a first period of time and a second keratolytic agent is provided for a second period of time).

44. The method of any one of the preceding claims, wherein the keratolytic agent is provided in a concentration greater than or equal to about 0.01% by weight (wt. %).

45. The method of any one of the preceding claims, wherein the keratolytic agent is provided in a concentration greater than or equal to about 0.1% by weight (wt. %).

46. The method of any one of the preceding claims, wherein the keratolytic agent is provided to the individual at a concentration of about 0.1 wt. % to about 10 wt. %.

47. The method of any one of the preceding claims, wherein the keratolytic agent is provided to the individual at concentration of about 0.1 wt. % to about 2 wt. % of selenium disulfide.

48. The method of any one of the preceding claims, wherein the keratolytic agent is provided to the individual at concentration of less than or equal to about 1 wt. %.

49. The method of any one of the preceding claims, wherein the keratolytic agent is provided to the individual at concentration of less than 0.5 wt. %.

50. The method of any one of the preceding claims, wherein the keratolytic agent is provided to the individual at concentration of less than 0.4 wt. %.

51. The method of any one of the preceding claims, wherein the keratolytic agent is provided to the individual at concentration of less than 0.2 wt. %.