Composition and instructions for hypersensitivity

Abstract

Provided herein are methods for treating diseases or disorders in or around the eye with pharmaceutical compositions containing selenium disulfide (SeS2), and methods for instructing treated individuals to limit or avoid exposure to light after administration to reduce adverse effects of the pharmaceutical compositions.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 959,738, filed January 10, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Selenium sulfide (SeS2) is indicated for the treatment of skin conditions such as seborrheic dermatitis, tinea versicolor, and dandruff. Selenium sulfide is typically used in commercial concentrations of 1% and 2.5% as shampoos, foams, or lotions, applied for several minutes and then rinsed off. The use of SeS2 may be associated with known side effects, listed in the package insert, which may include irritation, burning, and, rarely, hair loss or discoloration. Contact of large amounts of preparations containing high concentrations of selenium sulfide with the mucous membranes of the eyes may cause irritation (e.g., stinging), and prolonged contact of preparations containing SeS2 with the skin (e.g., overnight application) may cause local irritation.

[0003] Adverse events reported after topical ocular use of selenium sulfide-containing products include superficial punctate keratitis and conjunctivitis that resolved after treatment was discontinued. When SeS2 is applied topically to treat tinea versicolor, it may cause skin irritation in the genital area and / or skin folds. SeS2 lotions may also cause rebound oiliness of the scalp. AHFS Drug Information 2010.

[0004] Discoloration occurs in various shades of natural and dyed hair after topical application of SeS2 lotion. Hair discoloration is rare and is usually associated with inadequate or no rinsing after shampooing with SeS2 lotion. The manufacturer states that careful rinsing of hair after treatment with the drug can minimize hair discoloration. Shampooing with a 2.5% lotion of this drug can cause widespread hair loss, which reportedly resolves within 1 to 2 weeks after discontinuation of the drug.

[0005] SeS2 lotion has been reported to cause systemic toxicity after topical application to damaged skin. After prolonged topical application of the lotion to a woman with an open scalp wound, she developed signs and symptoms of systemic toxicity, including tremors, excessive sweating, garlicky breath, lower abdominal pain, weakness, lethargy, loss of appetite, and occasional vomiting. Signs and symptoms of toxicity resolved within 10 days after discontinuation of the drug. Selenium can be toxic at high doses (>400 μg daily) or when taken for extended periods. Acute selenium poisoning can be fatal due to cardiovascular failure and / or pulmonary edema. Gastrointestinal effects are typically the first symptom of acute selenium poisoning. Acute effects include vomiting, excessive salivation, diarrhea, abdominal pain, burning sensation of the nasal and / or oral mucosa, chemical burns of the gastrointestinal tract, and garlicky breath. Long-term poisoning resembles arsenic poisoning, with symptoms including hair loss, white stripes on the nails, nail inflammation, fatigue, irritation, nausea, vomiting, garlic-smelling breath, and a metallic taste. Selenium can also cause muscle tenderness, tremors, mental confusion, facial flushing, blood clotting disorders, liver and kidney damage, and other side effects. Acute systemic effects of selenium are not expected in the patient population for which the dosing regimen is proposed.

[0006] Nonspecific allergic reactions, including rashes and hives, have been reported rarely. Selenium compounds have UV-protective effects. Specifically, topical selenium compounds increase the minimum UV exposure required to induce skin redness and avoid skin damage from UVB exposure (irradiation with wavelengths of approximately 290 nm to approximately 320 nm). In some instances, this is because the primary function of intracellular selenium is the upregulation of the enzyme glutathione peroxidase (GPX) as an antioxidant.

[0007] In the 1950s and early 1960s, some researchers attempted to use SeS2 as an ophthalmic preparation to treat seborrheic blepharitis, which is typically associated with scaling of the eyelid margins and affects many patients with seborrheic dermatitis. Clinicians treated hundreds of patients for periods ranging from one month to one year using a variety of methods, including in-office application, home application, daily application, or every other day application.

[0008] Cohen et al. used SeS2 ophthalmic preparations in patients and were the first to investigate animal studies to determine a safe concentration for human use, concluding that 0.5% was safe. In reports describing their experience, most researchers concluded that 0.5% SeS2 was effective in treating seborrheic blepharitis and reported side effects focused primarily on keratitis. Keratitis is an inflammatory response of the cornea that causes significant pain and damage to superficial epithelial cells, typically identifiable using corneal fluorescein staining.

[0009] Various application methods were described by the researchers, ranging from careful in-office application with rinsing of excessive amounts of material to home application with thorough rinsing over a short period of time. The importance of careful application and rinsing to avoid adverse effects was clearly stated. Furthermore, it was recognized that patients who experienced severe reactions either had improperly applied the treatment to the eye or had failed to observe thorough rinsing procedures.

[0010] Lavyel 1960 described the use of Selsunef® ointment, a 0.5% SeS2 ointment manufactured by Abbott. Selsunef® was used in a clinical trial on 80 subjects, with the ointment applied gently and controlled by a physician and removed after 30 minutes with an absorbent cotton swab. Great care was always taken to ensure that none of the ointment entered the conjunctival sac. In one case where a patient administered Selsunef® to himself against medical advice, a fairly severe keratitis immediately developed. Summary of the Invention

[0011] Another common eye condition associated with blepharitis is meibomian gland dysfunction (MGD), in which a patient's meibomian glands do not produce enough meibum to prevent dry eyes. Meibum is an oily substance composed primarily of lipids that helps maintain the eye's tear film by preventing tear evaporation or retention. In MGD, blockage of the meibomian glands prevents meibomian gland secretion, resulting in dry eyes, pain, and blepharitis in many patients. To relieve blockage and restore lipid production (e.g., meibum production), ophthalmic preparations of SeS2 may be applied to the eyelids, eyelid margin, ocular surface, or surrounding tissues. Described herein are methods of using ophthalmic preparations containing SeS2, particularly to reduce or eliminate side effects, such as ocular keratitis. In some instances, administration may be performed by the patient at home (eg, chronically) (eg, daily, or less frequently if appropriate) to the eyelid or lid margin.

[0012] Adverse effects (e.g., pain, local irritation, inflammation, redness, keratosis, etc.) have been observed with application of SeS2 in or around the eye, particularly when high concentrations of SeS2 are utilized. In certain instances, administration of therapeutically effective concentrations of SeS2 (e.g., to the eyelid margin) has been found to minimize adverse effects while also providing therapeutic benefits. Furthermore, reduced exposure to light (e.g., UV light) after administration of a selenium disulfide composition has been found to further reduce the incidence of side effects in ophthalmic applications (e.g., methods involving administration to the eyelid margin of an individual).

[0013] Some embodiments provided herein are methods for treating a disease or disorder in or around an individual's eye. In some embodiments, the method comprises administering a therapeutically effective amount of a pharmaceutical composition to the individual's ocular surface, surrounding ocular tissue, eyelid, eyelid margin, or a combination thereof. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of selenium disulfide (SeS2) for an individual, such as the eyelid margin, in need thereof. In some embodiments, the individual limits, avoids, or is instructed (e.g., via oral communication and / or written instructions) to limit or avoid light exposure after administration (e.g., at least where the composition was administered, in one eye, or both eyes, etc.).

[0014] In some embodiments, limiting or avoiding exposure to light after administration of the composition reduces (e.g., the incidence and / or rate of) keratitis, such as in or around the eye (e.g., compared to administration without limiting or avoiding light exposure). In some examples, the keratitis is associated with photosensitivity. In some embodiments, light exposure is limited or avoided for any suitable period of time, such as at least 30 minutes. In some embodiments, light exposure is limited or avoided for at least 60 minutes. In some embodiments, light exposure is limited or avoided for at least 2 hours. In some examples, increasing the concentration and / or amount of selenium disulfide in the composition increases the rate and / or incidence of keratitis or other adverse effects. Thus, in certain embodiments, light is avoided for a longer period of time than when a composition with a lower concentration and / or amount of active agent is administered.

[0015] In some embodiments, the composition is administered to the eyelid margin of the individual. In certain embodiments, administration of the composition to the ocular surface is avoided. In some embodiments, light may be avoided after administration, but the composition is administered under good light conditions, such as to avoid unwanted administration of the composition to the ocular surface.

[0016] In some embodiments, the site where the composition was administered is generally maintained for a period of time after administration of the composition, or the individual is instructed to maintain the site where the composition was administered in low light conditions, in some embodiments, low light conditions are about 100 lux or less, about 50 lux or less, or about 25 lux or less.

[0017] In some embodiments, the site where the composition was administered is generally not exposed for a period of time after administration of the composition, or the individual is instructed to limit or avoid exposure of the site where the composition was administered to high light conditions. In some embodiments, the high light conditions are about 100 lux or more, about 500 lux or more, or about 1000 lux or more.

[0018] In some embodiments, the individual is administered or instructed to administer the composition at a specific time, thereby limiting or avoiding exposure to light after administration, or instructed to limit or avoid exposure to light. In some embodiments, the specific time is later than about 1 hour before sunset. In some embodiments, the specific time is after sunset (nighttime). In some embodiments, the specific time is before going to bed (e.g., within 1 hour, within 30 minutes, etc.).

[0019] In some embodiments, the individual is instructed to limit, avoid, or limit or avoid exposure to light after administration (e.g., at the site where the composition was administered, in one or both eyes, etc.) by blocking or being instructed to block some or all light (e.g., sunlight) at the site where the composition was administered during or after administration. In some embodiments, blocking light is accomplished by wearing headwear and / or eyewear that at least partially blocks light. In some embodiments, the headwear is a hat. In some embodiments, the eyewear is sunglasses or goggles.

[0020] In some embodiments, the individual self-administers the pharmaceutical composition.

[0021] In some embodiments, limiting exposure to light comprises limiting exposure to at least some wavelengths of light. In some embodiments, limiting exposure to light comprises limiting exposure to ultraviolet (UV) light. In some embodiments, limiting exposure to light comprises limiting exposure to sunlight. In some embodiments, the individual is instructed to stay indoors. In some embodiments, the individual is instructed to avoid sunlight or ultraviolet (UV) light (e.g., at least in the area where the pharmaceutical composition is administered).

[0022] In some embodiments, the disease or disorder in or around the eye is meibomian gland dysfunction (MGD), blepharitis, seborrheic blepharitis, Demodex infection, dry eye syndrome, 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.

[0023] In some embodiments, the composition comprises SeS2 at a therapeutically effective concentration. In some embodiments, the therapeutically effective concentration is about 0.1% to about 10% by weight (e.g., about 0.1% to about 10% by weight, or about 0.5% to about 1% by weight). In some embodiments, the composition is administered in a volume of less than 25 μL. In some embodiments, the composition is administered in a volume of about 1 μL to about 20 μL (e.g., about 2 μL to about 15 μL, or about 10 μL to about 3 μL).

[0024] In some embodiments, the composition or preparation is a semi-solid (e.g., gel, cream, paste), strip, emulsion, suspension, foam, lotion, spray, patch, implant (e.g., sustained-release, biodegradable, semi-degradable, or non-degradable), lipid-based (e.g., solid lipid nano / microparticles, liposomes, exosomes, micelles, micro / nanoemulsions, cubosomes, cochleates, niosomes, lipospheres), silica-based (e.g., mesoporous), polymer-based, nano- and / or microspheres, nano- and / or microcapsules, nano- and / or microparticles, etc. In some embodiments, the semi-solid is an ointment. In some embodiments, (i) the composition is administered in a sufficiently low volume, and (ii) after administration, light exposure at the site where the composition was administered is sufficiently low so that keratitis (e.g., of the individual's ocular surface) is reduced or avoided. In some embodiments, the concentration can be further reduced to support greater light exposure while minimizing the risk of phototoxicity. In some embodiments, the amount of light exposure and the period of avoidance of light exposure that is tolerated correlates with the dose and concentration of SeS2 administered.

[0025] Certain embodiments provided herein are methods of treating a disease or disorder in or around the eye of an individual in need thereof, the method comprising protecting the individual's ocular surface with a barrier. In certain embodiments, such processes further comprise administering a therapeutically effective amount of a pharmaceutical composition to the individual's ocular surface. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of selenium disulfide (SeS2). In some embodiments, protecting the individual's ocular surface comprises administering an ointment or hyaluronic acid (HA) to the ocular surface (e.g., whereby a barrier is formed by interaction of the hyaluronic acid (HA) with mucin on the ocular surface). In some embodiments, the hyaluronic acid (HA) has a molecular weight of at least 900 kDa. In some embodiments, the barrier is a contact lens.

[0026] In some embodiments, protecting the ocular surface comprises administering to the ocular surface (e.g., before and / or simultaneously with administration of the pharmaceutical composition) an additive molecule, wherein the additive molecule comprises a molecule configured to capture free radicals or photosensitive SeS2. In some embodiments, the free radical is a reactive oxygen species (ROS). In some embodiments, the additive molecule comprises a phenolic compound, vitamin E, vitamin C, carotene, ferritin, ceruloplasmin, selenium, reduced glutathione (GSH), manganese, ubiquinone, zinc, flavonoid, coenzyme Q, melatonin, bilirubin, taurine, or cysteine.

[0027] In some embodiments, the barrier prevents SeS2 from contacting the ocular surface.

[0028] In some embodiments, administering a therapeutically effective amount of a pharmaceutical composition to the individual's ocular surface, surrounding ocular tissue, or a combination thereof comprises applying the pharmaceutical composition with a finger, which can be the individual's finger.

[0029] Although selenium-containing shampoos are widely used commercially, no or few adverse effects are observed. It is surprising that adverse effects such as photosensitivity are prevalent in ophthalmic applications such as those described herein. In some instances, such prevalence of adverse effects is due to increased exposure duration (e.g., shortened shampooing), different exposure locations (e.g., topical / scalp vs. eye), different preparations (e.g., shampoo vs. the preparations described herein), or a combination of such differences. In certain embodiments, provided herein are compositions and methods of administering the compositions, wherein the compositions are not shampoos.

[0030] Since further aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, only illustrative embodiments of the present disclosure have been shown and described. As will be understood, the present disclosure is capable of other and different embodiments, and its various details can be modified in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. [Brief explanation of the drawings]

[0031] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "Figures" and "FIGs.") [Figure 1] FIG. 1 illustrates a flow chart showing the mechanisms by which light can interact with a photosensitive chemical and cause phototoxicity in an individual in contact with said photosensitive chemical. DETAILED DESCRIPTION OF THE INVENTION

[0032] definition The terms used herein are for the purpose of describing particular instances only and are not intended to limit the invention. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms "including," "includes," "having," "has," "with," or variations thereof are used in either the detailed description and / or claims, such terms are intended to be inclusive in a manner similar to the term "comprising."

[0033] The terms "about" or "approximately" mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, "about" can mean 1 or more than 1 standard deviation per practice for any value. When particular values ​​are described in this application and in the claims, unless otherwise specified, the term "about" should be assumed to mean an acceptable error range for the particular value.

[0034] The terms "individual," "patient," or "subject" are used interchangeably. None of the terms require or are limited to a condition characterized by the supervision (e.g., continuous or intermittent) of a medical professional (e.g., a physician, registered nurse, nurse practitioner, physician assistant, janitor, or hospice worker).

[0035] As used herein, the term "comprise" or its variations "comprises" or "comprising" indicates the inclusion of any recited features, but does not imply the exclusion of any other features. Thus, as used herein, the term "comprising" is inclusive and does not exclude additional, unrecited features. In some embodiments of any of the compositions and methods provided herein, "comprising" can be replaced with "consisting essentially of" or "consisting of." The phrase "consisting essentially of" is used herein to require specified characteristics or characteristics that do not materially affect the characteristics or function of the present disclosure. As used herein, the term "consisting of" is used to indicate the presence of only recited characteristics.

[0036] In some embodiments, provided herein are methods for treating a disease or disorder in or around an individual's eye with a therapeutically effective amount of a pharmaceutical composition. In certain embodiments, the composition includes selenium disulfide (SeS2). In some embodiments, the individual is instructed to limit, avoid, or otherwise limit or avoid exposure to light after administration. As discussed herein, in some instances, exposure of the treatment area to light, particularly sunlight or other ultraviolet light sources, is used to prevent, reduce, or limit the risk, incidence, and / or occurrence of side effects, such as keratitis. In some instances, prevention, reduction, or limitation of SeS2 side effects is greater and / or more likely when the SeS2 composition has a high concentration of SeS2 and / or when the SeS2 composition is provided at a high dose.

[0037] In some embodiments, the disease or disorder in or around the eye is a disease or disorder treated or treatable with a composition such as described herein. In some embodiments, the disease or disorder may be one or more conditions selected from the group including meibomian gland dysfunction (MGD), blepharitis, seborrheic blepharitis, Demodex infection, dry eye syndrome, hyperkeratosis, dermatitis, keratitis, contact lens discomfort, lid wiper's disease (LWE), keratoconjunctivitis sicca, Sjögren's syndrome, or ocular rosacea. 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 blepharitis. In some embodiments, the disease or disorder in or around the eye is seborrheic blepharitis. In some embodiments, the disease or disorder in or around the eye is MGD-related blepharitis. 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 a condition characterized by insufficient secretion of lipids.

[0038] In some embodiments, the light avoided in accordance with any method provided herein is light that may cause phototoxicity and / or other adverse effects in or around the eye when combined with therapeutic administration of a composition provided herein. In certain embodiments, all wavelengths of light are partially or completely blocked. In other embodiments, selected wavelengths of light are partially or completely blocked. In some embodiments, the light comprises infrared light, visible light, ultraviolet light, wavelengths thereof, and / or combinations thereof. In certain embodiments, the light comprises visible light and / or ultraviolet light. In some embodiments, the light comprises visible light. In some embodiments, the light comprises ultraviolet light. In some embodiments, ultraviolet light comprises both UVA light and UVB light. In some embodiments, the light comprises UVA light or UVB light. In some embodiments, the light is sunlight. In some embodiments, the light is not sunlight.

[0039] In certain embodiments, the methods provided herein provide treatments that include reducing (e.g., the occurrence or incidence) or eliminating photosensitivity reactions (e.g., adverse effects resulting from the combination of light and therapeutic administration of a composition provided herein), or photosensitivity (the terms are used interchangeably herein). In some examples, such adverse effects refer to adverse physiological responses such as, by way of non-limiting example, keratitis, inflammation, pain, irritation, flaking, redness, discoloration, or any combination thereof. In some examples, such adverse effects refer to grittiness, a foreign body sensation in the individual's eye, blurred vision, redness, tired eyes, symptoms of dry eye disorder, stinging, tearing, irritation, eyelid abnormalities, corneal abrasion, keratitis, photophobia, staining, or any combination thereof. Photoreactive chemicals can cause photosensitivity in individuals in contact with the photoreactive chemicals through direct or indirect mechanisms, such as those described in FIG. 1. Photosensitivity includes phototoxic and photoallergic effects.

[0040] 1 shows a non-limiting schematic of an exemplary mechanism by which a photoreactive chemical (010) can induce phototoxicity (100) in an individual. When ultraviolet (UV) radiation (020) or any other sufficiently energetic photon interacts with a photoreactive chemical (010), said photoreactive chemical (010) rises to an excited state (030), resulting in the transfer of energy from the photon to the photoreactive chemical (010). The excited state (030) species can release energy in the form of fluorescence (025) or can transfer energy to a second molecule, as further described by the indirect mode (040) or direct mode (080).

[0041] The indirect mode of phototoxicity (040) is facilitated by oxygen (055), where excited-state (030) species can donate energy to oxygen (055) via energy transfer or free radical generation (050). Both energy transfer and free radical generation (050) to oxygen (055) generate so-called reactive oxygen species (ROS), exemplified in Figure 1 by two common species, singlet oxygen and superoxide (060). ROS such as (060) are highly reactive and can cause the oxidation of various molecules, which may include drugs and DNA (070). After oxidation, the newly transformed molecules (070) can exert physiological effects in individuals in contact with the photoreactive chemical (010). In certain embodiments, the photoreactive chemical (010) enhances the inherently damaging (e.g., oxidizing) properties of UV radiation (020) by catalyzing the formation of ROS (060) at the site of contact with the photoreactive chemical (010). Therefore, preventing UV radiation, or other sufficiently energetic photons, from interacting with photoreactive chemicals (010) can provide protection from phototoxicity (100) and associated photosensitivity.

[0042] The direct mode of phototoxicity (080) is oxygen-independent. In the direct mode (080), the excited-state (030) species described herein can interact with (e.g., photobind to) endogenous molecules (090), including, but not limited to, small molecules, peptides, proteins, and nucleic acids. Photobinding of endogenous molecules (090) can directly exert phototoxicity (100) in a manner similar to that previously described.

[0043] In some embodiments, to avoid the possibility that SeS2 interacts with light, patients are instructed to avoid exposing the ocular surface and surrounding tissues to light after application. The time to avoid light can be determined based on the applied dose and concentration. Measures to avoid light exposure may include: (1) application at bedtime, after which the subject stays in bed without light exposure; (2) daytime application, so that the individual stays in a dim or dark environment after treatment; and (3) wearing protective headwear or eyewear (e.g., dark sunglasses or UV-protective sunglasses) to protect the treatment site from light.

[0044] In some embodiments, the pharmaceutical composition comprises SeS2 at a therapeutically effective concentration. In some embodiments, the pharmaceutical composition comprises SeS2 at a less than therapeutically effective concentration. In some embodiments, the pharmaceutical composition comprises SeS2 at a homeopathic concentration. In some embodiments, the pharmaceutical composition comprises SeS2 at a greater than therapeutically effective concentration.

[0045] In some embodiments, the therapeutically effective concentration is about 0.1% to about 2.5% by weight (e.g., about 0.5% to about 1% by weight). In some embodiments, the therapeutically effective concentration is at least about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, or about 2.5% by weight of selenium disulfide (SeS). %, about 1.25%, about 1.5%, about 1.75%, about 2.0%, about 2.5%, about 3.0%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 15.0% or more by weight. In some embodiments, the therapeutically effective concentration comprises up to about 11.0%, about 10.0%, about 9.0%, about 8.0%, about 7.0%, about 6.0%, about 5.0%, about 4.0%, about 3.0%, about 2.5%, about 2.0%, about 1.75%, about 1.5%, about 1.25%, about 1.0%, about 0.95%, about 0.9%, about 0.85%, about 0.8%, about 0.75%, about 0.70%, about 0.65%, about 0.60%, about 0.55%, about 0.5%, about 0.45%, about 0.4%, about 0.35%, about 0.3%, about 0.25%, or less by weight.In some embodiments, the therapeutically effective concentration is from about 0.01% to about 15.0% by weight, 0.01% to about 10.0% by weight, 0.01% to about 9.0% by weight, 0.01% to about 8.0% by weight, 0.01% to about 7.0% by weight, 0.01% to about 6.0% by weight, 0.01% to about 5.0% by weight, 0.01% to about 4.0% by weight, or about 0.01% to about 3.0% by weight. Amount%, 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% by weight, about 0.01% to about 0.05% by weight, about 0.05% to about 4.0% by weight, about 0.05% to about 3.0% by weight, about 0.05% to about 2.0% by weight, about 0.05% to about 0.05% by weight 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% by weight, about 0.1% to about 2.0% by weight, about 0.1% to about 1.5% by weight, about 0.1% to about 1.0% by weight, about 0.1% to about 0.5% by weight, about 0.5% to about 4.0% by weight %, about 0.5% to about 3.0% by weight, about 0.5% to about 2.0% by weight, about 0.5% to about 1.5% by weight, about 0.5% to about 1.0% by weight, about 1.0% to about 4.0% by weight, about 1.0% to about 3.0% by weight, about 1.0% to about 2.5% by weight, about 1.0% to about 2.0% by weight, about 1.0% to about 1.5% by weight, or any combination thereof. In some examples, administration or use of lower concentrations of SeS2 (e.g., 0.5% by weight) results in fewer adverse effects. In some examples, administration or use of lower concentrations of SeS2 (e.g., 0.5% by weight) results in fewer adverse effects when light is avoided after administration, such as administration in the evening or at night.

[0046] In some embodiments, the pharmaceutical composition is administered in a volume of less than 25 μL. In some embodiments, the pharmaceutical composition is administered in a volume of about 1 μL to about 20 μL (e.g., about 2 μL to about 15 μL, or about 3 μL to about 10 μL). In some embodiments, the volume of the pharmaceutical composition, or the volume of the pharmaceutical composition administered using the methods provided herein (e.g., using a swab or finger), is at most about 30 μL, at most about 25 μL, at most about 20 μL, at most about 15 μL, at most about 10 μL, or at most about 5 μL. In some embodiments, the volume is at least about 0.01 microliters (μL), at least about 0.05 μL, at least about 0.1 μL, at least about 0.5 μL, at least about 1 μL, at least about 5 μL, at least about 10 μL, at least about 15 μL, at least about 20 μL, or more. In some embodiments, the amount is about 0.01 μL to about 50 μL, about 0.1 μL to about 30 μL, about 0.5 μL to 25 μL, about 1 μL to 25 μL, about 10 μL to 25 μL, or about 2.5 μL to about 10 μL.

[0047] In some embodiments, the therapeutically effective amount of SeS2 is at least about 0.1 milligrams (mg), at least about 0.2 mg, at least about 0.3 mg, at least about 0.5 mg, at least about 1 mg, at least about 2 mg, at least about 2.5 mg, etc. In some embodiments, the therapeutically effective amount of selenium disulfide (SeS2) is about 25 mg or less, about 15 mg or less, about 10 mg or less, 7.5 mg or less, or about 5 mg or less. In some embodiments, the therapeutically effective amount of SeS2 is about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 8 mg, about 10 mg, etc. In some embodiments, the therapeutically effective amount of SeS2 is about 4 mg.

[0048] In some embodiments, the composition is a semi-solid. In some embodiments, the composition is an ointment. In some embodiments, the composition is applied using a finger. In some embodiments, the composition is applied using a swab.

[0049] In some embodiments, the pharmaceutical composition is applied to the ocular surface, surrounding ocular tissue, eyelid, eyelid margin, eyelid wiper, meibomian gland, mucocutaneous margin, eyelashes, lash line, lash follicle, tarsal gland, eyelid border, medial canthus, lacrimal papilla and punctum, skin or epidermal tissue within 1 cm of the ocular surface, skin or epidermal tissue within 2 cm of the ocular surface, or any combination thereof.

[0050] In some examples, the composition is self-administered. The composition may be administered by swab or finger. Alternatively and / or additionally, the composition is administered to the individual by a healthcare professional (e.g., a doctor, nurse, trained medical technician, etc.). Alternatively and / or additionally, the composition is administered to the individual by another individual or by a machine. In some embodiments, digital administration is preferred. In some examples, administering the compositions provided herein by finger provides improved therapeutic efficacy over, for example, administration using a swab.

[0051] In some examples, the composition is administered under favorable lighting conditions (e.g., sunlight, under light having at least 50 lux or more, at least 100 lux or more, about 500 lux or more, or about 1,000 lux or more). In some examples, limiting or avoiding exposure to light after administration of the composition reduces photosensitivity-associated keratitis by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 80%, or at least 90% compared to or relative to not limiting or avoiding exposure to light (e.g., either in the same individual with or without light exposure, or in different individuals with similar conditions with or without light exposure).

[0052] The period of time for limiting or avoiding light exposure may vary depending on the individual's illness, the dosage of the composition, the concentration of SeS2 in the composition, the individual's prior medical history, etc. In some examples, light exposure is limited or avoided for at least 30 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 3 hours, at least 6 hours, etc.

[0053] The amount of light permitted or prevented (e.g., limited, avoided, or instructed to do so) after administration of the composition may vary depending on the individual's disease, the dosage of the composition, the concentration of SeS2 in the composition, the individual's previous medical history, etc. In some examples, the individual is limited, avoided, or instructed to limit or avoid any high-intensity light (e.g., about 100 lux or more, about 500 lux or more, or about 1,000 lux or more). In some examples, the individual is permitted exposure to low-light conditions (e.g., about 100 lux or less, about 50 lux or less, about 25 lux or less, etc.), or the site where the composition was administered is exposed to or maintained in low-light conditions. In some embodiments, for a period following administration of the compound, the site where the composition was administered is generally maintained in low-light conditions, or the individual is instructed to maintain the site where the composition was administered in low-light conditions, as described herein. In some embodiments, the individual maintains the site where the composition was administered in low light conditions. In some embodiments, the individual reads printed instructions to maintain the site where the composition was administered in low light conditions. In some embodiments, the individual is provided with printed instructions to maintain the site where the composition was administered in low light conditions. In some embodiments, the individual is provided with auditory instructions to maintain the site where the composition was administered in low light conditions. In some embodiments, the individual is provided with non-auditory instructions to maintain the site where the composition was administered in low light conditions.

[0054] In some embodiments, the low light conditions are characterized by the physiological response of the observer to said light conditions. In some embodiments, the low light conditions are characterized by wavelength, lux (lumens / m 2), or a combination thereof. In some embodiments, the low light conditions are provided by night. In some embodiments, the low light conditions are provided by solar obstruction. In some embodiments, the low light conditions are provided by being indoors. In some embodiments, the low light conditions are provided by naturally occurring conditions (e.g., cloudy skies). In some embodiments, the low light conditions are provided by the exclusion of certain wavelengths or ranges of wavelengths of light. In some embodiments, the low light conditions are provided by a dark room. In some embodiments, the low light conditions are provided by the use of a safelight.

[0055] In some embodiments, the low light conditions are at most about 1000 lux, about 250 lux, about 100 lux, about 50 lux, about 25 lux, about 10 lux, about 1 lux, about 0.1 lux, about 0.01 lux, about 0.001 lux, or less. In some embodiments, the low light conditions are at least about 0.001 lux, about 0.01 lux, about 0.1 lux, about 1 lux, about 10 lux, about 25 lux, about 50 lux, about 100 lux, about 250 lux, about 1000 lux, or more. In some embodiments, the low light condition is from about 0.001 to about 1000 lux, from about 0.001 to about 250 lux, from about 0.001 to about 100 lux, from about 0.01 to about 1000 lux, from about 0.01 to about 250 lux, from about 0.01 to about 100 lux, from about 0.1 to about 1000 lux, from about 0.1 to about 250 lux, from about 0.1 to about 100 lux, from about 1 to about 100 lux, or from about 1 to about 1000 lux. The brightness is about 1000 lux, about 1 to about 200 lux, about 1 to about 100 lux, about 10 to about 1000 lux, about 10 to about 200 lux, about 10 to about 100 lux, about 25 to about 1000 lux, about 25 to about 250 lux, about 25 to about 100 lux, about 50 to about 1000 lux, about 50 to about 250 lux, or about 50 to about 100 lux.

[0056] In some embodiments, the individual is instructed to limit, avoid, or limit or avoid light exposure after administration by being instructed (e.g., directly or indirectly) to at least partially block or block some or all of the light from one or more, or any, light sources (e.g., sunlight) to the site where the composition was administered during and / or after administration. In some embodiments, the individual is instructed to limit, avoid, or limit or avoid light exposure after administration by being instructed to at least partially block or block light from the site where the composition was administered and surrounding tissues during and / or after administration.

[0057] In some embodiments, the individual is instructed to direct light after administration, direct and limit / avoid light after administration by at least partially directing or being instructed to direct some or all light (e.g., sunlight) to the site where the composition was administered.

[0058] In some embodiments, an individual is administered or instructed to administer the composition at a specific time, thereby limiting, avoiding, or instructed in such a manner to limit or avoid exposure to light after administration. In some embodiments, the specific time is about 1 hour before sunset. In some embodiments, the specific time is about 2 hours before sunset. In some embodiments, the specific time is approximately later than sunset. In some embodiments, the specific time is about 1 hour after sunset. In some embodiments, the specific time is about 2 hours after sunset. In some embodiments, the specific time is after sunset (nighttime). In some embodiments, the specific time is about 1 hour or more before bedtime. In some embodiments, the specific time is less than about 1 hour before bedtime. In some embodiments, the specific time is less than about 30 minutes before bedtime. In some embodiments, administration occurs at nighttime. In certain embodiments, nighttime administration is after 4:00 PM, after 5:00 PM, after 6:00 PM, etc.

[0059] In some embodiments, blocking light is achieved by wearing headwear and / or eyewear that at least partially blocks light. In some embodiments, blocking light is achieved by wearing headwear and / or eyewear that completely blocks light. In some embodiments, blocking light is achieved by wearing headwear or eyewear that at least partially blocks specific wavelengths of light. In some embodiments, the light blocked by the headwear and / or eyewear is not visible light. In some embodiments, the light blocked by the headwear and / or eyewear includes both visible light and other forms of radiation. In some embodiments, blocking light is achieved by wearing headwear and / or eyewear that at least partially blocks ultraviolet light, visible light, infrared light, x-rays, and / or gamma rays.

[0060] In some embodiments, the headwear is a hat. In some embodiments, the headwear is a hat with a peak or brim. In some embodiments, the headwear is a hat without a peak or brim.

[0061] In some embodiments, the eyewear is sunglasses or goggles. In some embodiments, the eyewear is contact lenses. In some embodiments, the eyewear comprises one or more lenses. In some embodiments, the eyewear comprises one or more polarized lenses. In some embodiments, the eyewear comprises one or more reflective lenses. In some embodiments, the eyewear comprises one or more shaded lenses. In some embodiments, the eyewear is blindfolded. In some embodiments, the eyewear comprises natural or synthetic fibers, or a combination thereof. In some embodiments, the eyewear comprises a reflective surface. In some embodiments, the eyewear comprises a lens or mirror. In some embodiments, the eyewear comprises fabric, polymer, plastic, metal, non-metal, plant material, plant-derived material, synthetic material, or any combination thereof.

[0062] In some embodiments, reduction or avoidance of keratitis is achieved by combining two conditions: i) administering the composition in a sufficiently small amount (even at a high concentration), and ii) after administration, exposure of the site to light to which the composition was administered is sufficiently low. In some instances, lower concentrations of SeS2 allow for higher light exposure to be maintained with minimal or reduced risk of phototoxicity. In some embodiments, the amount of light exposure tolerated and the period of avoidance of light exposure are at least partially correlated with the dose and / or concentration of the SeS2 composition administered.

[0063] In some embodiments, the adverse effects of SeS2 interacting with light are prevented or mitigated by protecting the individual's ocular surface with a barrier. In certain embodiments, the process further comprises administering a therapeutically effective amount of a pharmaceutical composition to the individual's ocular surface. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of selenium disulfide (SeS2). In some embodiments, the ocular surface is protected with a barrier prior to administering the pharmaceutical composition to the ocular surface. Alternatively and / or additionally, the ocular surface is protected with a barrier simultaneously with the process of administering the pharmaceutical composition to the ocular surface. The barrier may be any physical or chemical barrier that is pre-formed prior to application to the ocular surface. Alternatively and / or additionally, the barrier is formed on the ocular surface after application to the ocular surface.

[0064] In some examples, protecting the ocular surface of an individual involves administering an ointment, a polyvinyl alcohol (PVA) microemulsion, other micro- or nanoemulsions of polymers, or a liquid crystalline form of a polymer that can function as a barrier. Alternatively and / or additionally, protecting the ocular surface of an individual involves administering a lipid- or carbohydrate-based compound that can coat the ocular surface or cornea. For example, such lipid- or carbohydrate-based compounds include cross-linked dextran or high-density liposomes. Alternatively and / or additionally, protecting the ocular surface of an individual involves administering hyaluronic acid (HA) or any suitable HA-containing compound that interacts with mucins on the ocular surface and / or surrounding ocular tissues of the individual to form a barrier. Preferably, such a formed barrier prevents photosensitized SeS2 from contacting the ocular surface of the individual. While any suitable hyaluronic acid, hyaluronic acid polymer, or HA-containing compound suitable for application to the ocular surface is contemplated, preferred hyaluronic acids or hyaluronic acid polymers are those having a molecular weight of at least 700 kDa, at least 800 kDa, at least 900 kDa, at least 1000 kDa, at least 1100 kDa, at least 1200 kDa, at least 1300 kDa, at least 1400 kDa, at least 1500 kDa, at least 1600 kDa, at least 1700 kDa, at least 1800 kDa, at least 1900 kDa, at least 2100 kDa, at least 2200 kDa, at least 2300 kDa, at least 2400 kDa, at least 2500 kDa, at least 2600 kDa, at least 2700 kDa, at least 2800 kDa, at least 2900 kDa, at least 3000 kDa, at least 3100 kDa, at least 3200 kDa, at least 3300 kDa, at least 3400 kDa, at least 3500 kDa, at least 3600 kDa, at least 3700 kDa, at least 3800 kDa, at least 3900 kDa, at least 4000 kDa, at least 4100 kDa, at least 4200 kDa, at least 4300 kDa, at least 4400 kDa, at least 4500 kDa, at least 4600 kDa, at least 4700 kDa, at least 4800 kDa, at least These include those having a molecular weight of 0 kDa, at least 1500 kDa, at least 2000 kDa, at least 2500 kDa, at least 3000 kDa, or at least 3500 kDa, or 700 to 3500 kDa, 700 to 3000 kDa, 700 to 2500 kDa, 700 to 2000 kDa, 700 to 1500 kDa, 700 to 1300 kDa, or 700 to 1200 kDa.

[0065] In some examples, protecting the ocular surface includes administering an additive molecule to the ocular surface as a barrier. The additive molecule is configured, suitable, or capable of scavenging free radicals or photosensitized SeS2 so that the scavenged free radicals or photosensitized SeS2 do not reach or come into direct contact with the ocular surface, thereby reducing adverse effects on the ocular surface. In some embodiments, the additive molecule, when applied to the ocular surface, scavenges at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% of the free radicals or photosensitized SeS2. In some examples, the additive molecule comprises one or more of a phenolic compound, vitamin E, vitamin C, carotene, ferritin, ceruloplasmin, selenium, reduced glutathione (GSH), manganese, ubiquinone, zinc, flavonoid, coenzyme Q, melatonin, bilirubin, taurine, or cysteine. In some embodiments, the additive molecule is formulated with a suitable excipient (e.g., a buffer) in any suitable form (e.g., gel, hydrogel, ointment, cream, lotion, foam, spray, patch, implant (e.g., sustained-release, biodegradable, semi-degradable, or non-degradable), lipid-based (e.g., solid lipid nano / microparticles, liposomes, exosomes, micelles, micro / nanoemulsions, cubosomes, cochleates, niosomes, lipospheres), silica-based (e.g., mesoporous), polymer-based, nano- and / or microspheres, nano- and / or microcapsules, nano- and / or microparticles, etc.) for application to the ocular surface of an individual prior to administration of the pharmaceutical composition (e.g., SeS2-containing pharmaceutical composition). Alternatively and / or additionally, the additive molecule is added to the SeS2-containing pharmaceutical composition such that the additive molecule can be applied to the ocular surface simultaneously with the SeS2-containing pharmaceutical composition.

[0066] In some instances, the barrier is a contact lens or other type of transparent or opaque layer that creates a physical barrier on the ocular surface to protect it from photosensitized SeS2 or other reactive oxygen species (i.e., generated from the photoreaction of SeS2). The size of the contact lens or other type of transparent or opaque layer varies depending on the area of ​​protection. For example, the size of the contact lens or other type of transparent or opaque layer is determined to cover at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the individual's ocular surface.

[0067] The process of protecting an individual's ocular surface with a barrier from photosensitized SeS2 or other reactive oxygen species prevents or reduces adverse effects of photosensitized SeS2 or phototoxicity from other reactive oxygen species upon administration of the SeS2-containing pharmaceutical composition, thereby enabling the SeS2-containing pharmaceutical composition to be administered under good or high light conditions (e.g., sunlight, under light having at least 50 lux or more, at least 100 lux or more, at least 500 lux or more, or at least 1,000 lux or more). Furthermore, by preventing access of photosensitized SeS2 or other reactive oxygen species to the ocular surface during administration of the SeS2-containing pharmaceutical composition, such an administration process eliminates or at least reduces the need for further restriction, avoidance, or instructions to limit or avoid light exposure after administration. [Example]

[0068] Example 1 In vivo rabbit studies of SeS2-containing preparations. In preclinical studies conducted on rabbits, low doses (approximately 4 mg) of SeS2 at concentrations up to 2.5% by weight were observed to be safe. This dose, provided as an ointment and applied to the eyelid margin, was well tolerated and did not cause keratitis in treated individuals. When the dose was increased to approximately 20 mg, keratitis was observed in subjects. These findings indicate that keratitis and related side effects of SeS2 treatment may depend not only on the SeS2 concentration but also on the total dose administered.

[0069] Example 2 Three different concentrations were used in the clinical study: 0.1% by weight (10 subjects), 0.5% by weight (12 subjects), and 1% by weight (26 subjects). While some patients transitioned to daily application based on prespecified protocol criteria, most applications were performed biweekly. Of the subjects enrolled in the study, four developed keratitis, keratitis-related symptoms, or keratitis-related symptoms. All four subjects were treated using the 1% by weight concentration. In one case, the patient was treated for one month and showed improvement according to multiple ocular health indicators, but developed keratitis after the one-month visit. During the one-month visit, the patient received medication in the morning as part of an in-clinic evaluation. Approximately seven hours later, the patient began to experience significant pain. On examination the following morning, the patient presented with band-like corneal staining in the palpebral fissure, and a diagnosis of keratitis was made. The patient experienced no adverse events during the first month while applying the medication twice weekly (at home, before bedtime) and experienced significant improvements in the Total Ocular Surface Disease Index (OSDI), Visual Analog Scale (VAS), and Standardized Patient Assessment of Ocular Dryness (SPEED). After resolution of the keratitis, the patient continued taking the medication at bedtime without further episodes of keratitis.

[0070] A surprising incidence of patients who improved without adverse effects during home application of the drug and then developed keratitis several hours after in-clinic application was observed. This pattern of recurrence suggested a toxic reaction after daytime in-clinic SeS2 application. Three additional patients reported pain onset between 6 and 20 hours after application, indicating that this indeed followed the pattern of a toxic reaction. Two of the patients developed keratitis after a single daytime in-clinic application—the first application on the first day of the study. The final subject developed keratitis after an in-clinic application on day 14 of the study. Like the first patient, this final subject also applied the treatment at home every other week without adverse effects.

[0071] The proposal that SeS2 reacts with light to cause a photosensitive reaction was supported by the following factors: (1) the consistent occurrence of keratitis after in-clinic daytime application, (2) the performance of over 400 bedtime applications of 1 wt% SeS2 without a single episode of keratitis, and (3) the time lapse between the daytime application of 1 wt% SeS2 ointment and the onset of keratitis symptoms. Given that in-clinic daytime applications of 0.1 wt% and 0.5 wt% SeS2 ointment were also performed in nine and seven patients, respectively, without the development of keratitis, and that keratitis occurred in rabbits at high doses of approximately 20 mg but not at low doses of approximately 4 mg, this phenomenon may be related to both dose and concentration.

[0072] The period during which the drug product could be visualized on the eye was also tested, and it was concluded that after 5 hours, no drug product was evidently present.

[0073] SeS2 (2.5% by weight) can cause contact dermatitis due to its irritant properties. Giordano once applied SeS2 overnight (e.g., at night or before bedtime for overnight effects) to treat tinea versicolor, not because of concerns about sun exposure but because it allowed for prolonged skin exposure. Robinson and Yaffe used SeS2 cream (1% by weight) twice daily for two weeks for the same indication. The 32 cases described by Robinson and Yaffe indicate that daytime exposure was not a problem, as showering only once every three days was recommended to remove the SeS2 cream. None of the investigators encountered a single case of either contact or photocontact dermatitis, and there was no mention of potential phototoxic effects of SeS2. In some cases, overnight application is important when SeS2 concentrations are low, e.g., approximately 0.1% to 2.5% by weight (e.g., 0.5% by weight).

[0074] In one case, a patient applied SeS2 shampoo three consecutive nights as prescribed by a physician to treat asymptomatic hypopigmented macules on the face, neck, and upper extremities. Five days after the third treatment, the patient developed localized eczematous plaques on light-exposed areas of the face, neck, and upper extremities. In some cases, the dermatitis developed five days after the last application, suggesting that SeS2-induced dermatitis may be photoallergic. Five days is the minimum time for the sensitization process to be complete. Furthermore, phototoxicity and primary irritation reactions are seen when concentrations of photoreactive chemicals are high. Such phototoxic or irritation reactions are unlikely to occur after a time lag following discontinuation of any topical medication. The aforementioned eczematous plaques occurred primarily on sun-exposed areas, despite the patient having applied the shampoo to the entire body, indicating that the reaction was not primary irritant dermatitis. The worsening of sun exposure even three weeks later also supports an allergic mechanism. Photosensitivity dermatitis as a side effect of medication typically subsides 1–2 weeks after discontinuation of the offending medication and sunlight. In some cases, the offending medication may persist in the dermis, or proteins or cells may change, causing persistent photosensitivity.

[0075] The development of photosensitivity in response to selenium compositions (e.g., SeS2) contrasts with the known skin protective effects of some selenium compounds, particularly with respect to UVA (radiation with wavelengths of approximately 320 nm to approximately 400 nm) exposure. The previously observed UVA protective effect may be driven by selenium's ability to promote the synthesis of glutathione, a key component of fibroblasts and keratinocytes. In some instances, the contrast between UV protective effects and photosensitivity may stem from selenium solubility. Previous data demonstrating the UV protective effects of selenium compounds typically correspond to soluble selenium compounds. The protective effects of selenium compounds begin at low doses. In the ophthalmic treatments described herein, the active compound is insoluble selenium disulfide with minimal concentrations of soluble selenium (<5 ppm). The phototoxic effects observed in one of the ophthalmic studies described herein are observed at concentrations as low as at least approximately 0.5% and 1% by weight.

[0076] In some instances, certain concentrations of SeS2 may upset the balance between protective and sensitizing effects. In some instances, high levels of insoluble selenium can cause phototoxicity through elevated levels of glutathione or other proteins, inducing oxidative imbalance and cytotoxicity. This cellular toxicity and oxidative imbalance can be further exacerbated by UVA exposure.

[0077] Example 3 Seven additional subjects received 1% by weight selenium disulfide in a manner similar to that described in Example 2. There were two or three additional cases of adverse effects. Of these subjects, two developed keratitis after the first in-office application, and another patient's condition worsened after the second in-office application; however, the subject continued with one or two additional doses at home before experiencing pain (a typical scenario in which keratitis progresses).

[0078] Example 4 Human studies of SeS2-containing preparations. One of three concentrations of SeS2 (0.1%, 0.5%, and 1% by weight) will be applied to human subjects to determine safety and efficacy. The treatment, an ointment-based SeS2 composition, will be applied to the eyelid margin by the individual receiving the treatment (i.e., self-administration). In most instances, the treatment will be applied biweekly, although some patients will transition to daily application based on pre-specified protocol criteria. Because ointment-based compositions are known to mix with tears and cause blurred vision, individuals in this study will be encouraged to apply the treatment before bedtime to avoid the associated risks of vision loss. An additional component of the study will require individuals to apply the ointment in the presence of an ophthalmologist to demonstrate proper self-administration technique consistent with the study design. In-office application will be performed at specific, pre-defined time points. In these instances, the treatment will not be applied before bedtime but rather during daylight hours.

[0079] Keratitis was not observed in any patients receiving treatment at either the 0.1% or 0.5% wt. concentration. However, four patients noted symptoms of keratitis in the 1% wt. concentration cohort. It is noteworthy that all four patients describing symptoms of keratitis did so in accordance with the prescribed in-clinic evaluation, while none of the more than 400 bedtime treatment applications resulted in keratitis. Prior to the in-clinic evaluation after the onset of keratitis, at least one patient demonstrated improved health outcomes after one month of treatment, as measured by the Total Ocular Surface Disease Index (OSDI), Visual Analog Scale (VAS), and Standardized Patient Assessment of Ocular Dryness (SPEED). However, within seven hours of the in-clinic evaluation, the patient complained of significant pain near the treatment site. Subsequent fluorescein staining of the cornea indicated keratitis, observed as a band in the palpebral fissure.

[0080] At least three other individuals have developed keratitis symptoms following a pattern consistent with the first-described individual. All four report that pain began 6-20 hours after in-clinic evaluation, i.e., during the application of a 1% by weight concentration of SeS2. This pattern of occurrence suggests a correlation between the onset of keratitis and both the circumstances under which the treatment is administered and the concentration of the treatment administered.

[0081] Determining the duration for which treatment is evident. The duration for which the medication is visibly present on or near the individual's eye is assessed. The investigator concludes that the medication is no longer visibly present after 5 hours.

[0082] Example 5 Analysis of masked data from two ongoing studies using the same concentration of SeS2 (i.e., 0.5%) at overlapping sites demonstrates a clear and unexpected tolerability advantage of administering the medication only at night. In the first study, patients were instructed to administer the medication both in the evening between visits and during the daytime during regularly scheduled clinic visits as part of the study protocol. Study patients underwent a 2-week run-in with placebo administered twice weekly for 2 weeks. Once inclusion / exclusion criteria were met, patients were randomized to receive either SeS2 ointment / semisolid medication (i.e., 0.1%, 0.5%, or 1.0%) or placebo in a dose regimen involving either twice-weekly administration for 3 months or once-daily administration for 3 months.

[0083] In the second study, which was similar to the first, except that all daytime visits were eliminated, and ointment / semisolid SeS2 (e.g., 0.5%) was administered twice weekly in the evening at bedtime for three months. Compared with the first study, the second study (nighttime administration only) clearly demonstrated a significant reduction in ocular adverse events (75% reduction in the incidence of adverse events). Adverse events included grittiness, foreign body sensation, stinging, blurred vision, red, tired, watery eyes, irritation, eyelid abnormalities, burning, corneal abrasion, photophobia, staining, or dry eye disorder (DED). Adverse events were primarily tolerability-related, such as burning or stinging after application.

[0084] The rate of ocular adverse events (ocular AEs) and more serious adverse event discontinuations (DCs for AEs, primarily related to ocular tolerability) appears to be reduced by at least 50% when dosing is allowed only in the evening rather than the morning.

[0085] Example 6 In a study testing the efficacy of SeS2 in patients with meibomian gland disorder (MGD), subjects were allowed to apply the ointment to the eyelid margin using their choice of either a finger or a cotton-tipped applicator (e.g., a cotton swab).

[0086] Of 22 patients with meibomian gland disorder (MGD), 9 chose to use their fingers and 13 used applicators. Medication was applied twice weekly, with the final evaluation at 3 months, when the primary outcome of meibomian gland score (MGS) was assessed. The mean change from baseline in MGS for the 9 patients who used their fingers was 10 (+ / - 8.2) compared with 2.3 (+ / - 4.4) for the 13 patients who used applicators. This difference was statistically significant (p=0.03). Because creams, cosmetics, and ointments used on the eyelid margin are typically applied using applicators, the increased efficacy of medications when applied with the fingers was an unexpected finding.

[0087] 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. It is not intended that the present invention be limited by the specific examples provided within the specification. While the present invention has been described with reference to the foregoing specification, the description and illustration of the embodiments herein are not meant to be construed in a limiting sense. Numerous modifications, changes, and substitutions will occur to those skilled in the art without departing from the invention. Furthermore, it will be understood that all aspects of the present invention are not limited to the specific depictions, configurations, or relative proportions set forth herein, which depend upon a variety of conditions and variables. It will be appreciated that various alternatives to the embodiments of the present invention described herein may be utilized in practicing the invention. It is therefore contemplated that the present invention also covers any such alternatives, modifications, variations, or equivalents. 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.

Claims

1. 1. Use of selenium disulfide in the manufacture of a pharmaceutical composition for a method of treating meibomian gland dysfunction (MGD), dry eye syndrome, or contact lens discomfort (CLD) in an individual, said method comprising: administering a therapeutically effective amount of the pharmaceutical composition to the ocular surface, surrounding ocular tissue, or a combination thereof of the individual; The pharmaceutical composition comprises a therapeutically effective amount of selenium disulfide, and The pharmaceutical composition is administered within one hour of going to bed or overnight.

2. The use of claim 1, wherein the pharmaceutical composition comprises selenium disulfide in a therapeutically effective concentration.

3. The use of claim 2, wherein the therapeutically effective concentration is from about 0.1% to about 10% by weight.

4. 10. The use of claim 1, wherein the pharmaceutical composition is administered in a volume of less than 25 μL.

5. 2. The use of claim 1, wherein the pharmaceutical composition is a semi-solid, and the semi-solid is an ointment, a gel, a cream, or a paste.

6. The use of claim 1, wherein the pharmaceutical composition is administered to the individual within one hour of going to bed.

7. The use of claim 1 , wherein the pharmaceutical composition is administered at night.

8. The use according to claim 1, wherein the pharmaceutical composition is administered at sunset.

9. The use described in claim 1, wherein the method is a method for treating meibomian gland dysfunction (MGD).

10. The use described in claim 1, wherein the method is a method for treating dry eye syndrome.

11. The use described in claim 1, wherein the method is a method for treating contact lens discomfort (CLD).

12. The use of claim 1 , wherein the individual self-administers the pharmaceutical composition.

13. The use according to claim 12, wherein the pharmaceutical composition is applied digitally.

14. The use according to claim 12, wherein the pharmaceutical composition is administered at home.

15. The use of claim 1, wherein the pharmaceutical composition is administered after 4:00 PM.

16. 1. Use of selenium disulfide in the manufacture of a pharmaceutical composition for a method of treating meibomian gland dysfunction (MGD) in an individual, said method comprising: administering a therapeutically effective amount of the pharmaceutical composition to the ocular surface, surrounding ocular tissue, or a combination thereof of the individual; The pharmaceutical composition comprises a therapeutically effective amount of selenium disulfide (SeS ２ ), and The pharmaceutical composition is administered at bedtime.

17. 1. Use of selenium disulfide in the manufacture of a pharmaceutical composition for a method of treating meibomian gland dysfunction (MGD), dry eye syndrome, or contact lens discomfort (CLD) in an individual, said method comprising: administering a therapeutically effective amount of the pharmaceutical composition to the ocular surface, surrounding ocular tissue, or a combination thereof of the individual; The pharmaceutical composition comprises a therapeutically effective amount of selenium disulfide (SeS ２ ), and The pharmaceutical composition is administered at bedtime or within one hour of bedtime.

18. The use described in claim 17, wherein the method is a method for treating dry eye syndrome.

19. 19. The use of claim 18, wherein the individual suffers from meibomian gland dysfunction (MGD).

20. 18. The use of claim 17, wherein the pharmaceutical composition is administered at bedtime.

21. 18. The use of claim 17, wherein about 5 mg or less of the selenium disulfide is administered to the ocular surface, the surrounding ocular tissue, or a combination thereof.

22. 18. The use of claim 17, wherein the pharmaceutical composition is administered digitally to the ocular surface, the surrounding ocular tissue, or a combination thereof.

23. 23. The use of claim 22, wherein the pharmaceutical composition is applied to the eyelid margin of the individual.

24. 24. The use of claim 23, wherein the pharmaceutical composition is administered to the individual once every two weeks.

25. 25. The use of claim 24, wherein the pharmaceutical composition is administered to the individual in a volume of less than about 25 microliters (μL).

26. 18. The use of claim 17, wherein the individual applies a volume of the pharmaceutical composition of less than about 25 μL to the individual's eyelid margin.

27. 27. The use of claim 26, wherein the individual applies the pharmaceutical composition to the individual's eyelid margin once every two weeks.

28. 18. The use of claim 17, wherein the pharmaceutical composition comprises selenium disulfide in a therapeutically effective concentration.

29. 29. The use of claim 28, wherein the therapeutically effective concentration is about 0.5% by weight.

30. 30. The use of claim 29, wherein the individual uses a finger to apply the pharmaceutical composition in an amount of less than about 25 μL.

31. 31. The use of claim 30, wherein the individual applies the pharmaceutical composition to the eyelid margin of the individual.

32. 32. The use of claim 31 , wherein the individual is administered the pharmaceutical composition once every two weeks.

33. The use described in claim 32, wherein the method is a method for treating dry eye syndrome and the individual suffers from meibomian gland dysfunction (MGD).

34. 34. The use of claim 33, wherein the individual has a reduced incidence of any one or more of keratitis, inflammation, pain, irritation, flaking, redness, and discoloration.

35. 34. The use of claim 33, wherein the individual experiences a reduced incidence of any one or more of the following: grittiness, foreign body sensation in the eye, blurred vision, redness, tired eyes, symptoms of dry eye disorder, stinging, tearing, irritation, eyelid abnormalities, corneal abrasions, keratitis, photophobia, and staining.

36. 34. The use of claim 33, wherein the individual has improvement in one or more of the following measures: Meibomian Gland Score (MGS), Total Ocular Surface Disease Index (OSDI), Visual Analog Scale (VAS), Standard Patient Assessment of Ocular Dryness (SPEED), or a combination thereof.

37. The use described in claim 16, wherein less than about 5 mg of selenium disulfide is administered to the ocular surface, the surrounding ocular tissue, or a combination thereof.

38. The use described in claim 16, wherein the pharmaceutical composition is administered digitally to the ocular surface, the surrounding ocular tissue, or a combination thereof.

39. The use described in claim 38, wherein the pharmaceutical composition is applied to the eyelid margin of the individual.

40. The use of claim 39, wherein the pharmaceutical composition is administered to the individual once every two weeks.

41. The use described in claim 40, wherein the pharmaceutical composition is administered to the individual in an amount of less than about 25 microliters (μL).

42. The use described in claim 16, wherein the individual applies an amount of the pharmaceutical composition of less than about 25 μL to the eyelid margin of the individual.

43. The use described in claim 42, wherein the individual applies the pharmaceutical composition to the eyelid margin of the individual once every two weeks.

44. The use of claim 16, wherein the pharmaceutical composition comprises selenium disulfide at a therapeutically effective concentration.

45. The use described in claim 44, wherein the therapeutically effective concentration is about 0.5% by weight.

46. The use described in claim 45, wherein the individual uses a finger to apply an amount of the pharmaceutical composition of less than about 25 μL.

47. The use described in claim 46, wherein the individual applies the pharmaceutical composition to the eyelid margin of the individual.

48. The use of claim 47, wherein the individual is administered the pharmaceutical composition once every two weeks.

49. The use described in claim 48, wherein the method is a method for treating dry eye syndrome and the individual suffers from meibomian gland dysfunction (MGD).

50. The use of claim 49, wherein the individual has a reduced incidence of one or more of keratitis, inflammation, pain, irritation, flaking, redness, and discoloration.

51. The use of claim 49, wherein the individual has a reduced incidence of one or more of the following: grittiness, foreign body sensation in the eye, blurred vision, redness, tired eyes, symptoms of dry eye disorder, stinging, tearing, irritation, eyelid abnormalities, corneal abrasions, keratitis, photophobia, and staining.

52. The use described in claim 49, wherein the individual has improvement in one or more of the following indicators: Meibomian Gland Score (MGS), Total Ocular Surface Disease Index (OSDI), Visual Analog Scale (VAS), Standard Patient Assessment of Ocular Dryness (SPEED), or a combination thereof.

53. The use of claim 17, wherein the method is for treating meibomian gland dysfunction (MGD).

54. The use described in claim 16, wherein the individual has signs and symptoms of dry eye syndrome.

55. The use described in claim 53, wherein the individual has signs and symptoms of dry eye syndrome.

56. The use described in claim 53, wherein the pharmaceutical composition is administered digitally to the ocular surface, the surrounding ocular tissue, or a combination thereof.

57. The use described in claim 56, wherein the pharmaceutical composition is applied to the eyelid margin of the individual.

58. The use of claim 57, wherein the pharmaceutical composition is administered to the individual once every two weeks.

59. The use described in claim 58, wherein the pharmaceutical composition is administered to the individual in an amount of less than about 25 microliters (μL).

60. The use described in claim 58, wherein the individual applies an amount of the pharmaceutical composition of less than about 25 μL to the eyelid margin of the individual.

61. The use of claim 53, wherein the pharmaceutical composition contains selenium disulfide at a therapeutically effective concentration.

62. The use described in Claim 61, wherein the therapeutically effective concentration is about 0.5% by weight.

63. The use described in claim 62, wherein the individual applies a finger to apply an amount of the pharmaceutical composition of less than about 25 μL.

64. The use described in claim 63, wherein the individual applies the pharmaceutical composition to the eyelid margin of the individual.

65. The use of claim 64, wherein the individual is administered the pharmaceutical composition once every two weeks.

66. The use described in claim 65, wherein the method is for treating meibomian gland dysfunction (MGD) and the individual has signs and symptoms of dry eye disorder (DED).

67. The use described in claim 66, wherein the individual has a reduced incidence of one or more of keratitis, inflammation, pain, irritation, flaking, redness, and discoloration.

68. The use of claim 66, wherein the individual has a reduced incidence of one or more of the following: grittiness, foreign body sensation in the eye, blurred vision, redness, tired eyes, symptoms of dry eye disorder, stinging, tearing, irritation, eyelid abnormalities, corneal abrasions, keratitis, photophobia, and staining.

69. The use described in claim 66, wherein the individual has improvement in one or more of the following indicators: Meibomian Gland Score (MGS), Total Ocular Surface Disease Index (OSDI), Visual Analog Scale (VAS), Standard Patient Assessment of Ocular Dryness (SPEED), or a combination thereof.

Images