Composition and instructions for hypersensitivity

Abstract

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

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 959,738, filed Jan. 10, 2020, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Selenium sulfide (SeS2) is indicated for the treatment of skin diseases such as seborrheic dermatitis, vitiligo, and dandruff. Selenium sulfide is typically used as a shampoo, foam, or lotion at commercially available concentrations of 1% and 2.5% and is rinsed off after application for several minutes. Use of SeS2 may be associated with known side effects listed in the package insert, which may include irritation, a burning sensation, and rarely hair loss or discoloration. Contact of a large amount of a preparation containing high concentrations of selenium sulfide with the ocular mucosa may cause irritation (e.g., stinging), and contact of a preparation containing SeS2 with the skin for a long time (e.g., overnight application) may cause local irritation.

[0003] Adverse events reported after topical use of selenium sulfide-containing products in the eye include superficial punctate keratitis and conjunctivitis that resolved after discontinuation of treatment. When SeS2 is applied topically for the treatment of vitiligo, skin irritation may occur in the genital area and / or skin folds. SeS2 lotions may also cause rebound oiliness of the scalp. AHFS Drug Information 2010.

[0004] After topical application of SeS2 lotion, discoloration occurs in both natural and dyed hair of various shades. Hair discoloration is rare and is usually associated with insufficient or no rinsing after shampooing with SeS2 lotion. The manufacturer states that hair discoloration can be minimized by carefully rinsing the hair after treatment with this drug. Shampooing with a 2.5% lotion of this drug may cause widespread hair loss, which has been reported to resolve within 1-2 weeks after discontinuing the drug.

[0005] SeS2 lotion has been reported to cause systemic toxicity after topical application to damaged skin. A woman with open wounds on her scalp experienced signs and symptoms of systemic toxicity, including tremors, severe sweating, garlicky breath, lower abdominal pain, weakness, lethargy, loss of appetite, and occasional vomiting, after prolonged topical application of the lotion. The signs and symptoms of toxicity resolved within 10 days of discontinuing the drug. Selenium can be toxic in high doses (more than 400 μg per day) or with prolonged use. Acute selenium poisoning can be fatal due to cardiovascular failure and / or pulmonary edema. The first symptoms commonly seen in acute selenium poisoning are gastrointestinal effects. Acute effects include vomiting, excessive salivation, diarrhea, abdominal pain, burning sensation in the nasal and / or oral mucosa, chemical burns of the gastrointestinal tract, and garlicky breath. Long-term use of selenium can lead to poisoning similar to arsenic poisoning, with symptoms including hair loss, white horizontal stripes on the nails, nail inflammation, fatigue, irritation, nausea, vomiting, garlic breath, and a metallic taste. Selenium can also cause muscle tenderness, tremors, confusion, facial flushing, blood clotting disorders, liver and kidney damage, and other side effects. Acute systemic effects from selenium are not expected in the patient population for which the drug regimen was proposed.

[0006] Nonspecific allergic reactions, including rashes and hives, are rarely reported. Selenium compounds have UV protective effects. Specifically, topical selenium compounds cause skin redness, increasing the minimum amount of UV radiation required to avoid skin damage from UVB exposure (irradiation at wavelengths of approximately 290 nm to 320 nm). In some cases, 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 treat seborrheic blepharitis using SeS2 as an ophthalmic preparation. Seborrheic blepharitis is typically associated with scaling of the eyelid margins and affects many patients with seborrheic dermatitis. Clinicians treated hundreds of patients over periods ranging from one month to one year using various methods, including in-hospital, home, daily, or every-other-day applications.

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

[0009] Various application methods were described by researchers, ranging from cautious in-hospital application involving excessive rinsing to home application involving thorough rinsing in a short period. It was clearly stated that careful application and rinsing are crucial to avoid adverse effects. Furthermore, it was understood that in patients exhibiting severe reactions, the application of the treatment to the eyes was inadequate or thorough rinsing procedures were not observed.

[0010] Lavyel 1960 described the use of Selsunef® ointment, a 0.5% SeS2 ointment manufactured by Abbott. In a clinical trial, Selsunef® was used on 80 subjects, and physicians applied the ointment gently and controlledly, removing it with a cotton swab after 30 minutes. Great care was always taken to prevent any ointment from entering the conjunctival sac. In cases where patients administered Selsunef® to themselves against their physician's advice, fairly severe keratitis developed immediately. [Overview of the Initiative]

[0011] Another common eye disease associated with blepharitis is meibomian gland dysfunction (MGD), in which the patient's meibomian glands do not produce enough meibum, which is normally necessary to prevent dryness of the eye. Meibum is an oily substance mainly composed of lipids that helps maintain the tear film by preventing the evaporation or retention of tears. In MGD, obstruction of the meibomian glands prevents meibomian gland secretion, leading to dry eye, pain, and blepharitis in many patients. To alleviate meibomian gland obstruction and restore lipid production (e.g., meibum production), ophthalmic preparations of SeS2 may be applied to the eyelids, eyelid margins, ocular surface, or surrounding tissues. Described herein are methods of use of ophthalmic preparations containing SeS2, particularly in which side effects such as keratitis are reduced or eliminated. In some cases, administration may be performed at home by the patient (e.g., over a long period) (e.g., daily, or less frequently if appropriate) on the eyelid or eyelid margin.

[0012] Adverse effects (e.g., pain, local irritation, inflammation, redness, keratosis, etc.) have been observed with intraocular or periocular application of SeS2, particularly when high concentrations of SeS2 are used. In some cases, administration of therapeutically effective concentrations of SeS2 (e.g., to the eyelid margin) has been found to provide therapeutic benefits while minimizing adverse effects. Furthermore, reducing exposure to light (e.g., UV light) after administration of selenium disulfide compositions has been found to further reduce the occurrence of side effects in ophthalmic applications (e.g., methods including administration to the eyelid margin of an individual).

[0013] Some embodiments provided herein are methods for treating diseases or disorders in or around the eye of an individual. In some embodiments, the method involves administering a therapeutically effective amount of a pharmaceutical composition to the surface of the individual's eye, 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) to the individual, such as the eyelid margin of the individual in need. In some embodiments, the individual is instructed (e.g., via oral and / or written instructions) to limit, avoid, or restrict or avoid exposure to light after administration (e.g., at least at the site where the composition was administered, one eye, or both eyes).

[0014] In some embodiments, restricting or avoiding exposure to light after administration of the composition reduces keratitis (e.g., its incidence and / or rate) in or around the eye (compared to administration without restricting or avoiding light exposure). In some examples, keratitis is associated with photosensitivity. In some embodiments, exposure to light is restricted or avoided for any appropriate time, such as at least 30 minutes. In some embodiments, exposure to light is restricted or avoided for at least 60 minutes. In some embodiments, exposure to light is restricted 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. Therefore, in some embodiments, light is avoided for a longer period than when a composition with lower concentrations and / or smaller amounts of the active substance is administered.

[0015] In some embodiments, the composition is administered to the eyelid margin of the individual. In some 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 lighting conditions, for example, to avoid undesirable administration of the composition to the ocular surface.

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

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

[0018] In some embodiments, individuals are instructed to limit, avoid, or limit or avoid exposure to light after administration by being administered the composition at a specific time, or being instructed to administer it. In some embodiments, the specific time is later than about one 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 one hour, within 30 minutes, etc.).

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

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

[0021] In some embodiments, limiting exposure to light includes limiting exposure to light of at least certain wavelengths. In some embodiments, limiting exposure to light includes limiting exposure to ultraviolet (UV) light. In some embodiments, limiting exposure to light includes 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 (for example, at least in the place where the pharmaceutical composition is administered).

[0022] In some embodiments, the disease or disorder of the eye or surrounding area is meibomian gland dysfunction (MGD), blepharitis, seborrheic blepharitis, Demodex mite infection, dry eye syndrome, hyperkeratosis, dermatitis, keratitis, contact lens discomfort, lid wiper epitheliopathy (LWE), keratoconjunctivitis sicca, Sjögren's syndrome, or ocular rosacea. In some embodiments, the disease or disorder of the eye or surrounding area is blepharitis or seborrheic blepharitis.

[0023] In some embodiments, the composition contains 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 an amount of less than 25 μL. In some embodiments, the composition is administered in an amount 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 semi-solid (e.g., gel, cream, paste), strip, emulsion, suspension, foam, lotion, spray, patch, implantable tablet (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, the exposure of the site to light to the administered composition is sufficiently low, so that keratitis (e.g., of the surface of the individual's eye) is reduced or avoided. In some embodiments, the concentration can be further reduced to support more light exposure while minimizing the risk of phototoxicity. In some embodiments, the permissible amount of light exposure and the period of light exposure avoidance correlate with the dose and concentration of SeS2 administered.

[0025] One embodiment provided herein is a method for treating a disease or illness in or around the eye of an individual requiring treatment, comprising the step of protecting the ocular surface of the individual with a barrier. In certain embodiments, such a process further comprises the step of administering a therapeutically effective amount of a pharmaceutical composition to the ocular surface of the individual. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of selenium disulfide (SeS2). In some embodiments, protection of the ocular surface of the individual comprises administering an ointment or hyaluronic acid (HA) to the ocular surface (for example, this administration forms a barrier through the interaction of hyaluronic acid (HA) and 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 includes administering an additive molecule to the ocular surface (e.g., before and / or simultaneously with the administration of a pharmaceutical composition), the additive molecule including a molecule configured to capture free radicals or photosensitive SeS2. In some embodiments, the free radicals are reactive oxygen species (ROS). In some embodiments, the additive molecule includes 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, the step of administering a pharmaceutical composition to an individual's ocular surface, surrounding ocular tissue, or a combination thereof in a therapeutically effective amount includes applying the pharmaceutical composition with a finger. The finger can be the individual's finger.

[0029] Selenium-containing shampoos are widely commercially available and no or few adverse effects are observed. It is surprising that adverse effects such as photosensitivity are prevalent in ophthalmic applications as described herein. In some examples, such morbidity in adverse effects is due to an increase in exposure period (e.g., shortening of the shampoo), 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 a composition and a method of administering the composition that is not a shampoo.

[0030] Further aspects and advantages of the Disclosure will be readily apparent to those skilled in the art from the detailed description below; therefore, only exemplary embodiments of the Disclosure are shown and described. As will be understood, the Disclosure may also be possible in other embodiments and different embodiments, and their various details may be modified in various obvious ways without all departing from the Disclosure. Accordingly, the drawings and description are intended to be illustrative and not restrictive. [Brief explanation of the drawing]

[0031] Novel features of the present invention are described in particular in the appended claims. The features and advantages of the present invention will be better understood by referring to the following detailed description illustrating exemplary embodiments in which the principles of the present invention are used, and to the following appended drawings (also referred to herein as "Figures and FIG."). [Figure 1] Figure 1 illustrates a flowchart showing the mechanism by which light interacts with photosensitive chemicals and can cause phototoxicity in individuals in contact with the photosensitive chemicals. [Modes for carrying out the invention]

[0032] definition The terms used herein are intended to describe specific examples 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 otherwise expressly indicates. Furthermore, the terms “including,” “includes,” “having,” “has,” and “with,” or their variations thereof, are intended to be comprehensive in a manner similar to the term “comprising,” to the extent that they are used in the detailed description and / or in any of the claims.

[0033] The terms “about” or “approximately” mean that a particular value is within an acceptable margin of error as determined by those skilled in the art, which in part depends on how that value is measured or determined, for example, on the limitations of the measuring system. For example, “about” could mean a standard deviation of 1 or more for any given value. Where a particular value is described in this application and claims, unless otherwise specified, the term “about” should be assumed to mean an acceptable margin of error for that particular value.

[0034] The terms “individual,” “patient,” or “subject” are used interchangeably. No term requires, or is limited to, a condition characterized by supervision (e.g., continuous or intermittent) of a healthcare professional (e.g., physician, registered nurse, nurse practitioner, physician’s assistant, janitor, or hospice staff).

[0035] As used herein, the terms “comprise” or its variations “comprises” or “comprising” indicate that any detailed feature is included, but not that any other feature is excluded. Therefore, as used herein, the term “comprising” is comprehensive and does not exclude any additional, undetailed features. In some embodiments of any of the compositions and methods provided herein, “comprises” may be replaced with “consisting essentially of” or “consisting of.” The phrase “consisting essentially of” is used herein to require a specified feature or a feature that does not substantially affect the features or functions of the disclosure. As used herein, the term “consisting of” is used to indicate the presence of only the detailed features.

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

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

[0038] In some embodiments, the light avoided according to any method provided herein is light that may cause phototoxicity and / or other adverse effects when combined with a therapeutic administration of the compositions provided herein in or around the eye. 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 includes infrared, visible, ultraviolet, certain wavelengths thereof, and / or combinations thereof. In certain embodiments, the light includes visible light and / or ultraviolet light. In some embodiments, the light includes visible light. In some embodiments, the light includes ultraviolet light. In some embodiments, the ultraviolet light includes both UVA and UVB light. In some embodiments, the light includes either UVA or UVB light. In some embodiments, the light is sunlight. In some embodiments, the light is not sunlight.

[0039] In some embodiments, methods provided herein offer treatments including the reduction (e.g., incidence or incidence) or elimination of photosensitive reactions (e.g., adverse effects resulting from a combination of light and therapeutic administration of the compositions provided herein), or photosensitivity (as described herein is used interchangeably). In some examples, such adverse effects refer to adverse physiological reactions such as keratitis, inflammation, pain, irritation, flaking, redness, discoloration, or any combination thereof, in non-limiting examples. In some examples, such adverse effects refer to grittiness, foreign body sensation in the eye of an individual, blurred vision, redness, tired eyes, symptoms of dry eye disorder, stinging, lacrimation, irritation, eyelid abnormalities, corneal abrasion, keratitis, photophobia, staining, or any combination thereof. Photoreactive chemicals may cause photosensitivity in individuals in contact with such photoreactive chemicals through direct or indirect mechanisms, such as those described in Figure 1. Photosensitivity includes phototoxic and photoallergic effects.

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

[0041] The indirect mode of phototoxicity (040) is facilitated by oxygen (055), and the 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 oxidation of various molecules, including drugs and DNA (070). After oxidation, the newly transformed molecule (070) can exert physiological effects in an individual 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) may 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., photo-bond) endogenous molecules (090), including but not limited to small molecules, peptides, proteins, and nucleic acids. Photo-binding 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 of SeS2 interacting with light, patients are instructed to avoid exposure of the ocular surface and surrounding tissues to light after application. The time for avoiding light may be determined based on the dose and concentration applied. Measures to avoid light exposure may include: (1) application at bedtime, after which the subject remains in bed without light exposure; (2) daytime application, such that the individual remains in a dim or dark environment after the procedure; and (3) wearing protective headwear or eyewear (e.g., dark sunglasses or UV-blocking sunglasses) to protect the treatment site from light.

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

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

[0046] In some embodiments, the pharmaceutical composition is administered in an amount less than 25 μL. In some embodiments, the pharmaceutical composition is administered in an amount 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 amount of the pharmaceutical composition, or the amount 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 amount 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 amounts are approximately 0.01 μL to 50 μL, approximately 0.1 μL to 30 μL, approximately 0.5 μL to 25 μL, approximately 1 μL to 25 μL, approximately 10 μL to 25 μL, or approximately 2.5 μL to 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, or about 10 mg, etc. In some embodiments, the therapeutically effective amount of SeS2 is about 4 mg.

[0048] In some embodiments, the composition is 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, eyelids, eyelid margins, eyelid wipers, meibomian glands, mucocutaneous margins, eyelashes, ciliary glands, ciliary vesicles, meibomian glands, eyelid borders, medial canthus, lacrimal papillae and puncta, 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 may be administered to an individual by a healthcare professional (e.g., a doctor, nurse, skilled medical technician, etc.). Alternatively and / or additionally, the composition may be administered to an individual by another individual or machine. In some embodiments, finger administration is preferred. In some examples, finger administration of the compositions provided herein results in improved therapeutic efficacy compared to administration using, for example, a swab.

[0051] In some cases, the composition is administered under favorable light conditions (e.g., under sunlight, under light having at least 50 lux, at least 100 lux, about 500 lux, or about 1,000 lux). In some cases, limiting or avoiding exposure to light after administration of the composition reduces photosensitivity-related 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%, and at least 90% compared to not limiting or avoiding exposure to light (e.g., the same individual with or without light exposure, or separate individuals with similar conditions with or without light exposure).

[0052] The duration for which exposure to light is limited or avoided may vary depending on the individual's illness, the dosage of the composition, the concentration of SeS2 in the composition, the individual's previous medical history, etc. In some examples, exposure to light 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., restricted, avoided, or instructed to be restricted) after administration of the composition may also vary depending on the individual's disease, the dose of the composition, the concentration of SeS2 in the composition, the individual's previous treatment history, etc. In some examples, the individual is restricted, avoided, or instructed to restrict or avoid any high-intensity light (e.g., more than about 100 lux, more than about 500 lux, or more than about 1,000 lux). In some examples, the individual is permitted to be exposed to low-light conditions (e.g., less than or equal to about 100 lux, less than or equal to about 50 lux, less than or equal to about 25 lux, etc.), or the site where the composition was administered is exposed to or maintained under low-light conditions. In some embodiments, for a period after administration of the compound, the site where the composition was administered is generally maintained under low-light conditions as described herein, or the individual is instructed to maintain the site where the composition was administered under low-light conditions. In some embodiments, the individual maintains the site where the composition was administered under low-light conditions. In some embodiments, the individual reads printed instructions to maintain the site where the composition was administered under low-light conditions. In some embodiments, printed instructions to maintain the site where the composition was administered are provided. In some embodiments, auditory instructions to maintain the site where the composition was administered are provided. In some embodiments, non-auditory instructions to maintain the site where the composition was administered are provided.

[0054] In some embodiments, low light conditions are characterized by the observer's physiological response to the light conditions. In some embodiments, low light conditions are characterized by wavelength, lux (lumens / m²). 2) or a combination thereof are characterized in relation to the above. In some embodiments, low light conditions are provided by nighttime. In some embodiments, low light conditions are provided by obstruction of sunlight. In some embodiments, low light conditions are provided by being indoors. In some embodiments, low light conditions are provided by naturally occurring conditions (e.g., overcast weather). In some embodiments, low light conditions are provided by the exclusion of a specific wavelength or range of wavelengths of light. In some embodiments, low light conditions are provided by a darkroom. In some embodiments, low light conditions are provided by the use of safelights.

[0055] In some embodiments, 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, 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 100 lux, about 250 lux, about 1000 lux, or more. In some embodiments, low light conditions include approximately 0.001 to approximately 1000 lux, approximately 0.001 to approximately 250 lux, approximately 0.001 to approximately 100 lux, approximately 0.01 to approximately 1000 lux, approximately 0.01 to approximately 250 lux, approximately 0.01 to approximately 100 lux, approximately 0.1 to approximately 1000 lux, approximately 0.1 to approximately 250 lux, approximately 0.1 to approximately 100 lux, and approximately 1 to The ranges are approximately 1000 lux, 1 to 200 lux, 1 to 100 lux, 10 to 1000 lux, 10 to 200 lux, 10 to 100 lux, 25 to 1000 lux, 25 to 250 lux, 25 to 100 lux, 50 to 1000 lux, 50 to 250 lux, or 50 to 100 lux.

[0056] In some embodiments, the individual is instructed to limit, avoid, or limit or avoid post-administration light exposure by, for example, directly or indirectly, by, at least partially blocking or instructing to block some or all of the light from one or more or any light source (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 post-administration light exposure to the site and surrounding tissues where the composition was administered during and / or after administration by, for example, by, at least partially blocking or instructing to block post-administration light exposure.

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

[0058] In some embodiments, individuals are instructed to limit, avoid, or limit / avoid exposure to light after administration by being administered the composition at a specific time, or being instructed to administer it at a specific time. In some embodiments, the specific time is later than about one hour before sunset. In some embodiments, the specific time is later than about two hours before sunset. In some embodiments, the specific time is approximately later than sunset. In some embodiments, the specific time is later than about one hour after sunset. In some embodiments, the specific time is later than about two hours after sunset. In some embodiments, the specific time is after sunset (nighttime). In some embodiments, the specific time is at least about one hour before bedtime. In some embodiments, the specific time is less than about one hour before bedtime. In some embodiments, the specific time is less than 30 minutes before bedtime. In some embodiments, administration takes place at night. In some embodiments, nighttime administration is after 4:00 p.m., after 5:00 p.m., after 6:00 p.m., etc.

[0059] In some embodiments, blocking light is achieved by wearing headwear and / or eyewear that blocks light at least partially. In some embodiments, blocking light is achieved by wearing headwear and / or eyewear that blocks light completely. In some embodiments, blocking light is achieved by wearing headwear or eyewear that blocks at least partially certain 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 blocks at least partially 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 brim or brim. In some embodiments, the headwear is a hat without a brim 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 includes one or more lenses. In some embodiments, the eyewear includes one or more polarized lenses. In some embodiments, the eyewear includes one or more reflective lenses. In some embodiments, the eyewear includes one or more shaded lenses. In some embodiments, the eyewear is a blindfold. In some embodiments, the eyewear includes natural fibers or synthetic fibers, or a combination thereof. In some embodiments, the eyewear includes a reflective surface. In some embodiments, the eyewear includes lenses or mirrors. In some embodiments, the eyewear includes fabric, polymers, plastics, metals, nonmetals, plant materials, plant-derived materials, synthetic materials, or any combination thereof.

[0062] In some embodiments, mitigation or avoidance of keratitis is achieved by combining two conditions: i) administering the composition in a sufficiently small amount (even at high concentrations), and ii) ensuring that the site of administration is sufficiently exposed to light after administration. In some examples, lower concentrations of SeS2 allow for higher light exposure with minimal or reduced risk of phototoxicity. In some embodiments, the acceptable amount of light exposure and the duration of light exposure avoidance correlate at least partially with the dose and / or concentration of the administered SeS2 composition.

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

[0064] In some examples, protection of the individual's ocular surface includes administration of ointments, polyvinyl alcohol (PVA) microemulsions, other micro or nanoemulsions of polymers, or liquid crystal forms of polymers that can function as a barrier. Alternatively, and / or additionally, protection of the individual's ocular surface includes administration of lipid or carbohydrate-based compounds that can cover 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, protection of the individual's ocular surface includes administration of hyaluronic acid (HA), or any suitable HA-containing compound that interacts with mucin on the individual's ocular surface and / or surrounding ocular tissue to form a barrier. Preferably, such a formed barrier prevents photosensitized SeS2 from coming into contact with the individual's ocular surface. Any suitable hyaluronic acid, hyaluronic acid polymer, or HA-containing compound suitable for application to the ocular surface is intended, but preferred hyaluronic acid or hyaluronic acid polymer has a content 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, and at least 140 This includes molecules having molecular weights 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 700-3500 kDa, 700-3000 kDa, 700-2500 kDa, 700-2000 kDa, 700-1500 kDa, 700-1300 kDa, or 700-1200 kDa.

[0065] In some examples, protection of the ocular surface involves administering an additive molecule to the ocular surface as a barrier. The additive molecule is configured and suitable, or capable of capturing free radicals or photosensitized SeS2, so that the captured 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, captures 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 includes one or more of the following: phenolic compounds, vitamin E, vitamin C, carotene, ferritin, ceruloplasmin, selenium, reduced glutathione (GSH), manganese, ubiquinone, zinc, flavonoids, coenzyme Q, melatonin, bilirubin, taurine, or cysteine. In some embodiments, the additive molecule is prepared in any suitable form (e.g., gel, hydrogel, ointment, cream, lotion, foam, spray, patch, implantable tablet (e.g., sustained-release, biodegradable, semi-degradable, or non-degradable), lipid system (e.g., solid lipid nano / microparticles, liposomes, exosomes, micelles, micro / nanoemulsions, cubosomes, cochleates, niosomes, lipospheres), silica system (e.g., mesoporous), polymer system, nano and / or microspheres, nano and / or microcapsules, nano and / or microparticles, etc.) with a suitable excipient (e.g., buffer) for application to the ocular surface of an individual before 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 so that the additive molecule can be applied to the ocular surface simultaneously with the SeS2-containing pharmaceutical composition.

[0066] In some cases, 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., those produced from the photoreaction of SeS2). The size of the contact lens or other type of transparent or opaque layer varies depending on the area to be protected. 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] A process that protects the ocular surface of an individual with a barrier from photosensitized SeS2 or other reactive oxygen species allows the administration of a SeS2-containing pharmaceutical composition under good or high light conditions (e.g., under sunlight with at least 50 lux, or at least 100 lux, or at least 500 lux, or at least 1,000 lux) by preventing or mitigating the adverse effects of photosensitized SeS2 or phototoxicity from other reactive oxygen species during administration of the SeS2-containing pharmaceutical composition. 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 exposure to light after administration. [Examples]

[0068] Example 1 In vivo rabbit study on preparations containing SeS2. In preclinical studies conducted in rabbits, low doses of SeS2 at concentrations up to 2.5% by weight (approximately 4 mg) 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 the treated individuals. When the dose was increased to approximately 20 mg, keratitis was observed in the subjects. These findings suggest that keratitis and associated SeS2 treatment side effects may depend not only on the concentration of SeS2 but also on the total dose administered.

[0069] Example 2 The clinical study used three different concentrations: 0.1 wt% (10 subjects), 0.5 wt% (12 subjects), and 1 wt% (26 subjects). Most subjects received bi-weekly applications, while some patients transitioned to daily applications based on pre-specified protocol criteria. Of the subjects participating in the study, four developed keratitis, keratitis-related symptoms, or keratitis-related symptoms. All four subjects were treated with a 1 wt% concentration. In one case, the patient was treated for one month and improved according to several ophthalmic health indicators, but developed keratitis after a one-month visit. During the one-month visit, the patient received the drug in the morning as part of an in-hospital assessment. Approximately seven hours later, the patient began experiencing significant pain. At the examination the following morning, the patient showed a band of corneal staining in the palpebral fissure and was diagnosed with keratitis. The patient experienced no adverse events during the first month while taking the medication twice a week (at home, before bedtime), and showed significant improvements in the Total Ocular Surface Disease Index (OSDI), Visual Analog Scale (VAS), and Standard Patient Assessment of Dry Eyes (SPEED). After the resolution of keratitis, the patient continued taking the medication at bedtime and did not experience any further episodes of keratitis.

[0070] A remarkable incidence was observed in patients who improved without adverse effects while applying the drug at home, only to develop keratitis several hours after application at the clinic. This pattern of recurrence suggested a toxic reaction following daytime application of SeS2 in the hospital. Three more patients reported the onset of pain between 6 and 20 hours after application, indicating that this indeed follows a pattern of toxic reaction. Two of the patients developed keratitis after a single daytime application in the hospital—the first application on the first day of the study. The last subject developed keratitis after an in-hospital application on day 14 of the study. This last subject, like the first patient, applied the treatment at home every other week without adverse effects.

[0071] The suggestion that SeS2 reacts with light to induce a photosensitive reaction was supported by the following factors: (1) consistent development of keratitis after daytime application in the hospital, (2) more than 400 applications of 1 wt% SeS2 at bedtime without any development of keratitis, and (3) the time interval between daytime application of 1 wt% SeS2 ointment and the onset of symptoms of keratitis. Daytime applications of 0.1 wt% and 0.5 wt% in the hospital were also performed in 9 and 7 patients, respectively, without development of keratitis, and keratitis developed in rabbits at a high dose of approximately 20 mg but not at a low dose of approximately 4 mg, suggesting that this phenomenon is related to both dose and concentration.

[0072] The duration for which the drug product could be visualized on the eye was also tested. After 5 hours, it was concluded that the drug product was clearly not present.

[0073] SeS2 (2.5 wt%) may cause contact dermatitis due to its irritant effects. As a treatment for tinea versicolor, Giordano once applied SeS2 overnight (e.g., at night or before bedtime for overnight effect) not due to concerns about sun exposure, but to allow its prolonged exposure to the skin. Robinson and Yaffe used SeS2 cream (1 wt%) 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 to remove the SeS2 cream was recommended. None of the investigators encountered a single case of either contact dermatitis or photocontact dermatitis, and there is no mention of the potential phototoxic effects of SeS2. In some cases, at low concentrations of SeS2, e.g., about 0.1 wt% to 2.5 wt% (e.g., 0.5 wt%), overnight application is important.

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

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

[0076] In some cases, certain concentration levels of SeS2 can disrupt the balance between protective and sensitizing effects. In some cases, high levels of insoluble selenium can cause phototoxicity due to elevated levels of glutathione or other proteins, inducing oxidative imbalance and cytotoxicity. This cellular toxicity and oxidative imbalance may 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. These were two or three further cases of adverse effects. Of these subjects, two developed keratitis after the first in-hospital application, and another patient's condition worsened after the second in-hospital application, although the subjects continued with one or two more doses at home before experiencing pain requiring examination (a typical scenario of progressing keratitis).

[0078] Example 4 Human studies of modified compounds containing SeS2. One of three concentrations of SeS2 (0.1 wt%, 0.5 wt%, and 1 wt%) 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-administered). In most cases, the treatment will be applied every other week, but some patients will transition to daily application based on pre-specified protocol criteria. Because the ointment-based composition is known to mix with tears and cause blurred vision, individuals in this study will be encouraged to apply the treatment before bedtime to avoid risks associated with vision loss. Additional components of the study require individuals to apply the ointment in the presence of an ophthalmologist to demonstrate appropriate self-administration techniques consistent with the designed study. In-hospital applications will be performed at specific, pre-determined times. In these cases, the treatment will not be applied before bedtime but during daytime hours.

[0079] Keratitis is not observed in any patient treated with either 0.1% wt or 0.5% wt concentrations. However, four patients in the 1% wt concentration cohort report symptoms of keratitis. It should be noted that all four patients reporting symptoms of keratitis do so in accordance with prescribed in-hospital evaluations, while none of the more than 400 applications of the nighttime treatment cause keratitis. Prior to the in-hospital evaluation after the onset of keratitis, at least one patient demonstrates improved health outcomes after one month of treatment, as measured by the Total Ocular Surface Disease Index (OSDI), Visual Analog Scale (VAS), and Standard Patient Assessment of Dry Eyes (SPEED). However, within seven hours of the in-hospital evaluation, the patient complains of significant pain near the treatment site. Subsequent fluorescein corneal staining indicates keratitis, observed as a band across the palpebral fissure.

[0080] At least three other individuals exhibited symptoms of keratitis following a pattern consistent with the first individual described. All four reported that pain began 6–20 hours into the in-hospital assessment, i.e., during the application of a 1 wt% concentration of SeS2. This pattern of occurrence suggests a correlation between the onset of keratitis and both the circumstances under which the treatment was administered and the concentration of the treatment administered.

[0081] Determining the duration for which the treatment is clearly in effect. The duration for which the drug was clearly present in or near the individual's eye was evaluated. The researchers concluded that the drug was clearly no longer 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 benefit of administering the drug only at night. In the first trial, patients were instructed to administer the drug both in the evening, between visits, and during the day during regular scheduled clinic visits, as part of the study protocol. Study patients received a two-week infusion with placebo administered twice weekly for two weeks. Upon meeting the inclusion / exclusion criteria, patients were randomized to receive either SeS2 ointment / semi-solid drug (i.e., 0.1%, 0.5%, or 1.0%) or placebo in a dose regimen that included either twice-weekly administration for three months or once-daily administration for three months.

[0083] In the second trial, which was largely the same as the first trial, all daytime visits were eliminated, and ointment / semi-solid SeS2 (e.g., 0.5%) was administered twice a week in the evening at bedtime for three months. Compared to the first trial, the second trial (nocturnal administration only) showed a significant reduction in ocular adverse events (a 75% reduction in the incidence of adverse events). Adverse events included grittiness, foreign body sensation, stinging, blurred vision, redness, tired eyes, watery eyes, irritation, eyelid abnormalities, burns, corneal abrasions, photophobia, discoloration, or dry eye disorders (DED). Adverse events mainly consisted of tolerability-related events such as burning and stinging after application.

[0084] The rates of ocular adverse events (ocular AEs) and discontinuation due to more significant adverse events (DCs for AEs, primarily related to ocular tolerance) appear to decrease by at least 50% when medication is permitted only in the evening rather than in the morning.

[0085] Example 6 In studies testing the efficacy of SeS2 in patients with meibomian gland dysfunction (MGD), subjects were permitted to apply the ointment to the eyelid margin using either their finger or a cotton swab applicator.

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

[0087] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. The present invention is not intended to be limited by any specific examples provided herein. Although the present invention is described in relation to the foregoing specification, the descriptions and examples of embodiments herein are not intended to be constrained. Those skilled in the art will be able to conceive of many modifications, variations, and substitutions without departing from the present invention. Furthermore, it will be understood that all aspects of the present invention are not limited to any specific descriptions, configurations, or relative proportions described herein, depending on various conditions and variables. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in the practice of the present invention. Therefore, the present invention is also intended to extend to any such alternatives, modifications, variations, or equivalents. The following claims define the scope of the present invention, and it is intended that methods and structures within the scope of these claims and their equivalents are thereby encompassed.

Claims

1. A method for treating a disease or disorder in or around the eye of an individual, the method being The process includes administering a therapeutically effective amount of a pharmaceutical composition to the surface of an individual's eye, the surrounding eye tissue, or a combination thereof. Here, the pharmaceutical composition is a therapeutically effective amount of selenium disulfide (SeS ２ ) including, and a method in which the individual is instructed to limit or avoid exposure to light after administration, or to limit or avoid exposure to light after administration.

2. The method according to claim 1, wherein limiting or avoiding exposure to light after administration of the pharmaceutical composition reduces keratitis associated with photosensitivity.

3. The method according to any one of claims 1 to 2, wherein exposure to light is limited to or avoided for at least 30 minutes.

4. The method according to any one of claims 1 to 3, wherein exposure to light is limited to or avoided for at least 60 minutes.

5. The method according to any one of claims 1 to 4, wherein exposure to light is limited to or avoided for at least six hours.

6. The method according to any one of claims 1 to 5, wherein the pharmaceutical composition is administered under favorable light conditions.

7. The method according to any one of claims 1 to 6, wherein for a certain period after administration of the pharmaceutical composition, the site to which the pharmaceutical composition was administered is generally maintained under low light conditions, or the individual is instructed to maintain the site to which the pharmaceutical composition was administered under low light conditions.

8. The method according to any one of claims 1 to 7, wherein the low light conditions are approximately 100 lux or less, approximately 50 lux or less, or approximately 25 lux or less.

9. The method according to any one of claims 1 to 8, wherein for a certain period after administration of the pharmaceutical composition, the site to which the pharmaceutical composition was administered is generally not exposed to high light conditions, or the individual is instructed to limit or avoid exposure of the site to which the pharmaceutical composition was administered to high light conditions.

10. The method according to any one of claims 1 to 9, wherein the high light intensity condition is approximately 100 lux or more, approximately 500 lux or more, or approximately 1000 lux or more.

11. The method according to any one of claims 1 to 10, wherein the individual is instructed to limit or avoid exposure to light after administration by administering the pharmaceutical composition at a specific time, or by being instructed to administer the pharmaceutical composition at a specific time.

12. The method according to claim 11, wherein the aforementioned specific time is later than approximately one hour before sunset.

13. The method according to claim 12, wherein the specified time is after sunset.

14. The method according to claim 11, wherein the aforementioned specific time is before going to bed.

15. The method according to any one of claims 1 to 14, wherein the individual is instructed to limit or avoid post-administration light exposure, or to limit or avoid it, by blocking or being instructed to block some or all light from the site where the pharmaceutical composition is administered, during or after administration.

16. The method according to claim 15, wherein blocking light is achieved by wearing headwear or eyewear that blocks light at least partially.

17. The method according to claim 16, wherein the headwear is a hat.

18. The method according to claim 15, wherein the eyewear is sunglasses or goggles.

19. The method according to any one of claims 1 to 18, wherein the individual self-administers the pharmaceutical composition.

20. The method according to any one of claims 1 to 19, wherein limiting exposure to the light includes limiting exposure to at least some wavelengths of the light.

21. The method according to claim 20, wherein limiting exposure to the aforementioned light includes limiting exposure to ultraviolet (UV) light.

22. The method according to any one of claims 1 to 21, wherein limiting exposure to light includes limiting exposure to sunlight.

23. The method according to any one of claims 1 to 22, wherein the individual is instructed to remain indoors.

24. The method according to any one of claims 1 to 23, wherein the individual is instructed to avoid sunlight or ultraviolet (UV) light.

25. The method according to any one of claims 1 to 24, wherein the disease or disorder in or around the eye is meibomian gland dysfunction (MGD), blepharitis, seborrheic blepharitis, Demodex mite infection, dry eye syndrome, hyperkeratosis, dermatitis, keratitis, contact lens discomfort, lid wiper conjunctival epitheliopathy (LWE), keratoconjunctivitis sicca, Sjögren's syndrome, or rosacea.

26. The method according to any one of claims 1 to 25, wherein the disease or disorder in or around the eye is blepharitis or seborrheic blepharitis.

27. The method according to any one of claims 1 to 26, wherein the pharmaceutical composition contains selenium disulfide at a therapeutically effective concentration.

28. The method according to claim 27, wherein the therapeutically effective concentration is approximately 0.1% by weight to approximately 10% by weight.

29. The method according to any one of claims 1 to 28, wherein the pharmaceutical composition is administered in an amount of less than 25 μL.

30. The method according to any one of claims 1 to 29, wherein the pharmaceutical composition is administered in an amount of about 1 μL to about 20 μL.

31. The method according to any one of claims 1 to 30, wherein the pharmaceutical composition is semi-solid.

32. The method according to claim 31, wherein the semi-solid is an ointment, gel, cream, or paste.

33. The method according to any one of claims 1 to 32, wherein (i) the pharmaceutical composition is administered in a sufficiently low volume, and (ii) exposure of the site to light after administration of the pharmaceutical composition is sufficiently low so that keratitis is reduced or avoided.

34. The method according to any one of claims 1 to 33, wherein the concentration can be further reduced to minimize the risk of phototoxicity and support greater light exposure.

35. The permissible amount of light exposure and the period of light exposure avoidance depend on the administered SeS ２ The method according to any one of claims 1 to 34, which correlates with the dose and concentration of the substance.

36. A method for treating a disease or disorder in or around the eye of an individual, the method being A step of protecting the eye surface of the individual with a barrier, The process includes administering a therapeutically effective amount of a pharmaceutical composition to the surface of the eye of the individual, wherein the pharmaceutical composition is a therapeutically effective amount of selenium disulfide (SeS ２ Methods including )

37. The method according to claim 36, wherein protection of the ocular surface of the individual comprises administering hyaluronic acid (HA) to the ocular surface (for example, by the interaction of hyaluronic acid (HA) and mucin on the ocular surface to form a barrier).

38. The method according to claim 37, wherein the hyaluronic acid (HA) has a molecular weight of at least 900 kDa.

39. The step of protecting the eye surface of the individual involves free radicals or photosensitive SeS ２ The method according to claim 36, comprising administering an additive molecule that can capture or is suitable for capturing.

40. The method according to claim 39, wherein the free radical is a reactive oxygen species (ROS).

41. The method according to any one of claims 39 to 40, wherein the additive comprises a phenol compound, vitamin E, vitamin C, carotene, ferritin, ceruloplasmin, selenium, reduced glutathione (GSH), manganese, ubiquinone, zinc, flavonoid, coenzyme Q, melatonin, bilirubin, taurine, or cysteine.

42. The method according to claim 36, wherein the barrier is a contact lens.

43. The barrier is SeS ２ The method according to any one of claims 36 to 42, which prevents contact with the eye surface.

44. The method according to any one of claims 1 to 43, wherein the step of administering a therapeutically effective amount of the pharmaceutical composition to the eye surface of the individual, the surrounding eye tissue, or a combination thereof, includes applying the pharmaceutical composition with a finger.

45. The method according to claim 44, wherein the finger is the finger of the individual.

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