Topical formulations for reducing skin inflammation or redness

Abstract

Disclosed are topical compositions comprising a beta-alanine and a transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) agonist, such as menthol. Also disclosed are methods of reducing skin inflammation or redness in a subject, and methods of reducing the frequency or duration of an inflammatory skin disease, such as rosacea, symptom.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 316,158, filed on March 3, 2022, which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to cosmetics, and more particularly to topical compositions and their use for reducing skin inflammation or redness. Background Art

[0004] Dermal mast cells are skin-resident immune cells that rapidly respond to allergens by releasing granules containing inflammatory mediators such as histamine and serotonin. While mast cells play an important role in both adaptive and innate immunity, many inflammatory skin diseases are associated with mast cell activation, including rosacea, urticaria, mastocytosis, allergies, dermatitis, acne, psoriasis, and scleroderma. Mast cell activation is also thought to be a cause of other skin diseases, such as chronic flushing (e.g., alcohol-induced flushing, or flushing due to emotional reactions), and is associated with wound healing. Skin inflammation and / or redness, particularly of the facial skin, can be embarrassing and painful for the affected individual. Inflammatory skin diseases are also often chronic and incurable, requiring long-term treatment. Therefore, there is a need for topical compositions suitable for daily use that can reduce redness or inflammation. Summary of the invention

[0005] Disclosed herein are topical compositions comprising an effective amount of β-alanine and an effective amount of a transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) agonist. In some embodiments, the topical composition comprises about 0.2% to about 15% weight ratio (w / w) of β-alanine, for example, about 1% to about 10% w / w of β-alanine, or about 2.5% to about 7.5% w / w of β-alanine. In some examples, the effective amount is about 5% w / w of β-alanine. In some embodiments, the TRPM8 agonist is menthol. In some embodiments, the topical composition comprises about 0.1% to about 5% w / w of menthol, for example, about 0.1% to about 2% w / w of menthol, or about 0.5% to about 1.5% w / w of menthol. In some examples, the topical composition comprises about 0.5% w / w of menthol. The topical composition may include additional agents, such as topical UV protectants, antibiotics, steroids, nonsteroidal anti-inflammatory agents, calcineurin inhibitors, JAK inhibitors, α2-adrenergic receptor agonists, α1A-adrenergic receptor agonists, or combinations thereof. In some embodiments, the topical composition does not contain an anesthetic or topical steroid. The topical composition may be formulated into any form suitable for topical application, such as an ointment, cream, gel, lotion, shampoo, or soap. In some instances, the topical composition is formulated as an emollient or moisturizer, and / or is formulated for facial application.

[0006] Also disclosed herein is a method for reducing skin inflammation or redness, comprising applying an effective amount of a topical composition described herein to an area of ​​the subject's skin affected by inflammation or redness. In some embodiments, the skin area is affected by inflammatory skin diseases, chronic flushing or wounds. In some embodiments, the method includes selecting a subject suffering from inflammatory skin diseases, chronic flushing or wounds. Also disclosed herein is a method for reducing the frequency, duration or severity of the subject's rosacea symptoms. The method includes selecting a subject suffering from rosacea and applying the topical composition described herein to the skin area affected by rosacea. In some instances, the subject suffers from erythematotelangiectatic rosacea, papulopustular rosacea and / or lumpy rosacea. In some embodiments, the topical composition is repeatedly applied, for example, for a long time in the subject's days, weeks, months or even the rest of his life. In some embodiments, the topical composition is applied several times a week (e.g., about 3, 4, 5 or 6 times a week), once a day or twice a day. In some examples, the method further comprises administering a topical UV protectant, an antibiotic, a steroid, a nonsteroidal anti-inflammatory agent, a calcineurin inhibitor, a JAK inhibitor, an analgesic, an α2-adrenergic receptor agonist, an α1A-adrenergic receptor agonist, or a combination thereof before, after, or substantially simultaneously with the application of the topical composition.

[0007] The above and other objects, features and advantages of the present invention will become more apparent from the following detailed description with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 The itch scores reported by the patients subjectively after applying a cream containing the indicated concentrations of β-alanine to the face are shown. The doctor applied four β-alanine formulations (0%, 2.5%, 5.0% and 7.5% w / w β-alanine) to different locations on the cheek skin of each patient in sequence. Subjective itch scores (0 (no itch) to 10 (maximum itch)) were recorded within 5 minutes. The symbols on the bar graph represent individual patients (n=16). The bar height represents the mean. The error bars represent + / -SEM. **P<0.01; ****P<0.0001. P values ​​were calculated using the non-parametric ANOVA Kruskai-Wallis test.

[0009] Figure 2A and 2B The itch ( Figure 2A ) and overall discomfort ( Figure 2B ) score. The doctor applied each of the four preparations (0%, 0.5%, 1.0% and 1.5% w / w menthol with 5% w / w β-alanine) to different locations on the patient's cheek skin in sequence. The score ranges from 0 to 10, with 0 indicating no itching or discomfort and 10 indicating the most severe itching or discomfort. Each symbol represents an independent patient (n=10). The height of the bar represents the mean. The error bars represent + / -SEM. *P<0.05; **P<0.01. P values ​​were calculated using the nonparametric ANOVA Kruskai-Wallis test. DETAILED DESCRIPTION

[0010] β-alanine can inhibit mast cell activation, but topical use of β-alanine is limited by the pruritus (itching) that occurs after use. The pruritus induced by topical β-alanine creams is transient, so combining with an agent that can mask the pruritus caused by β-alanine for a short period of time may improve the tolerability of topical β-alanine compositions.

[0011] While many compounds are reported to “suppress itch” when applied topically, most are not suitable for long-term use and carry the risk of adverse side effects. For example, lidocaine and other related caine drugs, which are primarily used as anesthetics, can cause an unpleasant numbing sensation in the skin that lasts far longer than the approximately 3 minutes required to suppress β-alanine-induced itch. In addition, lidocaine and other related caine drugs may also have a slower onset of action than β-alanine-induced itch and thus may not be as effective in reducing itch. Systemic absorption of these drugs also carries the risk of CNS and cardiac toxicity, especially in patients with liver disease, and therefore are not suitable for long-term use. Similarly, camphor, which is primarily used as an anesthetic, can also produce adverse side effects after systemic absorption.

[0012] Low-potency topical steroids can also be used to suppress pruritus, but their onset of action may be too slow to provide benefit in masking beta-alanine-induced pruritus. In addition, the use of topical steroids on the face may induce acne, exacerbate rosacea, and carry the risk of developing striae and steroid addiction, especially with long-term use. Topical formulations of colloidal oatmeal and moisturizers improve barrier integrity and may reduce itch in settings with a defective barrier (eg, atopic dermatitis) but are unlikely to mask beta-alanine-induced pruritus.

[0013] The work disclosed herein sought to identify a compound that could mask the itch caused by beta-alanine but that was also well tolerated and suitable for long-term use.

[0014] the term

[0015] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. Unless the context clearly indicates otherwise, singular terms include plural referents. "Comprises A or B" means comprises A, or B, or A and B.

[0016] Suitable methods and materials are described below, however, methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure. In the event of a conflict, the present specification (including term explanations) shall prevail. In addition, the materials, methods, and examples are for illustrative purposes only and are not intended to be limiting.

[0017] To facilitate review of the various embodiments of the present disclosure, the following explanations of specific terms are provided:

[0018] About: Unless the context clearly indicates otherwise, "about" refers to a range of plus or minus 5% of the reference value. For example, "about 100 grams" means 95 grams to 105 grams. In another example, "about 5%" means 4.75% to 5.25%.

[0019] Acne: An inflammatory skin disease that can occur in the skin where sebaceous glands are connected to hair follicles. In healthy skin, sebaceous glands produce sebum, which is discharged to the skin's surface through pores (openings in the follicles). When someone has acne, the hair, sebum, and keratinocytes stick together inside the pores, preventing the sebum from reaching the skin's surface and the keratinocytes from falling off. The mixture of oils and cells allows bacteria to grow in the clogged follicles, causing inflammation. When the wall of the clogged follicle ruptures, the bacteria, skin cells, and sebum can spill into the nearby skin, forming a lesion or comedone.

[0020] Administration: Providing or giving an agent to a subject by any effective route. Administration includes topical application.

[0021] Agent: Any substance or compound that can be used to achieve a specific result. For example, an agent can be a topical composition that reduces redness or inflammation of the skin.

[0022] Analgesic: A drug that relieves pain. Non-limiting examples of topical analgesics include capsaicin, diclofenac, lidocaine, methyl salicylate, and triethanolamine salicylate.

[0023] Antibiotic: A compound or substance that kills or significantly slows the growth of bacteria, fungi, or other microorganisms. An “antibacterial agent” is a compound or substance that kills or significantly slows the growth of bacteria. An “antifungal agent” is a compound or substance that kills or significantly slows the growth of fungi.

[0024] β-Alanine: A non-essential β-amino acid (sometimes also called b-alanine). A β-amino acid is an amino acid in which the amino group is attached to the β-carbon (i.e., the carbon two atoms away from the carboxylic acid group). The IUPAC name for β-alanine is 3-aminopropionic acid. Purified β-alanine is commercially available, for example from Beyond Chemistry Labs TM Beta-alanine (GNCItem #369898); or beta-alanine (Sigma-Aldrich, #146064).

[0025] Control: Reference standard. The control can be any suitable positive or negative control. For illustrative purposes, several non-limiting control examples are provided. In one example, the control is a sample or measurement obtained from a subject before applying the disclosed topical composition. Another exemplary control is a subject to which a topical composition (empty vector) without β-alanine, a TRPM8 agonist, or both is applied, or a subject to which no topical composition is applied. In another example, a suitable control is a historical control or a standard reference value or range of values ​​(e.g., a previously obtained control sample or a sample group representing a baseline or "normal" value).

[0026] The difference between the test sample (e.g., applying the disclosed topical composition to a subject) and the control can be an increase or conversely a decrease. The difference can be qualitative (e.g., subjective observation) or quantitative (e.g., objective measurement). In some instances, the difference is statistically significant. In some instances, the increase relative to the control is at least about 5%, such as at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 500%, or greater than 500%. In some examples, the reduction relative to a control is at least about 5%, such as at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or about 100%.

[0027] Cosmetically acceptable vehicles: Many suitable cosmetically acceptable vehicles (carriers) (e.g., pharmaceutically acceptable carriers) have been described. For example, Remington: The Science and Practice of Pharmacy, 23rd Ed. (Academic Press), 2021 (ISBN 9780128200070), describes compositions and formulations suitable for delivering topical compositions. The use of the term "pharmaceutically acceptable carrier" does not mean that the product is only for pharmaceutical purposes. Instead, it means that the product is suitable for administration or consumption by a subject (e.g., a human). In a particular embodiment, the vehicle is a carrier for a topical composition, such as a liquid, gel, foam, cream, ointment, or lotion. Particularly useful vehicles are those that are cosmetically acceptable for topical application, such as one or more aqueous systems, glycerin, C 1-4 Alcohols, fatty alcohols, fatty ethers, fatty esters, polyols, glycols, vegetable oils, mineral oils, liposomes, lamellar lipid materials, silicone oils, water or combinations thereof.

[0028] The topical compositions disclosed herein can be formulated into any suitable product form. Such product forms include, but are not limited to, aerosol sprays, creams, dispersions, emulsions, foams, gels, liquids, lotions, mousses, ointments, patches, hair oils, powders, pump sprays, solids, solutions, sticks, towelettes, etc. The carrier can also be various existing skin lotions, gels, creams, ointments, toners, cleansers, moisturizers, or sunscreens, to which the disclosed topical compositions are added at the desired concentration.

[0029] Dermatitis: A general term for inflammation of the skin. It has many causes and forms. It often involves itching, dry skin, or a rash. In some cases, it can cause the skin to blister, ooze, crust, or peel. Three common types of dermatitis include atopic dermatitis, seborrheic dermatitis, and contact dermatitis. Atopic dermatitis is often referred to as eczema. Atopic dermatitis is often the result of a combination of factors, such as dry skin, environmental irritants, stress, hormonal changes, and bacteria on the skin. During a flare-up, patches of skin may appear rough, dry, and itchy. Seborrheic dermatitis (such as dandruff or cradle cap) most commonly occurs on the scalp, but can also occur on the face, chest, and around the eyes and ears. It often causes scaly patches, skin discoloration, and dandruff. Although the specific cause of seborrheic dermatitis is unknown, stress or lack of sleep can make the symptoms worse. Contact dermatitis occurs when a substance causes an adverse inflammatory reaction after contact with the skin. These reactions can develop into a rash that burns, stings, itches, or blister. Contact dermatitis can be the result of an allergic or irritant reaction. With irritant contact dermatitis, a foreign substance directly damages the skin and causes a reaction. With allergic contact dermatitis, a foreign substance may not directly damage the skin but causes the immune system to respond in a way that results in skin damage. Other types of dermatitis include hypoallergenic dermatitis, diaper dermatitis (diaper rash), pityriasis, neurodermatitis, nummular dermatitis, perioral / perioral dermatitis, stasis dermatitis, and dermatitis of neglect.

[0030] Dermatographia: An inflammatory skin disorder in which raised red bumps or localized hives appear on the skin when people scratch it. It can also occur when the skin is put under pressure or rubbed. This disorder is also called dermatographia, dermatographia, or dermatographia urticaria.

[0031] Effective amount: The amount of an agent (e.g., a topical composition) sufficient to obtain a desired result (e.g., reduce skin redness or inflammation). In some embodiments, the effective amount of the disclosed topical composition is an amount that reduces skin redness or inflammation or inhibits mast cell activation. In some embodiments, the effective amount of β-alanine is an amount that reduces skin redness or inflammation. In some examples, the effective amount of β-alanine inhibits mast cell activation. In some embodiments, the effective amount of a TRPM8 agonist is an amount that inhibits transient β-alanine-induced pruritus. The effective amount can be administered in a single dose or multiple doses (e.g., daily). However, the effective amount may depend on the subject, the subject's condition, and the mode of administration.

[0032] Excipient: An inactive substance used as a carrier for the active ingredient of a composition. Excipients may include substances used to increase the volume of the formulation of the active ingredient, facilitate and accurately administer the drug, stabilize the active ingredient, and make the delivery system visually and / or sensorially acceptable. Examples of cosmetically acceptable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc.

[0033] Extract: A solution or other preparation of at least some of the active ingredients of a plant or one or more parts thereof (such as roots, shoots, leaves, fruit or seeds). An extract may be a solvent extract, for example, when the plant or plant part is exposed to a liquid extraction solvent (e.g., water, alcohol, acetone, methylene chloride or chloroform) to remove the active ingredients. An extract originally obtained by solvent extraction can be converted to a dry form and still be considered an "extract".

[0034] Increase or decrease: a positive change or a negative change, respectively, relative to a control value. An increase is a positive change, such as an increase of at least 25%, at least 50%, at least 75%, at least 100%, at least 200%, at least 300%, at least 400%, or at least 500% compared to a control value. The increase can be in the range of, for example, 25% to 500%, 25% to 400%, 25% to 300%, 25% to 200%, 25% to 100%, 25% to 75%, 25% to 50%, 50% to 500%, 75% to 500%, 100% to 500%, 200% to 500%, 300% to 500%, 400% to 500%, 50% to 100%, 50% to 200%, 50% to 300%, 50% to 400%, 50% to 500%, 100% to 200%, 100% to 300%, 100% to 400%, 100% to 500%, or 250% to 500%.

[0035] A decrease is a negative change, e.g., a decrease of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% compared to a control value. The reduction can be in the range of, for example, 25% to 100%, 25% to 98%, 25% to 95%, 25% to 90%, 25% to 80%, 25% to 70%, 25% to 50%, 50% to 100%, 75% to 100%, 90% to 100%, 95% to 100%, 98% to 100%, 99% to 100%, 50% to 75%, 50% to 80%, 50% to 90%, 50% to 95%, 50% to 98%, 75% to 80%, 75% to 90%, 75% to 95%, or 75% to 98%.

[0036] Inflammation: A localized biological response that produces redness, swelling, and pain in response to a disruptive stimulus including infection, irritation, injury, or disease. Inflammation can be chronic or acute. Immune cells (such as dermal mast cells) initiate the inflammatory response and release inflammatory mediators (such as histamine, proinflammatory cytokines, or serotonin), resulting in increased blood flow and leakage of plasma fluid into the affected tissues.

[0037] Inflammatory skin disease: A skin disease associated with inflammation. Non-limiting examples include rosacea, acute or chronic urticaria, dermatographism, mastocytosis, dermatitis, acne, psoriasis, and scleroderma.

[0038] Mast cell: A resident inflammatory cell found in the dermis of the skin. Mast cell activation helps induce inflammation through the rapid release of various preformed mediators stored in mast cell granules, such as histamine, serotonin, proteases, and proinflammatory cytokines. Many mechanisms can activate mast cells to induce degranulation, such as IgE during allergic reactions, pathogens (bacteria, viruses, and parasites) or pathogen products, chemicals, neuropeptides, cytokines, or physical stimuli such as heat or mechanical injury. In addition, significant mast cell activation occurs during the early stages of wound healing.

[0039] Mastocytosis: A disease caused by the abnormal accumulation and activation of mast cells in the skin, bone marrow, and internal organs. The symptoms of mastocytosis are primarily due to the release of chemicals from mast cells that produce symptoms similar to those of an allergic reaction. Flushing due to mast cell-associated histamine release is a common symptom. In some cases, the massive release of chemicals from mast cells (degranulation) can result in the onset of a life-threatening allergic reaction (anaphylactic shock). The most common triggers include, but are not limited to, insect bites, physical stress (heat, cold, mechanical stimulation of the skin, exercise), emotional stress, alcohol, spicy foods, and medications, including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS), anesthetics, muscle relaxants, radiocontrast agents, etc.

[0040] Cutaneous mastocytosis is a type of mastocytosis that affects the skin. Subtypes of cutaneous mastocytosis include maculopapular cutaneous mastocytosis, solitary cutaneous mastocytoma, and diffuse cutaneous mastocytosis. Maculopapular cutaneous mastocytosis is characterized by itchy brown patches on the skin. The patches may appear on the scalp, neck, trunk, and extremities. Solitary cutaneous mastocytoma is a localized form of cutaneous mastocytosis. Typically, there is only one lesion, or up to 3 separate lesions, which are usually discovered early in life and resolve on their own with age. Diffuse cutaneous mastocytosis is the most severe form of cutaneous mastocytosis. The skin is diffusely thickened and has a rough texture, often without separate, obvious lesions. Other symptoms associated with DCM include itching, blistering, a drop in blood pressure (hypotension), diarrhea, gastrointestinal bleeding, redness of the skin (flushing), and anaphylactic shock.

[0041] Menthol: A monoterpenoid that can be produced synthetically or extracted from corn, mint, peppermint, or other mint oils. The preferred IUPAC name for menthol is 5-methyl-2-(propan-2-yl)cyclohexane-1-ol. Purified menthol is commercially available, for example, as Menthol Essential Oil (Oakland Gardens, 100% pure mint extract); or Menthol (Sigma-Aldrich, #M2772).

[0042] Psoriasis: An immune-mediated skin disease that causes noticeable signs of inflammation, such as raised plaques (which may look different on different skin types) and scaling on the skin. The red, itchy, scaly plaques most commonly appear on the knees, elbows, trunk, and scalp. Psoriasis is a chronic disease with no cure. Symptoms tend to come and go in cycles, flaring up for weeks or months before subsiding or going into remission for a period of time.

[0043] Rosacea: A chronic inflammatory skin disease characterized by erythema, papules, telangiectasias, edema, pustules, or a combination of these symptoms. Skin lesions usually occur in the central part of the face, such as the cheeks, forehead, chin, and nose. People with rosacea may also experience rhinophyma, facial flushing, or tingling, pain, or burning sensations. Signs and symptoms may persist for weeks to months and then subside for a period of time. The underlying cause of rosacea is unknown, but abnormalities in the innate immune system and neurovascular disorders have been shown to be involved. In addition, certain factors, such as Demodex (mite) colonization, microbial irritation, ultraviolet (UV) radiation, heat, and stress, may trigger or aggravate rosacea. Clinically, rosacea can be divided into papulopustular rosacea, erythematotelangiectatic rosacea, ocular rosacea, and nodular rosacea.

[0044] Scleroderma: A chronic autoimmune disease that affects the skin and other organs of the body. Scleroderma is characterized by thickening and tightness of the skin, as well as inflammation and scarring in many parts of the body, leading to problems in the lungs, kidneys, heart, intestinal system, and other parts. Localized scleroderma usually affects only the skin, but it can also affect muscles, joints, and bones. It does not affect internal organs. Symptoms include discolored patches on the skin (morphea); or streaks or thick, hard skin on the arms and legs (linear scleroderma). When linear scleroderma occurs on the face and forehead, it is called en coup de sabre. Systemic scleroderma is the most serious form of the disease and can affect the skin, muscles, joints, blood vessels, lungs, kidneys, heart, and other organs. There are two main forms of systemic scleroderma: limited cutaneous systemic sclerosis (formerly known as CREST syndrome) and diffuse cutaneous systemic sclerosis.

[0045] Skin care composition: A topical composition having an active ingredient that improves the condition, health, beauty, and / or cosmetic appearance of the skin. Such improvement can be, for example, a reduction in skin redness or inflammation. In some embodiments, the topical composition disclosed herein is a skin care composition.

[0046] Flushing or redness of the skin: Sudden redness of the face, neck, or upper chest due to increased blood flow. Flushing of the skin may be triggered by emotions, such as embarrassment, stress, anger, or excitement. Other triggers include diet (e.g., alcohol, spicy foods), hormonal changes, menopausal hot flashes, exercise, rapid temperature changes or heat exposure, and certain medications.

[0047] Subject: A living multicellular vertebrate, including humans and non-human mammals, such as non-human primates. In some examples, the subject is a human. In some embodiments, the subject suffers from chronic skin flushing or an inflammatory skin disease.

[0048] Topical composition: A composition formulated for topical application, typically to a specific body surface. For example, a topical composition can be applied topically to the skin, such as an area of ​​skin or lesion affected by redness or inflammation. In some examples, the topical compositions described herein are applied topically to the skin of the face. Topical compositions intended for application to the skin are "skin care compositions."

[0049] Transient receptor potential cation channel subfamily M (melastatin), member 8 (TRPM8): a temperature-regulated, nonselective Ca 2+ A permeable cation channel that is activated by cold or TRPM8 agonists. The channel is a homotetramer composed of four identical subunits with a transmembrane domain with six helices (S1-6). The first four, S1-4, act as voltage sensors and allow binding of channel agonists (e.g. menthol or icilin). S5, S6, and the connecting loop form the pore, which is a non-selective cation channel composed of a highly conserved hydrophobic region. Upon activation, the channel allows Na + and Ca 2+ Ions enter the cell, causing depolarization and generating an action potential. The signal is conducted from the primary afferent nerve, ultimately leading to a feeling of cold. TRPM8 is also known as cold and menthol receptor 1 (CMR1). It is encoded by the TRPM8 gene (see, e.g., GenBank Gene ID: 79054 (ncbi.nlm.nih.gov / genbank / )).

[0050] Treating, Treatment, or Therapy: A therapeutic intervention that improves the signs or symptoms of a disease or pathological condition, including objective or subjective parameters, such as alleviation, remission, slowing of the rate of degeneration or decline, or improvement in the subject's physical or mental health. Treatment may be assessed by objective or subjective parameters, including physical examination, patient self-assessment, blood or other clinical tests, etc. "Preventive" treatment is treatment given to a subject to reduce the risk of developing a disease or pathological condition.

[0051] TRPM8 agonist: An agent that activates TRPM8. Non-limiting examples include: menthol, borneol, linalool, geraniol, hydroxycitronellal, icilin, WS-12 (preferred IUPAC name: (1R, 2S, 5R)-N-(4-methoxyphenyl)-5-methyl-2-(propan-2-yl)cyclohexane-1-carboxamide), Frescolat MGA, Frescolat ML, PMD 38 (also known as p-menthane-3,8-diol; preferred IUPAC name: 2-(2-hydroxypropan-2-yl)-5-methylcyclohexane-1-ol), Coolact P, M8-Ag (see, e.g., Patel et al. (2014) Pain, 155(10):2097–2107), and Cooling Agent 10 (also known as menthoxypropanediol). See also Behrendt et al., (2004) Br J Pharmacol. 141(4):737–745.

[0052] Ultraviolet protectant (UV protectant): A compound that can be applied to the skin to block or absorb UV radiation. UV protectants can block or absorb UVA, UVB, or both. Non-limiting examples include aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, drometrizole trisiloxane, homosalate, meladate, octocrylene, octinoxate, octisalate, oxybenzone, padrimate O, para-aminobenzoic acid (PABA), ensuloxacin, sulisobenzone, titanium dioxide, triethanolamine salicylate, zinc oxide, ethylhexyl triazone, ecamsud, cilatriazole, bemotriazine, bis-octazoline, iron oxide, red veterinary petrolatum, and kaolin.

[0053] Unit dose: A physically discrete unit containing a predetermined quantity of active substances calculated to produce, individually or collectively, a desired effect. A single unit dose or multiple unit doses may be used to provide a desired effect or activity, such as reducing skin redness or inflammation. In another example, a unit dosage form contains multiple predetermined doses.

[0054] Urticaria: A condition commonly called hives. Hives can be triggered by a variety of factors, including certain foods, medications, and stress. Symptoms include itchy, raised, red or skin-colored bumps on the surface of the skin. Acute urticaria is the most common type. Symptoms usually last less than six weeks and can be triggered by insect bites or stings, medications, infections, or eating certain foods (such as nuts, chocolate, fish, tomatoes, eggs, berries, or milk). Chronic urticaria has symptoms that last longer than six weeks. The cause of chronic urticaria is often difficult to determine and is often unknown.

[0055] There are many physical forms of urticaria, which are hives that appear in response to physical stimuli. For example, papular urticaria is a condition in which hives appear as an allergic reaction to insect bites such as mosquitoes, fleas, mites, carpet beetles, or bed bugs. Cholinergic urticaria is a condition in which hives appear as an allergic reaction to an increase in body temperature. Cold urticaria is a condition in which hives appear in response to exposure to cold, and solar urticaria is a condition in which hives appear in response to exposure to sunlight.

[0056] I. Topical Compositions

[0057] Disclosed herein is a topical composition comprising an effective amount of β-alanine and an effective amount of a TRPM8 agonist. In some embodiments, an effective amount of β-alanine is the amount of β-alanine that reduces skin inflammation or redness when applied topically. In some examples, an effective amount of β-alanine reduces dermal mast cell activation when applied topically. In some embodiments, the effective amount of a TRPM8 agonist is the amount that reduces the transient itching caused by β-alanine. In some embodiments, the effective amount of a TRPM8 agonist is the amount that reduces the transient itching caused by β-alanine without causing eye irritation when applied to the facial skin (e.g., cheek) of a subject.

[0058] The topical composition comprises an amount of beta-alanine that is effective to reduce skin inflammation or redness and / or dermal mast cell activation when topically applied to a subject. In some embodiments, the topical composition comprises about 0.2% to about 20% by weight (w / w) beta-alanine. In some instances, the topical composition comprises about 0.2% to about 19%, about 0.2% to about 18%, about 0.2% to about 17%, about 0.2% to about 16%, about 0.2% to about 15%, about 0.2% to about 14%, about 0.2% to about 13%, about 0.2% to about 12%, about 0.2% to about 11%, about 0.2% to about 10%, about 0.2% to about 9%, about 0.2% to about 8%, about 0.2% to about 7%, about 0.2% to about 6%, about 0.2% to about 5%, about 0.2% to about 10 ...11%, about 0.2% to about 10%, about 0.2% to about 11%, about 0.2% to about 11%, about 0.2% to about 11%, about 0.2% to about 11%, about 0.2% to about 11%, about 0.2% to about 11%, about 0.2% to about 11%, about 0.2% to about 11%, about 0. about 4%, about 0.2% to about 3%, about 0.2% to about 2% w / w, about 0.5% to about 20%, about 1% to about 20%, about 2% to about 20%, about 3% to about 20%, about 4% to about 20%, about 5% to about 20%, about 6% to about 20%, about 7% to about 20%, about 8% to about 20%, about 9% to about 20%, about 10% to about 20%, about 11% to about 20%, about 12% to about 20%, about 13% to about 20%, about 14% to about 20%, about 15% to about 20%, about 16% to about 20%, about 17% to about 20%, about 18% to about 20%, about 19% to about 20%, about 21% to about 20%, about 22% to about 20%, about 23% to about 20%, about 24% to about 20%, about 25% to about 20%, about 26% to about 20%, about 27% to about 20%, about 28% to about 20%, about 29% to about 20%, about 30% to about 20%, about 31% to about 20%, about 32% to about 20%, about 33% to about 20%, about 34% to about 20%, about 36% to about 20%, about 37% to about 20%, about 38% to about 20%, about 39% to about 20%, about 40% to about 20%, about 41% to about 20%, about 42% to about 20%, about 43% to about 20%, about 44% to about 20%, about 45% to about 20%, about 46% 6% to about 20%, about 17% to about 20%, about 18% to about 20%, or about 19% to about 20%, about 0.5% to about 10%, about 1% to about 10%, about 2% to about 10%, about 3% to about 10%, about 4% to about 10%, about 5% to about 10%, about 6% to 10%, about 7% to 10%, about 8% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 2% to about 8%, about 2% to about 6%, about 4% to about 8%, about 2.5% to about 10%, about 2.5% to about 7.5%, about 2.5% to about 5%, about 5% to about 8%, about 1% to about 18%, about 2% to about 18%, about 5% to about 18%, about 10% to about 18%, about 15% to about 18%, about 5% to about 15%, about 7.5% to about 15%, or about 10% to about 15% w / w beta-alanine. In some instances, the topical composition includes 0.2% to 15% w / w beta-alanine. In some instances, the topical composition includes 1% to 10% w / w beta-alanine. In some instances, the topical composition includes 5% to 10% w / w beta-alanine. In some examples, the topical composition includes 2.5% to 10% w / w beta-alanine. In further examples, the topical composition includes 2.5% to 7.5% w / w beta-alanine.

[0059] In some embodiments, the topical composition comprises about 0.2%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% w / w beta-alanine. In some instances, the topical composition comprises about 5% w / w beta-alanine.

[0060] In some examples, the topical composition comprises no more than about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% w / w beta-alanine. In some examples, the topical composition comprises no more than about 15% beta-alanine.

[0061] The topical composition may include any suitable TRPM8 agonist, which may be formulated into a topical composition, and when topically applied to a subject, the transient itch caused by the beta-alanine in the topical composition may be effectively reduced. Non-limiting examples of suitable TRPM8 agonists include menthol, icilin, crysim-1, borneol, linalool, geraniol, hydroxycitronellal, WS-12, Frescolat MGA, Frescolat ML, PMD 38, Coolact P, M8-Ag, CoolingAgent 10, or a combination thereof. In some instances, the TRPM8 agonist is menthol, icilin, or a combination thereof. In some embodiments, the TRPM8 agonist is menthol.

[0062] The topical composition comprises an amount of TRPM8 agonist that is effective to reduce transient pruritus caused by beta-alanine in the topical composition when topically applied to a subject. In some embodiments, the topical composition comprises about 0.1% to about 20% by weight (w / w) of a TRPM8 agonist. In some instances, the topical composition comprises about 0.1% to about 19%, about 0.1% to about 18%, about 0.1% to about 17%, about 0.1% to about 16%, about 0.1% to about 15%, about 0.1% to about 14%, about 0.1% to about 13%, about 0.1% to about 12%, about 0.1% to about 11%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, about 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2% w / w, about 0.1% to about 1% w / w, about 0.1% to about 0.5% w / w, about 0.2% to about 20%, about 0.5% to about 20%, about 1% to about 20%, about 2% to about 20%, about 3% to about 20%, about 4% to about 20%, about 5% to about 20%, about 6% to about 20%, about 7% to about 20%, about 8% to about 20%, about 9% to about 20%, about 10% to about 20%, about 11% to about 20%, about 12% to about 20%, about 13% to about 20%, about 14% to about 20%, about 15% to about 20%, about 16% to about 20%, about 17% to about 20%, about 18% to about 20%, about 19% to about 20%, about 21% to about 20%, about 22% to about 20%, about 23% to about 20%, about 24% to about 20%, about 25% to about 20%, about 26% to about 20%, about 27% to about 20%, about 28% to about 20%, about 29% to about 20%, about 30% to about 20%, about 31% to about 20%, about 32% to about 20%, about 33% to about 20%, about 34% to about 20%, about 35% to about 20%, about 36% to about 20%, about 37% to about 20%, about 38% to about 20%, about 39% to about 20%, about 40% to about 20%, about 41% to about 20%, about 42% to about 20%, about 43% to about 20%, about 20%, about 18% to about 20%, about 19% to about 20%, about 0.2% to about 10%, about 0.5% to about 10%, about 1% to about 10%, about 2% to about 10%, about 3% to about 10%, about 4% to about 10%, about 5% to about 10%, about 6% to about 10%, about 7% to about 10%, about 8% to about 10%, about 9% to about 10%, about 0.2% to about 9%, about 0.2% to about 8%, about 0.2% to about 7%, about 0.2% to about 6%, about 0.2% to about 5%, about 0.2% to about 4%, about 0.2% to about 3%, about 0.2% to about 2%, About 0.2% to about 1%, about 0.2% to about 0.5%, about 0.5% to about 5%, about 0.5% to about 2%, about 0.5% to about 1.5%, about 1% to about 5%, about 2% to about 5%, about 3% to about 5%, about 4% to about 5%, about 2% to about 8%, about 2% to about 6%, about 4% to about 8%, about 5% to about 8%, about 1% to about 18%, about 2% to about 18%, about 5% to about 18%, about 10% to about 18%, about 15% to about 18%, about 5% to about 15%, about 7.5% to about 15%, or about 10% to about 15% w / w TRPM8 agonist. In some instances, the TRPM8 agonist is menthol. In some instances, the topical composition comprises 0.1% to 5% w / w menthol.In some examples, the topical composition comprises 0.1% to 2% w / w menthol. In some examples, the topical composition comprises 0.2% to 1% w / w menthol. In further examples, the topical composition comprises 0.5% to 1.5% w / w menthol.

[0063] In some embodiments, the topical composition comprises about 0.1%, about 0.2%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19% or about 20% w / w TRPM8 agonist. In some instances, the TRPM8 agonist is menthol. In some instances, the topical composition comprises about 0.5% w / w menthol.

[0064] In other embodiments, the topical composition comprises no more than about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19% or about 20% w / w TRPM8 agonist. In some instances, the TRPM8 agonist is menthol. In some instances, the topical composition comprises no more than about 5% menthol. In another example, the topical composition comprises no more than about 1% menthol.

[0065] In a non-limiting example, the topical composition includes about 0.2% to about 15% w / w of beta-alanine and about 0.1% to about 5% w / w of menthol. In some instances, the topical composition may include about 0.2% to about 15% w / w of beta-alanine and about 0.1% to about 2% w / w of menthol. In some instances, the topical composition includes about 0.2% to about 15% w / w of beta-alanine and about 0.2% to about 1% w / w of menthol. In some instances, the topical composition includes about 1% to about 10% w / w of beta-alanine and about 0.1% to about 5% w / w of menthol. In some instances, the topical composition includes about 1% to about 10% w / w of beta-alanine and about 0.2% to about 2% w / w of menthol. In some instances, the topical composition includes about 5% to about 10% w / w of beta-alanine and about 0.1% to about 5% w / w of menthol. In some examples, the topical composition includes about 5% to about 10% w / w beta-alanine and about 0.1% to about 2% w / w menthol. In some examples, the topical composition includes about 5% to about 10% w / w beta-alanine and about 0.2% to about 1% w / w menthol. In some examples, the topical composition includes about 2.5% to about 7.5% w / w beta-alanine and about 0.5% to about 1.5% w / w menthol.

[0066] In some embodiments, the topical composition comprises beta-alanine and menthol in an amount useful for reducing redness or inflammation when applied to skin affected by redness or inflammation.

[0067] In some embodiments, the disclosed topical compositions further include additional ingredients such as topical UV protectants, antibiotics, antiparasitics, steroids (e.g., corticosteroids), nonsteroidal anti-inflammatory agents, calcineurin inhibitors, JAK inhibitors, analgesics, α2-adrenergic receptor agonists, α1A-adrenergic receptor agonists, vitamins (e.g., vitamin A, C, or E), ceramides, extracts or other natural products, or combinations thereof.

[0068] Non-limiting examples of suitable topical UV protectants include aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, drometrizole trisiloxane, homosalate, meladide, octocrylene, cinoxate, octisalate, oxybenzone, padrimate O, para-aminobenzoic acid (PABA), ensulazole, sulibenzone, titanium dioxide, triethanolamine salicylate, zinc oxide, ethylhexyl triazone, ecamsud, cilatriazole, bemotriazine, bis-octatriazole, iron oxide, red veterinary petrolatum, and kaolin. The UV protectant can be added in an amount to provide a sun protection factor (SPF) of at least 5, for example, about SPF5, about SPF10, about SPF15, about SPF20, about SPF25, about SPF30, about SPF35, about SPF40, about SPF45, about SPF50, about SPF55, about SPF60, about SPF65, about SPF70, about SPF75, about SPF80 or more. In some examples, the UV protectant is added in an amount to provide a sun protection factor (SPF) of 5 to 80. In some examples, the UV protectant is added in an amount to provide a sun protection factor (SPF) of 15 to 80. In some examples, the UV protectant is added in an amount to provide a sun protection factor (SPF) of 15 to 40.

[0069] Topical antibiotics are antibiotics applied to the body surface. Antibiotics can be directed against bacteria, fungi, or any other microorganisms. Antibiotics can contain active agents, such as macrolide antibiotics (e.g., erythromycin), sulfonamide antibiotics (e.g., sulfacetamide), cyclic peptides (e.g., bacitracin, polymyxin), pseudomonas acid (e.g., mupirocin), aminomycin (e.g., neomycin), quinolones (e.g., ciprofloxacin or ofloxacin), nitroimidazoles (e.g., metronidazole), or a combination of active ingredients (e.g., bacitracin / polymyxin or neomycin / polymyxin B / bacitracin). Antibiotics can be narrow-spectrum or broad-spectrum. "Narrow-spectrum" antibacterial antibiotics target specific types of bacteria, such as gram-negative or gram-positive bacteria. "Broad-spectrum antibiotics" affect a variety of different types of bacteria. Antimicrobial agents also include cyclic lipopeptides (e.g., daptomycin), glycylcyclines (e.g., tigecycline), and oxazolidinones (e.g., linezolid). In some instances, the topical antibiotic is an azole antifungal agent, such as ketoconazole, itraconazole, clotrimazole, voriconazole, posaconazole, or miconazole. In some instances, the topical antibiotic is clindamycin, metronidazole, cyclosporine, or azathioprine.

[0070] Antiparasitics are used to treat parasitic infections such as protozoa, worms and ectoparasites (e.g. fleas, lice or mites). Suitable topical antiparasitics include, but are not limited to, ivermectin, lindane, permethrin, benzyl alcohol, malathion and crotamiton.

[0071] Suitable topical steroids include amcinonide, beclomethasone, betamethasone, clobetasol, clobetasone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinolone acetate, fludrocortisone, fluticasone, halcinonide, halobetasol, hydrocortisone, mometasone, prednicarbate and triamcinolone. In some embodiments, the steroid is a corticosteroid. Exemplary corticosteroids include hydrocortisone, clobetasone, beclomethasone, betamethasone, fluticasone, clobetasol and mometasone.

[0072] Non-limiting examples of suitable nonsteroidal anti-inflammatory agents include azelaic acid, nonsteroidal anti-inflammatory drugs (NSAIDs) and PDE4 inhibitors. NSAIDs have anti-inflammatory, analgesic and antipyretic effects. Although different NSAIDs have different structures, they all target (block) cyclooxygenase (COX) enzymes. Exemplary NSAIDs that can be topically applied include diclofenac (including diclofenac sodium and diclofenac hydroxyethylpyrrolidine), ibuprofen, ketoprofen, pheniramine and piroxicam. PDE4 inhibitors regulate the immune system by inhibiting phosphodiesterase-4 (PDE4), which helps prevent and reduce inflammation. An exemplary topical phosphodiesterase-4 (PDE4) inhibitor is crisaborole.

[0073] The topical composition may include one or more topical calcineurin inhibitors. Calcineurin inhibitors are immunosuppressive drugs that block T cell proliferation by inhibiting the signaling phosphatase calcineurin. Exemplary topical calcineurin inhibitors include cyclosporine, tacrolimus, and pimecrolimus.

[0074] The topical composition may include one or more topical JAK inhibitors (or JAK-STAT pathway inhibitors). Non-limiting examples of JAK inhibitors include abrocitinib, baricitinib, ruxolitinib, and upadacitinib. The topical compositions disclosed herein may also include a topical α2-adrenergic receptor agonist (e.g., brimonidine), α1A-adrenergic receptor agonist (e.g., oxymetazoline), or a combination thereof.

[0075] The topical composition may include vitamins. Non-limiting examples of vitamins include vitamin A (retinol and its analogs, such as retinyl palmitate), any of the 12 B vitamins (e.g., thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), B6, biotin (B7), folic acid (B9), B12 and its analogs), vitamin C (and its analogs, such as magnesium ascorbyl phosphate, ascorbyl palmitate, etc.), vitamin D (e.g., calcitriol (D3)), and vitamin E (tocopherol and its analogs, such as tocopherol acetate).

[0076] The topical composition may also include natural or synthetic ceramides, essential fatty acids (eg, omega-3 or omega-6 (eg, linoleic acid)), glycerin, glycols, polyols, hyaluronic acid, sodium PCA, or other moisturizing ingredients.

[0077] In some embodiments, the topical composition includes a natural product, such as a plant extract (including a tincture), such as from arnica (commonly known as wolfsbane, panther poison, mountain tobacco, and arnica), comfrey (comfrey), sesame (sesame), soy, tea (green, black, or white), matricaria (chamomile), arabica coffee (coffee or coffee berry), almond, angelica root, acacia, aloe, marshmallow, fennel, apple, avocado, basil, bayberry, bilberry, blue mallow flower, blackberry, burdock, borage, bergamot, buchu, cranberry, clover flower, calendula, clove, carrot, Chinese bark, cinnamon, clary sage, coltsfoot, cornflower, geranium, cucumber, dandelion, red algae, eucalyptus, echinacea, elderberry, fennel, fenugreek, garlic, gentian root, geranium, ginkgo, Ginseng, grapefruit, grape seed, coptis root, hops, hawthorn, henna, horse chestnut, horsetail, hibiscus, ivy, Irish moss, jasmine, juniper berry, kelp, kiwi, linden blossom, parsley, lavender, lemongrass, lemon peel, myrrh, mallow, mayflower, melon, mint, sweet osmanthus, milk thistle, nettle, oats, orange blossom, orange peel, oakmoss, peach, plantain, parsley, mint, primrose, papaya, quercetin, quince, rose buds, rose hips, rosemary, sage, elderberry, elm bark, spearmint, elderberry, sandalwood, wormwood, strawberry, sunflower, St. John's wort, tangerine, tansy, thyme, tomato, bearberry, violet, white lily, valerian root, watercress, black walnut, white birch, white willow bark, wild indigo, witch hazel, yucca, yarrow, or other plant sources.

[0078] The topical composition can include phytochemicals of synthetic or natural origin, such as sesquiterpene lactones, rosmarinic acid, sesamin, sesamol, sesaminol, sesamolin, isoflavones (e.g., genistein and daidzein), polyphenols (e.g., chlorogenic acid, ferulic acid, quinic acid, and condensed proanthocyanidins), epigallocatechin-3-gallate (EGCG), flavonoids (e.g., quercetin, theaflavins, kaempferol, apigenin, luteolin, rutin), catechins, terpenoids (e.g., bisoprolol, matricarbine, levorotatory glycol, chamaecyparis), caffeine, or a combination thereof.

[0079] The topical composition may include one or more local analgesics and / or anesthetics. An analgesic is a drug that relieves pain. An anesthetic is a substance that causes temporary sensory loss, including sensory loss of pain or itching. Non-limiting examples of suitable topical analgesics include capsaicin, diclofenac, lidocaine, methyl salicylate, and triethanolamine salicylate. Exemplary local anesthetics include lidocaine, pramoxine, benzocaine, dibucaine, and camphor. In some instances, the topical composition does not include camphor, lidocaine, methyl salicylate, pramoxine, benzocaine, dibucaine, or diclofenac. In some instances, the topical composition does not include a local anesthetic or analgesic other than a TRPM8 agonist (not including a local anesthetic or analgesic of a non-TRPM8 agonist). In some instances, the topical composition does not include a local anesthetic or analgesic other than menthol.

[0080] In some embodiments, the topical composition does not include a topical steroid (e.g., amcinonide, beclomethasone, betamethasone, clobetasol, clobetasone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinolone acetate, fludrocortisone, fluticasone, halcinonide, halobetasol, hydrocortisone, mometasone, prednicarbate, and triamcinolone).

[0081] Topical compositions can be formulated in any form suitable for application to body surfaces (i.e., skin), such as creams, lotions, gels, ointments, pastes, soaps, shampoos, solutions, suspensions, sprays, bioadhesives, paints, etc. Methods for preparing cosmetically acceptable topical compositions (e.g., creams, ointments, lotions, sprays, gels, pastes, aqueous solutions or suspensions) are described, for example, in Remington: The Science and Practice of Pharmacy, 23 rd Ed.(Academic Press),2021(ISBN 9780128200070).

[0082] Topical compositions can be formulated as creams. Creams are viscous liquids or semisolid emulsions of oil-in-water or water-in-oil. The cream base is usually washable and comprises an oil phase, an emulsifier and an aqueous phase. The oil phase, also referred to as the "inner" phase, is usually composed of petrolatum and a fatty alcohol (e.g., cetyl alcohol or stearyl alcohol). The aqueous phase usually (but not necessarily) exceeds the oil phase in volume and usually contains a humectant. The emulsifier in the cream formulation is usually a nonionic, anionic, cationic or amphoteric surfactant.

[0083] Topical compositions can be formulated as emulsions. Emulsions are preparations to be applied to the surface of the skin, usually without rubbing, and are generally liquid or semi-liquid preparations in which particles including the active agent are present in a water or alcohol base. Emulsions are generally suspensions of solids, preferably including liquid oily emulsions of the water-in-oil type. Emulsions can be used for large areas of the body because it is easier to apply a more fluid composition. It is usually necessary to subdivide the insoluble materials in the emulsion. Emulsions generally contain suspending agents to produce better dispersibility, as well as compounds that can be used to position and maintain the active agent in contact with the skin, such as methylcellulose, sodium carboxymethylcellulose, etc.

[0084] Topical compositions may be formulated as gels. Gels are semisolid suspension-type systems. Single-phase gels contain organic macromolecules substantially uniformly distributed throughout a carrier liquid, which is usually aqueous but may also contain alcohol or oil. Useful "organic macromolecules," particularly gelling agents, are cross-linked acrylic acid polymers, such as the "carbomer" series of polymers, for example, as Commercially available carboxypolyalkylenes. Hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulosic polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin may also be used. To prepare a uniform gel, a dispersant such as alcohol or glycerol may be added, or the gelling agent may be dispersed by grinding, mechanical mixing or stirring, or a combination thereof.

[0085] Topical compositions can be formulated into ointments. Ointments are semisolid preparations, usually based on vaseline or petroleum derivatives. Doctors can select the specific ointment base to be used according to the desired properties (such as emollients, etc.). Ointment bases are usually inert, stable, non-irritating and non-sensitizing. Ointment bases are divided into four categories: oily bases; emulsifiable bases; emulsion bases; and water-soluble bases (see, for example, Remington: The Science and Practice of Pharmacy, 23rd Ed. (Academic Press), 2021 (ISBN9780128200070)). Oily ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also referred to as absorbent ointment bases, are almost free of water or free of water, including, for example, hydroxystearic acid sulfates, anhydrous lanolin, and hydrophilic vaseline. Emulsion ointment bases are water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including, for example, acetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weights.

[0086] The topical composition can be formulated as a paste. Pastes are generally semisolid dosage forms in which the active agent is suspended in a suitable matrix. Depending on the nature of the matrix, pastes are divided into fatty pastes or pastes made from a single-phase aqueous gel. The matrix in the fatty paste is generally petrolatum or hydrophilic petrolatum, etc. Pastes made from a single-phase aqueous gel generally contain carboxymethylcellulose, etc. as a matrix.

[0087] Topical compositions can be formulated as soaps. Soaps are solid, liquid or cream products used with water for washing and cleaning. It is usually produced in solid molded forms (bar soaps), but can also appear in liquid or cream forms dispersed from dispensers. Soaps usually contain surfactants, which, when applied to a dirty surface in combination with water, can wet the dirt and effectively keep the particles in suspension so that they can be rinsed off with clean water. Traditionally, animal-based oils / fats (such as lard and tallow) are used to make soaps. However, commercial soaps usually use plant base oils. Common plant base oils include olive oil, coconut oil, palm kernel oil, palm oil, castor oil, apricot oil, avocado oil, almond oil, jojoba oil or other nut or seed oils, or lipids such as cocoa butter, mango butter or shea butter. Lye reacts with the base oil to form soap (saponification). Examples of lye include sodium hydroxide and potassium hydroxide. Sodium hydroxide is used to make solid soaps, while potassium hydroxide is used to make liquid soaps. The two are combined to make cream soaps. Soaps can be used as deodorants, or for cleaning and moisturizing.

[0088] Topical compositions can be formulated into shampoo (including other shampoos). Shampoo is a viscous liquid preparation containing detergent or soap for washing hair generally. Less commonly, shampoo is provided in a bar form, such as a soap bar. Shampoo includes a surfactant, such as ammonium lauryl sulfate, sodium lauryl sulfate, sodium lauryl ether sulfate, decyl glucoside and lauryl glucoside. Shampoo may also include a foam accelerator (such as lauramide DEA or cocamidopropyl betaine), a thickener (such as methylcellulose or carbomer), a conditioning agent (such as polyquaternium-10, guar hydroxypropyltrimonium chloride, polydimethylsiloxane, cyclomethicone or quaternium 80), a preservative (such as DMDM ​​hydantoin, methylparaben, sodium benzoate, benzyl alcohol and phenoxyethanol) and other ingredients, such as dyes, spices, pH buffers, chelating agents, sunscreens, vitamins, proteins and herbal extracts. Shampoos may also contain active ingredients such as zinc pyridone, salicylic acid, ketoconazole or selenium sulfide.

[0089] Disclosed topical compositions include solutions. Solutions are typically homogeneous mixtures prepared by dissolving one or more chemical substances (solutes) in a liquid so that the molecules of the dissolved substances are dispersed in the molecules of the solvent. Solutions may contain other cosmetically acceptable chemicals to buffer, stabilize and / or preserve the solutes. Common examples of solvents for preparing topical solutions are ethanol, water, propylene glycol or any other acceptable carrier. These can be applied in any manner, such as spraying them on the skin, applying them on the skin or wetting a bandage with the solution.

[0090] A bioadhesive is a composition that adheres or causes adhesion in living tissue. In clinical applications, bioadhesives can be used as tissue adhesives, hemostats, tissue sealants, wound dressings, delivery vehicles, medical device fixation, or other applications. Compared to traditional wound closure methods (including sutures, silk, or staples), bioadhesives are less likely to cause damage to tissues and can promote wound healing through different mechanisms. For example, bioadhesives can have antibacterial, anti-inflammatory, and antioxidant properties. Cyanoacrylate-based bioadhesives are the most widely used tissue adhesives for wound closure. Examples of bioadhesives include and

[0091] The disclosed topical compositions may include cosmetically acceptable viscosity enhancers and / or film formers. Viscosity enhancers increase the viscosity of the formulation, thereby inhibiting its diffusion beyond the application site. BalsamFir (Oregon) is an example of a suitable viscosity enhancer. The film former forms a protective film on the application site when dry. The film inhibits the removal of the active ingredient and keeps it in contact with the site. An example of a film former suitable for the present invention is Flexible Collodion, USP (see Remington: The Science and Practice of Pharmacy, 23rd Ed. (Academic Press), 2021 (ISBN 9780128200070)). Collodion is an ether / ethanol solution containing nitrocellulose (nitrocellulose), which leaves a nitrocellulose film after evaporation. Film formers can also be used as carriers. Solutions that dry to form a thin film are sometimes called coatings.

[0092] Creams, emulsions, gels, ointments, pastes, soaps, shampoos, bioadhesives, coatings, etc. can be applied to the affected surface of the subject, for example, applied to the skin affected by redness or inflammation of the subject (although shampoos are usually specifically used for hair and scalp). Solutions can be applied similarly, but more typically, droppers, swabs, sprayers, etc. are used to apply the solution to the affected area. The method of application generally depends on the viscosity of the composition to be applied. The composition can be applied directly to the target location, for example in the form of a topical preparation (e.g., ointment), or as a part of a dressing or bandage. The composition can be formulated into a unit dose to be applied to the skin by a device. The unit dose can be a reservoir of a topical composition in a carrier, such as an adhesive carrier that can adhere to the skin within a desired time (e.g., at least one day or longer).

[0093] Topical compositions can be formulated as emollients (humectants). Emollients soften and moisturize the skin and can be used to reduce itching or flaking. Dry skin can be caused by loss of water from the upper layers of the skin. Emollients work by forming an oily layer on top of the skin that locks moisture into the skin. Petrolatum, lanolin, mineral oil, and dimethicone are common emollients. Humectants, including glycerin, lecithin, and propylene glycol, draw moisture into the outer layers of the skin. Many moisturizing products also contain ingredients that soften keratin, such as urea, alpha-hydroxy acids (such as lactic / citric / glycolic acid), and allantoin. Compounds that protect the skin from irritation, such as zinc oxide or white petrolatum, can also be added.

[0094] The topical composition can be formulated for any external part of the body. In some non-limiting examples, the topical composition is formulated for the head, face (e.g., cheeks, nose, forehead, etc.), scalp, arms, hands, legs, feet, or torso. In some embodiments, the topical composition is formulated for the face (facial application).

[0095] The topical composition can be used in conjunction with an occlusive covering layer so that when the topical composition is applied to the body surface and thereafter, water evaporated from the body surface can be retained within the formulation. In some instances, the topical composition is used in conjunction with a wet dressing (e.g., wet compress therapy). For a wet dressing, gauze, bandages, etc. are soaked in water and applied to the affected area of ​​the skin, e.g., after application of the topical composition. A dry layer is then typically wrapped over the wet layer. The bandage is left on for several hours, e.g., overnight.

[0096] The topical composition can be formulated as a concentrate that can be used as an additive to existing skin care products. The concentrate can be formulated so that when a specific amount is added to a specific amount of skin care product, the resulting concentration of β-alanine and TRPM8 agonist is a desired concentration (effective amount).

[0097] 2. Usage

[0098] Also disclosed are methods for reducing skin inflammation or redness of a subject and methods for reducing the frequency, duration or severity of signs or symptoms of inflammatory skin diseases. The method includes applying an effective amount of a topical composition disclosed herein to the affected area of ​​the subject's skin. In some embodiments, the topical composition is used to reduce the method for skin inflammation or redness of a subject. The method includes applying an effective amount of a topical composition disclosed herein to the affected area of ​​the subject's skin. The affected area can be an area with signs or symptoms of inflammation or redness, or can be an area at risk of developing signs or symptoms of inflammation or redness, for example, an area of ​​the skin that is prone to inflammation or redness or has been inflamed or reddened in history. In some embodiments, the subject suffers from an inflammatory skin disease or chronic skin flushing.

[0099] In some embodiments, the affected skin area is subject to the influence of inflammatory skin diseases, such as rosacea, acute or chronic urticaria, skin scratch disease, mastocytosis, dermatitis, acne, psoriasis or scleroderma. In some embodiments, the affected skin area is subject to the influence of chronic skin flushing, such as, the chronic skin flushing caused by exercise, diet (e.g., alcohol, nuts, shellfish, etc.), hormone changes, menopause or emotions (e.g., stress, embarrassment or excitement). In some instances, chronic skin flushing is an alcohol flushing reaction. In some embodiments, the affected skin area is subject to the influence of wounds (e.g., skin abrasions). In some embodiments, the method includes selecting a subject suffering from inflammatory skin diseases or chronic skin flushing to apply a topical composition.

[0100] In some embodiments, a subject suffering from an inflammatory skin disorder (eg, rosacea, acute or chronic urticaria, dermatographism, mastocytosis, dermatitis, acne, psoriasis, or scleroderma) is selected for application of the disclosed topical compositions.

[0101] A topical composition that reduces redness can be identified by a reduction in redness relative to a suitable control (e.g., measurement before subject application or application of a blank (empty) carrier). The reduction in skin redness can be measured subjectively (qualitatively) or objectively (quantitatively). A topical composition that reduces inflammation can be identified by a reduction in dermal mast cell activity relative to a suitable control (e.g., measurement before subject application, application of a blank (empty) carrier, or reference to a historical "normal" value) after the topical composition is applied to the skin, resulting in a reduction in inflammatory mediators (e.g., cytokines, histamine, or serotonin). Inflammation reduction can also be visually identified as a reduction in redness in the skin area where the topical composition is applied. In some embodiments, an effective amount of a topical composition reduces the duration, frequency, or severity of skin inflammation or redness.

[0102] In some embodiments, application of the topical composition reduces redness or inflammation by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or even 100% (substantially resolves redness or inflammation). In some examples, redness or inflammation is reduced by about 5% to 100%, for example, by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 30% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 30% to about 60% To about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 100%, about 40% to about 50%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 50% to about 75%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 75% to about 100%, about 85% to about 100%, about 90% to about 100%, or about 95% to about 100% (substantially reduced redness or inflammation).

[0103] In some embodiments, the method reduces the frequency, duration or severity of the signs or symptoms of the inflammatory skin disease (e.g., rosacea, acute or chronic urticaria, dermatographism, mastocytosis, dermatitis, acne, psoriasis or scleroderma) of the subject. In some embodiments, the method includes selecting a subject with an inflammatory skin disease, and applying an effective amount of a topical composition disclosed herein to the skin area of ​​the subject affected by the inflammatory skin disease. In some instances, the inflammatory skin disease is rosacea. In a non-limiting example, the method includes selecting a subject with rosacea, and applying an effective amount of a topical composition to the skin area affected by rosacea. The subject can suffer from any type of rosacea. In some instances, the subject suffers from papulopustular rosacea, erythematotelangiectatic rosacea or lumpy rosacea.

[0104] The affected area can be an area that has signs or symptoms of an inflammatory skin disease, or an area that is at risk of developing signs or symptoms of an inflammatory skin disease, such as an area on the skin that is prone to symptoms, or an area that has had a flare-up in the past. In some examples, the affected area is an area that has signs or symptoms of rosacea, or an area that is at risk of developing signs or symptoms of rosacea, such as an area on the skin that is prone to rosacea, or an area that has had a flare-up in the past.

[0105] The frequency, duration or severity reduction of the signs or symptoms of inflammatory skin diseases are measured relative to a suitable control (e.g., a measurement before subject application, the application of a blank (empty) carrier or a reference to a historical "normal" value). The reduction of signs or symptoms can include, for example, reducing lesion size, lesion number, itching, redness, inflammation, skin thickness, skin damage or cracking, ulcers or duration of onset. In some instances, applying a topical composition reduces the signs or symptoms of inflammatory skin diseases by at least 5%, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or even 100% (signs or symptoms substantially subside). In some instances, the signs or symptoms are reduced by about 5% to 100%, for example, by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 30% to about 40% To about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 100%, about 40% to about 50%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 50% to about 75%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 75% to about 100%, about 85% to about 100%, about 90% to about 100%, or about 95% to about 100% (substantially resolved signs or symptoms).

[0106] In some embodiments, the reduction in the frequency of signs or symptoms includes increasing the duration of symptom relief (the time between symptom onsets). In some instances, new onsets do not occur for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months or more after application of the topical composition. In some examples, a new episode does not occur for about 1 to about 2 weeks, about 1 to about 3 weeks, about 1 to about 4 weeks, about 1 to about 6 weeks, about 1 to about 12 weeks, about 2 to about 4 weeks, about 2 to about 6 weeks, about 2 to about 8 weeks, about 2 to about 12 weeks, about 4 to about 6 weeks, about 4 to about 8 weeks, about 4 to about 12 weeks, about 6 to about 12 weeks, about 1 to about 4 months, about 1 to about 6 months, about 1 to about 12 months, about 2 months to about 4 months, about 2 months to about 6 months, about 2 months to about 8 months, about 2 months to about 12 months, about 4 months to about 6 months, about 4 months to about 8 months, about 4 months to about 12 months, or about 6 months to about 12 months.

[0107] The subject can be any mammalian subject, including humans or non-human mammals. In some embodiments, the subject is a human. The subject can be a child or an adult, for example, a child under 18 years of age or an adult over 18 years of age. In some instances, the child is under 5 years of age, under 12 years of age, or under 16 years of age. In a further embodiment, the child is about 1 to about 3 years old, about 1 to about 5 years old, about 1 to about 12 years old, about 3 to about 5 years old, about 5 to about 10 years old, about 5 to about 12 years old, about 5 to about 16 years old, about 5 to about 18 years old, about 10 to about 12 years old, about 10 to about 16 years old, about 12 to about 18 years old. In some embodiments, the age of an adult is more than about 18 years old, more than about 25 years old, more than about 30 years old, more than about 35 years old, more than about 40 years old, more than about 45 years old, more than about 50 years old, more than about 55 years old, more than about 60 years old, more than about 65 years old, more than about 70 years old, or more than about 75 years old. In further examples, the adult is about 18 to about 25, about 18 to about 35, about 18 to about 65, about 20 to about 35, about 25 to about 65, about 35 to about 65, about 40 to about 65, about 40 to about 80, about 65 to about 80, or over about 80 years old. In some examples, the subject is an adult female over the age of 30. In some examples, the subject is a postmenopausal adult female.

[0108] The appropriate dosage depends on factors such as the subject (e.g., human or non-human mammal), the age of the subject, the general condition of the subject, and / or the severity of the symptoms. Thus, an "effective amount" of a topical composition will fall within a relatively broad range that can be determined by testing and experimentation. The method can include measuring outcomes such as redness, inflammation, skin thickness, skin texture, skin dryness, lesion size, number of lesions, or itching (pruritus).

[0109] The topical composition can be applied in a single application or multiple applications. In some embodiments, the topical composition is applied as needed. For example, twice a week, three times a week, four times a week, five times a week, once a day, twice a day, three times a day, four times a day or more times. Application can last for hours, days, months or years. In some embodiments, the topical composition is applied for at least 7 days, for example, at least 10 days, at least 14 days, at least 20 days, at least 24 days, at least 28 days, at least 32 days, at least 36 days or longer. In some examples, the topical composition is applied for at least 7 days. In some embodiments, the topical composition is applied for at least one week, for example, at least two weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 12 weeks or longer. In some examples, the topical composition is applied in the rest of the subject's life. In some examples, the topical composition is applied once a day for one week, two weeks, three weeks, four weeks, six weeks, eight weeks, twelve weeks or longer. In some instances, the topical composition is applied at least four times per week for one, two, three, four, six, eight, twelve, or more weeks. In some instances, the topical composition is applied at least three times per week for one, two, three, four, six, eight, twelve, or more weeks. In a non-limiting example, the topical composition is applied once a day for the rest of the subject's life.

[0110] In some embodiments, the method also includes applying a topical UV protectant, antibiotic, steroid (e.g., corticosteroid), nonsteroidal anti-inflammatory agent, calcineurin inhibitor, JAK inhibitor, analgesic, α2-adrenergic receptor agonist, α1A-adrenergic receptor agonist, vitamin (e.g., vitamin A, B, C, D or E) or a combination thereof to the subject. Exemplary topical UV protectants, antibiotics, steroid (e.g., corticosteroid), nonsteroidal anti-inflammatory agent, calcineurin inhibitor, JAK inhibitor, analgesic, α2-adrenergic receptor agonist, α1A-adrenergic receptor agonist, vitamin are provided herein. Additional active ingredients may be applied before, during and / or after the topical composition is applied.

[0111] Example

[0112] The following examples are provided to illustrate particular features and / or embodiments. These examples should not be construed as limiting the disclosure to the particular features or embodiments described.

[0113] Example 1

[0114] Optimization of β-alanine concentration

[0115] β-Alanine powder (GNC, #369898) was mixed into In cream. The ingredients of the cream include water, aloe Barbadensis leaf juice, cyclopentasiloxane, disodium EDTA, emulsifying wax NF, ethylhexylglycerin, ethylhexyl stearate, phenoxyethanol, sorbitol and tocopheryl acetate. Stir the mixture until it is homogeneous.

[0116] A group of patients without skin diseases were selected for testing (n=16). The physician applied 0.1 ml of the cream to the cheek skin of each patient. Within 5 minutes, the patient reported the intensity of pruritus (itching) on ​​a scale of 0 (no itch) to 10 (worst itch). The process was repeated for all four formulations (0%, 2.5%, 5.0% or 7.5% w / w beta-alanine) on different areas of cheek skin. The efficacy of topical beta-alanine was determined based on the development of pruritus. Although significant pruritus occurred at the 2.5%, 5.0% and 7.5% doses, the itching was most severe at the 5.0% dose and did not increase further at the 7.5% dose ( Figure 1 ). Therefore, a 5% concentration of beta-alanine was selected for further study. The pruritus caused by topical application of beta-alanine cream was transient and lasted less than 5 minutes.

[0117] Example 2

[0118] Optimization of menthol concentration

[0119] Although beta-alanine has beneficial effects when applied to the skin, topical application can also cause transient pruritus, limiting its potential use and applications. Menthol was selected for testing as an agent that could mask short-term pruritus when added to a topical composition containing beta-alanine. Because menthol can cause eye irritation, the following study was designed to determine whether tolerable concentrations of menthol could relieve beta-alanine-induced pruritus.

[0120] A group of patients without inflammatory skin disease (n=10) were given four different facial topical preparations. All four preparations contained 5% w / w beta-alanine in a cream (see, e.g., Example 1), but each formulation contained a different concentration of menthol (0.0%, 0.5%, 1.0%, and 1.5% w / w). The physician sequentially applied 0.1 ml of each formulation to different areas of the cheek, with 10 minutes between each application. The patient was asked to rate the intensity of itching and overall discomfort on a scale of 0 (no itching) to 10 (maximum itching) over a period of 5 minutes. The same procedure was repeated for formulations containing 0.5%, 1.0%, and 1.5% w / w menthol. Itching was significantly reduced at all concentrations of menthol ( Figure 2A ). However, use of beta-alanine creams containing 1.0% and 1.5% menthol increased overall discomfort due to eye irritation and an unpleasant cooling sensation ( Figure 2B ).

[0121] A 0.5% concentration of menthol successfully reduced itching intensity without causing eye discomfort and will be selected for further testing.

[0122] Example 3

[0123] Clinical Trial Example - Facial Segmentation

[0124] An exemplary clinical trial design is described below for testing topical application of different concentrations of beta-alanine and 0.5% w / w menthol in patients with rosacea. Although testing is performed in patients with rosacea as an example, patients with other diseases (e.g., chronic flushing or inflammatory skin diseases) may be selected and tested in a similar manner.

[0125] A cohort of patients with a history of chronic rosacea facial flushing (duration >6 months, frequency >2x / week based on historical report) was selected. On admission, each patient was assessed at baseline using photographs, measurement of redness, and a clinician's erythema assessment. Patients were interviewed to determine triggers, family history, and characteristics of flushing (e.g., burning sensation).

[0126] The test composition was prepared by mixing 1%, 2% or 5% w / w β-alanine with 0.5% w / w menthol in any suitable lotion or cream as a base (e.g. The vehicle is a lotion or cream base without β-alanine and menthol. The patient is instructed to apply the vehicle to 1 / 2 of the face (e.g., the left side of the face) and the test composition (1%, 2% or 5% β-alanine with 0.5% menthol) to the other 1 / 2 of the face (e.g., the right side of the face) once a day for 4 weeks. The patients and doctors were blinded throughout the study.

[0127] Patients took pictures of their own faces each week at a fixed time (e.g., Sunday evening after removing makeup). Patients also took pictures of themselves when they noticed flare-ups. Patients kept a daily journal of events after application, noting the frequency of flushing and any sensations (e.g., burning) during flushing episodes, focusing on the right side of the face versus the left side (Patient Self-Assessment (PSA)).

[0128] After 4 weeks, the doctor evaluated the patient's condition using photographs, redness measurements, and clinical erythema assessments, with an emphasis on comparing the right and left sides of the face.

[0129] A similar design can be used to test different concentrations of menthol, for example, instead of testing 0.5% w / w menthol with different concentrations of β-alanine as described above, a certain concentration of β-alanine (e.g., 5% w / w) can be tested in a similar manner with different concentrations of menthol (e.g., 0, 0.25%, 0.5%, 1%, 1.5%, or 2% w / w). In addition, other TRPM8 agonists can be used in place of menthol and similarly tested as described herein.

[0130] Example 4

[0131] Clinical trial example - entire face

[0132] An exemplary clinical trial design is described below for testing the topical application of various compositions in patients with rosacea. Although testing in patients with rosacea is provided as an example, patients with other inflammatory skin diseases may be selected and tested in a similar manner.

[0133] A cohort of patients with a history of chronic rosacea facial flushing (duration >6 months, frequency >2x / week based on historical report) were selected for the study. At admission, each patient was assessed at baseline using photographs, measurement of redness, and a clinician's erythema assessment. Patients were interviewed to determine triggers, family history, and characteristics of the flushing (e.g., burning sensation).

[0134] The test composition was prepared by mixing 1%, 2% or 5% w / w β-alanine with 0.5% w / w menthol in any suitable lotion or cream as a base (e.g. The vehicle is a lotion or cream base without β-alanine and menthol. The patients are instructed to apply the vehicle or the test composition (1%, 2% or 5% w / w β-alanine with 0.5% w / w menthol) to the entire face once a day for 4 weeks. The patients and doctors will be blinded throughout the study.

[0135] Patients took pictures of their own faces at a fixed time each week (e.g., Sunday evening after removing makeup). Patients also took pictures of themselves when they noticed a flare-up. Patients kept a daily record of events after application, noting the frequency of flushing and any sensations (e.g., burning) during flushing episodes (Patient Self-Assessment (PSA)).

[0136] After 4 weeks, doctors assessed patients' conditions using photographs, redness measurements, and clinical erythema assessments. The primary outcome was the number and intensity of flushing episodes.

[0137] A similar design can be used to test different concentrations of menthol, for example, instead of 0.5% menthol with different concentrations of β-alanine as described above, a certain concentration of β-alanine (e.g., 5% w / w) can be tested in a similar manner with different concentrations of menthol (e.g., 0, 0.25%, 0.5%, 1%, 1.5%, or 2% w / w). In addition, other TRPM8 agonists can be used in place of menthol and similar tests can be performed as described herein.

[0138] Obviously, the precise details of the methods or compositions described may be changed or modified without departing from the spirit of the described aspects of the present disclosure. We claim all such modifications and variations that come within the scope and spirit of the following claims.

Claims

1. A topical composition comprising an effective amount of β-alanine and an effective amount of a transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) agonist.

2. The topical composition of claim 1, wherein the TRPM8 agonist is menthol, icilin, crysim-1, borneol, linalool, geraniol, hydroxycitronellal, WS-12, Frescolat MGA, FrescolatML, PMD38, Coolact P, M8-Ag, Cooling Agent 10, or a combination thereof.

3. A topical composition according to claim 1 or 2, wherein the TRPM8 agonist is menthol.

4. A topical composition according to any one of the preceding claims, comprising: a) about 0.2% to about 15% by weight (w / w) of β-alanine; b) about 1% to about 10% w / w β-alanine; or c) about 2.5% to about 7.5% w / w beta-alanine.

5. A topical composition according to any one of the preceding claims comprising about 5% w / w β-alanine.

6. A topical composition according to any one of claims 3 to 5, comprising: a) from about 0.1% to about 5% w / w menthol; b) from about 0.1% to about 2% w / w menthol; or c) about 0.5% to about 1.5% w / w menthol.

7. A topical composition according to any one of claims 3 to 6 comprising about 0.5% w / w menthol.

8. A topical composition according to any one of claims 3 to 7 comprising about 5% w / w β-alanine and about 0.5% w / w menthol.

9. The topical composition according to any one of the preceding claims, further comprising a topical ultraviolet protectant (UV protectant).

10. The topical composition of claim 9, wherein the topical UV protectant comprises aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, drometrizole trisiloxane, homosalate, meladide, octocrylene, cinoxate, octisalate, oxybenzone, padimamate O, para-aminobenzoic acid (PABA), ensulazole, sulibenzone, titanium dioxide, triethanolamine salicylate, zinc oxide, ethylhexyl triazone, ecamsud, cilatriazole, bemotriazine, bis-octazoline, iron oxide, red veterinary petrolatum, kaolin, or a combination thereof.

11. The topical composition of any of the preceding claims, further comprising a topical antibiotic, antiparasitic, steroid, nonsteroidal anti-inflammatory agent, calcineurin inhibitor, JAK inhibitor, analgesic, alpha2-adrenergic receptor agonist, alpha1A-adrenergic receptor agonist, or a combination thereof.

12. The topical composition of any of the preceding claims, further comprising metronidazole, clindamycin, ketoconazole, itraconazole, clotrimazole, voriconazole, posaconazole, miconazole, corticosteroids, azelaic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), crisaborole, ivermectin, tacrolimus, pimecrolimus, ruxolitinib, brimonidine, oxymetazoline, or a combination thereof.

13. The topical composition according to any one of the preceding claims, wherein the topical composition does not comprise an anesthetic other than a TRPM8 agonist or a topical steroid.

14. The topical composition of any one of the preceding claims, wherein the topical composition does not comprise camphor or lidocaine.

15. The topical composition according to any one of the preceding claims, wherein the topical composition is formulated as an ointment, cream, gel or lotion.

16. The topical composition of claim 15, wherein the composition is formulated as an emollient or moisturizer.

17. A topical composition according to any preceding claim, formulated for facial application.

18. A topical composition according to any one of claims 1 to 14 formulated as a shampoo or soap.

19. A topical composition according to any one of claims 1 to 18 for use in reducing skin inflammation or redness in a subject.

20. A method of reducing inflammation or redness of the skin of a subject, comprising applying an effective amount of the topical composition of any one of claims 1 to 18 to an area of ​​the subject's skin affected by inflammation or redness.

21. The topical composition of claim 19 or the method of claim 20, wherein The subject is selected as a subject suffering from inflammatory skin diseases or chronic skin flushing.

22. The topical composition or method of claim 21, wherein the inflammatory skin disorder is rosacea, acute or chronic urticaria, dermatographism, mastocytosis, dermatitis, acne, psoriasis, or scleroderma.

23. The topical composition or method of claim 21, wherein the chronic skin flushing is induced by exercise, diet, or emotion.

24. The method of claim 20, wherein the area of ​​skin affected by inflammation or redness is a wound.

25. A method for reducing the frequency or duration of symptoms of rosacea in a subject, comprising: Subjects with rosacea were selected; and Topically administering an effective amount of a topical composition according to any one of claims 1 to 18 to an area of ​​the subject's skin affected by rosacea, thereby reducing the frequency or duration of rosacea symptoms in the subject.

26. The method of claim 25, wherein the rosacea is erythematotelangiectatic rosacea, papulopustular rosacea, or nodular rosacea.

27. The topical composition or method according to any one of claims 19 to 26, wherein the topical composition is applied once or twice daily.

28. The topical composition or method of any one of claims 19 to 27, wherein the topical composition is applied for at least seven days.

29. The topical composition or method of any one of claims 19 to 28, further comprising administering to the subject metronidazole, corticosteroids, azelaic acid, ivermectin, tacrolimus, pimecrolimus, ruxolitinib, crisaborole, brimonidine, oxymetazoline, or a combination thereof.

30. A method of reducing skin inflammation or redness in a subject, comprising: Select subjects with skin inflammation or redness; and applying an effective amount of a topical composition to the area of ​​skin affected by inflammation or redness, wherein the topical composition comprises beta-alanine and a transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) agonist, This reduces skin inflammation or redness.

31. The method of claim 30, wherein the subject suffers from rosacea, acute or chronic urticaria, dermatographism, mastocytosis, dermatitis, acne, psoriasis, or scleroderma.

32. The method of claim 30 or 31 , wherein the TRPM8 agonist is menthol.

33. The method of any one of claims 30 to 32, wherein the topical composition comprises: a) about 1% to about 15% by weight (w / w) β-alanine; b) about 2.5% to about 10% w / w β-alanine; or c) about 2.5% to about 7.5% w / w beta-alanine.

34. The method of any one of claims 30 to 33, wherein the topical composition comprises about 5% w / w β-alanine.

35. The method of any one of claims 32 to 34, wherein the topical composition comprises: a) from about 0.1% to about 5% w / w menthol; b) from about 0.1% to about 2% w / w menthol; or c) about 0.5% to about 1.5% w / w menthol.

36. The method of any one of claims 32 to 35, wherein the topical composition comprises about 0.5% w / w menthol.

37. The method of any one of claims 31 to 36, wherein the topical composition comprises about 5% w / w β-alanine and about 0.5% w / w menthol.

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