Topical preparations that reduce skin irritation or redness

Abstract

Topical compositions are disclosed that include β-alanine and a transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) agonist (e.g., menthol). Methods of reducing skin inflammation or redness in a subject and reducing the frequency or duration of symptoms of an inflammatory skin condition (e.g., rosacea) are also disclosed. In some implementations, the topical composition includes about 0.2% to about 15% weight / weight (w / w) β-alanine, such as about 1% to about 10% w / w β-alanine, or about 2.5% to about 7.5% w / w β-alanine.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This case claims the benefit of U.S. Provisional Patent Application No. 63 / 316,158, filed March 3, 2022, which is incorporated by reference herein.

[0002] Field The present disclosure relates to cosmetic products, specifically topical compositions, and their use for reducing inflammation or redness of the skin. [Background technology]

[0003] background Cutaneous mast cells are skin-resident immune cells that respond rapidly to allergens by releasing granules containing inflammatory mediators (e.g., histamine and serotonin). Mast cells play an important role in both adaptive and innate immunity, but many inflammatory skin conditions involve mast cell activation, including rosacea, urticaria, mastocytosis, allergies, dermatitis, acne, psoriasis, and scleroderma. Mast cell activation is also thought to be the etiology of other skin conditions, such as chronic flushing (e.g., due to alcohol flushing, or emotional responses), and is also involved in wound healing. Inflammation and / or redness of the skin, especially facial skin, can be embarrassing and painful for affected individuals. Inflammatory skin conditions are also often chronic conditions with no cure, requiring long-term management. Thus, topical compositions suitable for daily use that can reduce redness or inflammation are desirable. Summary of the Invention [Means for solving the problem]

[0004] Abstract Disclosed herein is 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. In some implementations, the topical composition comprises about 0.2% to about 15% weight / weight (w / w) β-alanine, e.g., about 1% to about 10% w / w β-alanine, or about 2.5% to about 7.5% w / w β-alanine. In some examples, the effective amount is about 5% w / w β-alanine. In some implementations, the TRPM8 agonist is menthol. In some implementations, the topical composition comprises about 0.1% to about 5% w / w menthol, e.g., about 0.1% to about 2% w / w menthol, or about 0.5% to about 1.5% w / w menthol. In some examples, the topical composition comprises about 0.5% w / w menthol. The topical composition may include additional agents such as topical UV protection agents, antibiotics, steroids, nonsteroidal anti-inflammatory agents, calcineurin inhibitors, JAK inhibitors, α2-adrenergic receptor agonists, α1A-adrenergic receptor agonists, or combinations thereof. In some implementations, the topical composition does not include anesthetics or topical steroids. The topical composition may be formulated in any suitable form for topical application, such as an ointment, cream, gel, lotion, shampoo, or soap. In some examples, the topical composition is formulated as an emollient or moisturizer and / or is formulated for facial application.

[0005] Also disclosed herein is a method of reducing inflammation or redness of the skin, the method comprising administering an effective amount of a topical composition described herein to an area of ​​the skin of the subject affected by inflammation or redness. In some implementations, the area of ​​the skin is affected by an inflammatory skin condition, chronic flushing, or wound. In some implementations, the method comprises selecting a subject having an inflammatory skin condition, chronic flushing, or wound. Also disclosed is a method of reducing the frequency, duration, or severity of rosacea symptoms in a subject. The method comprises selecting a subject having rosacea and administering a topical composition described herein to an area of ​​the skin affected by rosacea. In some examples, the subject has erythematotelangiectatic rosacea, papulopustular rosacea, and / or phymatous rosacea. In some implementations, the topical composition is administered repeatedly, e.g., chronically for days, weeks, months, or even the rest of the subject's life. In some implementations, the topical composition is administered several times a week (e.g., about 3, 4, 5, or 6 times a week), daily, or twice a day. In some examples, the method further includes administering a topical UV protection agent, an antibiotic, a steroid, a nonsteroidal anti-inflammatory agent, a calcineurin inhibitor, a JAK inhibitor, an analgesic, an alpha2-adrenergic receptor agonist, an alpha1A-adrenergic receptor agonist, or a combination thereof, before, after, or substantially simultaneously with the topical composition.

[0006] The foregoing and other objects, features and advantages of the present invention will become more apparent from the following detailed description which proceeds with reference to the accompanying drawings. [Brief description of the drawings]

[0007] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]FIG. 1 shows subjective patient-reported scoring of itch in patients whose faces were treated with creams containing the indicated concentrations of β-alanine. Four β-alanine formulations (0%, 2.5%, 5.0%, and 7.5% w / w β-alanine) were applied sequentially by a physician to different locations on the cheek skin of each patient. Subjective scoring of itch (0 (none) to 10 (maximum itch)) was recorded over a 5-minute period. Symbols above the bar graphs represent individual patients (n=16). Bar height indicates the mean value. Error bars represent ±SEM. **P<0.01; ****P<0.0001. P values ​​were calculated using nonparametric ANOVA Kruskai-Wallis test.

[0008] [Diagram 2] Figures 2A and 2B show subjective patient-reported scoring for itching (Figure 2A) and overall discomfort (Figure 2B) of creams applied to the face containing 5% w / w β-alanine and the indicated concentrations of menthol. Each of the four formulations (0%, 0.5%, 1.0%, and 1.5% w / w menthol with 5% w / w β-alanine) was applied sequentially by a physician to different locations on the cheek skin of each patient. Scoring was on a 0-10 scale (0 being no itching or discomfort, and 10 being maximum itching or discomfort). Each symbol represents an individual patient (n=10). Bar height indicates the mean. Error bars represent ±SEM. *P<0.05; **P<0.01. P values ​​were calculated using nonparametric ANOVA Kruskai-Wallis test. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description Although β-alanine can suppress mast cell activation, topical use of β-alanine is limited due to the occurrence of pruritus (itch) after application. The pruritus induced by topical β-alanine creams is transient, therefore combination with an agent that can mask β-alanine-induced pruritus for a short period of time may improve the tolerability of topical β-alanine compositions.

[0010] Although many compounds are reported to "suppress itch" when applied topically, most are unsuitable for long-term use and have the risk of undesirable side effects. For example, lidocaine and other related caine drugs (which are primarily used as anesthetics) can produce an unpleasant numbing of the skin that lasts much longer than the approximately 3 minutes required to suppress β-alanine-induced itch. Furthermore, lidocaine and other related caine drugs can also have a slower onset of action than β-alanine-induced itch, and therefore are not effective in reducing itch. Systemic absorption of these drugs also carries the risk of CNS and cardiac toxicity, especially in patients with liver disease, making them unsuitable for long-term use. Similarly, camphor (which is also primarily used as an anesthetic) can have undesirable side effects after systemic absorption.

[0011] Low potency topical steroids can also be used to suppress pruritus, but their onset of action is likely too slow to provide benefit in masking β-alanine-induced pruritus. Furthermore, application of topical steroids to the face can induce acne, exacerbate rosacea, and carry the risk of developing striae and steroid addiction, especially with long-term use. Topical preparations of moisturizers and colloidal oatmeal can improve barrier integrity and reduce pruritus in situations where the barrier is compromised (e.g., atopic dermatitis), but are unlikely to provide any benefit in masking β-alanine-induced pruritus.

[0012] The studies disclosed herein sought to identify compounds that could mask β-alanine-induced itch, yet were well tolerated and suitable for long-term use.

[0013] term Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. "Comprising A or B" means including A, or B, or A and B.

[0014] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. In case of conflict, the present specification (including explanations of terms) will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0015] In order to facilitate review of the various implementations of the present disclosure, the following explanations of specific terms are provided.

[0016] About: Unless the context clearly indicates otherwise, "about" refers to a range of ±5% of the reference value. For example, "about 100 grams" refers to 95 grams to 105 grams. In another example, "about 5%" refers to 4.75% to 5.25%.

[0017] Acne: An inflammatory disorder of the skin that can occur on skin that has sebaceous glands connected to hair follicles. In healthy skin, the sebaceous glands make sebum that travels to the skin surface through pores, which have openings in the hair follicle. With acne, the hair, sebum, and keratinocytes stick together inside the pores, preventing the sebum from reaching the skin's surface and causing the keratinocytes to slough off. The mixture of oil and cells allows bacteria to grow in the clogged hair follicle, causing inflammation. When the wall of the clogged hair follicle breaks down, it spills bacteria, skin cells, and sebum into the nearby skin, creating a lesion or pimple.

[0018] Administration: Providing or giving a drug to a subject by any effective route. Administration includes topical application.

[0019] Medication: Any substance or compound useful for achieving a particular outcome. For example, the medication may be a topical composition that may reduce skin redness or inflammation.

[0020] Analgesic: A drug that relieves pain. Non-limiting examples of topical analgesics include capsaicin, diclofenac, lidocaine, methyl salicylate, and trolamine salicylate.

[0021] Antibiotic: A compound or substance that kills or substantially slows the growth of bacteria, fungi, or other microorganisms. An "antibacterial" is a compound or substance that kills or substantially slows the growth of bacteria. An "antifungal" is a compound or substance that kills or substantially slows the growth of fungi.

[0022] β-alanine: A non-essential β-amino acid (sometimes referred to as 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 carboxylate group). The IUPAC name for β-alanine is 3-aminopropanoic acid. Purified β-alanine can be obtained commercially (e.g., Beyond Raw® Chemistry Labs TM Beta-alanine (GNC Item # 369898); or β-alanine (Sigma-Aldrich, #146064)).

[0023] Control: Reference standard. Control can be any suitable positive or negative control. Some non-limiting examples of control are provided for illustrative purposes. In one example, the control is a sample or measurement obtained from a subject before administering the topical composition of the present disclosure. Another exemplary control is a subject that is administered a topical composition without β-alanine, TRPM8 agonist, or both (blank vehicle), or is not administered any topical composition. In a further example, a suitable control is a historical control or a standard reference value or range of values ​​(e.g., a control sample obtained previously, or a group of samples that represent baseline or "normal" values).

[0024] The difference between the test sample (e.g., administering a topical composition of the present disclosure 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 examples, the difference is statistically significant. In some examples, the increase relative to the control is at least about 5%, e.g., 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 more than 500%. In some examples, the reduction relative to the control is at least about 5%, e.g., 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%.

[0025] Cosmetically acceptable vehicle: Many suitable cosmetically acceptable vehicles (carriers) (e.g., pharma- ceutically acceptable carriers) have been described. For example, Remington: The Science and Practice of Pharmacy, 23rd Edition (Academic Press), 2021 (ISBN 9780128200070) describes compositions and formulations suitable for delivery of topical compositions. Use of the term "pharma-ceutically acceptable carrier" does not suggest that the product is useful only for pharmaceutical purposes. Rather, it suggests that the product is suitable for administration or consumption by a subject (e.g., a human). In certain implementations, the vehicle is a carrier for a topical composition (e.g., a liquid, gel, foam, cream, ointment, or lotion). Particularly useful vehicles are those that are cosmetically acceptable for topical application (e.g., 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).

[0026] The topical composition disclosed herein can be formulated in any suitable product form. Such product forms include, but are not limited to, aerosol spray, cream, dispersion, emulsion, foam, gel, liquid, lotion, mousse, ointment, patch, pomade, powder, pump spray, solid, liquid, stick, towelette, etc. The carrier can also be various existing skin lotions, gels, creams, ointments, toners, cleansers, moisturizers or sunscreens to which the topical composition of the present disclosure is added at desired concentration.

[0027] Dermatitis: A general term for skin inflammation. It has many causes and forms. It is usually accompanied by itching, dry skin or a rash. In some instances, it may 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 commonly 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 flare-ups, patches of skin may appear rough, dry, and itchy. Seborrheic dermatitis (e.g., dandruff or cradle cap) is most common 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. The exact cause of seborrheic dermatitis is unknown, but stress or lack of sleep can exacerbate the condition. Contact dermatitis occurs when a substance causes an adverse inflammatory response upon contact with the skin. These responses can develop into a rash that burns, stings, itches, or becomes blistering. Contact dermatitis can be the result of an allergic or irritant reaction. With irritant contact dermatitis, a foreign substance directly damages the skin and triggers a reaction. With allergic contact dermatitis, a foreign substance may not directly damage the skin, but triggers a reaction of the immune system in a way that can cause skin damage. Other types of dermatitis include asteatotic dermatitis, diaper dermatitis, dyshidrotic dermatitis, neurodermatitis, nummular dermatitis, perioral dermatitis / periorificial dermatitis, stasis dermatitis, and dermatitis neglecta.

[0028] Dermatographia: An inflammatory skin condition that produces raised welts or a localized honeycomb-like reaction when individuals scratch their skin. It can also occur when the skin is exposed to pressure or friction. The condition is also called skin writing, dermographia, or dermatographic urticaria.

[0029] Effective amount: A sufficient amount of an agent (e.g., a topical composition) to obtain a desired result (e.g., to reduce skin redness or inflammation). In some implementations, the effective amount of the topical composition of the present disclosure is an amount that reduces skin redness or inflammation or inhibits mast cell activation. In some implementations, the effective amount of β-alanine is an amount that reduces skin redness or inflammation. In some examples, the effective amount of β-alanine is an amount that inhibits mast cell activation. In some implementations, the effective amount of TRPM8 agonist is an amount that inhibits transient β-alanine-induced itch. The effective amount can be administered, for example, daily, in a single dose, or in several doses. However, the effective amount can depend on the subject, the condition of the subject, and the mode of administration.

[0030] Excipient: An inert substance used as a carrier for the active ingredient of the composition. Excipients may include substances used to bulk formulations containing the active ingredient, allow convenient and accurate dosing, stabilize the active ingredient, and make the delivery system optically and / or organoleptically acceptable. Examples of cosmetically acceptable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.

[0031] Extract: A solution or other preparation of at least some of the active ingredients of one or more of a plant or parts thereof (e.g., its roots, shoots, leaves, fruits, or seeds). The extract may be a solvent extract, for example, when the plant or plant parts are exposed to a liquid extraction solvent (e.g., water, alcohol, acetone, dichloromethane, or chloroform) to remove the active ingredients. The extract initially obtained by solvent extraction may be converted to a dry form but still be considered an "extract".

[0032] Increase or decrease: a positive or negative change, respectively, relative to a control value. An increase is a positive change (e.g., 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 the control value). The increase may be, for example, within the range of 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%.

[0033] 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 may be in the range of, for example, 25%-100%, 25%-98%, 25%-95%, 25%-90%, 25%-80%, 25%-70%, 25%-50%, 50%-100%, 75%-100%, 90%-100%, 95%-100%, 98%-100%, 99%-100%, 50%-75%, 50%-80%, 50%-90%, 50%-95%, 50%-98%, 75%-80%, 75%-90%, 75%-95%, or 75%-98%.

[0034] Inflammation: A localized biological reaction that can result in redness, swelling, and pain as a result of an injurious stimulus (including infection, irritation, injury, or disease). Inflammation can be chronic or acute. Immune cells (e.g., dermal mast cells) initiate the inflammatory response, releasing inflammatory mediators (e.g., histamine, pro-inflammatory cytokines, or serotonin) that are responsible for increased blood flow and leakage of plasma fluid into the affected tissue.

[0035] Inflammatory skin condition: A skin condition associated with inflammation. Non-limiting examples include rosacea, acute or chronic urticaria, dermatographia, mastocytosis, dermatitis, acne, psoriasis, and scleroderma.

[0036] Mast cells: A type of resident inflammatory cell found in the dermal layer of the skin. Mast cell activation aids in the induction of inflammation by rapidly releasing a variety of favorable mediators (e.g., histamine, serotonin, proteases, and proinflammatory cytokines) stored within mast cell granules. 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 (e.g., heat and mechanical injury). Furthermore, significant mast cell activation is observed in the early stages of wound healing.

[0037] Mastocytosis: A condition caused by 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, resulting in symptoms similar to allergic reactions. Flushing, caused by mast cell-associated histamine release, is a common symptom. In some cases, the release of large amounts of chemicals from mast cells (degranulation) can lead to a life-threatening episode of anaphylaxis (anaphylactic shock). The most common triggers include, but are not limited to, insect stings, physical stress (heat, cold, mechanical irritation of the skin, exercise), emotional stress, alcohol, spicy foods and drugs (including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS), narcotics, muscle relaxants, x-ray imaging agents, among others).

[0038] 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 can also occur on the scalp, neck, trunk, and extremities. Solitary cutaneous mastocytoma is a localized form of cutaneous mastocytosis. Typically, there is a single lesion or up to three individual lesions, which are usually found early in life and resolve spontaneously with age. Diffuse cutaneous mastocytosis is the most severe form of cutaneous mastocytosis. The skin is diffusely thickened and coarse-textured, and generally has no individual, well-defined lesions. Additional symptoms associated with DCM include itching, blistering, drop in blood pressure (hypotension), diarrhea, gastrointestinal bleeding, redness of the skin (flushing) and anaphylactic shock.

[0039] Menthol: A monoterpenoid that can be synthetically produced or obtained from oils of corn, mint, peppermint, or other mints. The preferred IUPAC name for menthol is 5-methyl-2-(propan-2-yl)cyclohexan-1-ol. Refined menthol can be obtained commercially (e.g., menthol essential oil (Oakland Gardens, 100% pure Mentha arvensis extract); or menthol (Sigma-Aldrich, #M2772)).

[0040] Psoriasis: An immune-mediated disease of the skin that causes visible signs of inflammation, such as raised plaques on the skin (plaques may look different on different skin types) and scales on the skin. Red, itchy, scaly patches are most commonly found on the knees, elbows, trunk and scalp. Psoriasis is a chronic disease with no cure. Symptoms tend to come in cycles of flare-ups over weeks or months, then subside or go into remission for a period of time.

[0041] Rosacea: A chronic inflammatory skin disease characterized by erythema, papules, telangiectasias, edema, pustules, or a combination of these symptoms. Skin lesions commonly occur on the central face (e.g., cheeks, forehead, chin, and nose). Individuals with rosacea may also experience rhinophyma, flushing, or a stinging, pain, or burning sensation. Signs and symptoms may flare up over a period of weeks to months and then resolve over a period of time. The underlying cause of rosacea is unknown, but abnormalities in the innate immune system and neurovascular dysregulation have been implicated. Additionally, certain factors (e.g., acne mite (mite) colonization, microbial irritation, ultraviolet (UV) radiation, heat, and stress) may initiate a flare-up or exacerbate rosacea. Clinically, rosacea can be categorized into papulopustular, erythematous telangiectatic, ocular, and phymatous rosacea.

[0042] Scleroderma: A chronic autoimmune disease that affects the skin and other organs of the body. Scleroderma is characterized by thickening and tightening of the skin along with inflammation and scarring in many body parts, leading to problems in the lungs, kidneys, heart, intestinal system and other areas. Localized scleroderma typically affects only the skin, but can also affect muscles, joints and bones. It does not affect internal organs. Symptoms include discolored patches on the skin (patellar scleroderma); or streaks or bands of thick, hard skin on the arms and legs (linear scleroderma). When linear scleroderma occurs on the face and forehead, it is called morphea en sabre. Systemic scleroderma is the most severe 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 sclerosis: limited cutaneous systemic sclerosis (previously called CREST syndrome) and diffuse cutaneous systemic sclerosis.

[0043] Skin care composition: A topical composition having active ingredients that can improve the condition, health, aesthetics and / or cosmetic appearance of the skin. Such improvement can be, for example, reducing redness or inflammation of the skin. In some implementations, the topical compositions disclosed herein are skin care compositions.

[0044] Skin flushing or flush: Sudden reddening of the face, neck, or upper chest due to increased blood flow. Skin flushing can be triggered by emotions (e.g., embarrassment, stress, anger, or excitement). Other triggers include diet (e.g., alcohol use, hot or spicy foods), hormonal changes, hot flashes from menopause, exercise, sudden changes in temperature or heat exposure, and certain medications.

[0045] Subject: A living multi-cellular vertebrate animal, a category that includes humans and non-human mammals (e.g., non-human primates). In some examples, the subject is a human. In some implementations, the subject has a chronic skin flush or an inflammatory skin condition.

[0046] Topical composition: A composition formulated for topical application, typically applied externally to a particular body surface. For example, the topical composition may be applied topically to the skin (e.g., to lesions or areas of the skin affected by redness or inflammation). In some examples, the topical compositions described herein are applied topically to facial skin. A topical composition intended for application to the skin is a "skin care composition."

[0047] Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8): A thermoregulated, nonselective Ca channel activated by cold or TRPM8 agonists. 2+ Permeable cation channel. 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 constitute the pore, a nonselective cation channel consisting of highly conserved hydrophobic regions. Upon activation, the channel allows Na+, Na++, and Na++ into the cell. + and Ca 2+It allows the entry of ions, resulting in depolarization and the generation of action potentials. The signal is conducted down the primary afferent fibers, ultimately resulting in the sensation 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 / )).

[0048] Treating, treatment, or therapy: A therapeutic intervention that ameliorates the signs or symptoms of a disease or pathological condition (including objective or subjective parameters such as abatement, remission, slowing the rate of degeneration or decline, or improving the physical or mental well-being of a subject). Treatment may be evaluated by objective or subjective parameters (including physical examination, patient self-assessment, blood or other laboratory tests, etc.). A "prophylactic" treatment is a treatment administered to a subject for the purpose of reducing the risk of developing a disease or pathological condition.

[0049] TRPM8 agonist: A drug that activates TRPM8. Non-limiting examples include: menthol, borneol, linalool, geraniol, hydroxy-citronellal, 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-methylcyclohexan-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 methoxypropanediol). See also Behrendt et al., (2004) Br J Pharmacol. 141(4): 737-745.

[0050] Ultraviolet protection agent (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, meladimate, octocrylene, octinoxate, octisalate, oxybenzone, padimate O, para-aminobenzoic acid (PABA), ensulizole, sulisobenzone, titanium dioxide, trolamine salicylate, zinc oxide, ethylhexyl triazone, ecamsule, silatriazole, bemotrizinol, bisoctrizole, iron oxide, red veterinary petrolatum, and kaolin clay.

[0051] Unit dose: A physically discrete unit containing a predetermined amount of active material calculated to individually or collectively produce a desired effect. A single unit dose or multiple unit doses can be used to provide a desired effect or activity (e.g., reducing redness or irritation of the skin). In another example, the unit dosage form contains a multiple of the predetermined dose.

[0052] Urticaria: A condition commonly known as hives. Hives can be triggered by many things, including certain foods, medicines, and stress. Symptoms include itchy, raised, red, or skin-colored welts on the skin surface. Acute urticaria is the most common type. Symptoms typically last less than six weeks and can be caused by insect bites or stings, medicines, infections, or consuming certain foods, such as nuts, chocolate, fish, tomatoes, eggs, berries, or milk. Chronic urticaria symptoms last for more than six weeks. The cause of chronic urticaria is usually difficult to identify and often remains unknown.

[0053] There are many physical urticaria, which is urticaria that appears in response to physical stimuli.For example, papular urticaria is a condition where an individual develops urticaria as an allergic reaction to the bites of insects such as mosquitoes, fleas, mites, crickets or bedbugs.Cholinergic urticaria is a condition where an individual develops urticaria as an allergic reaction caused by an increase in body temperature.Cold urticaria is a condition where an individual develops urticaria when exposed to cold, and solar urticaria is a condition where an individual develops urticaria due to exposure to sunlight.

[0054] I. Topical Compositions Disclosed herein is a topical composition comprising an effective amount of β-alanine and an effective amount of a TRPM8 agonist.In some implementations, the effective amount of β-alanine is the amount of β-alanine that reduces skin inflammation or redness when applied topically.In some examples, the effective amount of β-alanine reduces skin mast cell activation when applied topically.In some implementations, the effective amount of TRPM8 agonist is the amount that reduces the transient itching induced by β-alanine.In some implementations, the effective amount of TRPM8 agonist is the amount that reduces the transient itching induced by β-alanine without causing eye irritation when applied to the facial skin (e.g., cheek) of a subject.

[0055] The topical composition comprises an amount of β-alanine effective to reduce skin inflammation or redness and / or skin mast cell activation when topically applied to a subject. In some implementations, the topical composition comprises about 0.2% to about 20% weight / weight (w / w) β-alanine. In some examples, 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% ~ 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% ~ 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 about 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 β-alanine. In some examples, the topical composition comprises 0.2% to 15% w / w β-alanine. In some examples, the topical composition comprises 1% to 10% w / w β-alanine. In some examples, the topical composition comprises 5% to 10% w / w β-alanine.In some examples, the topical composition comprises 2.5% to 10% w / w β-alanine. In further examples, the topical composition comprises 2.5% to 7.5% w / w β-alanine.

[0056] In some implementations, 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 β-alanine. In some examples, the topical composition comprises about 5% w / w β-alanine.

[0057] 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 β-alanine. In some examples, the topical composition comprises no more than about 15% β-alanine.

[0058] The topical composition can include any suitable TRPM8 agonist that can be formulated in topical composition, and when it is applied topically to a subject, it is effective in reducing the transient itch induced by β-alanine in the topical composition.Non-limiting examples of suitable TRPM8 agonists include menthol, icilin, crysim-1, borneol, linalool, geraniol, hydroxy-citronellal, WS-12, Frescolat MGA, Frescolat ML, PMD 38, Coolact P, M8-Ag, Cooling Agent 10, or combinations thereof.In some examples, the TRPM8 agonist is menthol, icilin, or combinations thereof.In some implementations, the TRPM8 agonist is menthol.

[0059] The topical composition comprises an amount of a TRPM8 agonist effective to reduce transient itch induced by β-alanine in the topical composition when topically applied to a subject. In some implementations, the topical composition comprises about 0.1% to about 20% weight / weight (w / w) of a TRPM8 agonist. In some examples, the topical composition may comprise from about 0.1% to about 19%, from about 0.1% to about 18%, from about 0.1% to about 17%, from about 0.1% to about 16%, from about 0.1% to about 15%, from about 0.1% to about 14%, from about 0.1% to about 13%, from about 0.1% to about 12%, from about 0.1% to about 11%, from about 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 15%, from about 0.1% to about 16%, from about 0.1% to about 17%, from about 0.1% to about 18%, from about 0.1% to about 19%, from about 0.1% to about 20%, from about 0.1% to about 25%, from about 0.1% to about 26%, from about 0.1% to about 27%, from about 0.1% to about 28%, from about 0.1% to about 30%, from about 0.1% to about 35%, from about 0.1% to about 36%, from about 0.1% to about 37%, from about 0.1% to about 38%, from about 0.1% to about 39%, from about 0.1% to about 40%, from about 0.1% to about 42%, from about 0.1% to about 44%, from about 0.1% to about 46%, from about 0.1% to about 48%, from about 0.1% to about 49%, from 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 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 The composition comprises 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 of a TRPM8 agonist.In some examples, the TRPM8 agonist is menthol. In some examples, the topical composition comprises 0.1%-5% w / w menthol. In some examples, the topical composition comprises 0.1%-2% w / w menthol. In some examples, the topical composition comprises 0.2%-1% w / w menthol. In further examples, the topical composition comprises 0.5%-1.5% w / w menthol.

[0060] In some implementations, 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 of the TRPM8 agonist. In some examples, the TRPM8 agonist is menthol. In some examples, the topical composition comprises about 0.5% w / w of menthol.

[0061] In other implementations, the topical composition comprises 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 or less of a TRPM8 agonist. In some examples, the TRPM8 agonist is menthol. In some examples, the topical composition comprises about 5% or less of menthol. In another example, the topical composition comprises about 1% or less of menthol.

[0062] In non-limiting examples, the topical composition comprises about 0.2% to about 15% w / w β-alanine and about 0.1% to about 5% w / w menthol. In some examples, the topical composition may comprise about 0.2% to about 15% w / w β-alanine and about 0.1% to about 2% w / w menthol. In some examples, the topical composition comprises about 0.2% to about 15% w / w β-alanine and about 0.2% to about 1% w / w menthol. In some examples, the topical composition comprises about 1% to about 10% w / w β-alanine and about 0.1% to about 5% w / w menthol. In some examples, the topical composition comprises about 1% to about 10% w / w β-alanine and about 0.2% to about 2% w / w menthol. In some examples, the topical composition comprises about 5% to about 10% w / w β-alanine and about 0.1% to about 5% w / w menthol. In some examples, the topical composition comprises about 5% to about 10% w / w β-alanine and about 0.1% to about 2% w / w menthol. In some examples, the topical composition comprises about 5% to about 10% w / w β-alanine and about 0.2% to about 1% w / w menthol. In some examples, the topical composition comprises about 2.5% to about 7.5% w / w β-alanine and about 0.5% to about 1.5% w / w menthol.

[0063] In some implementations, the topical composition comprises beta-alanine and menthol in amounts useful for reducing redness or inflammation when administered to skin affected by redness or inflammation.

[0064] In some implementations, the topical compositions of the present disclosure further comprise additional ingredients, such as a topical UV protection agent, an antibiotic, an antiparasitic agent, a steroid (e.g., a corticosteroid), a nonsteroidal anti-inflammatory agent, a calcineurin inhibitor, a JAK inhibitor, an analgesic, an alpha2-adrenergic receptor agonist, an alpha1A-adrenergic receptor agonist, a vitamin (e.g., vitamin A, C, or E), a ceramide, an extract or other natural product, or a combination thereof.

[0065] Non-limiting examples of suitable topical UV protection agents include aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, drometrizole trisiloxane, homosalate, meladimate, octocrylene, octinoxate, octisalate, oxybenzone, padimate O, para-aminobenzoic acid (PABA), ensulizole, sulisobenzone, titanium dioxide, trolamine salicylate, zinc oxide, ethylhexyl triazone, ecamsule, scilatriazole, bemotrizinol, bisoctrizole, iron oxide, red veterinary petrolatum, and kaolin clay. The UV protection agent may be added in an amount to provide a sun protection factor (SPF) of at least 5, for example, about SPF 5, about SPF 10, about SPF 15, about SPF 20, about SPF 25, about SPF 30, about SPF 35, about SPF 40, about SPF 45, about SPF 50, about SPF 55, about SPF 60, about SPF 65, about SPF 70, about SPF 75, about SPF 80 or greater. In some examples, the UV protection agent is added in an amount to provide a sun protection factor (SPF) of 5 to 80. In some examples, the UV protection agent is added in an amount to provide a sun protection factor (SPF) of 15 to 80. In some examples, the UV protection agent is added in an amount to provide a sun protection factor (SPF) of 15 to 40.

[0066] Topical antibiotics are antibiotics that are applied to a body surface. Antibiotics may target bacteria, fungi, or any other microorganism. Antibiotics may include active agents such as macrolide antibiotics (e.g., erythromycin), sulfa antibiotics (e.g., sulfacetamide), cyclic peptides (e.g., bacitracin, polymyxin), psuedomonic acids (e.g., mupirocin), ammyroglycosides (e.g., neomycin), or quinolones (e.g., ciprofloxacin or ofloxacin), nitroimidazoles (e.g., metronidazole), or combinations of active ingredients (e.g., bacitracin / polymyxin or neomycin / polymyxin B / bacitracin). The antibiotics may be narrow spectrum or broad spectrum. "Narrow spectrum" antibacterial antibiotics may target a specific type of bacteria (e.g., gram-negative or gram-positive bacteria). "Broad spectrum antibiotics" may affect many different types of bacteria. Antibacterial agents also include cyclic lipopeptides (e.g., daptomycin), glycylcyclines (e.g., tigecycline), and oxazolidinones (e.g., linezolid). In some examples, the topical antibiotic is an azole antifungal agent (e.g., ketoconazole, itraconazole, clotrimazole, voriconazole, posaconazole, or miconazole). In some examples, the topical antibiotic is clindamycin, metronidazole, cyclosporine, or azathioprine.

[0067] Antiparasitic agents are used in the management and treatment of infections by parasites (e.g., protozoans, helminths, and ectoparasites (e.g., fleas, lice, or ticks). Suitable topical antiparasitic agents include, but are not limited to, ivermectin, lindane, permethrin, benzyl alcohol, malathion, and crotamiton.

[0068] Suitable topical steroids include amcinonide, beclomethasone, betamethasone, clobetasol, clobetasone, desonide, desoximethasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, mometasone, prednicarbate, and triamcinolone. In some implementations, the steroid is a corticosteroid. Exemplary corticosteroids include hydrocortisone, clobetasone, beclomethasone, betamethasone, fluticasone, clobetasol, and mometasone.

[0069] 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. Different NSAIDs have different structures, but they all target (block) cyclooxygenase (COX) enzymes. Exemplary NSAIDs that can be applied topically include diclofenac (including diclofenac sodium and diclofenac hydroxyethylpyrrolidine), ibuprofen, ketoprofen, felbinac, 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.

[0070] The topical composition can comprise one or more topical calcineurin inhibitors.Calcineurin inhibitors are immunosuppressive drugs that block T cell proliferation by inhibiting the signal transduction phosphatase calcineurin.Exemplary topical calcineurin inhibitors include cyclosporine, tacrolimus and pimecrolimus.

[0071] The topical composition can 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 composition disclosed herein can also include topical alpha2-adrenergic receptor agonists (e.g., brimonidine), alpha1A-adrenergic receptor agonists (e.g., oxymetazoline), or combinations thereof.

[0072] The topical composition may contain vitamins. Non-limiting examples of vitamins include vitamin A (retinol and its analogs (e.g., retinyl palmitate)), any of the 12 B-complex vitamins (e.g., thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), B6, biotin (B7), folic acid (B9), B12, and their analogs), vitamin C (and its analogs (e.g., magnesium ascorbyl phosphate, ascorbyl palmitate, etc.)), vitamin D (e.g., calcitriol (D3)), and vitamin E (tocopherol and its analogs (e.g., tocopheryl acetate)).

[0073] 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.

[0074] In some implementations, the topical composition includes natural products, such as plant extracts (including tinctures), from, for example, Arnica montana (commonly known as wolf's bane, leopard's bane, mountain tobacco, and mountain arnica), Symphytum (comfrey), Sesamum indicum (sesame), soybean, Camellia sinensis (green, black, or white tea), Matricaria recutita (chamomile), Coffea arabica (coffee or coffee berry), almond, angelica root, acacia, aloe, althea anise, apple, avocado, basil, bayberry, bilberry, blue malva, flower), blackberry, burdock, borage, bergamot, buchu, cannabis, cranberry, clover flower, calendula, clove, carrot, cinchona bark, cinnamon, clary sage, coltsfoot, cornflower, cranesbill, cucumber, dandelion, dulse, eucalyptus, echinacea, elderberry, fennel, fenugreek Leek, garlic, gentian root, geranium, ginkgo, ginseng, grapefruit, grape seed, goldenseal, hops, hawthorn, henna, horse chestnut, horsetail, hibiscus, ivy, Irish moss, jasmine, juniper berry, kelp, kiwi, linden flower, lovage, lavender, lemongrass, lemon peel, myrrh, mallow, meadowsweet sweet)(mayflower), melon, mint, melilot (hayflower), milk thistle, nettle, oatmeal, orange blossom, orange peel, oakmoss, peach, plantain, parsley, peppermint, primrose, papaya, cassia, quince, rosebud, rosehip, rosemary, sage, sambucuselder, slippery elm bark, spearmint, sambucus, sandalwood, artemisia, strawberry, sunflower, St. John's wort, tangerine, tansy, thyme, tomato, bearberry, violet, white lily, valerian root, watercress, walnut (bblack walnut), birch, white willow bark, wild indigo, witch hazel, yucca, yarrow, or other plant sources.

[0075] The topical composition may include synthetic or naturally derived phytochemicals such as sesquiterpene lactones, rosmarinic acid, sesamin, sesamol, sesaminol, sesamolin, isoflavones (e.g., genistein and daidzein), polyphenolics (e.g., chlorogenic acid, ferulic acid, quinic acid, and condensed proanthocyanidins), epigallocatechin-3-gallate (EGCG), flavonoids (e.g., quercetin, theaflavin, kaempferol, apigenin, luteolin, rutin), catechins, terpenoids (e.g., bisoprole, matrysin, levomenol, chamazulene), caffeine, or combinations thereof.

[0076] The topical composition may include one or more topical analgesics and / or anesthetics. An analgesic is a drug that relieves pain. An anesthetic is a substance that induces a temporary loss of sensation, which may include a loss of sensation of pain or itch. Non-limiting examples of suitable topical analgesics include capsaicin, diclofenac, lidocaine, methyl salicylate, and trolamine salicylate. Exemplary topical anesthetics include lidocaine, pramoxine, benzocaine, dibucaine, and camphor. In some examples, the topical composition does not include camphor, lidocaine, methyl salicylate, pramoxine, benzocaine, dibucaine, or diclofenac. In some examples, the topical composition does not include topical anesthetics or analgesics other than TRPM8 agonists (excluding topical anesthetics or analgesics that are not TRPM8 agonists). In some examples, the topical composition does not include topical anesthetics or analgesics other than menthol.

[0077] In some implementations, the topical composition does not include a topical steroid (e.g., amcinonide, beclomethasone, betamethasone, clobetasol, clobetasone, desonide, desoximethasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, mometasone, prednicarbate, and triamcinolone).

[0078] The topical composition may be formulated in any form suitable for application to a body surface (i.e., skin) (e.g., cream, lotion, gel, ointment, paste, soap, shampoo, liquid, suspension, spray, bioadhesive, paint, etc.). Methods for producing 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, 23rd Edition (Academic Press), 2021 (ISBN 9780128200070).

[0079] The topical composition may be formulated as a cream. Creams are viscous liquid or semi-solid emulsions, either oil-in-water or water-in-oil. Cream bases are often washable with water and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal" phase, is generally composed of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol. The aqueous phase usually, though not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant.

[0080] The topical composition can be formulated as a lotion. A lotion is a preparation that should be applied to the skin surface generally without friction, and is typically a liquid or semi-liquid preparation in which particles containing active agents are present in a water or alcohol base. Lotions are usually suspensions of solids, and preferably contain a liquid oily emulsion of the oil-in-water type. Lotions can be used for large body surfaces due to the ease of applying more fluid compositions. In general, insoluble materials in lotions need to be finely divided. Lotions typically contain a suspending agent to produce a better dispersion and a compound that is useful for localizing and retaining active agents in contact with the skin (e.g., methylcellulose, sodium carboxymethylcellulose, etc.).

[0081] The topical composition may be formulated as a gel. A gel is a semi-solid suspension-type system. A single-phase gel contains organic polymers distributed substantially uniformly throughout a carrier liquid, which is typically aqueous but may contain alcohol or oil. Useful "organic polymers" (specifically gelling agents) are crosslinked acrylic acid polymers (e.g., the "carbomer" family of polymers, e.g., carboxypolyalkylenes available commercially under CARBOPOL®). Hydrophilic polymers (e.g., polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol); cellulose polymers (e.g., hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose); gums (e.g., tragacanth and xanthan gum); sodium alginate; and gelatin are also useful. To prepare a uniform gel, a dispersing agent (e.g., alcohol or glycerin) may be added, or the gelling agent may be dispersed by trituration, mechanical mixing or stirring, or a combination thereof.

[0082] The topical composition may be formulated as an ointment. Ointments are semi-solid preparations typically based on petrolatum or petroleum derivatives. The specific ointment base to be used may be selected by one skilled in the art based on the desired properties, such as emolliency. Ointment bases are generally inert, stable, non-irritating, and non-sensitizing. Ointment bases are divided into four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases (see, for example, Remington: The Science and Practice of Pharmacy, 23rd Edition (Academic Press), 2021 (ISBN 9780128200070)). Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semi-solid hydrocarbons obtained from petroleum. Emulsifiable ointment bases (also known as absorbent ointment bases) contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions and include, for example, acetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Water-soluble ointment bases are prepared from polyethylene glycols of various molecular weights.

[0083] The topical composition may be formulated as a paste. Pastes are generally semi-solid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided into fatty pastes or those made from a single-phase aqueous gel. The base in fatty pastes is generally petrolatum or hydrophilic petrolatum, etc. Pastes made from a single-phase aqueous gel generally incorporate carboxymethylcellulose, etc., as a base.

[0084] The topical composition may be formulated as a soap. Soap is a solid, liquid, or creamy product used with water for cleaning and purifying. It is usually produced in a solid molded form (soap bar), but may also be in the form of a liquid or cream dispensed from a dispenser. Soap typically contains surfactants, which when combined with water and applied to a soiled surface, wet the soil and effectively hold the particles in suspension so that they can be washed away with clean water. Animal-based oils / fats (e.g., lard and tallow) were traditionally used to make soap. However, commercial soaps typically use vegetable base oils. Common vegetable base oils include olive oil, coconut oil, palm kernel oil, palm oil, castor oil, apricot oil, avocado oil, almond oil, jojoba oil, hemp oil, or other nut or seed oils, or butters (e.g., cocoa butter, mango butter, or shea butter). Lye is reacted with the base oil to make soap (saponification). Examples of lye include sodium hydroxide and potassium hydroxide. Sodium hydroxide is used to make bar soap, while potassium hydroxide is used to make liquid soap. Using a combination of the two makes a creamy soap. The soap can be used as a deodorant bar or to cleanse and moisturize.

[0085] The topical composition can be formulated as a shampoo (including other hair rinses). Shampoos are typically viscous liquid preparations that contain detergents or soaps for washing hair. Less commonly, shampoos are also available in bar form (solid soap). Shampoos contain surfactants (e.g., ammonium lauryl sulfate, sodium lauryl sulfate, sodium laureth sulfate, decyl glucoside, and lauryl glucoside). Shampoos may also contain foam boosters (e.g., lauramide DEA or cocamidopropyl betaine), thickeners (e.g., methylcellulose or carbomer), conditioning agents (e.g., polyquaternium-10, guar hydroxypropyltrimonium chloride, dimethicone, cyclomethicone, or quaternium 80), preservatives (e.g., DMDM ​​hydantoin, methylparaben, sodium benzoate, benzyl alcohol, and phenoxyethanol), and other ingredients (e.g., dyes, fragrances, pH buffers, chelating agents, opacifiers, vitamins, proteins, and herbal extracts). Shampoos may also contain active ingredients (e.g., zinc pyrithione, salicylic acid, ketoconazole, or selenium sulfide).

[0086] The topical compositions of the present disclosure include solutions. Solutions are generally homogeneous mixtures prepared by dissolving one or more chemicals (solutes) in a liquid, so that the molecules of the dissolved substance are dispersed among the molecules of the solvent. The solutions may contain other cosmetically acceptable chemicals to buffer, stabilize and / or preserve the solute. Common examples of solvents used in preparing topical solutions are ethanol, water, propylene glycol or any other acceptable vehicle. They may be applied in any manner, such as spraying them on the skin, painting them on the skin, or wetting a bandage with the solution.

[0087] Bioadhesives are compositions that adhere to or cause adhesion to living tissue. In clinical applications, bioadhesives can be used as tissue adhesives, hemostats, tissue sealants, wound dressings, delivery vehicles for medical device fixation or other applications. Compared to traditional wound closure methods, including sutures, wires, or staples, bioadhesives are less likely to damage tissue and may promote wound healing through different mechanisms. For example, bioadhesives may have antibacterial, anti-inflammatory, and antioxidant properties. Cyanoacrylate-based bioadhesives are the most widely used tissue adhesives for wound closure. Examples of bioadhesives include FocalSeal®, DuraSeal®, Coseal®, Tisseel®, and Bioglue®.

[0088] The topical compositions of the present disclosure may include a cosmetically acceptable viscosity enhancer and / or film former. Viscosity enhancers increase the viscosity of the formulation so as to inhibit its spread beyond the application site. Balsam Fir (Oregon) is an example of a suitable viscosity enhancer. Film formers, when dry, form a protective film over the application site. The film inhibits removal of the active ingredient and holds it in contact with the site. An example of a film former suitable for use in the present invention is Flexible Collodion (USP) (see Remington: The Science and Practice of Pharmacy, 23rd Edition (Academic Press), 2021 (ISBN 9780128200070)). Collodion is an ethyl ether / ethanol solution containing pyroxylin (nitrocellulose) that evaporates leaving a thin film of pyroxylin. The film former may also serve as a carrier. Solutions that dry to form a thin film are sometimes referred to as paints.

[0089] Creams, lotions, gels, ointments, pastes, soaps, shampoos, bioadhesives, paints, and the like may be administered to the affected surface of a subject (e.g., spread over the subject's skin affected by redness or inflammation (although shampoos are typically applied specifically to the hair and scalp)). Solutions may be administered similarly, but are more typically applied to the affected area with a dropper, swab, sprayer, or the like. The method of application generally depends on the viscosity of the composition to be applied. The composition may be applied directly to the target location, for example, in a topical preparation (e.g., an ointment) or as part of a dressing or bandage. The composition may be formulated as a unit dose for administration by a device to the skin. The unit dose may be a reservoir of the topical composition in a carrier (e.g., an adhesive carrier that can adhere to the skin for a desired period of time (e.g., at least one day or longer)).

[0090] The topical composition may be formulated as an emollient (moisturizer). Emollients can be used to soften and moisturize the skin, reducing itching or flaking. Dry skin may be caused by loss of water in the upper layers of the skin. Emollients function by forming an oily layer on top of the skin, trapping water in the skin. Petrolatum, lanolin, mineral oil and dimethicone are common emollients. Humectants, including glycerin, lecithin and propylene glycol, draw water into the outer layers of the skin. Many emollient products also have ingredients that soften keratin, such as urea, alpha hydroxy acids, such as lactic / citric / glycolic acid and allantoin. Compounds that protect the skin against irritation, such as zinc oxide or white petrolatum, may also be included.

[0091] The topical composition can be formulated for application to any external part of the body.In some non-limiting examples, the topical composition is formulated for application to the head, face (e.g., cheek, nose, forehead, etc.), scalp, arm, hand, leg, foot, or body.In some implementations, the topical composition is formulated for application to the face (facial application).

[0092] The topical composition can be used in combination with an occlusive covering layer, so that the evaporation of water from the body surface is maintained within the formulation during and after application to the body surface.In some examples, the topical composition is used in combination with a wet dressing (e.g., wet wrap therapy).For wet dressing, gauze, bandage, etc., is soaked in water and applied to the affected area of ​​skin, for example, after administration of the topical composition.The wet layer is then often wrapped with a dry layer.The bandage is left on for several hours (e.g., overnight).

[0093] The topical composition can be formulated as a concentrate that can be used as an additive in 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 the desired concentration (effective amount).

[0094] II. How to use Also disclosed are methods for reducing skin inflammation or redness in a subject, and methods of reducing the frequency, duration, or severity of signs or symptoms of an inflammatory skin condition. The methods include administering an effective amount of a topical composition disclosed herein to an affected area of ​​the skin of the subject. In some implementations, the topical composition is used in a method of reducing skin inflammation or redness in a subject. The methods include administering an effective amount of a topical composition disclosed herein to an affected area of ​​the skin of the subject. The affected area can be an area that has signs or symptoms of inflammation or redness, or it can be an area that is at risk of developing signs or symptoms of inflammation or redness, such as an area of ​​skin that is prone to inflammation or redness or has historically had inflammation or redness. In some implementations, the subject has an inflammatory skin condition or chronic skin flushing.

[0095] In some implementations, the affected area of ​​skin is affected by an inflammatory skin condition (e.g., rosacea, acute or chronic urticaria, dermatographia, mastocytosis, dermatitis, acne, psoriasis, or scleroderma). In some implementations, the affected area of ​​skin is affected by chronic flushing (e.g., chronic flushing induced by exercise, diet (e.g., alcohol, nuts, shellfish, etc.), hormonal changes, menopause, or emotions (e.g., stress, embarrassment, or excitement). In some examples, the chronic flushing is an alcohol flushing reaction. In some implementations, the affected area of ​​skin is affected by wounds (e.g., abrasion of the skin). In some implementations, the method includes selecting a subject with an inflammatory skin condition or chronic flushing for administration of the topical composition.

[0096] In some implementations, a subject having an inflammatory skin condition (e.g., rosacea, acute or chronic urticaria, dermatographia, mastocytosis, dermatitis, acne, psoriasis, or scleroderma) is selected for application of the topical composition of the present disclosure.

[0097] A topical composition that reduces redness can be identified by a reduction in redness relative to an appropriate control (e.g., the subject's pre-administration measurements or administration of a blank (empty) vehicle). Reduction in skin redness can be measured subjectively (qualitative) or objectively (quantitative). A topical composition that reduces inflammation can be identified by a reduction in cutaneous mast cell activity in a subject following administration of the topical composition to the skin, and ultimately a reduction in inflammatory mediators (e.g., cytokines, histamine, or serotonin) relative to an appropriate control (e.g., the subject's pre-administration measurements, administration of a blank (empty) vehicle, or a historical reference to "normal" values). Reduction in inflammation can also be identified visually as a reduction in redness in an area of ​​skin to which the topical composition is administered. In some implementations, an effective amount of the topical composition reduces the duration, frequency, or severity of skin inflammation or redness.

[0098] In some implementations, administration 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% (redness or inflammation is substantially resolved). In some examples, the redness or inflammation is about 5% to 100%, e.g., 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% , 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% (redness or inflammation is substantially dissipated).

[0099] In some implementations, the method reduces the frequency, duration, or severity of signs or symptoms of an inflammatory skin condition (e.g., rosacea, acute or chronic urticaria, dermatographia, mastocytosis, dermatitis, acne, psoriasis, or scleroderma) in a subject. In some implementations, the method includes selecting a subject having an inflammatory skin condition and administering an effective amount of a topical composition disclosed herein to an area of ​​the subject's skin affected by the inflammatory skin condition. In some examples, the inflammatory skin condition is rosacea. In a non-limiting example, the method includes selecting a subject having rosacea and administering an effective amount of the topical composition to an area of ​​the skin affected by the rosacea. The subject can have any type of rosacea. In some examples, the subject has papulopustular rosacea, erythematous telangiectatic rosacea, or phymatous rosacea.

[0100] The affected area may be an area that has signs or symptoms of an inflammatory skin condition, or it may be an area that is at risk of developing signs or symptoms of an inflammatory skin condition, such as an area that is prone to developing symptoms or has had a flare-up in its medical history. 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 of ​​skin that is prone to developing rosacea or has had a flare-up in its medical history.

[0101] The reduction in frequency, duration, or severity of signs or symptoms of an inflammatory skin condition is measured against an appropriate control (e.g., the subject's pre-dose measurements, application of a blank (empty) vehicle, or a historical reference to a "normal" value). Reduction in signs or symptoms can include, for example, reduction in lesion size, lesion count, itching (pruritus), redness, inflammation, skin thickness, peeling or cracked skin, sores, or duration of flare-ups. In some examples, administration of the topical composition reduces a sign or symptom of the inflammatory skin condition 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% (the sign or symptom is substantially resolved). In some examples, the signs or symptoms are from about 5% to about 100%, e.g., from about 5% to about 10%, from about 5% to about 20%, from about 5% to about 30%, from about 5% to about 40%, from about 5% to about 50%, from about 10% to about 20%, from about 10% to about 30%, from about 10% to about 40%, from about 10% to about 50%, from about 10% to about 60%, from about 10% to about 70%, from about 10% to about 80%, from about 20% to about 30%, from about 20% to about 40%, from about 20% to about 50%, from about 20% to about 60%, from about 20% to about 70%, from about 20% to about 80%, from about 30% 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%.

[0102] In some implementations, reducing the frequency of signs or symptoms includes increasing the duration of symptom remission (the time between relapses of symptoms).In some examples, new relapses 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 longer, after administration of the topical composition. In some instances, a new flare-up 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.

[0103] The subject can be any mammalian subject, including a human or a non-human mammal. In some implementations, the subject is a human. The subject can be a child or an adult, e.g., a child under 18 years old or an adult 18 years old or older. In some examples, the child is less than 5 years old, less than 12 years old, or less than 16 years old. In further examples, 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 10 to about 18 years old, about 12 to about 16 years old, about 12 to about 18 years old. In some examples, the adult is greater than about 18 years old, greater than about 25 years old, greater than about 30 years old, greater than about 35 years old, greater than about 40 years old, greater than about 45 years old, greater than about 50 years old, greater than about 55 years old, greater than about 60 years old, greater than about 65 years old, greater than about 70 years old, or greater than about 75 years old. In further examples, the adult is greater than about 18 to about 25 years old, greater than about 18 to about 35 years old, greater than about 18 to about 65 years old, greater than about 20 to about 35 years old, greater than about 25 to about 65 years old, greater than about 35 to about 65 years old, greater than about 40 to about 65 years old, greater than about 40 to about 80 years old, greater than about 65 to about 80 years old, or greater than about 80 years old. In some examples, the subject is a female adult greater than 30 years old. In some examples, the subject is a menopausal female adult.

[0104] The appropriate dosage may depend on the subject (e.g., human or non-human mammal), the subject's age, general condition, and / or the severity of symptoms, among other factors. Thus, the "effective amount" of the topical composition falls within a relatively broad range that can be determined through testing and clinical trials. The method may include measuring outcomes (e.g., redness, inflammation, skin thickness, skin texture, skin dryness, lesion size, number of lesions, or itching (pruritus)).

[0105] The topical composition may be administered as a single dose or multiple doses. In some implementations, the topical composition is administered 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 frequently. Administration may be over the course of hours, days, months, or years. In some implementations, the topical composition is administered 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 administered for at least 7 days. In some implementations, the topical composition is administered for at least 1 week, for example, at least 2 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 administered for the remainder of the subject's life. In some examples, the topical composition is administered once a day for 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, or longer. In some examples, the topical composition is administered at least 4 times a week for 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, or longer. In some examples, the topical composition is administered at least 3 times a week for 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, or longer. In a non-limiting example, the topical composition is administered once a day for the rest of the subject's life.

[0106] In some implementations, the method further comprises administering to the subject a topical UV protection agent, an antibiotic, a steroid (e.g., a corticosteroid), a nonsteroidal anti-inflammatory agent, a calcineurin inhibitor, a JAK inhibitor, an analgesic agent, an alpha2-adrenergic receptor agonist, an alpha1A-adrenergic receptor agonist, a vitamin (e.g., vitamin A, B, C, D, or E), or a combination thereof. Exemplary topical UV protection agents, antibiotics, steroids (e.g., a corticosteroid), a nonsteroidal anti-inflammatory agent, a calcineurin inhibitor, a JAK inhibitor, an analgesic agent, an alpha2-adrenergic receptor agonist, an alpha1A-adrenergic receptor agonist, a vitamin are provided herein. The additional active ingredient may be administered before, during, and / or after administration of the topical composition. EXAMPLES

[0107] Working Example The following examples are provided to illustrate particular features and / or implementations. These examples should not be construed as limiting the disclosure to the particular features or implementations described.

[0108] Example 1 Optimization of β-alanine concentration β-Alanine powder (GNC, #369898) was mixed into Versapro® cream at concentrations of 0%, 2.5%, 5.0% or 7.5% w / w. The ingredients of Versapro® cream include water, Aloe Barbadensis leaf juice, cyclopentasiloxane, disodium EDTA, emulsifying wax NF, ethylhexglyglycering, ethylhexyl stearate, phenoxyethanol, sorbitol, and tocopheryl acetate. The mixture was stirred until homogeneous.

[0109] A cohort of patients without skin disease was selected for the study (n=16). Each patient had 0.1 ml of cream applied by a physician to the skin of the cheek. Over the course of 5 minutes, the patient reported the intensity of pruritus (itch) on a scale of 0 (no itching) to 10 (maximum itching). The process was repeated for all four formulations (0%, 2.5%, 5.0% or 7.5% w / w β-alanine) using different areas of the cheek skin. The efficacy of topical β-alanine was determined based on the occurrence of pruritus. Pruritus was evident at the 2.5%, 5.0%, and 7.5% doses, but itching was greatest at 5.0% and no further increase was noted at 7.5% (Figure 1). Thus, the 5% β-alanine concentration was selected for further testing. Pruritus induced by topical β-alanine cream was transient and lasted less than 5 minutes.

[0110] Example 2 Optimizing menthol concentration Although β-alanine has beneficial effects when applied to the skin, topical application also induces transient pruritus, limiting its potential use and application.Menthol was selected for testing as an agent that can mask short-term pruritus when added to topical compositions with β-alanine.Because menthol can cause eye irritation, the following test is designed to determine whether an acceptable concentration of menthol can provide relief from β-alanine-induced pruritus.

[0111] A cohort of patients (n=10) without inflammatory skin conditions were given four different topical formulations for facial application. All four formulations contained 5% w / w β-alanine in Versapro® cream (see, e.g., Example 1), but each contained a different concentration of menthol (0.0%, 0.5%, 1.0%, and 1.5% w / w). Physicians applied 0.1 ml of each formulation sequentially to separate areas of the cheek with a 10-minute pause between each application. Patients were asked to rate the degree of itching and overall discomfort over the course of a 5-minute period on a scale of 0 (no itching) to 10 (maximum itching). The same process was repeated for the 0.5%, 1.0%, and 1.5% w / w menthol-containing formulations. Itching was significantly reduced at all concentrations of menthol (Figure 2A). However, overall discomfort was increased with the 1.0% and 1.5% menthol-containing β-alanine creams, which was attributed to eye irritation and an unpleasant cold sensation (Figure 2B).

[0112] A menthol concentration of 0.5% successfully reduced the intensity of itching without promoting ocular discomfort and is therefore selected for further testing.

[0113] Example 3 Clinical trial example - split face The following describes an exemplary clinical trial design for testing topical application of 0.5% w / w menthol with various concentrations of β-alanine in patients with rosacea. Although testing of patients with rosacea is provided as an example, patients with other conditions (e.g., chronic flushing or inflammatory skin conditions) may be selected and tested in a similar manner.

[0114] A cohort of patients with a history of chronic rosacea flushing (>6 months duration based on medical history report, frequency >2 times / week) is selected. At intake, a physician evaluates each patient's baseline condition using photographs, measuring redness, and a clinician's erythema assessment. Physicians interview patients to identify precipitating factors, family history, and characteristics of flushing (e.g., burning sensation).

[0115] Test compositions are made by mixing 1%, 2%, or 5% w / w β-alanine and 0.5% w / w menthol as a base (e.g., OLAY® complete lotion moisturizer) in any suitable lotion or cream (see, e.g., Example 1). The vehicle is the lotion or cream base without β-alanine and menthol. Patients are instructed to apply the vehicle to one half of the face (e.g., the left side of the face) and the test composition (either 1%, 2%, or 5% β-alanine with 0.5% menthol) to the other half of the face (e.g., the right side of the face) once a day for four weeks. Patients and physicians are double-blinded throughout the study.

[0116] Patients will self-photograph their face at set times each week (e.g., Sunday night after removing makeup). Patients will also self-photograph whenever they notice a flare-up. Patients will keep a daily diary of post-application events, noting the frequency of flushing and any sensations (e.g., burning) experienced during flushing episodes with emphasis on the right vs. left side of the face (Patient Self-Assessment (PSA)).

[0117] After 4 weeks, the physician will assess the patient's condition using photographs, measurements of redness, and a clinician's erythema assessment, focusing on comparing the right side vs. the left side of the face.

[0118] A similar design can be used to test various concentrations of menthol. For example, instead of testing 0.5% w / w menthol with varying concentrations of β-alanine as described above, a set concentration of β-alanine (e.g., 5% w / w) can be tested in a similar manner with varying concentrations of menthol (e.g., 0, 0.25%, 0.5%, 1%, 1.5%, or 2% w / w). Additionally, other TRPM8 agonists can be used in place of menthol and similarly tested as described herein.

[0119] Example 4 Clinical trial example - whole face The following describes an exemplary clinical trial design for testing 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 conditions can be selected and tested in a similar manner.

[0120] A cohort of patients with a history of chronic rosacea flushing (>6 months duration based on medical history report, frequency >2 times / week) will be selected for the study. At intake, a physician will assess each patient's baseline condition using photographs, measuring redness, and a clinician's erythema assessment. Physicians will interview patients to identify precipitating factors, family history, and characteristics of flushing (e.g., burning sensation).

[0121] Test compositions are made by mixing 1%, 2%, or 5% w / w β-alanine with 0.5% w / w menthol as a base (e.g., OLAY® complete lotion moisturizer) in any suitable lotion or cream (see, e.g., Example 1). The vehicle is the lotion or cream base without β-alanine and menthol. Patients are instructed to apply either the vehicle or the test composition (1%, 2%, or 5% w / w β-alanine with 0.5% menthol) to the entire face once a day for four weeks. Patients and physicians are double-blinded throughout the study.

[0122] Patients photograph themselves on their face at set times each week (e.g., Sunday night after removing makeup). Patients also photograph themselves whenever they notice a flare-up. Patients keep a daily diary of events after application, noting the frequency of flushing and any other sensations (e.g., burning) experienced during flushing episodes (Patient Self-Assessment (PSA)).

[0123] After 4 weeks, physicians will assess each patient's condition using photography, measurements of redness, and a clinician's erythema assessment. The primary outcome measures the number and intensity of flushing episodes.

[0124] A similar design can be used to test various concentrations of menthol. For example, instead of testing 0.5% menthol with varying concentrations of β-alanine as described above, a set concentration of β-alanine (e.g., 5% w / w) can be tested in a similar manner with varying concentrations of menthol (e.g., 0, 0.25%, 0.5%, 1%, 1.5%, or 2% w / w). Additionally, other TRPM8 agonists can be used in place of menthol and similarly tested as described herein.

[0125] It will be apparent that the exact details of the methods or compositions described may be changed or modified without departing from the spirit of the described aspects of this disclosure, and 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. 2. The topical composition of claim 1, wherein the TRPM8 agonist is menthol, icilin, crysim-1, borneol, linalool, geraniol, hydroxy-citronellal, WS-12, Frescolat MGA, Frescolat ML, PMD 38, Coolact P, M8-Ag, Cooling Agent 10, or a combination thereof.

3. The topical composition of claim 1 or claim 2, wherein the TRPM8 agonist is menthol.

4. a) from about 0.2% to about 15% weight / weight (w / w) β-alanine; b) about 1% to about 10% w / w β-alanine; or c) about 2.5% to about 7.5% w / w β-alanine; 20. The topical composition of any one of the preceding claims, comprising:

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

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

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. 10. The topical composition of any one of the preceding claims, further comprising a topical ultraviolet light protection agent (UV protectant).

10. 10. The topical composition of claim 9, wherein the topical UV protection agent comprises aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, drometrizole trisiloxane, homosalate, meladimate, octocrylene, octinoxate, octisalate, oxybenzone, padimate O, para-aminobenzoic acid (PABA), ensulizole, sulisobenzone, titanium dioxide, trolamine salicylate, zinc oxide, ethylhexyl triazone, ecamsule, scilatriazole, bemotrizinol, bisoctrizole, iron oxide, red veterinary petrolatum, kaolin clay, or combinations thereof.

11. 13. The topical composition of any one 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 combinations thereof.

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

13. 20. The topical composition of any one of the preceding claims, wherein the topical composition does not contain any anesthetic or topical steroid other than a TRPM8 agonist.

14. 2. The topical composition according to any one of the preceding claims, wherein the topical composition does not contain camphor or lidocaine.

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

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

17. 13. A topical composition according to any one of the preceding claims, formulated for facial application.

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

19. 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. 20. A method of reducing skin inflammation or redness in a subject, comprising administering 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. 21. The topical composition of claim 19 or the method of claim 20, wherein the subject is selected as a subject having an inflammatory skin condition or chronic skin flushing.

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

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

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

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

26. 26. The method of claim 25, wherein the rosacea is erythematous telangiectatic rosacea, papulopustular rosacea, or phymatous rosacea.

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

28. The topical composition or method of any one of claims 19 to 27, wherein the topical composition is administered for at least 7 days.

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

30. 1. A method of reducing skin inflammation or redness in a subject, the method comprising: Selecting a subject having skin inflammation or redness; and administering an effective amount of a topical composition to an area of ​​skin affected by inflammation or redness, thereby reducing skin inflammation or redness, wherein said topical composition comprises β-alanine and a transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) agonist; The method includes:

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

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

33. The topical composition comprises: a) from about 1% to about 15% weight / 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 β-alanine; The method according to any one of claims 30 to 32, comprising:

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

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

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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