Methods for treating skin disorders and their symptoms

Abstract

Topically applied compositions containing a TRPV3 inhibitor, such as KM-001, significantly reduce the severity of skin lesions, pruritus, and combinations thereof in patients suffering from skin disorders such as keratosis gracilis, lichen simplex chronicus, and ichthyosis. The present disclosure provides TRPV3 inhibitor compositions and methods for treating skin disorders. In embodiments, the present disclosure provides a composition comprising KM-001, an aqueous phase, and an oil phase, wherein the concentration of KM-001 is about 0.1% to about 5.6% by weight. In embodiments, the composition is a cream. In embodiments, the concentration of KM-001 is about 0.2% to about 3% by weight. In embodiments, the concentration of KM-001 is about 0.3% by weight. In embodiments, the concentration of KM-001 is about 1% by weight.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 338,586, filed May 5, 2022, the entire contents of which are incorporated herein by reference for all purposes. [Background technology]

[0002] For skin to function properly, a complex homeostasis of the epidermal keratinocyte layer, including proliferation, differentiation, and cell signaling, must be maintained (Proksch E, Brandner JM, and Jensen JM. The skin: an indispensable barrier, Exp Dermatol, 2008;17:1063-72). Disruption of this homeostasis can lead to skin diseases, which are often life-threatening conditions. One of the main factors that determine skin health is proper calcium homeostasis, which is primarily controlled by membrane calcium ion channels (Elsholz F, Harteneck C, Muller W, and Friedland K. Calcium--a central regulator of keratinocyte differentiation in health and disease. Eur J Dermatol. 2014;24:650-61). The transient receptor potential cation channel, subfamily V, member 3 (TRPV3) is a cation channel that is relatively highly permeable to calcium. First cloned in 2002, it has been identified as a novel drug target in the skin, which may provide new approaches for the treatment of keratosis and pruritus (Bakthavatchalam, Rajagopal, and S. David Kimball. 2010. Chapter 3-Modulators of Transient Receptor Potential Ion Channels. in John E. Macor (ed.), Annual Reports in Medicinal Chemistry (Academic Press); Broad LM, Mogg AJ, Eberle E, Tolley M, Li DL, Knopp KL. TRPV3 in Drug Development. Pharmaceuticals (Basel). 2016 Sep9;9(3):55). TRPV3 is shown to be a central regulator in skin diseases, as it controls proliferation, differentiation, and apoptosis of human epidermal keratinocytes.Specifically, its activation inhibits keratinocyte proliferation and induces apoptosis (Borbiro I, Lisztes E, Toth BI, Czifra G, Olah A, Szollosi AG, Szentandrassy N, Nanasi PP, Peter Z, Paus R, Kovacs L, Biro T. Activation of transient receptor potential vanilloid-3 inhibits human hair growth. J Invest Dermatol. 2011 Aug;131(8):1605-14). It is thought to be involved in the control of keratinocyte migration and wound healing, possibly through the release of nitric oxide (NO) (Miyamoto T, Petrus MJ, Dubin AE, and Patapoutian A. TRPV3 regulates nitric oxide synthase-independent nitric oxide synthesis in the skin, Nat Commun 2011;2:369). TRPV3 is involved in both hair morphogenesis and the hair follicle cycle, and also plays a role in maintaining the skin barrier, as loss of TRPV3 causes deleterious changes in epidermal barrier structure (Moqrich A, Hwang SW, Earley TJ, Petrus MJ, Murray AN, Spencer KS, Andahazy M, Story GM, Patapoutian A. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science. 2005 Mar4;307(5714):1468-72).

[0003] Various studies have provided some insight into how TRPV3 regulates keratinocyte structure and function. A key protein interaction partner appears to be EGFR (Cheng X, Jin J, Hu L, Shen D, Dong XP, Samie MA, et al. TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation. Cell. 2010;141:331-43). This receptor is thought to form a signaling complex with TRPV3, and activation of EGFR increases the activity of TRPV3 channels, stimulating downstream second messengers to maintain epidermal homeostasis. In cases of keratosis such as punctate palmoplantar keratoderma (PPPK), the association of identified AAGAB mutations with EGFR activation has been shown to result in persistent sensitization of TRPV3 and increased Ca delivery to cells. +2An uninterrupted influx of ions may occur. Similarly, keratin 16 (Krt16), mutated in PC, is a direct target of EGFR- and Erk1 / 2-mediated signaling, and overexpression in mice increases EGFR activity in a dose-dependent manner (Wang YN, and Chang WC. Induction of disease-associated keratin 16 gene expression by epidermal growth factor is regulated through cooperation of transcription factors Sp1 and c-Jun. J Biol Chem. 2003;278:45848-57; Chen YJ, Wang YN, and Chang WC. ERK2-mediated C-terminal serine phosphorylation of p300 is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression. J Biol Chem. 2007;282:27215-28). The proteolytically inactive rhomboid protein iRhom2 is important for palmoplantar epidermal homeostasis and is a key regulator of Krt16 expression (Maruthappu T, Chikh A, Fell B, Delaney PJ, Brooke MA, Levet C, et al. Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16. Nat Commun. 2017;8:14174), regulating cytoskeletal stress response, barrier integrity, and signaling through p63 and ADAM17 / EGFR.

[0004] TRPV3 activity has also been associated with certain pathological skin conditions. Multiple "gain of function" mutations in TRPV3 that result in TRPV3 channels remaining constantly open have been identified in Olmsted syndrome (OS) (Yadav M, Goswami C. TRPV3 mutants causing Olmsted Syndrome induce impaired cell adhesion and nonfunctional lysosomes. Channels (Austin). 2017 May4;11(3):196-208). This rare genetic skin disease is characterized by the development of severe and sometimes amputating palmoplantar keratosis, perioral keratotic plaques, diffuse alopecia, extreme pruritus, and pain (Duchatelet S, Hovnanian A. Olmsted syndrome: clinical, molecular and therapeutic aspects. Orphanet J Rare Dis. 2015;17;10:33). A mouse strain DS-Nh carrying a "gain of function" mutation in TRPV3 has been generated (Yoshioka T, Hikita I, Asahikawa M, Hirasawa T, Deguchi M, Matsutani T, Oku H, Horikawa T, Arimura A. Spontaneous scratching behaviour in DS-Nh mice as a possible model for pruritus in atopic dermatitis. Immunology. 2006 Jul;118(3):293-301). DS-Nh mice spontaneously develop dermatitis-associated pruritus similar to human atopic dermatitis and OS.

[0005] Based on the above mechanism of action, TRPV3 activity inhibitors have untapped therapeutic potential for skin diseases such as keratosis, dermatitis, and pruritus associated with or caused by skin diseases. TRPV3 inhibitors can improve keratinocyte proliferation and differentiation and reduce hyperkeratosis and lesions. Therefore, the development of TRPV3 inhibitor compositions that are safe and effective for treating skin disorders and effective methods of administering such compositions to safely treat skin disorders would be of great benefit to patients. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Proksch E,Brandner JM,and Jensen JM.The skin:an indispensable barrier,Exp Dermatol,2008;17:1063-72 [Non-Patent Document 2] Elsholz F, Harteneck C, Muller W, and Friedland K. Calcium--a central regulator of keratinocyte differentiation in health and disease. Eur J Dermatol. 2014;24:650-61 [Non-Patent Document 3] Bakthavatchalam,Rajagopal, and S.David Kimball.2010.Chapter 3-Modulators of Transient Receptor Potential Ion Channels.in John E.Macor(ed.),Annual Reports in Medicinal Chemistry (Academic Press) [Non-Patent Document 4] Broad LM,Mogg AJ,Eberle E,Tolley M,Li DL,Knopp KL.TRPV3 in Drug Development.Pharmaceuticals(Basel).2016 Sep9;9(3):55 [Non-Patent Document 5] Borbiro I,Lisztes E,Toth BI,Czifra G,Olah A,Szollosi AG,Szentandrassy N,Nanasi PP,Peter Z,Paus R,Kovacs L,Biro T.Activation of transient receptor potential vanilloid-3 inhibits human hair growth.J Invest Dermatol.2011 Aug;131(8):1605-14 [Non-Patent Document 6] Miyamoto T, Petrus MJ, Dubin AE, and Patapoutian A. TRPV3 regulates nitric oxide synthase-independent nitric oxide synthesis in the skin, Nat Commun 2011;2:369 [Non-Patent Document 7] Moqrich A, Hwang SW, Earley TJ, Petrus MJ, Murray AN, Spencer KS, Andahazy M, Story GM, Patapoutian A. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin.Science.2005 Mar4;307(5714):1468-72 Summary of the Invention [Means for solving the problem]

[0007] The present invention provides TRPV3 inhibitor compositions and methods for treating skin disorders.

[0008] In an embodiment, the present disclosure provides a composition, the composition comprising: [ka] , an aqueous phase, and an oil phase, and the concentration of KM-001 is about 0.1% to about 5.6% by weight. In an embodiment, the composition is a cream. In an embodiment, the concentration of KM-001 is about 0.2% to about 3% by weight. In an embodiment, the concentration of KM-001 is about 0.3% by weight. In an embodiment, the concentration of KM-001 is about 1% by weight.

[0009] In an embodiment, the cream has a pH of about 4 to about 6. In an embodiment, the cream has a pH of about 4.5 to about 5.5.

[0010] In an embodiment, the cream comprises (a) about 20% to about 40% by weight of an oil phase, and (b) about 60% to about 80% by weight of an aqueous phase. In an embodiment, the oil phase comprises triglycerides, C 13~21 In an embodiment, the triglyceride concentration is about 9% to about 13% by weight of triglyceride. In an embodiment, the triglyceride concentration is about 11% by weight. In an embodiment, the triglyceride is a medium chain triglyceride (MCT). In an embodiment, the MCT is caprylic capric triglyceride. In an embodiment, the C 13~21 The concentration of the fatty alcohol is about 10% by weight to about 14% by weight. 13~21 The concentration of fatty alcohol is about 12% by weight. 13~21 The fatty alcohol is octyldodecanol. In an embodiment, the oil phase is free of polyoxypropylene stearyl ether.

[0011] In an embodiment, the cream further comprises an antioxidant, a preservative, a viscosity modifier, a pH modifier, or a mixture thereof. In an embodiment, the antioxidant is propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene, or a mixture thereof. In an embodiment, the antioxidant comprises propyl gallate and butylated hydroxyanisole (BHA). In an embodiment, the concentration of propyl gallate is about 0.02% to about 0.08% by weight, and the concentration of BHA is about 0.05% to about 0.2% by weight. In an embodiment, the cream comprises about 0.05% by weight of propyl gallate and 0.1% by weight of BHA.

[0012] In an embodiment, the concentration of the preservative is about 0.1% to about 2% by weight. In an embodiment, the preservative is a glycol ether, a phenol ether, a benzoate, or a mixture thereof. In an embodiment, the concentration of the preservative is about 0.05% to about 0.4% by weight of phenoxyethanol, about 0.5% to about 2% by weight of sodium benzoate, or a mixture thereof. In an embodiment, the viscosity modifier is a copolymer of acrylamide and sodium acryloyldimethyltaurate, polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof. In an embodiment, the concentration of the viscosity modifier is about 1.5% to about 5% by weight of a copolymer of acrylamide and sodium acryloyldimethyltaurate dispersed in isohexadecane. In an embodiment, the pH adjuster is 10% citric acid. In an embodiment, the cream further comprises glycerin, propylene glycol, or a mixture thereof.

[0013] In an embodiment, the viscosity of the cream is at least about 15,000 mPa·s when measured at 25° C. using rotational viscosimetry. In an embodiment, the viscosity of the cream is from about 15,000 mPa·s to about 75,000 mPa·s when measured at 25° C. using rotational viscosimetry. In an embodiment, the viscosity of the cream is from about 19,500 mPa·s to about 45,200 mPa·s when measured at 25° C. using rotational viscosimetry. In an embodiment, the cream is an oil-in-water emulsion. In an embodiment, the emulsion droplets have an average diameter of less than about 13 μm. In an embodiment, the emulsion droplets have an average diameter of less than about 10 μm. In an embodiment, the aqueous phase is a gel at about 2° C. to about 40° C.

[0014] In an embodiment, about 2 grams to about 4 grams of cream containing 1% by weight of KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 Topical administration to the skin provides about 50 μg / g to about 6000 μg / g of KM-001 in one or more layers of the skin as measured by matrix-assisted laser desorption / ionization (MALDI). In embodiments, about 3 grams of a cream containing 1% by weight KM-001 is applied to about 500 cm of the skin of a patient in need thereof. 2 When administered topically, KM-001 is delivered to one or more skin layers at about 50 μg / g to about 6000 μg / g as measured by (matrix assisted laser desorption / ionization) MALDI.

[0015] In an embodiment, about 2 grams to about 4 grams of cream containing 1% by weight of KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 When administered topically, about 2000 μg / g to about 6000 μg / g of KM-001 is provided to the epidermis as measured by MALDI (matrix assisted laser desorption / ionization). In an embodiment, about 2 grams to about 4 grams of cream containing 1% by weight of KM-001 is administered to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2When topically administered to the skin, about 2000 μg / g to about 6000 μg / g of KM-001 is provided to the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum, or a combination thereof, as measured by MALDI (matrix-assisted laser desorption / ionization). In embodiments, about 2 grams to about 4 grams of a cream containing 1% by weight KM-001 is administered to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 Topical administration to the skin provides about 500 μg / g to about 800 μg / g of KM-001 in the dermis as measured by MALDI (matrix assisted laser desorption / ionization). In embodiments, about 2 grams to about 4 grams of cream containing 1% by weight KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 When topically administered to the skin, KM-001 is provided to the dermis at a concentration equivalent to about 1% to about 16% of the KM-001 in the epidermis as measured by MALDI. In an embodiment, about 2 grams to about 4 grams of a cream containing 1% by weight KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 When administered topically, about 100 μg / g to about 3500 μg / g of KM-001 is provided to the subcutaneous tissue as measured by MALDI (matrix assisted laser desorption / ionization). In an embodiment, about 2 grams to about 4 grams of cream containing 1% by weight of KM-001 is administered to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 When administered topically, KM-001 is delivered to hair follicles at approximately 50 μg / g to approximately 1200 μg / g as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0016] In an embodiment, when the cream is administered topically to the skin of a patient in need of treatment, about 0.05% to about 20% by weight of KM-001 present in the composition applied to the skin penetrates into the stratum corneum, epidermis, or dermis as measured by in vitro penetration testing (IVPT). In an embodiment, when the cream is administered topically to the skin of a patient in need of treatment, about 1% to about 10% by weight of KM-001 present in the composition applied to the skin penetrates into the stratum corneum as measured by IVPT. In an embodiment, when the cream is administered topically to the skin of a patient in need of treatment, about 0.2% to about 8% by weight of KM-001 present in the composition applied to the skin penetrates into the epidermis as measured by IVPT. In an embodiment, when the cream is administered topically to the skin of a patient in need of treatment, about 0.05% to about 3% by weight of KM-001 present in the composition applied to the skin penetrates into the dermis as measured by IVPT.

[0017] In embodiments, local administration results in a peak plasma concentration (C max ) is less than about 40 ng / mL. In embodiments, local administration results in an area under the plasma drug concentration time curve (AUC) of KM-001 of less than about 500 ng / mL*hr.

[0018] In embodiments, the present disclosure provides a method for treating skin disorders or pruritus, comprising topically administering to the skin of a patient in need thereof a therapeutically effective amount of a KM-001-containing composition described herein. [Brief description of the drawings]

[0019] [Figure 1] Distribution of KM-001 in skin samples from minipigs treated with placebo (MSI, overlay, H&E images).

[0020] [Diagram 2] Distribution of KM-001 in skin samples from minipigs treated with 1% F3 of KM-001 (MSI, overlay, H&E images).

[0021] [Diagram 3]Distribution of KM-001 in skin samples from minipigs treated with 1% F4 of KM-001 (MSI, overlay, H&E images).

[0022] [Figure 4] Distribution of KM-001 in skin samples from minipigs administered 1% ointment of KM-001 (MSI, overlay, H&E images).

[0023] [Diagram 5] 1 shows a matrix-assisted laser desorption / ionization (MALDI) image of a pig skin tissue section as described in Example 2.

[0024] [Figure 6] 1 shows the comparative effects of KM-001 on scratching behavior in DS-Nh mice.

[0025] [Figure 7] 1 shows the comparative effects of KM-001 on skin lesions developed in DS-Nh mice.

[0026] [Figure 8] 1 shows the effect of the test treatments on the skin morphology of DS-Nh mice.

[0027] [Figure 9A] FIG. 1 shows the visual appearance of exemplary compositions M1, M2 and M3 described in Example 9 and their respective vehicle (P-placebo) after incubation at 25° C. for 24 hours.

[0028] [Figure 9B] 1 shows the visual appearance of exemplary compositions M6, M10, M13 and M14 and their respective vehicle (P-placebo) after incubation at 25° C. for 24 hours.

[0029] [Figure 10] The RapidOxy induction period is defined.

[0030] [Figure 11A] 4 shows the mean blood concentrations of the test substances after dermal administration to male minipigs.

[0031] [Figure 11B] 4 shows the mean blood concentrations of the test substances after dermal administration to female minipigs.

[0032] [Figure 12A] A-D show how the affected area of ​​a patient with pachyonychia congenita improved at each time point: screening visit / baseline (T0) (12A), visit 3 (12B), visit 8 (Figure 12C) and follow-up visit 8 (Figure 12D). [Figure 12B] A-D show how the affected area of ​​a patient with pachyonychia congenita improved at each time point: screening visit / baseline (T0) (12A), visit 3 (12B), visit 8 (Figure 12C) and follow-up visit 8 (Figure 12D). [Figure 12C] A-D show how the affected area of ​​a patient with pachyonychia congenita improved at each time point: screening visit / baseline (T0) (12A), visit 3 (12B), visit 8 (Figure 12C) and follow-up visit 8 (Figure 12D). [Figure 12D] A-D show how the affected area of ​​a patient with pachyonychia congenita improved at each time point: screening visit / baseline (T0) (12A), visit 3 (12B), visit 8 (Figure 12C) and follow-up visit 8 (Figure 12D). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] definition Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the aforementioned patents, patent applications, and publications and this disclosure, the present disclosure will control.

[0034] For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0035] As used herein, the term "about" refers to plus or minus 10% of the referenced numerical value, unless otherwise specified or clear from the context, and except where such range exceeds 100% of the possible values ​​or falls below 0% of the possible values ​​(such as when the content of the component is less than 0% or the total content of the composition is more than 100%). For example, an amount of any of the TRPV3 inhibitors disclosed herein that is "about 1% by weight" means that the TRPV3 inhibitor can be present in any amount ranging from 0.9% to 1.1% by weight of the composition. In embodiments, the terms "% by weight" and "weight percent concentration" are used interchangeably.

[0036] The term "a" or "an" refers to one or more of that entity, for example, "a solvent" refers to one or more solvents, or at least one solvent. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein. Furthermore, reference to an "element" by the indefinite article "a" or "an" does not exclude the possibility that a plurality of elements are present, unless the context clearly requires that there is only one element.

[0037] As used herein, the term "skin" refers to any of the layers of the skin, including the epidermis, dermis, and subcutaneous tissue. The epidermis includes five layers, from the outermost layer to the innermost layer: the stratum corneum, the stratum lucidum, the stratum granulosum, the stratum spinosum, and the stratum basale. For example, the stratum corneum is the surface layer of the skin.

[0038] As used herein, the term "topical composition" refers to any formulation designed to be applied to the skin.

[0039] As used herein, "aqueous" refers to a composition that contains more than 50% water by weight. In an embodiment, the aqueous composition of the present disclosure contains more than 75% water by weight. In an embodiment, the aqueous composition of the present disclosure contains more than 90% water by weight.

[0040] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound that can achieve an intended result when administered to a patient. For example, an effective amount of a TRPV3 inhibitor in a composition is an amount necessary to reduce at least one symptom of a skin disorder in a patient. The actual amount, including an "effective amount" or a "therapeutically effective amount," will vary depending on a variety of conditions, such as the severity of the disease, the size and health of the patient, and the size of the wound to be treated. A skilled physician can easily determine the appropriate amount using methods well known in the medical field.

[0041] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0042] As used herein, "treat" or "treatment" refers to one or more of alleviating, alleviating, delaying, alleviating, curing, improving or managing at least one symptom of a condition of interest. The term "treatment" can also refer to one or more of arresting the progression of a condition, delaying the onset of a condition (i.e., the period before symptoms are clinically apparent), reducing the risk of onset or worsening of a condition, or repairing or normalizing the skin.

[0043] KM-001 composition In embodiments, the present disclosure relates to compositions comprising any of the TRPV3 inhibitors disclosed in US Patent Application No. US2002 / 0332697 A1, the entire contents of which are incorporated herein by reference. In US 2002 / 0332697 A1, one of the TRPV3 inhibitors, KM-001, was found to inhibit TRPV3 with an IC50 of about 3 nM. The KM-001 compound also significantly reduced Ca+2 flux in keratinocytes and normalized differentiation markers. However, the TRPV3 inhibitors disclosed in US 2002 / 0332697 A1 were not readily soluble in aqueous compositions, resulting in low bioavailability to target cells and / or tissues. The present application, in embodiments, addresses this problem in the art and provides TRPV3 inhibitor compositions that are safe, bioavailable, and effective in treating skin diseases.

[0044] In embodiments, a composition of the disclosure comprises a TRPV3 inhibitor having the chemical structure of KM-001, [ka]

[0045] The compositions of the present disclosure are generally formulated for topical use, for example, as creams, ointments, pastes, lotions, or gels. Creams or lotions contain an emulsion of an aqueous phase and a hydrophobic (oily) phase, and can be classified as oil-in-water (o / w) emulsions or water-in-oil (w / o) emulsions. In an embodiment, the compositions of the present disclosure are oil-in-water emulsions. In an o / w emulsion, the oil phase is dispersed in a discontinuous, continuous aqueous phase, whereas in a w / o emulsion, the aqueous phase is dispersed in a discontinuous, continuous oil phase. Addition of emulsifiers to o / w or w / o emulsions can stabilize the emulsion and inhibit / delay phase separation that would otherwise destabilize the emulsion.

[0046] In an embodiment, the composition of the present disclosure is formulated as a cream. In an embodiment, the composition of the present disclosure may be formulated as an ointment, which is a semi-solid preparation of a hydrocarbon (e.g., petrolatum, mineral oil, paraffin, silicone oil, synthetic hydrocarbon), or a paste that is a mixture of a powder and an ointment to improve porosity (breathability) and make the paste less likely to be removed or to migrate to areas of the skin that do not require treatment. In an embodiment, the gel composition typically comprises a viscous cellulose ether or carbomer in a mixture of water and alcohol. In an embodiment, the gel typically dries on the skin, leaving a thin film containing the active ingredient (e.g., TRPV3 inhibitor), and may therefore be more suitable for hairy areas of the skin than other types of topical formulations.

[0047] In embodiments, the compositions of the invention include a therapeutically effective amount of any of the TRPV3 inhibitors disclosed herein (e.g., KM-001 or KM-023). The concentration of the TRPV3 inhibitors disclosed herein (e.g., KM-001 or KM-023) is typically in the range of about 0.1% to about 6% by weight, and may be about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.2%, about 1.4%, about 1.6%, about 1.8%, about 2.0%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9 ...2%, about 3.3%, about 3.4%, about 3.5%, about 3. %, about 2.4 wt%, about 2.6 wt%, about 2.8 wt%, about 3.0 wt%, about 3.2 wt%, about 3.4 wt%, about 3.6 wt%, about 3.8 wt%, about 4.0 wt%, about 4.2 wt%, about 4.4 wt%, about 4.6 wt%, about 4.8 wt%, about 5.0 wt%, about 5.2 wt%, about 5.4 wt%, about 5.6 wt%, about 5.8 wt%, or about 6.0 wt% (including all ranges between any of these values ​​or ranges).

[0048] In embodiments, the compositions of the present disclosure are formulated as a cream, gel, or a creamy consistency. In embodiments, the present disclosure provides a cream, the cream comprising: [ka] The composition includes an aqueous phase and an oil phase, and the concentration of KM-001 is about 0.1% by weight to about 5.6% by weight, for example, 0.2% by weight to about 2% by weight, about 0.3% by weight to about 1.0% by weight, about 0.5% by weight, about 5% by weight, about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1.0% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, about 2.0% by weight, about 2.1% by weight, about 2.2% by weight, about 2.3% by weight, about 2.4% by weight, about 2.5% by weight, about 2.6% by weight, about 2.7% by weight, about 2.8% by weight, about 2.9% by weight, about 3.0% by weight, about 3.1% by weight, about 3.2% by weight, about 3.3% by weight, about 3.4% by weight, about 3.5% by weight, about 3.6% by weight, about 3.7% by weight, about 3.8% by weight, about 3.9% by weight, about 4.0 ... 0.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, or about 5.6% by weight (including all ranges between any of these values). In an embodiment, the concentration of KM-001 is about 0.2% to about 3% by weight. In an embodiment, the concentration of KM-001 is about 0.3% by weight. In an embodiment, the concentration of KM-001 is about 1% by weight.

[0049] In an embodiment, the composition of the present disclosure (e.g., cream) has a pH of about 4.0 to about 6.0, for example, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, or about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0 (including any value or range therebetween). In an embodiment, the composition of the present disclosure has a pH of about 4.0 to about 5.0. In an embodiment, the composition of the present disclosure has a pH of about 4.5 to about 5.5. In an embodiment, the composition of the present disclosure has a pH of about 4.9 to about 5.1. In an embodiment, the composition of the present disclosure has a pH of about 4.0.

[0050] In an embodiment, the cream comprises (a) about 20% to about 40% by weight of an oil phase, and (b) about 60% to about 80% by weight of an aqueous phase. In an embodiment, the composition (e.g., cream) comprises about 20% to about 40% by weight of an oil phase, e.g., about 20.0%, about 20.2%, about 20.4%, about 20.6%, about 20.8%, about 30.2%, about 30.4%, about 30.6%, about 30.8% or about 40.0% by weight (including any value or range therebetween). In embodiments, the composition comprises about 60% to about 80% by weight of an aqueous phase, e.g., about 60.0%, about 60.2%, about 60.4%, about 60.6%, about 60.8%, about 70.0%, about 70.2%, about 70.4%, about 70.6%, about 70.8%, or about 80.0% by weight (including any value or range therebetween).

[0051] In an embodiment, the composition is an oil-in-water emulsion. In an embodiment, the aqueous phase is a gel at about 2°C to about 40°C, for example, about 2°C, about 4°C, about 6°C, about 8°C, about 10°C, about 12°C, about 14°C, about 16°C, about 18°C, about 20°C, about 22°C, about 24°C, about 26°C, about 28°C, about 30°C, about 32°C, about 34°C, about 36°C, about 38°C, or about 40°C (including any value or range therebetween). In embodiments, the average diameter of the emulsion droplets is less than about 13 μm, e.g., less than about 13 μm, about 12.9 μm, about 12.8 μm, about 12.7 μm, about 12.6 μm, about 12.5 μm, about 12.4 μm, about 12.3 μm, about 12.2 μm, about 12.1 μm, about 12.0 μm, about 11.9 μm, about 11.8 μm, about 11.7 μm, about 11.6 μm, The average diameter of the emulsion droplets is less than about 11.5 μm, about 11.4 μm, about 11.3 μm, about 11.2 μm, about 11.1 μm, about 11.0 μm, about 10.9 μm, about 10.8 μm, about 10.7 μm, about 10.6 μm, about 10.5 μm, about 10.4 μm, about 10.3 μm, about 10.2 μm, about 10.1 μm, or about 10.0 μm (including all values ​​and ranges therebetween). In an embodiment, the average diameter of the emulsion droplets is less than about 13 μm. In an embodiment, the average diameter of the emulsion droplets is less than about 10 μm.

[0052] In an embodiment, the oil phase comprises a triglyceride, C 13~21 In an embodiment, the oil phase comprises a triglyceride. In an embodiment, the concentration of the triglyceride is about 9% by weight to about 13% by weight, for example, about 9.0% by weight, about 9.1% by weight, about 9.2% by weight, about 9.5% by weight, about 9.6% by weight, about 9.7% by weight, about 9.8% by weight, about 9.9% by weight, about 10.0% by weight, about 10.1% by weight, about 10.2% by weight, about 10.3% by weight, about 10.4% by weight, about 10.5% by weight, about 10.6% by weight, about 10.7% by weight, about 10.8% by weight, about 10.9% by weight, about 11.0% by weight, about 12.0% by weight, about 13.0% by weight, about 14.0% by weight, about 15.0% by weight, about 16.0% by weight, about 17.0% by weight, about 18.0% by weight, about 19.0% by weight, about 20.0% by weight, about 21.0% by weight, about 22.0% by weight, about 23.0% by weight, about 24.0% by weight, about 25.0% by weight, about 26.0% by weight, about 27.0% by weight, about 28.0% by weight, about 29.0% by weight, about 30.0% by weight, about 31.0% by weight, about 32.0% by weight, about 33.0% by weight, about 34.0% by weight, about 35.0% by weight, about 36.0% by weight, about 37.0% by weight, about 38.0% by weight, about 39.0% by weight, about 39 0.1%, about 11.2%, about 11.3%, about 11.4%, about 11.5%, about 11.6%, about 11.7%, about 11.8%, about 11.9%, about 12.0%, about 12.1%, about 12.2%, about 12.3%, about 12.4%, about 12.5%, about 12.6%, about 12.7%, about 12.8%, about 12.9%, or about 13.0% by weight, including all values ​​and ranges therebetween. In an embodiment, the concentration of triglycerides is about 11% by weight. In an embodiment, the triglycerides are 6 ~C 12 (For example, C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , or C 12 ) medium chain triglyceride (MCT). In an embodiment, the MCT is caprylic capric triglyceride.

[0053] In an embodiment, the oil phase comprises 13~21 Fatty alcohols (e.g., C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , or C 21 In an embodiment, C 13~21The concentration of the fatty alcohol is about 10% by weight to about 14% by weight, for example, about 10.0% by weight, about 10.1% by weight, about 10.2% by weight, about 10.3% by weight, about 10.4% by weight, about 10.5% by weight, about 10.6% by weight, about 10.7% by weight, about 10.8% by weight, about 10.9% by weight, about 11.0% by weight, about 11.1% by weight, about 11.2% by weight, about 11.3% by weight, about 11.4% by weight, about 11.5% by weight, about 11.6% by weight, about 11.7% by weight, about 11.8% by weight, about 11.9 ... 2.0%, about 12.1%, about 12.2%, about 12.3%, about 12.4%, about 12.5%, about 12.6%, about 12.7%, about 12.8%, about 12.9%, about 13.0%, about 13.1%, about 13.2%, about 13.3%, about 13.4%, about 13.5%, about 13.6%, about 13.7%, about 13.8%, about 13.9%, or about 14.0% by weight, including all values ​​and ranges therebetween. 13~21 The concentration of fatty alcohol is about 12% by weight. 13~21 The fatty alcohol is octyldodecanol.

[0054] In embodiments, the compositions or formulations of the present disclosure further comprise pharmacologically acceptable preservatives, antioxidants, solvents, viscosity enhancing agents (i.e., viscosity modifiers), pH adjusting agents (i.e., pH modifiers), emollients, moisturizers, colorants, and fragrances. In embodiments, the compositions of the present disclosure further comprise antioxidants, preservatives, viscosity modifiers, pH adjusting agents, or mixtures thereof.

[0055] In an embodiment, the composition (e.g., cream) of the present disclosure comprises an antioxidant. In an embodiment, the antioxidant comprises a phenolic compound such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tertiary butylhydroquinone, a natural antioxidant such as tocopherol (vitamin E), ascorbic acid (vitamin C), polyphenols (e.g., propyl gallate), flavonoids, retinol (vitamin A), or a mixture thereof. In an embodiment, the antioxidant is propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene, or a mixture thereof. In an embodiment, the antioxidant is a mixture of propyl gallate and butylated hydroxyanisole (BHA). In embodiments, the concentration of propyl gallate is about 0.02% to about 0.08% by weight, e.g., about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, or about 0.08% by weight (including all values ​​and ranges therebetween). In an embodiment, the concentration of BHA is about 0.05% to about 0.2% by weight, for example, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, 0.17%, about 0.18%, about 0.19%, or about 0.2% by weight (including all values ​​and ranges therebetween). In an embodiment, the composition comprises about 0.05% propyl gallate and about 0.1% BHA by weight.

[0056] In embodiments, the compositions (e.g., creams) of the present disclosure include a preservative. In embodiments, the preservative (e.g., for inhibiting or preventing the growth of microorganisms, fungi, etc. in topical formulations) is selected from the group consisting of triclosan, methylisothiazolinone, methylchloroisothiazolinone, chlorphenesin, chloroxylenol, iodopropynyl butylcarbamate, methyldibromoglutaronitrile, formaldehyde, benzylhemiformal, diazolidinyl urea, imidazolidinyl urea, 2-bromo-2-nitropropane-1,3-diol, DMD Contains M hydantoin, MDM hydantoin, quaternium-15, sodium hydroxymethylglycinate, phenoxyethanol, 2-butoxyethanol, 2-(2-butoxyethoxy)ethanol, 2-(2-ethoxy)ethanol, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzoic acid (and its salts), sorbic acid (and its salts), salicylic acid (and its salts), alcohol or mixtures thereof. In an embodiment, the concentration of the preservative is about 0.05% to about 2% by weight, for example, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0% by weight (including any value or range therebetween). In an embodiment, the preservative is a glycol ether, a phenol ether, a benzoate, or a mixture thereof. In an embodiment, the preservative is phenoxyethanol. In an embodiment, the preservative is sodium benzoate. In embodiments, the concentration of phenoxyethanol is about 0.05% to about 0.4% by weight, e.g., about 0.05%, about 0.1%, about 0.2%, about 0.3% or about 0.4% by weight (including any value or range therebetween).In embodiments, the concentration of sodium benzoate is about 0.5% to about 2% by weight, e.g., about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0% by weight (including any value or range therebetween). In embodiments, the preservative is about 0.05% to about 0.4% by weight of phenoxyethanol, or about 0.5% to about 2% by weight of sodium benzoate, or a mixture thereof.

[0057] In an embodiment, a composition (e.g., a cream) of the present disclosure has a pH of about 4.5 to about 5.5 and includes a preservative, which in an embodiment is sodium benzoate, which exerts antimicrobial activity at acidic pH.

[0058] In an embodiment, the composition (e.g., cream) of the present disclosure includes a pharma- ceutically acceptable solvent. In an embodiment, the composition of the present disclosure includes acetone, 2-methylpentane-2,4-diol, propylene glycol, caprylic capric triglyceride (available as MIGLYOL 812N from Oleochemicals), octyldodecanol, limonene, 1,3-butanediol, 1,3-dioxolane, 1,3-propanediol, 1,5-pentanediol, 1,6-hexanediol, 1-decene, 1-heptanol, 1-hexanol, N-butyl acetate, ethyl acetate, methyl acetate, dimethyl isosorbide, α-terpineol, benzyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, isosorbide dimethyl ether, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol ... Pyrtetradecanoic acid, N-methyl-2-pyrrolidone, oleic acid, polyethylene glycol 400, polysorbate 20, polysorbate 80, propylene carbonate, propylene glycol diacetate, acetonitrile, chlorobenzene, cyclohexane, 1,4-dioxane, methanol, ethanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, nitromethane, pyridine, sulfolane, toluene, xylene or mixtures thereof.

[0059] In some embodiments, the compositions (e.g., creams) of the present disclosure include a thickening agent. In embodiments, thickening agents (i.e., viscosity modifiers), including thickening or gelling agents, include substances that can increase the viscosity of the composition. In embodiments, viscosity modifiers include substances that can increase the viscosity of the composition without substantially altering the efficacy of the active ingredients therein. In embodiments, viscosity modifiers can also increase the physical stability of the compositions of the present disclosure. In embodiments, the viscosity enhancing agent, viscosity modifier, or thickening agent is a lipid thickener, such as cetyl alcohol, stearyl alcohol, carnauba wax, stearic acid, naturally derived thickeners, such as hydroxyethylcellulose, gum arabic, guar gum, locust bean gum, xanthan gum, gelatin, hyaluronic acid, gum arabic, agar, algin, alginic acid, ammonium alginate, amylopectin, calcium alginate, calcium carrageenan, carnitine, carrageenan, dextrin ... Langmuir gum, guar hydroxypropyltrimonium chloride, hydroxypropyl chitosan, hydroxypropyl guar, karaya gum, kelp, natto gum, potassium alginate, potassium carrageenan, propylene glycol alginate, sclerotium gum, sodium carboxymethyl dextran, sodium carrageenan, tragacanth gum, mineral thickeners such as hectorite, hydrated silica, silica, bentonite, magnesium aluminum silicate, synthetic thickeners such as carbomer (water-swellable acrylic polymer sold under the trademarks ULTREZ 30 (Lubrizol), ULTREZ 21 (Lubrizol), TEGO Carbomer 140 G (Evonik), and SEPINEO P600 (acrylamide / AMPS copolymer, Seppic)).

[0060] In an embodiment, the viscosity modifier is a copolymer of acrylamide and sodium acryloyldimethyltaurate (e.g., SEPINEO P600), polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof. In an embodiment, the viscosity modifier is a copolymer of acrylamide and sodium acryloyldimethyltaurate dispersed in isohexadecane. In an embodiment, the concentration of the copolymer of acrylamide and sodium acryloyldimethyltaurate is about 1.5% by weight to about 5% by weight (e.g., about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, about 2.0% by weight, about 2.1% by weight, about 2.2% by weight, about 2.3% by weight, about 2.4% by weight, about 2.5% by weight, about 2.6% by weight, about 2.7% by weight, about 2.8% by weight, about 2.9% by weight, about 3.0% by weight, about 4.0% by weight, about 5.0% by weight, about 6.0% by weight, about 7.0% by weight, about 8.0% by weight, about 9.0% by weight, about 10 ... %, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, or about 5.0% by weight, including any value or range therebetween. In an embodiment, the viscosity modifier is about 1.5% to about 5% by weight of a copolymer of acrylamide and sodium acryloyldimethyltaurate dispersed in isohexadecane, polyoxyethylene sorbitan monooleate, sorbitan oleate, or mixtures thereof.

[0061] In an embodiment, the viscosity modifier or thickener in the composition of the present disclosure comprises a carboxylic acid polymer, a crosslinked polyacrylate polymer, a polyacrylamide polymer, a polysaccharide, a gum or a mixture thereof.In an embodiment, the carboxylic acid polymer comprises a crosslinked compound containing one or more monomers derived from acrylic acid, substituted acrylic acid, and the salts and esters of these acrylic acids and substituted acrylic acids, and the crosslinker comprises two or more carbon-carbon double bonds and is derived from a polyhydric alcohol (see U.S. Patent Application Nos. 5,087,445, 4,509,949, and 2,798,053, which are incorporated herein by reference in their entirety, and CTFA International Cosmetic Ingredient Dictionary, Fourth edition, 1991, pp. 12 and 80).

[0062] In an embodiment, the composition of the present disclosure includes a pH adjusting agent. In an embodiment, the pH adjusting agent (i.e., pH adjusting agent or pH modifying agent) includes any pharma- ceutically acceptable buffer capable of buffering in an acceptable pH range (e.g., pH 4-5), such as citrate buffer or acetate buffer. In an embodiment, the pH adjusting agent is 10% citric acid.

[0063] In embodiments, the compositions (e.g., creams) of the present disclosure further comprise an emollient. In embodiments, the pharma- ceutically acceptable emollients (or moisturizers) in the compositions of the present disclosure include vegetable oils, petrolatum, cetyl alcohol, cetearyl alcohol, cholesterol, cocoa butter, shea butter, isopropyl myristate, isopropyl palmitate, lanolin, liquid paraffin, polyethylene glycol, shea butter, silicone oil, stearic acid, stearyl alcohol, castor oil, and the like. In an embodiment, the pharma- ceutically acceptable moisturizing agents in the composition of the present disclosure include hyaluronic acid, glycerin, alpha hydroxy acids (e.g., glycolic acid, lactic acid, citric acid), propylene glycol, aloe vera gel, erythritol, xylitol, sorbitol, fructose, glucose, glycerin, glycerol polymers, glycol, 1,2,6-hexanetriol, honey, hydrogenated honey, hydrogenated starch hydrolysates, inositol, lactitol, maltitol, maltose, mannitol, PEG-15 butanediol, polyglyceryl sorbitol, pyrrolidone carboxylate, potassium PCA, propylene glycol, sodium glucuronate, sodium PCA, sucrose, trehalose, urea, panthenol (vitamin B5), peptides, amino acids, and salicylic acid. In an embodiment, the cream includes glycerin, propylene glycol, or a mixture thereof.

[0064] In embodiments, the compositions (e.g., creams) of the present disclosure optionally include a chelating agent. In embodiments, the pharma- ceutically acceptable chelating agent in the compositions of the present disclosure includes disodium ethylenediaminetetraacetic acid (EDTA), tetrasodium EDTA, or a mixture thereof.

[0065] In embodiments, compositions (e.g., creams) of the present disclosure optionally include an ultraviolet light absorbing agent. In embodiments, the chemical UV absorbers in the compositions of the present disclosure include para-aminobenzoic acid (PABA), PABA esters (glyceryl PABA, amyl dimethyl PABA, and octyl dimethyl PABA), butyl PABA, ethyl PABA, ethyl dihydroxypropyl PABA, benzophenones (oxybenzone, sulisobenzone, benzophenone, and benzophenones 1-12), cinnamates (octyl methoxycinnamate, isoamyl p-methoxycinnamate, octyl methoxycinnamate, cinnamoyl cinnamate, diisopropyl methyl cinnamate, DEA-methoxycinnamate, ethyl diisopropyl cinnamate, glyceryl octanoate dimethoxycinnamate, and ethyl methoxycinnamate), cinnamate esters, salicylates (such as homomethyl salicylate, benzyl salicylate, glycol salicylate, and isopropyl benzyl salicylate), anthranilic acid, ethyl urocanate, homosalate, octyl methyl salicylate, ethyl ... cutisalate, dibenzoylmethane derivatives (e.g., avobenzone), octocrylene, octyl triazone, digalloyl trioleate, glyceryl aminobenzoate, dihydroxyacetone containing lawsone, ethylhexyl triazone, dioctyl butamido triazone, benzylidene malonate polysiloxane, terephthalidene dicamphor sulfonic acid, disodium phenyl dibenzimidazole tetrasulfonate, diethylamino hydroxybenzoyl hexyl benzoate, bis diethylamino hydroxybenzoyl benzoate, bis benzoxazoyl phenyl ethylhexyl imino triazine, drometrizole trisiloxane, methylene bis benzotriazolyl tetramethyl butyl phenol, and bis ethylhexyloxyphenol methoxyphenyl triazine, 4-methylbenzylidene camphor, isopentyl-4-methoxycinnamate, or mixtures thereof. In embodiments, the physical UV absorber comprises kaolin, talc, petrolatum, metal oxides (eg, titanium dioxide, zinc oxide), or mixtures thereof.

[0066] In embodiments, the viscosity of the compositions of the present disclosure is in accordance with the U.S.P. <912> at 25° C. using a rotational viscosity method (Brookfield RVD VII viscometer) as described in, for example, at least about 15,000 mPa·s, e.g., at least about 15,500 mPa·s, about 16,000 mPa·s, about 17,000 mPa·s, about 18,000 mPa·s, about 19,000 mPa·s, about 20,000 mPa·s, about 25,000 mPa·s, about 30,000 mPa·s, about 35,000 mPa·s, about 40,000 mPa·s, about 45,000 mPa·s, about 50,000 mPa·s, about 55,000 mPa·s, about 60,000 mPa·s, about 65,000 mPa·s, or about 70,000 mPa·s.

[0067] In an embodiment, the viscosity of the cream is from about 15,000 mPa·s to about 90,000 mPa·s, e.g., about 15,000 mPa·s, about 20,000 mPa·s, about 25,000 mPa·s, about 30,000 mPa·s, about 35,000 mPa·s, about 40,000 mPa·s, about 45,000 mPa·s, or about 50,000 mPa·s when measured at 25° C. using a rotational viscosity method. 00 mPa·s, about 50,000 mPa·s, about 55,000 mPa·s, about 60,000 mPa·s, about 65,000 mPa·s, about 70,000 mPa·s, about 75,000 mPa·s, about 80,000 mPa·s, about 85,000 mPa·s, or about 90,000 mPa·s (including any value or range therebetween). In an embodiment, the viscosity of the cream is about 15,000 mPa·s to about 75,000 mPa·s when measured at 25° C. using a rotational viscosimetry. In an embodiment, the viscosity of the cream is about 19,500 mPa·s to about 45,200 mPa·s when measured at 25° C. using a rotational viscosimetry. In an embodiment, the viscosity measurement is performed at a constant shear rate (revolutions per minute) after pre-treating the sample at the same rate. In an embodiment, the viscosity of the composition is measured using a Brookfield Viscometer RVDVII+, small sample adapter (SSA) and SSA spindle set mobile number 34.

[0068] In an embodiment, the composition of the present disclosure is administered topically to deliver a pharmacologic level of a TRPV3 inhibitor (e.g., KM-001) to the epidermis.In an embodiment, the composition of the present disclosure is administered topically to deliver a pharmacologic level of a TRPV3 inhibitor (e.g., KM-001) to one or more of the suprabasal layers of the epidermis (e.g., the cornified membrane, the granular layer and the spinous layer, and the upper dermis).In an embodiment, the topical administration of the composition of the present invention allows the TRPV3 inhibitor to penetrate the entire suprabasal layer of the epidermis. In embodiments, local administration of the composition of the present disclosure may provide a local concentration of a TRPV3 inhibitor (e.g., KM-001) of about 60 μg / g to about 160 mg / g, e.g., about 60 μg / g, about 70 μg / g, about 80 μg / g, about 90 μg / g, about 100 μg / g, about 200 μg / g, about 300 μg / g, about 400 μg / g, about 500 μg / g, about 600 μg / g, about 700 μg / g, about 800 μg / g, about 900 μg / g, about 1000 μg / g, about 5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 35 mg / g, about 40 mg / g, about 45 mg / g, about 50 mg / g, about 55 mg / g, about 60 mg / g, about 65 mg / g, about 70 mg / g, about 75 mg / g, about 80 mg / g, about 85 mg / g, about 90 mg / g, about 95 mg / g, about 100 mg / g, about 110 mg / g, about 115 mg / g, about 120 mg / g, about 125 mg / g, about 130 mg / g, about 135 mg / g, about 140 mg / g, about 145 mg / g, about 150 mg / g, about 155 mg / g, or about 160 mg / g (including all ranges between any of these values).

[0069] Following topical administration of a composition of the present disclosure, the local concentration of a TRPV3 inhibitor (e.g., KM-001) in the dermis, as measured by the IVPT methods described herein, is in the range of about 1.5% to 16% by weight of the total amount of KM-001 in the skin, and is in the range of about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0%, about 10.0%, about 10.0%, about 11.0%, about 12.0%, about 13.0%, about 14.0%, about 15.0%, about 16.0%, about 17.0%, about 18.0%, about 19.0%, about 20.0%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, about 25.0%, about 26.0%, about 27.0%, about 28.0%, about 29.0%, about 30.0%, about 31.0%, about 32.0%, about 33.0%, about 34.0%, about 35.0%, about 36.0%, about 37.0%, about 38.0%, about 39.0%, about 40.0%, about 41.0%, about 42.0%, about 43.0%, about 44.0%, about 45.0%, about 46.0%, about 47.0%, about 48.0%, about 49.0%, about 50.0%, about 51.0%, about 52.0%, about 53.0%, about 54.0%, about 55.0%, about 56.0%, about 57.0%, about 58. 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 15.5%, or about 16.0% by weight (including all ranges between any of these values).

[0070] In embodiments, upon topical administration to the skin of a patient in need of treatment, about 0.05% to about 20% by weight, e.g., about 0.05% by weight, about 0.1% by weight, about 0.2% by weight, about 0.4% by weight, about 0.6% by weight, about 0.8% by weight, about 1.0% by weight, about 1.5% by weight, about 2.0% by weight, about 2.5% by weight, about 3.0% by weight, about 3.5% by weight, about 4.0% by weight, about 4.5% by weight, about 5.0% by weight, about 5.5% by weight, about 6.0% by weight, about 6.5% by weight, about 7.0% by weight, about 7.5% by weight, about 8.0% by weight, about 8.5% by weight, about 9.0% by weight, about 10.0% by weight, about 15.0% by weight, about 16.0% by weight, about 17.0% by weight, about 18.0% by weight, about 19.0% by weight, about 20.0% by weight, about 21.0% by weight, about 22.0% by weight, about 23.0% by weight, about 24.0% by weight, about 25.0% by weight, about 26.0% by weight, about 27.0% by weight, about 28.0% by weight, about 29.0% by weight, about 30.0% by weight, about 31.0% by weight, about 32.0% by weight, about 33.0% by weight, about 34.0% by weight, about 35.0% by weight, about 36.0% by weight, about 37.0% by weight, about 38.0% by weight, about 39.0% by weight, about 40 0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 15.5%, about 16.0%, about 16.5%, about 17.0%, about 17.5%, about 18.0%, about 18.5%, 19.0%, about 19.5%, or about 20.0% by weight (including any value or range therebetween) of KM-001 penetrates the stratum corneum, epidermis or dermis. In an embodiment, when topically administered to the skin of a patient in need of treatment, about 1 wt% to about 10 wt% of KM-001 present in the composition applied to the skin penetrates the stratum corneum as measured by IVPT. In an embodiment, when topically administered to the skin of a patient in need of treatment, about 0.2 wt% to about 8 wt% of KM-001 present in the composition applied to the skin penetrates the epidermis as measured by IVPT. In an embodiment, when topically administered to the skin of a patient in need of treatment, about 0.05 wt% to about 3 wt% of KM-001 present in the composition applied to the skin penetrates the dermis as measured by IVPT.

[0071] In embodiments, the cream, when topically administered to the skin of a patient in need thereof, provides a concentration of from about 50 μg / g to about 6000 μg / g, e.g., about 50 μg / g, about 60 μg / g, about 70 μg / g, about 80 μg / g, about 90 μg / g, about 100 μg / g, about 150 μg / g, about 200 μg / g, about 250 μg / g, about 300μg / g, about 350μg / g, about 400μg / g, about 450μg / g, about 500μg / g, about 550μg / g, about 600μg / g, about 650μg / g, about 700μg / g, about 750μg / g, about 800μg / g, about 850μg / g, about 900μ g / g, approximately 950μg / g, approximately 1000μg / g, approximately 1100μg / g, approximately 1200μg / g, approximately 1300μg / g, approximately 1400μg / g, approximately 1500μg / g, approximately 1600μg / g, approximately 1700μg / g, approximately 1800μg / g, approximately 1900μg / g, Approximately 2000μg / g, approximately 2100μg / g, approximately 2200μg / g, approximately 2300μg / g, approximately 2400μg / g, approximately 2500μg / g, approximately 2600μg / g, approximately 2700μg / g, approximately 2800μg / g, approximately 2900μg / g, approximately 3000μg / g, approximately 3 100μg / g, about 3200μg / g, about 3300μg / g, about 3400μg / g, about 3500μg / g, about 3600μg / g, about 3700μg / g, about 3800μg / g, about 3900μg / g, about 4000μg / g, about 4100μg / g, about 4200 In one embodiment, about 4300 μg / g, about 4400 μg / g, about 4500 μg / g, about 4600 μg / g, about 4700 μg / g, about 4800 μg / g, about 4900 μg / g, about 5000 μg / g, about 5100 μg / g, about 5200 μg / g, about 5300 μg / g, about 5400 μg / g, about 5500 μg / g, about 5600 μg / g, about 5700 μg / g, about 5800 μg / g, about 5900 μg / g or about 6000 μg / g (including any value or range therebetween) of KM-001 is permeated throughout the skin strip.In an embodiment, when the cream is administered topically to the skin of a patient in need thereof, about 50 μg / g to about 6000 μg / g of KM-001 present in the composition applied to the skin (1% by weight) penetrates throughout the skin section as measured by MALDI. In an embodiment, when the cream is administered topically to the skin of a patient in need thereof, about 2000 μg / g to about 3000 μg / g of KM-001 present in the composition applied to the skin (1% by weight) penetrates throughout the skin as measured by MALDI. In an embodiment, when the cream is administered topically to the skin of a patient in need thereof, about 2000 μg / g to about 6000 μg / g of KM-001 present in the composition applied to the skin (1 weight percent concentration) penetrates throughout all layers of the epidermis, particularly the suprabasal layers of the epidermis as measured by MALDI. In an embodiment, when the cream is administered topically to the skin of a patient in need thereof, about 500 μg / g to about 800 μg / g of KM-001 present in the composition applied to the skin (1% by weight) penetrates into the dermis as measured by MALDI. In an embodiment, when the cream is administered topically to the skin of a patient in need thereof, it penetrates from the skin into the dermis and results in a dermal concentration of KM-001 of about 1% to about 16% (e.g., about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 7.0%, about 8.0%, about 9.0%, about 10 ... about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 15.5% or about 16.0% (including any value or range therebetween). In an embodiment, when the cream is administered topically to the skin of a patient in need thereof, about 100 μg / g to about 3500 μg / g of KM-001 present in the composition applied to the skin (1% by weight) penetrates into the subcutaneous tissue as measured by MALDI. In embodiments, when the cream is administered topically to the skin of a patient in need thereof, from about 50 μg / g to about 1200 μg / g of KM-001 present in the composition applied to the skin (1% by weight) penetrates into hair follicles as measured by MALDI.

[0072] In an embodiment, about 2 grams to about 4 grams (e.g., about 2 g, about 2.1 g, about 2.2 g, about 2.3 g, about 2.4 g, about 2.5 g, about 2.6 g, about 2.7 g, about 2.8 g, about 2.9 g, about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, or about 4.0 g (including any value or range therebetween) of cream comprising 1% by weight of KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 (For example, about 410 cm 2 , about 420cm 2 , about 430cm 2 , about 440cm 2 , about 450cm 2 , about 460cm 2 , about 470cm 2 , about 480cm 2 , approx. 490cm 2 , about 500cm 2 , about 510cm 2 , about 520cm 2 , about 530cm 2 , about 540cm 2 , about 550cm 2 , approx. 560cm 2 , approx. 570cm 2 , about 580cm 2 , approx. 590cm 2 , or about 600 cm 2When topically administered to the skin (including any value or range therebetween), the concentration of the active ingredient in ... 0μg / g, approximately 600μg / g, approximately 650μg / g, approximately 700μg / g, approximately 750μg / g, approximately 800μg / g, approximately 850μg / g, approximately 900μg / g, approximately 950μg / g, approximately 1000μg / g, approximately 1100μg / g, approximately 1200μg / g, approximately 1300μg / g, approximately 1400μg / g, approximately 1500μg / g, approximately 1600μg / g, approximately 1700μg / g, approximately 1800μg / g, approximately 1900μg / g, approximately 2000μg / g, approximately 2100μg / g, approximately 2200μg / g, approximately 2 300μg / g, approximately 2400μg / g, approximately 2500μg / g, approximately 2600μg / g, approximately 2700μg / g, approximately 2800μg / g, approximately 2900μg / g, approximately 3000μg / g, approximately 3100μg / g, approximately 3200μg / g, approximately 3300μg / g, approximately 3400μg / g, approximately 3500μg / g, approximately 3600μg / g, approximately 3700μg / g, approximately 3800μg / g, approximately 3900μg / g, approximately 4000μg / g, approximately 4100μg / g, approximately 4200μg / g, approximately 4300μg / g, approximately 4 400 μg / g, about 4500 μg / g, about 4600 μg / g, about 4700 μg / g, about 4800 μg / g, about 4900 μg / g, about 5000 μg / g, about 5100 μg / g, about 5200 μg / g, about 5300 μg / g, about 5400 μg / g, about 5500 μg / g, about 5600 μg / g, about 5700 μg / g, about 5800 μg / g, about 5900 μg / g, or about 6000 μg / g (including any value or range therebetween) of KM-001 is provided to one or more skin layers.

[0073] In an embodiment, about 3 grams of cream containing 1% by weight of KM-001 is applied to about 500 cm of skin. 2Topical administration to the skin provides about 50 μg / g to about 6000 μg / g of KM-001 in one or more layers of the skin as measured by MALDI (matrix assisted laser desorption / ionization). In embodiments, about 2 grams to about 4 grams of cream containing 1% by weight KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 Topical administration to the skin provides about 2000 μg / g to about 6000 μg / g of KM-001 to the epidermis as measured by MALDI (matrix assisted laser desorption / ionization). In an embodiment, about 3 grams of a cream containing 1% by weight of KM-001 is applied to about 500 cm of the skin of a patient in need thereof. 2 When administered topically, about 2000 μg / g to about 6000 μg / g of KM-001 is provided to the epidermis as measured by MALDI (matrix assisted laser desorption / ionization). In an embodiment, about 2 grams to about 4 grams of cream containing 1% by weight of KM-001 is administered to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 Topical administration to the skin of a patient in need thereof provides about 2000 μg / g to about 6000 μg / g of KM-001 to the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum, or a combination thereof, as measured by MALDI. In embodiments, about 2 grams to about 4 grams of a cream containing 1% by weight KM-001 is administered to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 Topical administration to the skin provides about 500 μg / g to about 800 μg / g of KM-001 in the dermis as measured by MALDI. In embodiments, about 3 grams of cream containing 1% by weight KM-001 is applied to about 500 cm of the skin of a patient in need thereof. 2 When topically administered to the skin, about 500 μg / g to about 800 μg / g of the KM-001 is provided to the dermis as measured by MALDI. In an embodiment, about 2 grams to about 4 grams of a cream containing 1% by weight of KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2When topically administered to the skin, approximately 1% to approximately 16% (e.g., approximately 1.0%, approximately 1.5%, approximately 2.0%, approximately 2.5%, approximately 3.0%, approximately 3.5%, approximately 4.0%, approximately 4.5%, approximately 5.0%, approximately 5.5%, approximately 6.0%, approximately 6.5%, approximately 7.0%, approximately 7.5%, approximately 8.0%, approximately 8.5%, approximately 9.0%) of KM-001 in the epidermis was detected as 1.0% to 1.5% (e.g., approximately 1.0%, approximately 1.5%, approximately 2.0%, approximately 2.5%, approximately 3.0%, approximately 3.5%, approximately 4.0%, approximately 4.5%, approximately 5.0%, approximately 5.5%, approximately 6.0%, approximately 6.5%, approximately 7.0%, approximately 7.5%, approximately 8.0%, approximately 8.5%, approximately 9.0%) of KM-001 in the epidermis as measured by MALDI. KM-001 is provided in the dermis at a concentration equivalent to about 0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 15.5%, or about 16.0% (including any value or range therebetween). In an embodiment, about 2 grams to about 4 grams of cream containing 1% by weight KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 Topical administration to the skin provides about 100 μg / g to about 3500 μg / g of KM-001 in the subcutaneous tissue as measured by MALDI. In embodiments, about 2 grams to about 4 grams of cream containing 1% by weight KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 When administered topically, about 50 μg / g to about 1200 μg / g of KM-001 is delivered to the hair follicles as measured by MALDI.

[0074] It is well known that the skin is an effective barrier, therefore the active agent in a topical composition must be small enough to be able to penetrate it in a dissolved state. If the active agent crystallizes or precipitates from the composition before (or during) application, the available dose of the active agent will be reduced. It is therefore important to select solvents and other ingredients / excipients that maintain the solubility (and chemical stability) of the active ingredient (e.g., KM-001) during transportation, storage, and use.

[0075] In an embodiment, the induction time for a sample containing 100 pbw oil phase and 1 pbw KM-001 is at least 500 minutes when measured by RapidOxy test at 120°C, 700 kPa initial pressure, and 2% ΔP using 3-5 g sample. In an embodiment, the cream meets the European Pharmacopoeia 5.1.3 A criterion after one year storage at 25°C ± 2°C and 60% ± 5% relative humidity. In an embodiment, the cream meets the European Pharmacopoeia 5.1.3 A criterion after six months storage at 40°C ± 2°C and 75% ± 5% relative humidity. In an embodiment, the cream meets the USP 5.1.3 A criterion after six months storage at 40°C ± 2°C and 75% ± 5% relative humidity. <51> In an embodiment, the solubility of KM-001 in the oil phase is about 10% to about 15% by weight at 10°C to 30°C.

[0076] In embodiments, the compositions of the present disclosure facilitate delivery of TRPV3 inhibitors to the intended layer(s) of the skin to treat various skin conditions (e.g., skin disorders and / or pruritus as described herein) while minimizing systemic exposure of the TRPV3 inhibitor. Systemic exposure is undesirable as it increases the likelihood of off-target effects that may affect the tolerability or safety of the composition. Furthermore, any TRPV3 inhibitors that are distributed systemically may not be available to the target tissue, i.e., the skin, to treat the intended skin disorder(s) and / or pruritus. The compositions of the present disclosure provide a peak plasma concentration (C max ) and plasma drug concentration time area under the curve (AUC) values, the systemic exposure levels are low. For example, the compositions of the present disclosure have a C maxValues ​​below approximately 40 ng / mL (measured after 28 days in patients treated topically with a daily dose of approximately 0.4 mg / kg*day of a TRPV3 inhibitor).In an embodiment, the max value after 28 days ranges from undetectable to about 0.1 ng / mL, about 0.2 ng / mL, about 0.3 ng / mL, about 0.4 ng / mL, about 0.5 ng / mL, about 0.6 ng / mL, about 0.7 ng / mL, about 0.8 ng / mL, about 0.9 ng / mL, about 1.0 ng / mL, about 1.5 ng / mL, about 2.0 ng / mL, about 2.5 ng / mL, about 3.0 ng / mL, about 3.5 ng / mL, about 4.0 ng / mL, about 4.5 ng / mL, about 5.0 ng / mL, about 6.0 ng / mL, about 6.5 ng / mL, about 7.0 ng / mL, about 7.5 ng / mL, about 8.0ng / mL, approximately 8.5ng / mL, approximately 9.0ng / mL, approximately 9.5ng / mL, approximately 10.0ng / mL, approximately 10.5ng / mL, approximately 11.0ng / mL, approximately 11.5ng / mL, approximately 12.0ng / mL, approximately 12.5ng / mL, approximately 13.0ng / mL, approximately 13.5ng / mL, approximately 14.0ng / mL, approximately 14.5ng / mL, approximately 15.0ng / mL, approximately 15.5ng / mL, approximately 16.0ng / mL, approximately 16.5ng / mL, approximately 17.0ng / mL, approximately 17.5ng / mL, approximately 18.0ng / mL, approximately 18.5ng / mL, approximately 19.0ng / mL , about 19.5ng / mL, about 20.0ng / mL, about 20.5ng / mL, about 21.0ng / mL, about 21.5ng / mL, about 22.0ng / mL, about 22.5ng / mL, about 23.0ng / mL, about 23.5ng / mL, about 24.0ng / mL, about 24.5ng / mL, about 25.0ng / mL, approximately 25.5ng / mL, approximately 26.0ng / mL, approximately 26.5ng / mL, approximately 27.0ng / mL, approximately 27.5ng / mL, approximately 28.0ng / mL, approximately 28.5ng / mL, approximately 29.0ng / mL, approximately 29.5ng / mL, approximately 30.0ng / mL, approximately 30 0.5ng / mL, about 31.0ng / mL, about 31.5ng / mL, about 32.0ng / mL, about 32.5ng / mL, about 33.0ng / mL, about 33.5ng / mL, about 34.0ng / mL, about 34.5ng / mL, about 35.0ng / mL, about 35.5ng / mL, about 36.0ng / mL, about 36.5ng / mL, about 37.0ng / mL, about 37.5ng / mL, about 38.0ng / mL, about 38.5ng / mL, about 39.0ng / mL, about 39.5ng / mL, or about 40.0ng / mL (including all ranges between any of these values).In embodiments, topical administration of a composition (e.g., a cream) of the present disclosure results in a peak plasma concentration (C) of KM-001. max ) less than about 40 ng / mL.

[0077] In embodiments, the AUC of the TRPV3 inhibitor (e.g., KM-001) (measured after 28 days in patients treated topically with the TRPV3 inhibitor at a dose of about 0.4 mg / kg*day per day) is less than about 500 ng / mL*hr. In embodiments, the AUC of the TRPV3 inhibitor measured under such conditions ranges from undetectable to about 1 ng / mL*hr, about 5 ng / mL*hr, about 10 ng / mL*hr, about 15 ng / mL*hr, about 20 ng / mL*hr, about 25 ng / mL*hr, about 30 ng / mL*hr, about 35 ng / mL*hr, about 40 ng / mL*hr, about 45 ng / mL*hr, about 50 ng / mL*hr, about 55 ng / mL*hr, about 60 ng / mL*hr, about 65 ng / mL*hr, about 70 ng / mL*hr, about 80 ng / mL*hr, about 90 ng / mL*hr, about 100 ng / mL*hr, about 120 ng / mL*hr, about 140 ng / mL*hr, about 160 ng / mL*hr, about 180 ng / mL*hr, about 190 ng / mL*hr, about 210 ng / mL*hr, about 220 ng / mL*hr, about 230 ng / mL*hr, about 240 ng / mL*hr, about 250 ng / mL*hr, about 260 ng / mL*hr, about 270 ng / mL*hr, about 280 ng / mL*hr, about 300 ng / mL*hr, about 350 ng / mL*hr, about 360 ng / mL*hr, about 370 ng / mL*hr, about 380 ng / mL*hr L*hr, about 75ng / mL*hr, about 80ng / mL*hr, about 85ng / mL*hr, about 90ng / mL*hr, about 95ng / mL*hr, about 100ng / mL*hr, about 150ng / mL*hr, about 200ng / mL*hr, about 250ng / mL*hr, about 300ng / mL*hr, about 350ng / mL*hr, about 400ng / mL*hr, about 450ng / mL*hr, or about 500ng / mL*hr, including all ranges between any of these values. In embodiments, local administration results in an area under the plasma drug concentration time curve (AUC) of KM-001 of less than about 500ng / mL*hr.

[0078] Methods for Treating Skin Disorders and Pruritus The compositions of the present disclosure, comprising about 0.2% to about 2% by weight, particularly about 0.3% or about 1.0% by weight of a TRPV3 inhibitor (e.g., KM-001), may be applied at least once a day to an area of ​​the skin of a patient suffering from skin disorders and / or pruritus. In some embodiments, the compositions of the present invention described herein may be applied as needed or more than once a day, for example, twice a day (e.g., morning and evening), three times a day (morning, midday, and evening), or four or more times a day. The amount applied to the patient's skin may be adjusted based on the concentration of the TRPV3 inhibitor (e.g., KM-001) in the composition, the severity of the skin disorder and / or pruritus, and the extent of the clinical response. For example, a composition with a high content of a TRPV3 inhibitor (e.g., about 1.0% by weight of KM-001) may be applied less frequently than a composition with a low content of a TRPV3 inhibitor (e.g., about 0.3% by weight of KM-001). Similarly, when the severity of skin disorders and / or pruritus is low, the frequency or concentration of administration of the TRPV3 inhibitor can be reduced.In an embodiment, the composition of the present invention can be administered prophylactically to a patient who is predisposed to a skin disorder, for example, to delay or prevent the formation of symptoms of skin disorders (e.g., keratinopathy and / or pruritus).

[0079] As discussed herein, the amount of the composition of the present disclosure applied daily can vary based on the severity of the disease, the surface area of ​​the patient's affected skin, and the frequency of application.

[0080] In an embodiment, a suitable dosage of the TRPV3 inhibitor (e.g., KM-001) of the composition of the present disclosure can be expressed as the amount of TRPV3 inhibitor (e.g., KM-001) administered per kg of patient body weight per day. Expressed in this manner, a suitable daily dosage of the TRPV3 inhibitor (e.g., KM-001) can range from about 0.1 to about 1 mg / kg / day (about 0.1 mg / kg / day, about 0.15 mg / kg / day, about 0.2 mg / kg / day, about 0.25 mg / kg / day, about 0.3 mg / kg / day, about 0.35 mg / kg / day, about 0.4 mg / kg / day, about 0.45 mg / kg / day, about 0.5 mg / kg / day, about 0.6 mg / kg / day, about 0.7 mg / kg / day, about 0.8 mg / kg / day, about 0.9 mg / kg / day, about 10 mg / kg / day, about 15 ... g / kg / day, about 0.55 mg / kg / day, about 0.6 mg / kg / day, about 0.65 mg / kg / day, about 0.7 mg / kg / day, about 0.75 mg / kg / day, about 0.8 mg / kg / day, about 0.85 mg / kg / day, about 0.9 mg / kg / day, about 0.95 mg / kg / day or about 1.0 mg / kg / day (including all ranges between any of these values).

[0081] In embodiments, a suitable dosage of the TRPV3 inhibitor (e.g., KM-001) of the disclosed compositions is applied to 1 cm of skin per day. 2 The amount of TRPV3 inhibitor (e.g., KM-001) administered per day can be expressed as the amount of TRPV3 inhibitor (e.g., KM-001) administered per day. Expressed in this manner, a suitable daily dose of the TRPV3 inhibitor (e.g., KM-001) is about 10 μg / cm2 / day to about 1000 μg / cm2 / day. 2 / day range (approximately 10μg / cm 2 / day, approximately 20μg / cm 2 / day, approximately 30μg / cm 2 / day, approximately 40μg / cm 2 / day, approximately 50μg / cm 2 / day, approximately 60μg / cm 2 / day, approximately 70μg / cm 2 / day, approximately 80μg / cm 2 / day, approximately 90μg / cm 2 / day, approximately 100μg / cm 2 / day, approximately 150μg / cm 2 / day, approximately 200μg / cm 2 / day, approximately 250μg / cm 2 / day, approximately 300μg / cm 2 / day, approximately 350μg / cm 2 / day, approximately 400μg / cm 2 / day, approximately 450μg / cm 2 / day, approximately 500μg / cm 2 / day, approximately 550μg / cm 2 / day, approximately 600μg / cm 2 / day, approximately 650μg / cm 2 / day, approximately 700μg / cm 2 / day, approximately 750μg / cm 2 / day, approximately 800μg / cm 2 / day, approximately 850μg / cm 2 / day, approximately 900μg / cm 2 / day, approximately 950μg / cm 2 / day, or approximately 1000 μg / cm 2 / day (including all ranges between these any values).

[0082] The compositions of the present disclosure may be administered for a prescribed period of time (e.g., 1, 2, 3, 4 weeks, or more) until the patient's skin disease and / or pruritus is resolved or at least treated sufficiently to discontinue treatment temporarily. In some embodiments, the compositions of the present invention may be administered indefinitely to patients suffering from chronic skin disease or pruritus. In embodiments, the dosage of the TRPV3 inhibitor (e.g., KM-001) may be adjusted to prevent recurrence of the skin disease and / or pruritus, or to provide an appropriate maintenance dose to prevent recurrence. Dose adjustments may be provided by changing the concentration of the TRPV3 inhibitor (e.g., KM-001) in the topical composition, applying the same concentration at different daily frequencies, applying different amounts of the topical composition, or a combination of these adjustments. Thus, to reduce the daily application of the TRPV3 inhibitor (e.g., KM-001), the patient may switch to a topical composition with a lower concentration of the TRPV3 inhibitor, apply the topical composition less frequently, apply less of the topical composition, or combine these methods. Similarly, the daily dose of a TRPV3 inhibitor (e.g., KM-001) can be increased by switching to a topical composition having a higher concentration of the TRPV3 inhibitor, applying the topical composition more frequently, applying the topical composition in greater quantities, or a combination of these methods.

[0083] In embodiments, the present disclosure provides methods of use for treating various skin disorders described herein, as well as for treating symptoms associated with (e.g., caused by or manifested by) such skin disorders, such as pruritus.

[0084] The compositions and methods of the present disclosure are effective in reducing the symptoms of various skin diseases described herein, for example, reducing the size and severity of skin lesions.For example, the reduction in symptoms can be measured by Investigator Global Assessment (IGA) of disease severity using the IGA score chart shown in Table 9 of Example 6.

[0085] The compositions of the present invention comprising at least one TRPV3 inhibitor (e.g., KM-001) described herein are suitable for treating various skin disorders. For example, skin diseases treatable by the compositions of the present disclosure include keratosis. Keratosis is characterized by a significant thickening of the epidermis of the skin. Keratosis can be classified in various ways, whether it is hereditary or acquired, and by clinical features, with diffuse keratosis affecting most of the palms and soles, focal keratosis affecting mainly pressure sites, and punctate keratosis causing small bumps on the palms and soles. In most cases, the abnormal skin appears only on the palms and soles (non-migratory palmoplantar keratosis), but it can also spread to the upper parts of the hands and feet (migratory).

[0086] Specific types of keratosis treatable by the compositions and methods of the present disclosure include diffuse hereditary palmoplantar keratosis (e.g., Unner-Toast type (autosomal dominant), Vorner type (autosomal dominant), Mal de Meleda type (autosomal dominant or recessive), Huriez syndrome (autosomal dominant), Olmsted syndrome (inheritance unknown), Vauwinkel syndrome (autosomal dominant), PPK with sensorineural hearing loss (mitochondrial inheritance), Bart-Pumphrey syndrome (autosomal dominant), sudomotor ectodermal dysplasia (autosomal dominant), Papillon-Lefèvre syndrome (autosomal recessive), Nagashima type palmoplantar keratoderma (autosomal recessive), diffuse palmoplantar keratoderma with woolly hair and arrhythmic cardiomyopathy (autosomal recessive), focal hereditary palmoplantar keratodermas (e.g. palmoplantar keratoderma linear / round type (autosomal dominant), hereditary painful keratoderma (autosomal dominant), Howell-Evans syndrome or Twill syndrome (autosomal dominant) , [tyrosinemia (autosomal recessive), pachyonychia congenita (autosomal dominant), striated palmoplantar keratosis with woolly hair and dilated keratosis (autosomal recessive)], punctate palmoplantar keratosis (e.g., punctate keratosis (autosomal dominant), filiform keratosis (autosomal dominant), acral keratosis (acral keratoelastosis, autosomal dominant). Keratoses treatable by the compositions and methods of the present disclosure further include acquired palmoplantar keratoses, which may be focal or diffuse. Such acquired keratoses may occur in association with a variety of skin and internal conditions, such as inflammatory skin diseases (e.g., eczema or psoriasis), infections, drugs or toxins, internal cancers, systemic inflammatory diseases, circulatory disorders, sunburn, etc.

[0087] Ichthyosis is another class of skin disorder treatable by the compositions and methods of the present disclosure.Ichthyosis refers to a group of relatively rare skin disorders characterized by the presence of excess dry scale on the surface of the skin, which dry scales become persistently dry and thick, causing the skin to have a "fish scale" appearance.Ichthyosis is considered a disorder of keratinization or keratinization, and is caused by abnormal epidermal differentiation or metabolism.

[0088] Ichthyosis-like skin diseases may be classified according to clinical symptoms, genetic and histological findings. There are at least 20 types of ichthyosis. Some types are inherited at birth, others are acquired during adulthood. Hereditary ichthyosis may be congenital or may have a delayed onset. Ichthyosis vulgaris is autosomal dominant, meaning that the abnormal gene is inherited from a parent. Penetrance is 90%, with onset delayed until at least 3 months of age. Recessive X-linked ichthyosis primarily affects males who have one X chromosome with the abnormal gene. Females are usually protected by having a normal second X chromosome. Onset may be congenital or may be delayed by up to 6 months. In autosomal recessive congenital ichthyosis, one abnormal gene is inherited from each parent. Congenital ichthyosa-like erythroderma (CIE) is a variant of autosomal recessive congenital ichthyosis (ARCI) and is a rare epidermal disorder characterized by the appearance of fine whitish scales on a generalized erythematous background. Keratinotic ichthyosis can be recessive or dominant and is present at birth with a collodion membrane. Harley Quinn ichthyosis is a rare and severe form of ichthyosis that causes the entire body to be covered with hard, thickened, armor-like plates of skin from birth. Harley Quinn ichthyosis is also known as Harley Quinn type ichthyosis or Harley Quinn fetus. Lamellar ichthyosis is a rare genetic disorder. Infants with lamellar ichthyosis are usually born with a shiny, waxy layer of skin (called a collodion membrane) that usually falls off within the first 2 weeks of life. The skin beneath the collodion membrane is red and scaly. Epidermolytic ichthyosis (EI) is a rare inherited skin disorder. It appears at or shortly after birth as red, scaly, severely blistered skin. Hyperkeratosis develops within a few months and worsens over time. Blister formation decreases but may still occur after skin trauma or during the summer. The skin may become itchy, smelly, and prone to infection. Other symptoms may include decreased sweating, nail abnormalities, and impaired growth in severe cases. Superficial epidermolytic ichthyosis (SEI), formerly called Siemens bullous ichthyosis (IBS), is a rare keratinization disorder with epidermal detachment. Although hyperkeratotic, the skin is abnormally fragile and prone to shedding of the outer layer of the epidermis, resulting in localized areas of flaking.Netherton syndrome (rotatory linear ichthyosis) is a rare genetic disorder characterized by scaling of the skin, hair abnormalities, increased susceptibility to atopic eczema (a skin disorder characterized by dry, red, flaking skin), elevated IgE levels, and other associated symptoms. Netherton syndrome is inherited as an autosomal recessive trait. Pachyonychia congenita (PC) is a rare group of autosomal dominant skin disorders caused by mutations in one of five different keratin genes. Pachyonychia congenita is often accompanied by thickened toenails, plantar keratosis, and plantar pain.

[0089] Other types of ichthyosis treatable by the compositions and methods of the present disclosure include Chanarin-Dorfman syndrome (neutral lipid storage disease), CHILD syndrome (hemihemidysplasia), Conradi-Hunnermann syndrome (X-linked dominant chondrodysplasia punctata), Darier's disease, epidermal nevus (ichthyosis histrionicus, linear epidermal nevus), epidermal keratosis variabilis (EHK), erythrokeratosis variabilis (EKV), Giroux-Barbeau syndrome, Hailey-Hailey disease ( Benign familial pemphigus, Curth-Macklin histriotic ichthyosis, depilatory follicular keratosis, KID syndrome (keratitis, ichthyosis, hearing loss), multiple sulfatase deficiency, peeling skin syndrome, pityriasis rubra pilaris (PRP), Refsum disease (phytanic acid storage disease), Ladd syndrome, Sjogren-Larsson syndrome, Tay syndrome (trichothiodystrophy, IBIDS syndrome).

[0090] In embodiments, the compositions and methods of the present disclosure may be used to treat keratosis, lichen simplex chronicus, pruritic diseases, and ichthyosis. Particular keratosis treatable by the compositions and methods of the present disclosure includes Mal de Meleda keratosis, Olmsted syndrome, Papillon-Lefevre syndrome, Nagashima palmoplantar keratosis, congenital pachyonychia, and punctate palmoplantar keratosis. Particular ichthyosis treatable by the compositions and methods of the present disclosure includes recessive X-linked ichthyosis and Harley Quinn ichthyosis.

[0091] The disclosed compositions and methods can also be used to treat pruritus or itching. Pruritus or itching can be defined as an unpleasant sensation of the skin that induces the urge to scratch. It is a characteristic finding of many skin diseases and also an abnormal sign of some systemic diseases. Pruritus can be localized or systemic, and can occur as an acute or chronic symptom. Itching that lasts for more than 6 weeks is called chronic pruritus.

[0092] Itch or pruritus that appears as a symptom or component of various disorders (e.g., atopic eczema, dermatitis herpetiformis, lichen simplex chronicus, prurigo nodularis) can also be treated by the compositions and methods of the present disclosure. These conditions are rarely diagnosed in the absence of itching / itch. Chronic itch associated with the following skin diseases can also be treated by the compositions and methods of the present disclosure: dermatitis herpetiformis, dermatomyositis, pemphigoid, Sjogren's syndrome, genetically related itch (Darier's disease, Hailey-Hailey disease, ichthyosis, Sjogren-Larsson syndrome), infection and infestation related itch (arthropod reactions, dermatophytosis, folliculitis, impetigo contagiosa and other bacterial infections, insect bites, pediculosis, scabies, viral), inflammation related itch (aging and senile scratching), and chronic itching associated with the skin diseases (aging and senile scratching). asteatosis (dry skin) including pruritus, atopic eczema, contact dermatitis (irritant, allergic), drug reactions, "invisible dermatosis", lichen planus, lichen simplex chronicus, mastocytosis (urticaria pigmentosa), miliaria, psoriasis, scarring, urticaria), neoplastic associated itch (cutaneous T-cell lymphoma or mycosis fungoides (especially Sézary syndrome), cutaneous B-cell lymphoma, leukemia cutis), pregnancy associated itch (pemphigoid gestationis, polymorphous exanthema gestationis, prurigo gravida). Specific systemic causes of chronic pruritus treatable by the compositions and methods of the present disclosure may include endocrine and metabolic disorders such as chronic renal failure, diabetes (which may be localized to the scalp), hyperthyroidism, hypothyroidism, liver disease (with or without cholestasis), malabsorption, menopausal pruritus, infectious diseases such as helminthiasis, HIV infection, parasitic diseases, neoplastic and hematological disorders such as Hodgkin's disease, iron deficiency, leukemia, non-Hodgkin's lymphoma, multiple myeloma, plasmacytoma, polycythemia vera, visceral tumors such as carcinoid syndrome and solid tumors of the cervix, prostate, or colon, pregnancy-related disorders such as pruritus pregnancy (with or without cholestasis), drug-induced, such as allopurinol, amiodarone, angiotensin-converting enzyme inhibitors, estrogens, hydrochlorothiazide, hydroxyethylcellulose, opioids, simvastatin. Other causes of chronic pruritus may be neurological disorders (abscess, infarction, multiple sclerosis, paresthesia, back pain, tumors) or psychiatric disorders (anxiety disorders, depression, obsessive-compulsive disorder).

[0093] In embodiments, the compositions and methods of the present disclosure are suitable for treating itching or pruritus and are effective in treating pruritic symptoms alone, or in treating skin disorders such as keratosis or lichen simplex chronicus with associated pruritic symptoms. Specific Embodiments 1. A cream, [ka] and, An aqueous phase; and an oil phase, The cream, wherein the concentration of KM-001 is about 0.1% by weight to about 5.6% by weight. 2. The cream according to embodiment 1, wherein the concentration of KM-001 is from about 0.2% to about 3% by weight. 3. A cream according to embodiment 1 or 2, wherein the concentration of KM-001 is about 0.3% by weight. 4. A cream according to embodiment 1 or 2, wherein the concentration of KM-001 is about 1% by weight. 5. The cream according to any one of the preceding embodiments, wherein the cream has a pH of about 4 to about 6. 6. The cream according to any one of embodiments 1 to 5, wherein the pH of the cream is from about 4.5 to about 5.5. 7. The cream comprises: (a) about 20% by weight to about 40% by weight of the oil phase; (b) about 60% to about 80% by weight of said aqueous phase. 8. The oil phase is composed of triglycerides, C 13~21 8. A cream according to any one of the preceding embodiments, comprising a fatty alcohol, or a mixture thereof. 9. The cream according to embodiment 8, wherein the concentration of the triglyceride is from about 9% to about 13% by weight. 10. A cream according to embodiment 8 or 9, wherein the concentration of triglyceride is about 11% by weight. 11. A cream according to any one of embodiments 8 to 10, wherein the triglyceride is a medium chain triglyceride (MCT). 12. The cream of embodiment 11, wherein the MCT is caprylic capric triglyceride. 13. Said C 13~21 13. A cream according to any one of embodiments 8 to 12, wherein the concentration of fatty alcohol is from about 10% to about 14% by weight. 14. Said C 13~21 14. A cream according to any one of embodiments 8 to 13, wherein said concentration of fatty alcohol is about 12% by weight. 15. Said C 13~21 15. A cream according to any one of embodiments 8 to 14, wherein the fatty alcohol is octyldodecanol. 16. A cream according to any one of the preceding embodiments, wherein the oil phase is free of polyoxypropylene stearyl ether. 17. A cream according to any one of the preceding embodiments, wherein the cream further comprises an antioxidant, a preservative, a viscosity adjuster, a pH adjuster or a mixture thereof. 18. A cream according to embodiment 17, wherein the antioxidant is propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene or a mixture thereof. 19. A cream according to embodiment 18, wherein the antioxidant is a mixture of propyl gallate and BHA. 20. The cream of embodiment 19, wherein the concentration of the propyl gallate is from about 0.02% to about 0.08% by weight, and the concentration of the BHA is from about 0.05% to about 0.2% by weight. 21. A cream according to embodiment 20, wherein the cream comprises about 0.05% by weight of propyl gallate and about 0.1% by weight of BHA. 22. The cream of embodiment 17, wherein the concentration of the preservative is from about 0.05% to about 4% by weight. 23. A cream according to embodiment 22, wherein the preservative is a glycol ether, a phenol ether, a benzoate or a mixture thereof. 24. The cream of embodiment 23, wherein the preservative is about 0.05% to about 0.4% by weight of phenoxyethanol, about 0.5% to about 2% by weight of sodium benzoate, or a mixture thereof. 25. The cream according to embodiment 17, wherein the viscosity modifier is a copolymer of acrylamide and sodium acryloyldimethyltaurate, polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof. 26. The cream of embodiment 25, wherein the viscosity modifier is about 1.5% by weight to about 5% by weight of a copolymer of acrylamide and sodium acryloyldimethyltaurate dispersed in isohexadecane, polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof. 27. A cream according to embodiment 17, wherein the pH adjuster is 10% citric acid. 28. The cream of any one of the preceding embodiments, wherein the cream further comprises glycerin, propylene glycol, or a mixture thereof. 29. The cream of any one of the preceding embodiments, wherein the viscosity of the cream is at least about 15,000 mPa·s when measured at 25° C. using a rotational viscosimetry. 30. A cream according to embodiment 29, wherein the viscosity of the cream is from about 15,000 mPa·s to about 75,000 mPa·s when measured at 25° C. using a rotational viscosimetry. 31. A cream according to embodiment 29, wherein the viscosity of the cream is from about 19,500 mPa·s to about 45,200 mPa·s when measured at 25° C. using a rotational viscosimetry. 32. The cream of any one of the preceding embodiments, wherein the cream is an oil-in-water emulsion. 33. A cream according to embodiment 32, wherein the emulsion droplets have an average diameter of less than about 13 μm. 34. The cream of embodiment 32, wherein the average diameter of the emulsion droplets is less than about 10 μm. 35. A cream according to any one of the preceding embodiments, wherein the aqueous phase is a gel at about 2°C to about 40°C. About 2 grams to about 4 grams of the cream containing 36.1% by weight of KM-001 was applied to about 400 cm of the skin. 2 ~about 600cm 2 2. The cream of embodiment 1, wherein when topically administered to one or more skin layers, about 50 μg / g to about 6000 μg / g of KM-001 is provided to one or more skin layers as measured by (matrix assisted laser desorption / ionization) MALDI. 36A. In an embodiment, about 3 grams of cream containing 1% by weight of KM-001 is applied to about 500 cm of skin. 2 37. The cream of embodiment 36, wherein when topically administered to one or more skin layers, about 50 μg / g to about 6000 μg / g of KM-001 is provided in one or more skin layers as measured by (matrix assisted laser desorption / ionization) MALDI. About 2 grams to about 4 grams of the cream containing 37.1% by weight of KM-001 was applied to about 400 cm of the skin. 2 ~about 600cm 2 37. The cream of embodiment 36, which when topically administered provides about 2000 μg / g to about 6000 μg / g of KM-001 to the epidermis as measured by (matrix assisted laser desorption / ionization) MALDI. About 2 grams to about 4 grams of the cream containing 38.1% by weight of KM-001 was applied to about 400 cm of the skin. 2 ~about 600cm 2 37. The cream of embodiment 36, wherein when topically administered to the skin, about 2000 μg / g to about 6000 μg / g of KM-001 is provided to the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum, or a combination thereof, as measured by (matrix assisted laser desorption / ionization) MALDI. About 2 grams to about 4 grams of the cream containing 39.1% by weight of KM-001 was applied to about 400 cm of the skin. 2 ~about 600cm 2 37. The cream of embodiment 36, wherein when topically administered to the dermis, about 500 μg / g to about 800 μg / g of KM-001 is provided to the dermis as measured by (matrix assisted laser desorption / ionization) MALDI. About 2 grams to about 4 grams of the cream containing 40.1% by weight of KM-001 is applied to about 400 cm of the skin of a patient in need thereof. 2 ~about 600cm 2 2. The cream of embodiment 1, which when topically administered to the dermis provides KM-001 in the dermis at a concentration equivalent to about 1% to about 16% of said KM-001 in the epidermis as measured by MALDI. About 2 grams to about 4 grams of the cream containing 41.1% by weight of KM-001 was applied to about 400 cm of the skin. 2 ~about 600cm 2 37. The cream of embodiment 36, wherein when topically administered to the subcutaneous tissue, about 100 μg / g to about 3500 μg / g of KM-001 is provided to the subcutaneous tissue as measured by (matrix assisted laser desorption / ionization) MALDI. About 2 grams to about 4 grams of the cream containing 42.1% by weight of KM-001 was applied to about 400 cm of the skin. 2 ~about 600cm 2 37. The cream of embodiment 36, wherein when topically administered to the hair follicles, about 50 μg / g to about 1200 μg / g of KM-001 is provided to the hair follicles as measured by (matrix assisted laser desorption / ionization) MALDI. 43. The cream of any one of the preceding embodiments, wherein when topically administered to the skin of a patient in need of said cream, from about 0.05% by weight to about 20% by weight of said KM-001 present in the composition applied to said skin penetrates the stratum corneum, epidermis, or dermis of said skin as measured by in vitro penetration testing (IVPT). 44. The cream of embodiment 43, wherein when said cream is topically administered to the skin of a patient in need thereof, from about 1% by weight to about 10% by weight of said KM-001 present in the composition applied to said skin penetrates the stratum corneum as measured by IVPT. 45. The cream of embodiment 43, wherein when the cream is topically administered to the skin of a patient in need thereof, from about 0.2% by weight to about 8% by weight of the KM-001 present in the composition applied to the skin penetrates the epidermis as measured by IVPT. 46. ​​The cream of embodiment 43, wherein when the cream is topically administered to the skin of a patient in need thereof, from about 0.05% by weight to about 3% by weight of the KM-001 present in the composition applied to the skin penetrates the dermis as measured by IVPT. 47. The maximum plasma concentration (C max ) is less than about 40 ng / mL. 48. The cream of any one of the preceding embodiments, wherein said topical administration results in an area under the plasma drug concentration-time curve (AUC) of KM-001 of less than about 500 ng / mL*hr. 49. A method for treating skin disorders or pruritus, comprising topically administering to the skin of a patient in need thereof a therapeutically effective amount of KM-001 in a composition according to any one of the preceding embodiments. 50. The method of embodiment 49, wherein the KM-001 is administered at a dose of about 0.5 g to about 5 g per day. 51. The therapeutically effective amount of KM-001 is 20 μg / cm 2 / day ~ approx. 150μg / cm 2 The method of embodiment 49 or 50, wherein the daily dose is 100 mg / day. 52. The method of any one of embodiments 49-51, wherein the KM-001 is administered at a dose of about 0.015 mg / kg / day to about 0.5 mg / kg / day. 53. The maximum plasma concentration (C max 53. The method of any one of embodiments 49-52, wherein the IL-10 level is less than about 40 ng / mL. 54. The method of any one of embodiments 49-53, wherein the area under the plasma drug concentration time curve (AUC) is less than about 500 ng / mL*hr. 55. The method of any one of embodiments 49-54, wherein the skin disorder is keratosis, lichen simplex chronicus, pruritus or ichthyosis. 56. The method of embodiment 55, wherein the skin disorder is a keratosis selected from the group consisting of Mal de Meleda keratosis, Olmsted syndrome, Papillon-Lefevre syndrome, palmoplantar keratosis, Nagashima palmoplantar keratosis, pachyonychia congenita, and punctate keratosis, and an ichthyosis selected from the group consisting of recessive X-linked ichthyosis and Harley Quinn ichthyosis. 57. The method of embodiment 56, wherein the skin disorder is palmoplantar keratosis. 58. The method of embodiment 57, wherein said palmoplantar keratosis is punctate palmoplantar keratosis or pachyonychia congenita. 59. The method of any one of embodiments 49-58, wherein the topical administration reduces the severity of the skin disorder by at least one level on the IGA scale. 60. The method of any one of embodiments 49-59, wherein the pruritus is pruritus associated with keratosis. 61. The method of any one of embodiments 49-59, wherein the pruritus is pruritus associated with lichen simplex chronicus. 62. The method of any one of embodiments 49-61, wherein said topical administration reduces the severity of said pruritus by at least 1 level on the PP-NRS scale. 63. The method of embodiment 62, wherein the severity of the pruritus is reduced by about 1 level to about 10 levels on the PP-NRS scale. 64. The method of any one of embodiments 49-63, wherein the composition is administered twice a day. 65. The method of embodiment 64, wherein the composition is administered topically once in the morning and once in the evening. 66. The method of any one of embodiments 49-65, wherein the composition is administered topically for about 20 days to about 40 days. 67. The method of any one of embodiments 49-66, wherein the composition is administered topically for about 28 days. 68. The method of any one of embodiments 49 to 67, wherein the composition is administered topically to the suprabasal layer of the epidermis. 69. The method of embodiment 68, wherein the suprabasal layer of the epidermis is the cornified membrane, the granular and spinous layers, the upper dermis, or a combination thereof. 70. The method of embodiment 69, wherein the suprabasal layers of the epidermis are the cornified membrane, the granular and spinous layers, and the upper dermis. 71. The method of any one of embodiments 68-70, wherein after administration of the composition, the local concentration of KM-001 in the suprabasal layer of the epidermis is from about 60 μg / g to about 160 mg / g. 72. The method of any one of embodiments 68-70, wherein the local concentration of KM-001 in the upper dermis is in the range of about 1.5% by weight to about 16% by weight of the total amount of KM-001 in the skin. EXAMPLES

[0094] Example 1: Ointment and cream type emulsion preparations KM-001 is relatively soluble in triglycerides and fatty alcohols. Solubility studies have shown that an oil phase containing approximately 11% by weight of medium chain triglycerides and 12% by weight of octyldodecanol can completely and efficiently dissolve 1% by weight of KM-001 without the risk of recrystallization, resulting in a physically stable emulsion. The ointment composition was formulated as shown in Table 1 below. [Table 1]

[0095] The cream-type emulsions were found to have improved tolerability compared to the PEG-based ointment compositions. Furthermore, the cream compositions did not require heating during formulation (as in the PEG-based ointment), improving the stability of KM-001. Examples of three cream-type emulsions are shown in Table 2 below. [Table 2-1] [Table 2-2]

[0096] The 00293.0435, 200293.0440 and 200293.0600 formulations were tested using an in vitro skin permeation test (IVPT) using split thickness human abdominal skin of approximately 0.5 mm thickness. Skin samples (approximately 2 cm 2 ) was placed in a test cell using PBS pH 7.2 + 0.25 Tween® 80 receptor fluid and maintained at a temperature of 32 + / - 1°C in a room maintained at 21.1 ± 0.81°C and RH 48.13 ± 16.1%. Skin samples were treated with 5 mg / cm2 of the ointment and cream emulsion compositions for 24 hours. 2 Doses of 100 mg / kg were tested and receptor fluid samples were collected at specified time points.

[0097] The samples were then prepared for chromatographic separation on an HPLC column and mass spectrometric detection. The LC-MS / MS conditions are summarized below.

[0098] Column: Phenomenex: Kinetex C18 (2.6 μm, 50 x 2.1 mm)

[0099] Mobile phase A: 1000 mL water + 0.1% formic acid

[0100] Mobile phase B: 1000 mL acetonitrile + 0.1% formic acid

[0101] Retention time: KM-001 (approx. 0.91 min) and KM-001-D4 (approx. 0.90 min) [Table 21]

[0102] Mass transitions (m / z): KM-001 (417.279>274.700, 150 ms present) and KM-001-D4 (421.286>278.800, 150 ms present).

[0103] Comparative data on the penetration of KM-001 from ointment and cream emulsions into skin layers including the stratum corneum, epidermis, and dermis are shown below. [Table 3]

[0104] Advanced emulsions 200293.0435 and 200293.0440 have been developed with several advantages over the preliminary PEG-based ointments, which are outlined below.

[0105] Emulsions 200293.0435 and 200293.0440 are classified as creams. These compositions use lipophilic excipients as the main solvent for KM-001. The concentration of the lipophilic solvent allowed KM-001 to be dissolved at concentrations comparable to PEG-based ointments, but combined with regulatory and pharmaceutical industry approval, it showed the potential for improved local tolerance. The lipophilic solvents used in 200293.0435 and 200293.0440 generally offer improved local tolerance over polar solvents used in PEG-based ointments (e.g., Transcutol HP, propylene carbonate, propanediol 1.2, super purified PEG 400).

[0106] Formulations 200293.0435 and 200293.0440 were able to dissolve the target amount of KM-001 while using a 3-fold lower concentration of propylene glycol than PEG-based ointments, thereby reducing the local tolerance issues that can occur with high concentrations of glycol and other polar solvents while maintaining the beneficial effects of PG, such as solubility and adequate dermal delivery of KM-001.

[0107] In emulsions 200293.0435 and 200293.0440, it was also possible to use water as a vehicle, which was considered to be advantageous from a tolerability standpoint compared to anhydrous and polar solvent-containing PEG ointments.

[0108] The polymeric viscosity modifier Sepioneo P600 stabilized the emulsion without the need for additional surfactants, such as those used in PEG-based ointments (Tween® 85), which was also considered advantageous from the point of view of topical tolerance.

[0109] The cream formulation has significant sensory advantages compared to PEG-based ointments: the advanced cream prototype offers a non-greasy and highly pleasant texture, facilitating and enhancing patient acceptance of the treatment.

[0110] The cream formulation employs a cold process that supports the chemical stability of KM-001. The PEG ointment process required heat to dissolve certain ingredients. From a scale-up perspective, a cold process could provide advantages.

[0111] Formulations 200293.0435 and 200293.0440 contain pharmaceutical grade excipients that comply with the United States Pharmacopoeia (USP) or European Pharmacopoeia (Ph.Eur.) or are listed in the FDA's IID. All raw materials in the emulsions were used at the same or lower concentrations as in FDA-approved topical products.

[0112] In vitro skin permeation testing (IVPT) demonstrated improved delivery of KM-001 to the epidermis and dermis from the cream formulation compared to the PEG ointment formulation (see Table 3). These results were obtained using an emulsion solvent system that offers local tolerability advantages over PEG-based ointments.

[0113] Example 2: Evaluation of KM-001-containing formulations in a miniature pig animal model The PEG-based ointments listed in Table 1 were found to have unstable physical properties due to granulation and hardening over time. Furthermore, some of the excipients are not currently approved for use in human pharmaceuticals by the appropriate regulatory agencies (e.g., US FDA). It was therefore desirable to develop a more stable formulation with improved toxicity and skin irritation properties and pharma- ceutical acceptable excipients.

[0114] Minipigs (Sus domesticus) are considered one of the major animal species used in translational research, surgical models and surgical training, and are increasingly being used as a non-rodent option in preclinical toxicity testing of pharmaceuticals, replacing dogs and monkeys. The use of pigs in this setting has unique advantages, as pigs have similar anatomical and physiological characteristics to humans, including the cardiovascular, urinary, integumentary and digestive systems [Swindle MM (ed.),Swine as Models in Biomedical Research and Toxicology Testing,Veterinary Pathology March 2012 vol.49 no.2 344-356].

[0115] Four formulations (200293.0435 and 200293.0438, and placebo versions of these formulations without KM-001) were evaluated in minipigs as described below. Minipigs were housed under a 12-h light / dark cycle. The pigs' housing environment was controlled by an HVAC system (heating, ventilation, and air conditioning) at temperatures ranging from 16 to 27°C and relative humidity of 30 to 70%, with sufficient fresh air circulation. The test creams (KM-001 and placebo) were applied at 3 g of formulation per site per pig twice daily (on weekends formulations were applied once daily) for 14 days.

[0116] On the day before testing with the cream containing KM-001, pigs received a prophylactic loading dose of the antibiotic pen & strep injectable suspension (1 mL / 10 kg, IM) and cefazolin HCl (30 mg / kg, IV) and marbofloxacin (2 mg / kg, slow IV) prior to cannulation (i.e., blood sample collection).

[0117] Procedure: Apply KM-001 cream to the animal's back (25x20cm (500cm 2 ) onto the shaved area of ​​the skin. The test skin area was covered. Approximately 3 g per area per pig was used for each treatment. Treatments were repeated twice daily for 14 days.

[0118] Blood samples were taken at 0 (baseline), 0.5, 1, 2, 6 and 24 hours after application of the cream composition containing KM-001. Blood samples were also taken at 0 (baseline), 0.5, 1, 2, 6 and 24 hours after application of the cream containing KM-001 for 14 days. For comparison, blood samples were also taken from animals administered a placebo cream after the 14-day study.

[0119] On the planned termination day, four skin biopsies were taken from the treatment sites of each animal using a 4 mm puncher. Three biopsies from each set were flash frozen and the other was fixed in PFA 4% for paraffin embedding. Full thickness punch biopsies were taken from three random sites on the back on day 3 (end of the last day of treatment) for evaluation. After several days of washout, one additional skin biopsy was taken on the back to evaluate possible clearance. Biopsies were taken from each animal and flash frozen without the use of tissue fixation or embedding reagents (e.g., OCT or paraffin).

[0120] The Draize test was performed twice daily on all animals on the day the cream formulation was applied (prior to application and approximately 6 hours after application). The Draize scoring system used is shown in Table 4 below. [Table 4] On the final day of the study, four skin biopsies were taken from each test animal (placebo and KM-001 formulations). These skin samples were evaluated using quantitative mass spectrometry imaging (MALDI MSI) to obtain biodistribution data of KM-001, KM-001 penetration profiles and absolute quantification of KM-001 within the minipig skin biopsy samples, allowing comparison of the two different KM-001 cream formulations (200293.0435 (F3) and 200293.0438 (F4)). Nine (9) minipig biopsies were evaluated (three tissues treated with formulation F3, three tissues treated with formulation F4 and three tissues treated with placebo cream). The results are shown in Table 5 below. [Table 5]

[0121] MALDI imaging was performed by the following method: Sectioning of minipig skin samples was performed at a thickness of 10 μm at a temperature of -21 °C using a cryostat (HM360, Microm). Minipig skin pieces were collected on superfrost slides for both MSI acquisition and H&E (hematoxylin & eosin) staining, and if not used immediately, were placed in a desiccator for 15 min and then stored at -80 °C. KM-001 dilution series was prepared in water / methanol 50 / 50 (v / v). Each point was spotted (1 μL / drop) on untreated minipig skin tissue sections provided by ImaBiotech. Then, the slides were dried under vacuum for 15 min. To best detect KM-001, 40 mg / mL DHB MALDI matrix in methanol / water + 1% TFA, 7:3 (v / v) plus 5 μM KM-001-d4 was selected. This matrix was sprayed using an automated spray system (TM-Sprayer, HTX Imaging) onto a dilution series of KM-001 spotted onto untreated minipig control skin sections and study samples provided by ImaBiotech. MALDI-FTICR acquisition global parameters: -Mode: CASI -Ionization: Positive Mass range: 417 ± 15 Da for KM-001 and KM-001-d4 analyses -Laser frequency: 2000Hz - Spatial resolution: 200μm in the calibration range of KM-001, 50μm in placebo and treated human skin tissue sections. -Acquisition area: In the calibration range of the KM-001, each standard deposit (17 concentrations) is imaged individually. For example, an entire skin tissue section from a minipig was imaged with mass spectrometry imaging. All MSI acquisitions were performed with a data reduction ratio of 0.95. Data reduction is necessary due to the large amount of data generated by MALDI when imaging an area.

[0122] The same MALDI method and the same mass spectrometer were used for all MSI acquisitions.

[0123] Nine (9) MALDI imaging acquisitions were obtained with a spatial resolution of 50 μm using the CASI technique in positive ion mode to image the KM-001 drug and its related internal standard (KM-001-d4) in the six treated tissues. Based on the distribution and absolute quantification, a penetration profile of KM-001 was constructed. The lower limit of quantification (LLOQ) and upper limit of quantification (ULOQ) were assessed to be 6.8 μg / g tissue and 804.0 μg / g tissue, respectively. KM-001 was distributed mainly in the epidermis, showing high exposure (estimated to be 67.3 μg / g–5.7 mg / g in samples treated with the ULOQ-F3 formulation and 2.6–147.3 mg / g in samples treated with the F4 formulation). Penetration was observed throughout all suprabasal layers of the epidermis, including the cornified tunica, granular and spinous layers (indicated by yellow arrows in Figures 1–4).

[0124] Dermal penetration was limited but significant (15.9% of the epidermal signal was detected in the dermis for F3 formulation samples vs. 1.5% for F4 formulation samples). Some exposure was observed in the subcutaneous tissue (average of 117 μg / g for 200293.0435 formulation samples vs. 3.5 mg / g for 200293.0438 formulation samples). On average (n=3), KM-001 F4 formulation treatment group 4 appears to have slightly deeper skin penetration compared to the F3 formulation treatment group (600 μm vs. 400 μm).

[0125] In comparison, a similar study was conducted using a KM-001 ointment-based formulation (formulation 200293.0600). Images of the groups treated with 0.3% KM-001 ointment and 1% KM-001 ointment revealed limited penetration, mainly to the epidermis. Exposure in the top layer of the epidermis was comparable to the F3 and F4 formulations, but no penetration into the lower layers of the epidermis was detected, and no dermal penetration was observed in samples treated with the 200293.0600 ointment formulation.

[0126] The skin distribution of KM-001 was evaluated in porcine biopsies from minipigs topically treated with PEG ointment containing KM-001 at a 1% weight percent concentration of 200293.0600. MSI data showed strong exposure of the upper epidermis to KM-001, low exposure of the dermis and limited exposure of the subcutaneous tissue. The epidermis shows fairly uniform exposure throughout the epidermis, while the subcutaneous tissue has very heterogeneous exposure to KM-001 concentrated in certain areas. A calibration curve was generated with a lower limit of quantification (LLOQ) of 4.8 μg per g of tissue and an upper limit of quantification of 1052 μg / g.

[0127] The concentration of KM-001 in the epidermis shows a large variation [132-1104 μg / g], with a mean value of 541 μg / g. In the dermis, the concentration is much lower, for example, around 4 μg / g, which is close to the limit of quantification. In the subcutaneous tissue region, the mean concentration is 18 μg / g.

[0128] Finally, considering the entire section (the closest approach to homogenization followed by LCMS / MS), the average concentration of KM-001 was determined to be 26 μg / g. [Table 6]

[0129] Thus, the KM-001 cream-based formulations (F3 and F4) show superior skin penetration profiles compared to the KM-001 ointment-based formulation (200293.0600) by delivering KM-001 molecules to the site of action (i.e., all suprabasal epidermal layers) while also reaching the upper dermis (see Tables 5 and 6: 2554.4 μg / g (F3) and 5261.1 μg / g (F4) vs. 541 μg / g (PEG ointment) in the epidermis, and 539.3 μg / g (F3) and 882 μg / g (F4) vs. 4 μg / g (PEG ointment) in the dermis).

[0130] Example 3: Mouse C57BL / 6J model (oral administration) The efficacy of KM-001 was evaluated in the acetone-ether-water (AEW)-induced pruritus model in C57BL / 6J male mice, induced by daily application of an acetone / ether (1:1) mixture and water to the animals' cheeks. KM-001 (10 mg / kg, 1 mg / kg, 0.1 mg / kg, 0.01 mg / kg) was orally administered to 20 mice. The time spent scratching and the number of bouts during a 20-min period were recorded by an observer. Blood and skin samples were collected at 0, 0.5 h, 1 h, and 1.5 h after administration.

[0131] Topical application of AEW twice daily for 5 days significantly increased spontaneous scratching time and scratching frequency in C57 BL / 6J mice. Oral administration of KM-001 (0.1 mg / kg) significantly decreased scratching time and scratching frequency (p<0.001 for scratching time, p<0.01 for scratching frequency). Treatment with KM-001 (0.01 mg / kg) tended to decrease scratching time and scratching frequency. In animals treated with 0.1 mg / kg KM-001, the maximum plasma concentration (C max) 1.34 ng / mL was detected. In animals treated with 0.01 mg / kg, KM-001 was not detected in plasma. The results of this study showed that KM-001 (0.1 mg / kg) exerted a strong antipruritic effect on the AEW-induced dry skin pruritus model in mice.

[0132] Example 4: Mouse DS-Nh model (local administration) DS-Nh mice housed under conventional conditions spontaneously develop dermatitis and skin abnormalities characterized by hyperkeratosis, reduced proliferation and differentiation of basal keratinocytes, and keratinization of skin appendages. DS / Nh mice were treated twice daily (25 μg ointment per cheek per mouse) with KM-001 1% and 0.3% ointments for 14 consecutive days without compound-related toxicity. At baseline, significant scratching behavior was observed in all mice. Treatment with vehicle and positive control tacrolimus 0.1% only marginally affected this behavior (10% and 20% reduction, respectively). KM-001 0.3% ointment treatment reduced scratching by more than 40% on day 14, and KM-001 1% ointment reduced scratching by more than 80% compared to unmedicated controls. Changes in scratching behavior on days 14 and 0 (before the first application of experimental or control ointments) are shown in FIG.

[0133] At the end of the study, mice were sacrificed and skin biopsies were paraffin embedded, stained with hematoxylin and eosin (H&E), and evaluated microscopically (Figure 7). As expected, the skin of control mice showed characteristic pathology: thickening of the epidermis, abnormalities in the epidermal layer structure, and fusion and keratinization of the skin appendages. After 2 weeks of treatment, only about 30% of mice in the vehicle-treated group showed any form of normalization of skin lesions, while 0.1% treatment with tacrolimus showed partial normalization in 40% of mice. In contrast, both groups administered KM-001 ointment showed significant improvement in skin histology, with normalization seen in about 70% of mice (Figure 8). Animals treated with KM-001 1% ointment achieved 70% improvement along with complete normalization of the skin, including restoration of hair follicles and sweat glands.

[0134] Example 5. Systemic exposure to KM-001 (topical administration) I: The blood concentrations of KM-001 were evaluated using a validated analytical method as part of toxicity studies in minipigs and rats. In minipigs, administration of KM-001 at a dose of 4.5 mg / kg / day resulted in C max The C value was 10.8 ng / ml and the AUC value was 159.1 (ng / mL*hr) (Table 7). Based on dose-linear extrapolation from the minipig PK data after 13 weeks of percutaneous administration and considering the lower clinical dose (mg / kg basis), the human systemic exposure was C max The estimated Cmax was approximately 1.3 ng / mL (0.3% cream) and 4 ng / mL (1% cream), with AUCs estimated to be approximately 10 ng / mL*hr (0.3%) and 32 ng / mL*hr (1%) (Table 5). In a 28-day oral repeated dose toxicity study in rats, the total body Cmax at the NOAEL of 10 mg / kg / day was 1.2 mg / kg / day. max The C was 968 ng / mL and the AUC was 8357 ng / mL*hr. When comparing the systemic exposure levels in rats to the estimated systemic exposure levels in humans after topical administration as planned in human clinical trials, max The margin of safety for the 1% cream gel was approximately 242-fold, and the margin of safety for the AUC was 836-fold (0.3%) and 261-fold (1%), respectively. [Table 7]

[0135] II: Minipigs were treated with KM-001 cream (0.3 and 1 weight percent concentrations) applied dermally twice daily for two weeks, with a one-week recovery period to evaluate the toxicokinetic profile after recovery from treatment-related effects. Each test item was administered topically in doses of 3 grams twice daily (6 hours apart) to the relevant groups. Two additional groups were treated similarly with the control KM-001 cream placebo or the reference KM-001 1% PEG ointment.

[0136] In control animals, no detectable amounts of KM-001 were found after a single application and 14 days of KM-001 cream placebo.After the first administration (day 1), KM-001 was detectable in the plasma of animals treated with the test or reference substances at levels similar to or slightly higher than the lower limit of quantification.

[0137] On day 14, all minipigs were exposed systemically to KM-001 after repeated dermal dosing with the test or reference articles. Males and females treated with KM-001 0.3% cream (test item 1) and KM-001 1% PEG ointment (reference item) were similarly exposed to KM-001, although females treated with KM-001 1% cream (test item 2) appeared to have slightly higher exposure than males. However, it should be noted that animals treated with KM-001 1% cream had higher exposure than animals treated with the reference item containing the same concentration of KM-001. Exposure to KM-001 in animals treated with test items 1 and 2 increased approximately proportionally with dose. After 14 days of twice daily dermal application, plasma levels of KM-001 were detectable even 24 hours after treatment. The behavior of the plasma concentrations at the last measured time point did not allow a reliable estimation of the elimination phase of the test substance. [Table 8]

[0138] Example 6. Treatment of punctate keratosis and pachyonychia congenita Patients with type 1 punctate palmoplantar keratoderma or pachyonychia congenita are treated with 0.3% or 1% KM-001 cream applied to the affected areas of the skin twice daily for 84 consecutive days. The tolerability and efficacy of the KM-001 composition (measured by improvement in the appearance of the lesions) is evaluated using the IGA scoring method described below and in Table 9 before treatment with the compositions of the invention and after treatment with the compositions of the invention for the prescribed duration and dosing schedule. The IGA score is selected using the designated descriptors that best describe the overall appearance of the patient's lesions at a given time point. Not all characteristics under the morphological description need to be present. When assessing the severity of the disease, excoriation (i.e., abrasion or damage to the skin due to the patient's own picking, scratching, rubbing, etc.) is usually not taken into account. A change in the IGA score of one or more levels (e.g., 1, 2, 3, or 4 levels) indicates an improvement in the patient's condition, i.e., a reduction in the severity of the disease. The compositions and methods of the present disclosure provide a reduction in disease severity of at least one level on the IGA score following treatment with a composition of the present disclosure. An example of improvement in the affected foot of a patient with pachyonychia congenita is shown in Figures 12A-D. [Table 9]

[0139] Example 7: Treatment of pruritus in patients with lichen simplex chronicus Patients with pruritus due to Lichen Simplex Chronicus (LSC) are treated with 0.3% or 1% KM-001 cream or a negative control cream containing no KM-001. Patients' LSC lesions (lesions covering at least 0.5% and up to 2% of the patient's body surface area (BSA)) are treated with KM-001 or control cream. Pruritus is assessed on the Peak Pruritus Numeric Scale (PP-NRS; patients rate their level of itch over the past 24 hours using a scale of 0 to 10, with 0 being no itch and 10 being the worst itch imaginable).

[0140] After at least 28 days of treatment, patients treated with the compositions of the present invention show improvement in LSC lesions, as indicated by an improvement (reduction) in IGA scores when comparing the appearance of lesions before and after treatment for individual patients. The mean IGA scores of patients treated with KM-001 compositions according to the present disclosure are statistically significantly lower than the IGA scores of patients treated with a control formulation not containing KM-001.

[0141] After at least 28 days of treatment, patients treated with the compositions of the present invention experience improved levels of itch when comparing individual patient pre- and post-treatment PP-NRS scores, such that the mean PP-NRS scores of patients treated with KM-001 compositions according to the present disclosure are statistically significantly lower, e.g., by 4 or more points on the PP-NRS scale, compared to the PP-NRS scores of patients treated with a control formulation not containing KM-001.

[0142] Example 8, Batch Formulation The unit amounts of each component in an exemplary batch formulation of 1% KM-001 cream are as follows: [Table 22]

[0143] Example 9. Saturation solubility of KM-001 in selected solvent mixtures Saturation solubility was measured by shake flask method using excess API at room temperature (RT). Equilibrium was assumed to be reached after 24 h and excess solids were separated by ultrafiltration before dilution and quantification. Quantification of KM-001 for saturation solubility studies was performed using a certified UPLC-UV analytical method.

[0144] The saturation solubility of KM-001 in the solvent mixtures is summarized in Table 10. Images of the samples and their respective vehicles after storage at 25° C. for 24 h are shown in Figures 11A-B. [Table 10]

[0145] M1, M13, and M14 are designed for emulsion (cream-gel) concepts, while M2, M3, M6, and M10 are designed to simulate petrolatum-based ointments. Mineral oil was used as a substitute for petrolatum and other hydrocarbons that make up the semi-solid (e.g., petrolatum) or solid (e.g., wax) components of the ointment. Mixtures containing Colicream OD (octyldodecanol) or Alamol E showed higher saturated solubility for KM-001. Model ointment blends containing "light mineral oil" showed lower saturated solubility. Results showed that loading doses up to 1% are theoretically possible in emulsion and ointment concepts. As shown in Figures 11A and 11B, mixtures with higher KM-001 saturated solubility values ​​showed a stronger yellow color due to the API.

[0146] Example 10. Evaluation of antioxidant blends using a model oil phase Screening of the effectiveness of antioxidant blends was performed using a RapidOxy instrument. The RapidOxy methodology is based on the principle of O2 consumption during oxidation reactions. RapidOxy applies high pressure at high temperature to accelerate the oxidation process and measures the consumption of O2 as a change in partial pressure. The induction time or induction period is defined as the time required for the O2 partial pressure to drop to a certain value (Figure 10). A typical RapidOxy test protocol is shown in Table 11. [Table 11]

[0147] The RapidOxy method was used to evaluate the protective effect of pharmaceutical antioxidants on individual oils and model oil phases before and after incorporation of KM-001. Individual antioxidants (butylated hydroxytoluene [BHT], butylated hydroxyanisole [BHA], and propyl gallate) and antioxidant combinations with established synergistic effects were also evaluated. Antioxidant combination #1 (AO1) incorporates 0.1 weight percent concentrations of butylated hydroxytoluene (BHT) and 0.1 weight percent concentrations of butylated hydroxyanisole (BHA). Antioxidant combination #2 (AO2) incorporates 0.1 weight percent concentrations of BHA and 0.05 weight percent concentrations of propyl gallate.

[0148] The RapidOxy study highlighted the oxidative susceptibility of several excipients, vehicle mixtures, and KM-001, and the protective effect of various antioxidants. The results are summarized in Table 12.

[0149] The data showed that Alamol E was more sensitive to oxidation than Miglyol, and the addition of 1% KM-001 reduced the induction time for both excipients. Therefore, Alamol E was used as a model oxidation-sensitive solvent, rather than the more stable Miglyol, to evaluate the effects of individual antioxidants and antioxidant mixtures. The oxidation sensitivity of KM-001 was tested at 1 weight percent concentration in all experiments. The addition of KM-001 to Alamol E significantly reduced the induction time, indicating the oxidation sensitivity of KM-001. A similar trend was observed after the addition of 1% KM-001 to the vehicle mixture of Miglyol and RapOxM5. 0.1% of BHA was more effective as a sole antioxidant compared to 0.1% of BHT, and propyl gallate was the most efficient antioxidant when used alone.

[0150] The antioxidant combination AO2 (0.1 weight percent BHA and 0.05 weight percent propyl gallate) had a longer induction time, indicating that this antioxidant system was more effective than AO1 (0.1 weight percent BHT + 0.1 weight percent BHA) or any single antioxidant. The effectiveness of the AO2 antioxidant mixture was further confirmed in experiments using a RapOxM5 vehicle mixture spiked with 1% KM-001.

[0151] Study of the oxidative sensitivity of vehicle mixtures revealed that certain vehicle mixtures were more reactive to oxygen, i.e., RapOxM3, RapOxM4 and RapOxM6 vehicles had significantly shorter induction times than RapOxM1, RapOxM2 and RapOxM5.

[0152] Conclusions: Screening of antioxidant combinations in a model system using the RapidOxy method demonstrated that mixture AO2 (0.1% BHA, 0.05% propyl gallate) provided the most effective protection of the oil and active ingredients. [Table 12-1] [Table 12-2] [Table 12-3]

[0153] Example 11. Evaluation of the Preservative Efficacy of Candidate Antimicrobial Preservative Systems Preservative efficacy testing (PET) screening was performed on samples stored at room temperature for one month. The identity and composition of the prototypes of the cream-gel concept are shown in Table 13, and the identity and composition of the prototypes of the petrolatum-based ointment are shown in Table 14.

[0154] Two different antimicrobial preservative systems were evaluated in the cream-gel concept prototypes: (a) 0.2% sodium benzoate + 1% phenoxyethanol, and (b) 0.02% propylparaben + 0.18% methylparaben + 1% phenoxyethanol. The petrolatum-based ointment prototype did not contain an antimicrobial preservative because it is an anhydrous system and could theoretically have self-preserving properties. [Table 13] [Table 14]

[0155] PET was performed according to the procedures described in the Eur.Ph. and USP chapters. The results obtained were evaluated according to the acceptance criteria laid down in the European Pharmacopoeia 5.1.3 test criteria for topical products shown in Table 15. The relevant acceptance criteria are Ph.Eur. Criterion A applies in the general case of preparations for dermal application. [Table 15]

[0156] The PET screening results of the cream-gel concept prototype are shown in Table 16, and the PET screening results of the petrolatum-based ointment prototype are shown in Table 17. [Table 16] [Table 17]

[0157] The BP200293.0435 and BP200293.0440 prototypes of the cream-gel concept showed promising results in PET after one month of storage at room temperature and were therefore further evaluated for stability at accelerated storage conditions (40 °C) for three months. The efficacy of the antimicrobial preservative system of these samples, i.e., 0.2% sodium benzoate + 1% phenoxyethanol, was evaluated according to the acceptance criteria A of Ph.Eur.5.1.3 for preparations for skin application and USP 10001 for topical products. <51> The results were evaluated according to the acceptance criteria (Table 18). [Table 18]

[0158] PET results for BP200293.0435 and BP200293.0440 prototype samples stored for 3 months at accelerated conditions are shown in Tables 19 and 20. [Table 19] [Table 20]

[0159] Both BP200293.0435 and BP200293.0440 formulations passed USP acceptance criteria and European Pharmacopoeia Criterion A. These studies verified the efficacy data of the resulting preservative system, which was stable at room temperature for one month, and demonstrated that 0.2% sodium benzoate + 1% phenoxyethanol is a suitable antimicrobial preservative system for BP200293.0435 and BP200293.0440 formulations.

Claims

1. It is a cream, 【Chemistry 1】 and, Water phase and Including an oil phase, The cream wherein the concentration of KM-001 is approximately 0.1% by weight to approximately 5.6% by weight.

2. The cream according to claim 1, wherein the concentration of KM-001 is approximately 0.2% by weight to approximately 3% by weight.

3. The cream according to claim 1, wherein the concentration of KM-001 is approximately 0.3% by weight.

4. The cream according to claim 1, wherein the concentration of KM-001 is approximately 1% by weight.

5. The cream according to claim 1, wherein the pH of the cream is approximately 4 to approximately 6.

6. The cream according to claim 1, wherein the pH of the cream is approximately 4.5 to approximately 5.

5.

7. The aforementioned cream is (a) The oil phase in an amount of approximately 20% to approximately 40% by weight, (b) The cream according to claim 1, comprising about 60% to about 80% by weight of the aqueous phase.

8. The oil phase is triglycerides, C １３～２１ The cream according to claim 1, comprising fatty alcohols or a mixture thereof.

9. The cream according to claim 8, wherein the concentration of the triglyceride is about 9% by weight to about 13% by weight.

10. The cream according to claim 8, wherein the concentration of the triglyceride is about 11% by weight.

11. The cream according to claim 8, wherein the triglyceride is a medium-chain triglyceride (MCT).

12. The cream according to claim 11, wherein the MCT is caprylic / capric triglyceride.

13. Said C １３～２１ The cream according to claim 8, wherein the concentration of fatty alcohol is about 10% to about 14% by weight.

14. Said C １３～２１ The cream according to claim 8, wherein the concentration of fatty alcohol is about 12% by weight.

15. Said C １３～２１ The cream according to claim 8, wherein the fatty alcohol is octyldodecanol.

16. The cream according to claim 1, wherein the oil phase does not contain polyoxypropylene stearyl ether.

17. The cream according to claim 1, further comprising an antioxidant, a preservative, a viscosity modifier, a pH adjuster, or a mixture thereof.

18. The cream according to claim 17, wherein the antioxidant is propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene, or a mixture thereof.

19. The cream according to claim 18, wherein the antioxidant comprises propyl gallate and BHA.

20. The cream according to claim 19, wherein the concentration of the propyl gallate is about 0.02% by weight to about 0.08% by weight, and the concentration of the BHA is about 0.05% by weight to about 0.2% by weight.

21. The cream according to claim 20, wherein the cream comprises about 0.05% by weight of propyl gallate and about 0.1% by weight of BHA.

22. The cream according to claim 17, wherein the concentration of the preservative is about 0.05% by weight to about 4% by weight.

23. The cream according to claim 22, wherein the preservative is a glycol ether, a phenol ether, a benzoate, or a mixture thereof.

24. The cream according to claim 23, wherein the cream comprises about 0.05% to about 0.4% by weight of phenoxyethanol, about 0.5% to about 2% by weight of sodium benzoate, or a mixture thereof.

25. The cream according to claim 17, wherein the viscosity modifier is a copolymer of acrylamide and sodium acryloyldimethyltaurate, polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof.

26. The cream according to claim 25, wherein the viscosity modifier is a copolymer of acrylamide and sodium acryloyldimethyltaurate in an amount of about 1.5% to about 5% by weight, dispersed in isohexadecane, polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof.

27. The cream according to claim 17, wherein the pH adjusting agent is 10% citric acid.

28. The cream according to claim 1, further comprising glycerin, propylene glycol, or a mixture thereof.

29. The cream according to claim 1, wherein the viscosity of the cream is at least about 15,000 mPa·s when measured at 25°C using the rotational viscosity method.

30. The cream according to claim 29, wherein the viscosity of the cream is approximately 15,000 mPa·s to approximately 75,000 mPa·s when measured at 25°C using the rotational viscosity method.

31. The cream according to claim 29, wherein the viscosity of the cream is approximately 19,500 mPa·s to approximately 45,200 mPa·s when measured at 25°C using the rotational viscosity method.

32. The cream according to claim 1, wherein the cream is an oil-in-water emulsion.

33. The cream according to claim 32, wherein the average diameter of the droplets of the emulsion is less than approximately 13 μm.

34. The cream according to claim 33, wherein the average diameter of the emulsion droplets is less than approximately 10 μm.

35. The cream according to claim 1, wherein the aqueous phase is a gel at a temperature of about 2°C to about 40°C.

36. Approximately 2 to 4 grams of the cream containing 1% by weight of KM-001 is applied to approximately 400 cm² of the skin of the patient who requires it. ２ ~Approx. 600cm ２ The cream according to claim 1, wherein when administered locally, the KM-001 is provided in one or more skin layers at a concentration of approximately 50 μg / g to approximately 6000 μg / g, as measured by matrix-assisted laser desorption / ionization (MALDI).

37. Approximately 3 grams of the cream containing 1% by weight of KM-001 is applied to approximately 500 cm² of the skin of the patient who requires it. ２ The cream according to claim 36, wherein when administered topically, the KM-001 is provided in one or more skin layers at a concentration of approximately 50 μg / g to approximately 6000 μg / g, as measured by MALDI.

38. About 2 grams to about 4 grams of the cream containing 1% by weight of KM-001 is applied topically to about 400 cm ２ to about 600 cm ２ of the skin of a patient who needs it, and when measured by MALDI, the cream according to claim 36 provides about 2000 μg / g to about 6000 μg / g of the KM-001 in the epidermis.

39. Approximately 2 to 4 grams of the cream containing 1% by weight of KM-001 is applied to approximately 400 cm² of the skin of the patient who requires it. ２ ~Approx. 600cm ２ The cream according to claim 36, wherein when administered topically, the KM-001 is provided in the basal layer, spinous layer, granular layer, stratum lucidum, stratum corneum, or a combination thereof, as measured by MALDI, at a concentration of approximately 2000 μg / g to approximately 6000 μg / g.

40. Approximately 2 to 4 grams of the cream containing 1% by weight of KM-001 is applied to approximately 400 cm² of the skin of the patient who requires it. ２ ~Approx. 600cm ２ The cream according to claim 36, wherein when administered locally, approximately 500 μg / g to approximately 800 μg / g of KM-001 is provided to the dermis as measured by MALDI.

41. Approximately 2 to 4 grams of the cream containing 1% by weight of KM-001 is applied to approximately 400 cm² of the skin of the patient who requires it. ２ ~Approx. 600cm ２ The cream according to claim 1, wherein when administered locally, KM-001 is provided to the dermis at a concentration corresponding to approximately 1% to approximately 16% of the KM-001 in the epidermis, as measured by MALDI.

42. Approximately 2 to 4 grams of the cream containing 1% by weight of KM-001 is applied to approximately 400 cm² of the skin of the patient who requires it. ２ ~Approx. 600cm ２ The cream according to claim 36, wherein when administered locally, the KM-001 is provided to the subcutaneous tissue in an amount of approximately 100 μg / g to approximately 3500 μg / g, as measured by MALDI.

43. Approximately 2 to 4 grams of the cream containing 1% by weight of KM-001 is applied to approximately 400 cm² of the skin of the patient who requires it. ２ ~Approx. 600cm ２ The cream according to claim 36, wherein when administered locally, the KM-001 is provided to the hair follicles in an amount of approximately 50 μg / g to approximately 1200 μg / g, as measured by MALDI.

44. The cream according to claim 1, wherein when administered topically to the skin of a patient requiring the cream, an in vitro penetration test (IVPT) shows that approximately 0.05% to approximately 20% by weight of the KM-001 present in the composition applied to the skin penetrates into the stratum corneum, epidermis, or dermis.

45. The cream according to claim 44, wherein when administered topically to the skin of a patient requiring the cream, approximately 1% to approximately 10% by weight of the KM-001 present in the composition applied to the skin penetrates the stratum corneum, as measured by IVPT.

46. The cream according to claim 44, wherein when administered topically to the skin of a patient requiring the cream, approximately 0.2% to approximately 8% by weight of the KM-001 present in the composition applied to the skin penetrates the epidermis, as measured by IVPT.

47. The cream according to claim 44, wherein when administered topically to the skin of a patient requiring the cream, approximately 0.05% to approximately 3% by weight of the KM-001 present in the composition applied to the skin penetrates into the dermis, as measured by IVPT.

48. Local administration allows for the maximum plasma concentration (C) of KM-001. ｍａｘ The cream according to claim 1, wherein the concentration is less than approximately 40 ng / mL.

49. The cream according to claim 1, wherein, upon local administration, the area under the plasma drug concentration-time curve (AUC) of KM-001 is less than approximately 500 ng / mL* hours.

50. A cream according to any one of claims 1 to 49 for treating a skin disorder or itching, characterized in that it is administered topically to the skin of a patient in need thereof.

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