Methods of treating dermatological conditions and symptoms thereof

Abstract

A topical application composition comprising a TRPV3 inhibitor, such as KM-001, significantly reduces the severity of dermatological lesions, pruritus, and combinations thereof in patients suffering from dermatological disorders, such as keratosis, chronic simple moss, and ichthyosis.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 338,586, filed on May 5, 2022, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Background Art

[0003] In order for the skin to function properly, the complex homeostasis of the epidermal keratinocyte layer must be maintained, including proliferation, differentiation and cell signaling (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 dermatological diseases, which are often life-threatening. One of the main factors determining skin health is proper calcium homeostasis, which is mainly regulated 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). Transient receptor potential cation channel subfamily V member 3 (TRPV3) is a cation channel that shows relatively high permeability to calcium. It was first cloned in 2002 and identified as a novel drug target in the skin, providing a potential new approach to treating keratosis and pruritus (Bakthavatchalam, Rajagopal and S. David Kimball. 2010. Chapter 3-Modulators of Transient Receptor Potential Ion Channels. See: 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 9 9; 9 (3): 55). TRPV3 has been shown to be a central regulator in skin diseases because it regulates proliferation, differentiation and apoptosis of human epidermal keratinocytes. Specifically, its activation leads to the inhibition of keratinocyte proliferation and the induction of apoptosis (Borbíró I, Lisztes E, Tóth BI, Czifra G, Oláh A, AG, Szentandrássy N, Nánási PP, Péter Z, Paus R, Kovács L, Bíró T. Activation of transient receptor potential vanilloid-3 inhibits human hair growth. J Invest Dermatol. 2011 Aug; 131(8): 1605-14). It is involved in the control of keratinocyte migration and wound healing, most likely 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). It is also involved in hair morphogenesis and hair follicle cycling, and plays a role in the maintenance of the skin barrier, as loss of TRPV3 causes deleterious changes in the 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 Mar 4;307(5714):1468-72).

[0004] Various studies have provided some insights 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). It is speculated that this receptor forms a signaling complex with TRPV3, whereby activation of EGFR leads to increased TRPV3 channel activity, stimulation of downstream second messengers, and epidermal homeostasis. In the case of keratotic diseases such as punctate palmoplantar keratoderma (PPPK), the identified AAGAB mutation and its association with EGFR activation may lead to persistent sensitization of TRPV3 and Ca. +2Ions flow into cells continuously. Similarly, keratin 16 (Krt16), which is mutated in PC, is a direct target of EGFR and Erk1 / 2-mediated signaling, and its overexpression in mice dose-dependently enhances EGFR activity (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 serinephosphorylation 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 in the homeostasis of the palmoplantar epidermis 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), and regulates cytoskeletal stress responses, barrier integrity, and signaling of p63 and ADAM17 / EGFR.

[0005] TRPV3 activity is also associated with certain pathological skin conditions. Multiple "gain of function" mutations of TRPV3 have been identified in Olmsted syndrome (OS), in which TRPV3 channels remain constantly open (Yadav M, Goswami C. TRPV 3mutants causing Olmsted Syndrome induce impaired cell adhesion and nonfunctional lysosomes. Channels (Austin). 2017 May 4; 11 (3): 196-208). This rare hereditary skin disease is characterized by severe (sometimes disabling) palmoplantar keratoderma, perioral hyperkeratotic 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 with a "gain of function" TRPV3 mutation has been generated (Yoshioka T, Hikita I, Asakawa M, Hirasawa T, Deguchi M, Matsutani T, Oku H, Horikawa T, Arimura A. Spontaneous scratching behavior 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 pruritus, which is associated with a dermatitis similar to human atopic dermatitis and OS.

[0006] Based on the above mechanism of action, inhibitors of TRPV3 activity have untapped therapeutic potential for dermatological conditions such as keratosis, dermatitis, and pruritus associated with or caused by dermatological conditions. TRPV3 inhibitors can improve keratinocyte proliferation and differentiation, thereby reducing hyperkeratosis and lesions.

[0007] Therefore, the development of safe and effective TRPV3 inhibitor compositions for treating dermatological conditions, as well as effective methods of administering such compositions to safely treat dermatological conditions would be of great benefit to patients. Summary of the invention

[0008] The present disclosure provides a TRPV3 inhibitor composition and a method of treating a dermatological disorder.

[0009] In an embodiment, the present disclosure provides a composition comprising:

[0010]

[0011] Aqueous phase; and an oil phase, wherein the concentration of KM-001 is about 0.1 wt % to about 5.6 wt %. In an embodiment, the composition is a cream. In an embodiment, the concentration of KM-001 is about 0.2 wt % to about 3 wt %. In an embodiment, the concentration of KM-001 is about 0.3 wt %. In an embodiment, the concentration of KM-001 is about 1 wt %.

[0012] In embodiments, the pH of the cream is from about 4 to about 6. In embodiments, the pH of the cream is from about 4.5 to about 5.5.

[0013] 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 Fatty alcohols or mixtures thereof. In embodiments, the concentration of triglycerides is from about 9% to about 13% by weight of triglycerides. In embodiments, the concentration of triglycerides is about 11% by weight. In embodiments, the triglycerides are medium chain triglycerides (MCT). In embodiments, MCT is caprylic capric triglyceride. In embodiments, C 13-21 The concentration of the fatty alcohol is from about 10% 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.

[0014] In embodiments, the cream further comprises an antioxidant, a preservative, a viscosity modifier, a pH adjusting agent or a mixture thereof. In embodiments, the antioxidant is propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene or a mixture thereof. In embodiments, the antioxidant comprises propyl gallate and butylated hydroxyanisole (BHA). In embodiments, the concentration of propyl gallate is from about 0.02% by weight to about 0.08% by weight, and the concentration of BHA is from about 0.05% by weight to about 0.2% by weight. In embodiments, the cream comprises about 0.05% by weight of propyl gallate and 0.1% by weight of BHA.

[0015] In an embodiment, the concentration of the preservative is from about 0.1% by weight 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 from about 0.05% by weight to about 0.4% by weight of phenoxyethanol, from about 0.5% by weight 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 acryloyldimethyl taurate, polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof. In an embodiment, the concentration of the viscosity modifier is a copolymer of acrylamide and sodium acryloyldimethyl taurate dispersed in isohexadecane of from about 1.5% by weight to about 5% by weight. In an embodiment, the pH adjusting agent is 10% citric acid. In an embodiment, the cream further comprises glycerol, propylene glycol, or a mixture thereof.

[0016] In an embodiment, the viscosity of the cream is at least about 15,000 mPa·s, measured using a rotational viscosity method at 25°C. In an embodiment, the viscosity of the cream is about 15,000 mPa·s to about 75,000 mPa·s, measured using a rotational viscosity method at 25°C. In an embodiment, the viscosity of the cream is about 19,500 mPa·s to about 45,200 mPa·s, measured using a rotational viscosity method at 25°C. In an embodiment, the cream is an oil-in-water emulsion. In an embodiment, the average diameter of the globules of the emulsion is less than about 13 μm. In an embodiment, the average diameter of the globules of the emulsion is less than about 10 μm. In an embodiment, the aqueous phase is a gel at about 2°C to about 40°C.

[0017] In an embodiment, about 2 grams to about 4 grams of a cream comprising 1% by weight KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provides about 50 μg / g to about 6000 μg / g of KM-001 in one or more skin layers as measured by (matrix-assisted laser desorption / ionization) MALDI. In an embodiment, about 3 grams of a cream containing 1 wt % KM-001 is topically applied to about 500 cm of a patient in need thereof. 2 The skin provides about 50 μg / g to about 6000 μg / g of KM-001 in one or more skin layers as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0018] In an embodiment, about 2 grams to about 4 grams of a cream comprising 1% by weight KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2The skin provides about 2000 μg / g to about 6000 μg / g of KM-001 in the epidermis as measured by (matrix-assisted laser desorption / ionization) MALDI. In an embodiment, about 2 grams to about 4 grams of a cream containing 1 wt % KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin of the present invention provides about 2000 μg / g to about 6000 μg / g of KM-001 in the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum or a combination thereof, as measured by (matrix-assisted laser desorption / ionization) MALDI. In an embodiment, about 2 grams to about 4 grams of a cream containing 1% by weight of KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provides about 500 μg / g to about 800 μg / g of KM-001 in the dermis as measured by (matrix-assisted laser desorption / ionization) MALDI. In an embodiment, about 2 grams to about 4 grams of a cream containing 1 wt % KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provides a concentration of KM-001 in the dermis equivalent to about 1% to about 16% of 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 topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provides about 100 μg / g to about 3500 μg / g of KM-001 in the subcutaneous tissue as measured by (matrix-assisted laser desorption / ionization) MALDI. In an embodiment, about 2 grams to about 4 grams of a cream containing 1% by weight KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 Skin from 100% tantalum provides about 50 μg / g to about 1200 μg / g of KM-001 in the hair follicles as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0019] In an embodiment, the cream is topically applied to the skin of a patient in need so that about 0.05% by weight to about 20% by weight of KM-001 presented in the form of an applied composition in the skin penetrates into the stratum corneum, epidermis or dermis, as measured by an in vitro permeation test (IVPT). In an embodiment, topical application to the skin of a patient in need allows about 1% by weight to about 10% by weight of KM-001 presented in the form of an applied composition in the skin to penetrate into the stratum corneum, as measured by IVPT. In an embodiment, topical application to the skin of a patient in need allows about 0.2% by weight to about 8% by weight of KM-001 presented in the form of an applied composition in the skin to penetrate into the epidermis, as measured by IVPT. In an embodiment, topical application to the skin of a patient in need allows about 0.05% by weight to about 3% by weight of KM-001 presented in the form of an applied composition in the skin to penetrate into the dermis, as measured by IVPT.

[0020] In embodiments, topical administration provides a maximum plasma concentration (C ) of KM-001 of less than about 40 ng / mL. max In embodiments, topical administration provides an area under the plasma drug concentration-time curve (AUC) of KM-001 of less than about 500 ng / mL*h.

[0021] In an embodiment, the present disclosure provides a method of treating a skin disorder or pruritus, the method comprising topically applying to the skin of a patient in need thereof a therapeutically effective amount of a composition comprising KM-001 as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Shown is the distribution of KM-001 in placebo-treated minipig skin samples (MSI, overlay and H&E images).

[0023] Figure 2 Shown is the distribution of KM-001 in minipig skin samples treated with KM-001 1% F3 (MSI, overlay and H&E images).

[0024] Figure 3 Shown is the distribution of KM-001 in minipig skin samples treated with KM-001 1% F4 (MSI, overlay and H&E images).

[0025] Figure 4 Shown is the distribution of KM-001 in minipig skin samples treated with KM-001 1% ointment (MSI, overlay and H&E images).

[0026] Figure 5 A matrix-assisted laser desorption / ionization (MALDI) image of a porcine skin tissue section as described in Example 2 is shown.

[0027] Figure 6 Shown is the comparative effect of KM-001 on the scratching behavior of phenotypic DS-Nh mice.

[0028] Figure 7 Shown is the comparative effect of KM-001 on skin pathology developed by DS-Nh mice.

[0029] Figure 8 Shown are the effects of the test treatments on skin morphology of DS-Nh mice.

[0030] Fig.9A Shown are the visual appearance of exemplary compositions M1, M2 and M3 as described in Example 9 and their corresponding vehicle (P - Placebo) after incubation at 25°C for 24 hours.

[0031] Fig. 9B Shown are the visual appearance of exemplary compositions M6, M10, M13, and M14 and their corresponding vehicles (P - Placebo) after incubation at 25°C for 24 hours.

[0032] Fig.10 The definition of the RapidOxy induction period is shown.

[0033] Fig.11A Shown are mean blood levels of test article following skin application in male minipigs.

[0034] Fig. 11B Shown are mean blood levels of test article following skin application in female minipigs.

[0035] Fig. 12A -D shows the improvement of the affected area in patients with pachyonychia congenita at the following time points: Screening Visit / Baseline (T0) ( Fig. 12A ); Visit 3( Fig. 12B ); Visit 8( Fig. 12C ); and additional visit 8 ( Fig.12D ). DETAILED DESCRIPTION

[0036] definition

[0037] Throughout this disclosure, various patents, patent applications, and publications are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety for all purposes to more fully describe the state of the art as of the date of this disclosure as known to those skilled in the art. This disclosure will govern in the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure.

[0038] For convenience, certain terms used 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 ordinary technicians in the field to which this disclosure belongs.

[0039] As used herein, the term "about" refers to plus or minus 10% of the reference number, unless otherwise specified or otherwise apparent from the context, and unless such a range would exceed 100% of a possible value, or be less than 0% of a possible value, such as less than 0% ingredient content, or greater than 100% total composition content. For example, reference to an amount of any TRPV3 inhibitor disclosed herein as "about 1% by weight" means that the TRPV3 inhibitor may be present in any amount within the range of 0.9% to 1.1% by weight of the composition. In embodiments, the terms "% by weight" and "% w / w" are used interchangeably.

[0040] The term "a" or "an" refers to one or more of the entity; for example, "solvent" refers to one or more solvents or at least one solvent. Therefore, the terms "a" (or "an"), "one or more" and "at least one" are used interchangeably herein. In addition, the indefinite article "a" or "an" referring to an "element" does not exclude the possibility that more than one element is present, unless the context clearly requires that there is one and only one element.

[0041] As used herein, the term "skin" refers to any layer of the skin, including the epidermis, dermis, and subcutaneous tissue. The epidermis has five sublayers, including the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale, which are listed from the outermost layer to the innermost layer. For example, the stratum corneum is the surface layer of the skin.

[0042] As used herein, the term "topical composition" refers to any formulation designed for application to the skin.

[0043] As used herein, the term "aqueous" is a composition wherein the composition contains greater than 50% by weight of water. In an embodiment, the aqueous composition of the present disclosure contains greater than 75% by weight of water. In an embodiment, the aqueous composition of the present disclosure contains greater than 90% by weight of water.

[0044] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound that is capable of achieving the desired result when administered to a patient. For example, an effective amount of a TRPV3 inhibitor in a composition is an amount required to reduce at least one symptom of a skin disorder in a patient. The actual amount comprising an "effective amount" or "therapeutically effective amount" will vary depending on a variety of conditions, including but not limited to the severity of the disorder and the size and health of the patient, or the size of the wound to be treated. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.

[0045] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0046] As used herein, "treat" or "treating" means to alleviate, lessen, delay, reduce, reverse, improve or control one or more of at least one symptom of a condition in a subject. The term "treat" may also mean to prevent, delay the onset of a condition (i.e., before the clinical manifestation of a condition), reduce the risk of occurrence or worsening of a condition, or restore or normalize the skin.

[0047] KM-001 Composition

[0048] In an embodiment, the present disclosure relates to a composition comprising any TRPV3 inhibitor disclosed in U.S. Patent Application Publication No. US 2002 / 0332697A1, which is incorporated herein by reference in its entirety. In US 2002 / 0332697A1, 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 in keratinocytes. +2 flux and normalize differentiation markers. However, the TRPV3 inhibitors disclosed in US2002 / 0332697 A1 are not easily soluble in aqueous compositions, resulting in low bioavailability to target cells and / or tissues. In embodiments, the present application solves this problem in the art and provides a safe, bioavailable and effective TRPV3 inhibitor composition in the treatment of dermatological conditions.

[0049] In an embodiment, the compositions of the present disclosure comprise a TRPV3 inhibitor having the chemical structure of KM-001:

[0050]

[0051]

[0052] Compositions of the present disclosure are usually formulated for topical use, for example as creams, ointments, pastes, lotions or gels. Creams or lotions include an emulsion of an aqueous phase and a hydrophobic (oil) phase, and can be classified as an oil-in-water (o / w) or water-in-oil (w / o) emulsion. In an embodiment, compositions of the present disclosure are oil-in-water emulsions. In o / w emulsions, the oil phase is discontinuous and is dispersed in a continuous aqueous phase, and in w / o emulsions, the aqueous phase is discontinuous and is dispersed in a continuous oil phase. Emulsifiers can be added to o / w or w / o emulsions to stabilize the emulsion and suppress / slow down the phase separation that will make the emulsion unstable.

[0053] In an embodiment, the composition of the present disclosure is formulated into a cream. In an embodiment, the composition of the present disclosure may be formulated into an ointment, which is a semisolid preparation of hydrocarbons (e.g., petrolatum, mineral oil, paraffin, silicone oil, and synthetic hydrocarbons), or a paste, which is a mixture of a powder and an ointment to improve porosity (breathability) and make the paste more difficult to remove or migrate to skin areas where treatment is not required. In an embodiment, the gel composition typically comprises a viscous cellulose ether or carbomer in a water-alcohol mixture. In an embodiment, the gel typically dries on the skin and leaves a thin film containing the active ingredient (e.g., a TRPV3 inhibitor), and the gel may be more suitable for hairy areas of the skin compared to other types of topical preparations.

[0054] In an embodiment, the composition of the present disclosure comprises a therapeutically effective amount of any TRPV3 inhibitor disclosed herein (e.g., KM-001 or KM-023). The concentration of the TRPV3 inhibitor of the present disclosure (e.g., KM-001 or KM-023) is generally in the range of about 0.1% by weight to about 6% by weight, including 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 1.2% by weight, about 1.4% by weight, about 1.6% by weight, about 1.8% by weight, about 2.0% by weight, About 2.2 weight %, about 2.4 weight %, about 2.6 weight %, about 2.8 weight %, about 3.0 weight %, about 3.2 weight %, about 3.4 weight %, about 3.6 weight %, about 3.8 weight %, about 4.0 weight %, about 4.2 weight %, about 4.4 weight %, about 4.6 weight %, about 4.8 weight %, about 5.0 weight %, about 5.2 weight %, about 5.4 weight %, about 5.6 weight %, about 5.8 weight % or about 6.0 weight %, including all ranges between these values ​​or ranges.

[0055] In an embodiment, the composition of the present disclosure is formulated into a cream, a gel or a gel-like cream. In an embodiment, the present disclosure provides a cream comprising:

[0056]

[0057] an aqueous phase; and an oil phase, wherein the concentration of KM-001 is from about 0.1 wt % to about 5.6 wt %, for example, from 0.2 wt % to about 2 wt %, from about 0.3 wt % to about 1.0 wt %, from about 0.5 wt % to about 5 wt %, including about 0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt %, about 1.0 wt %, about 1.1 wt %, about 1.2 wt %, about 1.3 wt %, about 1.4 wt %, about 1.5 wt %, about 1.6 wt %, about 1.7 wt %, about 1.8 wt %, about 1.9 wt %, about 2.0 wt %, about 2.1 wt %, about 2.2 wt %, about 2.3 wt %, about 2.4 wt %, about 2.5 wt %, about 2.6 wt %, about 2.7 wt %, about 2.8 wt %, about 2.9 wt %, about 3.0 wt %, about 3.1 wt %, about 3.2 wt %, about 3.3 wt %, about 3.4 wt %, about 3.5 wt %, about 3.6 wt %, about 3.7 wt %, about 3.8 wt %, about 3.9 wt %, about 4.0 wt %, about 4.1 wt %, about 4.2 wt %, about 4.3 wt %, about 4.4 wt %, about 4.5 wt %, about 4.6 wt %, about 4.7 wt %, about 4.8 wt %, about 4.9 wt %, about 5.0 wt %, about 5.1 wt %, about 5.2 wt %, about 5.3 wt %, about 5.4 wt %, about 5.5 wt %, or about 5.6 wt %, including all ranges between any of these values. In embodiments, the concentration of KM-001 is about 0.2 wt % to about 3 wt %. In embodiments, the concentration of KM-001 is about 0.3 wt %. In embodiments, the concentration of KM-001 is about 1 wt %.

[0058] In embodiments, the pH of the composition of the present disclosure (e.g., cream) is about 4.0 to about 6.0, such as 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 embodiments, the pH of the composition of the present disclosure is about 4.0 to about 5.0. In embodiments, the pH of the composition of the present disclosure is about 4.5 to about 5.5. In embodiments, the pH of the composition of the present disclosure is about 4.9 to about 5.1. In embodiments, the pH of the composition of the present disclosure is about 4.0.

[0059] In embodiments, 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 embodiments, the composition (e.g., cream) comprises an oil phase having a weight % of about 20% to about 40% by weight, 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%, including any value or range therebetween. In embodiments, the composition comprises from about 60 wt % to about 80 wt % aqueous phase, e.g., about 60.0 wt %, about 60.2 wt %, about 60.4 wt %, about 60.6 wt %, about 60.8 wt %, about 70.0 wt %, about 70.2 wt %, about 70.4 wt %, about 70.6 wt %, about 70.8 wt %, or about 80.0 wt %, including any value or range therebetween.

[0060] In embodiments, the composition is an oil-in-water emulsion. In embodiments, 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 globules of the emulsion is less than about 13 μm, for example, 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 In an embodiment, the average diameter of the globules of the emulsion is less than about 13 μm. In an embodiment, the average diameter of the globules of the emulsion is less than about 10 μm.

[0061] In an embodiment, the oil phase comprises triglycerides, C 13-21Fatty alcohol or mixtures thereof. In embodiments, the oil phase comprises triglycerides. In embodiments, the concentration of triglycerides is from about 9 wt % to about 13 wt %, for example, about 9.0 wt %, about 9.1 wt %, about 9.2 wt %, about 9.5 wt %, about 9.6 wt %, about 9.7 wt %, about 9.8 wt %, about 9.9 wt %, about 10.0 wt %, about 10.1 wt %, about 10.2 wt %, about 10.3 wt %, about 10.4 wt %, about 10.5 wt %, about 10.6 wt %, about 10.7 wt %, about 10.8 wt %, about 10.9 wt %, about 11.0 wt % %, about 11.1 wt %, about 11.2 wt %, about 11.3 wt %, about 11.4 wt %, about 11.5 wt %, about 11.6 wt %, about 11.7 wt %, about 11.8 wt %, about 11.9 wt %, about 12.0 wt %, about 12.1 wt %, about 12.2 wt %, about 12.3 wt %, about 12.4 wt %, about 12.5 wt %, about 12.6 wt %, about 12.7 wt %, about 12.8 wt %, about 12.9 wt % or about 13.0 wt %, including all values ​​and ranges therebetween. In embodiments, the concentration of triglycerides is about 11 wt %. In embodiments, triglycerides are C6-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.

[0062] In an embodiment, the oil phase comprises C 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 wt % to about 14 wt %, for example, about 10.0 wt %, about 10.1 wt %, about 10.2 wt %, about 10.3 wt %, about 10.4 wt %, about 10.5 wt %, about 10.6 wt %, about 10.7 wt %, about 10.8 wt %, about 10.9 wt %, about 11.0 wt %, about 11.1 wt %, about 11.2 wt %, about 11.3 wt %, about 11.4 wt %, about 11.5 wt %, about 11.6 wt %, about 11.7 wt %, about 11.8 wt %, about 11.9 wt %. %, about 12.0 wt %, about 12.1 wt %, about 12.2 wt %, about 12.3 wt %, about 12.4 wt %, about 12.5 wt %, about 12.6 wt %, about 12.7 wt %, about 12.8 wt %, about 12.9 wt %, about 13.0 wt %, about 13.1 wt %, about 13.2 wt %, about 13.3 wt %, about 13.4 wt %, about 13.5 wt %, about 13.6 wt %, about 13.7 wt %, about 13.8 wt %, about 13.9 wt %, or about 14.0 wt %, including all values ​​and ranges therebetween. In embodiments, C 13-21 The concentration of fatty alcohol is about 12% by weight. 13-21 The fatty alcohol was octyldodecanol.

[0063] In an embodiment, the composition or formulation of the present disclosure further comprises a pharmacologically acceptable preservative, an antioxidant, a solvent, a viscosity enhancer (i.e., a viscosity modifier), a pH adjuster (i.e., a pH adjuster), an emollient, a humectant, a colorant, and a fragrance. In an embodiment, the composition of the present disclosure further comprises an antioxidant, a preservative, a viscosity modifier, a pH adjuster, or a mixture thereof.

[0064] In embodiments, the compositions of the present disclosure (e.g., creams) include antioxidants. In embodiments, antioxidants include phenolic compounds such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tert-butylhydroquinone, natural antioxidants such as tocopherol (vitamin E), ascorbic acid (vitamin C), polyphenols (e.g., propyl gallate), flavonoids, retinol (vitamin A), or mixtures thereof. In embodiments, the antioxidant is propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene, or mixtures thereof. In embodiments, the antioxidant is a mixture of propyl gallate and butylated hydroxyanisole (BHA). In an embodiment, the concentration of propyl gallate is from about 0.02% to about 0.08% by weight, for example, from about 0.02% by weight, from about 0.03% by weight, from about 0.04% by weight, from about 0.05% by weight, from about 0.06% by weight, from about 0.07% by weight, or from about 0.08% by weight, including all values ​​and ranges therebetween. In an embodiment, the concentration of BHA is from about 0.05% by weight to about 0.2% by weight, for example, from about 0.05% by weight, from about 0.06% by weight, from about 0.07% by weight, from about 0.08% by weight, from about 0.09% by weight, from about 0.1% by weight, from about 0.11% by weight, from about 0.12% by weight, from about 0.13% by weight, from about 0.14% by weight, from about 0.15% by weight, from about 0.16% by weight, from 0.17% by weight, from about 0.18% by weight, from about 0.19% by weight, or from about 0.2% by weight, including all values ​​and ranges therebetween. In an embodiment, the composition comprises about 0.05 wt % propyl gallate and about 0.1 wt % BHA.

[0065] In an embodiment, a composition (eg, a cream) of the present disclosure comprises a preservative. In embodiments, preservatives (e.g., to inhibit or prevent the growth of microorganisms, fungi, etc. in topical formulations) include triclosan, methylisothiazolinone, methylchloroisothiazolinone, chlorphenesin, chloroxylenol, iodopropynyl butylcarbamate, methyldibromoglutaronitrile, formaldehyde, formaldehyde benzyl alcohol hemiacetal, diazolidinyl urea, imidazolidinyl urea, 2-bromo-2-nitropropane-1,3-diol, DMDM ​​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), alcohols, or mixtures thereof. In embodiments, the concentration of preservative is from about 0.05% by weight to about 2% by weight, for example, from about 0.05% by weight, from about 0.1% by weight, from about 0.2% by weight, from about 0.3% by weight, from about 0.4% by weight, from about 0.5% by weight, from about 0.6% by weight, from about 0.7% by weight, from about 0.8% by weight, from about 0.9% by weight, from about 1.0% by weight, from about 1.1% by weight, from about 1.2% by weight, from about 1.3% by weight, from about 1.4% by weight, from about 1.5% by weight, from about 1.6% by weight, from about 1.7% by weight, from about 1.8% by weight, from about 1.9% by weight or from about 2.0% by weight, including any value or scope therebetween. In embodiments, preservative is glycol ether, phenol ether, benzoate or its mixture. In embodiments, preservative is phenoxyethanol. In embodiments, preservative is sodium benzoate. In an embodiment, the concentration of phenoxyethanol is from about 0.05% by weight to about 0.4% by weight, for example, from about 0.05% by weight, from about 0.1% by weight, from about 0.2% by weight, from about 0.3% by weight, or from about 0.4% by weight, including any value or range therebetween. In an embodiment, the concentration of sodium benzoate is from about 0.5% by weight to about 2% by weight, for example, from about 0.5% by weight, from about 0.6% by weight, from about 0.7% by weight, from about 0.8% by weight, from about 0.9% by weight, from about 1.0% by weight, from about 1.1% by weight, from about 1.2% by weight, from about 1.3% by weight, from about 1.4% by weight, from about 1.5% by weight, from about 1.6% by weight, from about 1.7% by weight, from about 1.8% by weight, from about 1.9% by weight, or from about 2.0% by weight, including any value or range therebetween. In an embodiment, the preservative is from about 0.05% to about 0.4% by weight phenoxyethanol, or from about 0.5% to about 2% by weight sodium benzoate, or a mixture thereof.

[0066] In an embodiment, the pH of the composition of the present disclosure (e.g., cream) is about 4.5 to about 5.5 and comprises a preservative. In an embodiment, the preservative is sodium benzoate, which provides antimicrobial activity at acidic pH.

[0067] In an embodiment, the composition of the present disclosure (e.g., cream) comprises a pharmaceutically acceptable solvent. In an embodiment, the composition of the present disclosure comprises acetone, 2-methylpentane-2,4-diol, propylene glycol, caprylic capric triglyceride (available as MIGLYOL 812N from Oleochemicals), octyldodecanol, limonene, 1,3-butylene glycol, 1,3-dioxolane, 1,3-propylene glycol, 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, dimethyl isosorbide, dimethyl sulfoxide, ethyl acetate, Esters, isopropyl myristate, 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, sulfoxide, toluene, xylene or a mixture thereof.

[0068] In some embodiments, the compositions of the present disclosure (e.g., creams) comprise a thickener. In an embodiment, a thickener (i.e., a viscosity modifier) ​​comprising a thickener or gelling agent comprises a substance that can increase the viscosity of the composition. In an embodiment, a viscosity modifier comprises a substance that can increase the viscosity of the composition without substantially changing the efficacy of the active ingredient in the composition. In an embodiment, a viscosity modifier can also increase the physical stability of the compositions of the present disclosure. In an embodiment, viscosity enhancers, viscosity modifiers, or thickeners include lipid thickeners such as cetyl alcohol, stearyl alcohol, carnauba wax, stearic acid; thickeners of natural origin such as hydroxyethyl cellulose, gum arabic, guar gum, locust bean gum, xanthan gum, gelatin, hyaluronic acid, acacia, agar, algin, alginic acid, ammonium alginate, pullulan, calcium alginate, calcium carrageenan, carnitine, carrageenan, dextrin, gellan gum, guar gum, gum hydroxypropyltrimonium chloride, hydroxypropyl chitosan, hydroxypropyl guar gum, 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, silicon dioxide, bentonite, magnesium aluminum silicate; synthetic thickeners such as carbomer (water-swellable acrylic acid polymer sold under the trade names ULTREZ 30 (Lubrizol), ULTREZ 21 (Lubrizol), TEGO Carbomer 140G (Evonik) and SEPINEO P600 (acrylamide / AMPS copolymer; Seppic).

[0069] In an embodiment, the viscosity modifier is a copolymer of acrylamide and sodium acryloyldimethyl taurate (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 acryloyldimethyl taurate dispersed in isohexadecane. In an embodiment, the concentration of the copolymer of acrylamide and sodium acryloyldimethyl taurate is from about 1.5 wt % to about 5 wt % (e.g., about 1.5 wt %, about 1.6 wt %, about 1.7 wt %, about 1.8 wt %, about 1.9 wt %, about 2.0 wt %, about 2.1 wt %, about 2.2 wt %, about 2.3 wt %, about 2.4 wt %, about 2.5 wt %, about 2.6 wt %, about 2.7 wt %, about 2.8 wt %, about 2.9 wt %, about 3.0 wt % %, about 3.1 wt %, about 3.2 wt %, about 3.3 wt %, about 3.4 wt %, about 3.5 wt %, about 3.6 wt %, about 3.7 wt %, about 3.8 wt %, about 3.9 wt %, about 4.0 wt %, about 4.1 wt %, about 4.2 wt %, about 4.3 wt %, about 4.4 wt %, about 4.5 wt %, about 4.6 wt %, about 4.7 wt %, about 4.8 wt %, about 4.9 wt %, or about 5.0 wt %, including any value or range therebetween). In embodiments, the viscosity modifier is about 1.5 wt % to about 5 wt % of a copolymer of acrylamide and sodium acryloyldimethyltaurate, polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof, dispersed in isohexadecane.

[0070] In an embodiment, the viscosity modifier or thickener in the composition of the present disclosure comprises a carboxylic acid polymer, a cross-linked polyacrylate polymer, a polyacrylamide polymer, a polysaccharide, a gum, or a mixture thereof. In an embodiment, the carboxylic acid polymer comprises a cross-linked compound containing one or more monomers derived from acrylic acid, substituted acrylic acid, and salts and esters of these acrylic acid and substituted acrylic acid, wherein the cross-linking agent contains two or more carbon-carbon double bonds and is derived from a polyol (see U.S. Pat. Nos. 5,087,445; 4,509,949; 2,798,053; incorporated herein by reference in their entirety, and CTFA International Cosmetic Ingredient Dictionary, Fourth Edition, 1991, pages 12 and 80).

[0071] In an embodiment, the composition of the present disclosure comprises a pH adjusting agent. In an embodiment, the pH adjusting agent (i.e., pH adjusting agent or pH modifier) ​​comprises any pharmaceutically acceptable buffer capable of buffering in an acceptable pH range (e.g., pH 4-5), such as citric acid buffer and acetate buffer. In an embodiment, the pH adjusting agent is 10% citric acid.

[0072] In an embodiment, the composition of the present disclosure (e.g., cream) further comprises an emollient. In an embodiment, the pharmaceutically acceptable emollient (or moisturizer) in the composition of the present disclosure comprises vegetable oil, 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, etc. In an embodiment, the pharmaceutically acceptable humectant in the composition of the present disclosure comprises hyaluronic acid, glycerol, alpha hydroxy acid (e.g., glycolic acid, lactic acid, citric acid), propylene glycol, aloe vera gel, erythritol, xylitol, sorbitol, fructose, glucose, glycerol, glycerol polymer, ethylene glycol, 1,2,6-hexanetriol, honey, hydrogenated honey, hydrogenated starch hydrolysate, inositol, lactitol, maltitol, maltose, mannitol, PEG-15 butylene glycol, polyglyceryl sorbitol, salts of pyrrolidone carboxylic acid, PCA potassium, propylene glycol, sodium glucuronate, sodium PCA, sucrose, trehalose, urea, panthenol (vitamin B5), peptides, amino acids and salicylic acid. In an embodiment, the cream comprises glycerol, propylene glycol or a mixture thereof.

[0073] In an embodiment, the composition of the present disclosure (eg, cream) optionally includes a chelating agent. In an embodiment, the pharmaceutically acceptable chelating agent in the composition of the present disclosure comprises disodium ethylenediaminetetraacetate (EDTA), tetrasodium EDTA, or a mixture thereof.

[0074] In an embodiment, the composition of the present disclosure (e.g., cream) optionally includes a UV absorber. In an embodiment, the chemical UV absorber in the composition of the present disclosure comprises 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 benzophenone-1 to 12), cinnamate (octyl methoxycinnamate, isopentyl p-methoxycinnamate, octyl methoxycinnamate, cinoxate, methyl diisopropyl cinnamate, DEA methoxycinnamate, ethyl diisopropyl cinnamate, glyceryl caprylate dimethoxycinnamate and ethyl methoxycinnamate), cinnamate, salicylate (homomethyl salicylate, benzyl salicylate, glycol salicylate, isopropyl salicylate esters, anthranilates, ethyl urocanate, homosalate, octyl salicylate, dibenzoylmethane derivatives (e.g., avobenzone), octyl propene, octyl triazolone, diformyl trioleate, aminobenzoic acid glyceryl ester, safflower with dihydroxyacetone, ethylhexyl triazone, dioctyl butyramido triazone, benzalmalonate polysiloxane, terephthaloyl dicamphor sulfonic acid, sodium phenyl dibenzimidazole tetrasulfonate, diethylaminohydroxybenzoyl hexyl benzoate, bis diethylaminohydroxybenzoyl benzoate, bisbenzoxazolylphenylethylhexyliminotriazine, drometrizole trisiloxane, methylene bisbenzotriazolyl tetramethylbutylphenol and bisethylhexyloxyphenol methoxyphenyl triazine, 4-methylbenzylidene camphor, isopentyl 4-methoxycinnamate or a mixture thereof. In an embodiment, the physical UV absorber comprises kaolin, talc, petrolatum, and metal oxides (eg, titanium dioxide and zinc oxide), or mixtures thereof.

[0075] In embodiments, the viscosity of the compositions of the present disclosure is 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 at 25° C. using USP <912> The viscosity was measured by the rotational viscosity method (Brookfield RVDVII viscometer) described in .

[0076] In an embodiment, the viscosity of the cream is from about 15,000 mPa·s to about 90,000 mPa·s, e.g., 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, 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, measured using rotational viscometry at 25°C. In an embodiment, the viscosity of the cream is about 15,000 mPa s to about 75,000 mPa s, which is measured using a rotational viscometer at 25°C. In an embodiment, the viscosity of the cream is about 19,500 mPa s to about 45,200 mPa s, which is measured using a rotational viscometer at 25°C. In an embodiment, the viscosity measurement is performed at a constant shear rate (revolutions per minute) after pre-treating the sample at the same speed. In an embodiment, the viscosity of the composition is measured using a Brookfield viscometer RVDVII+, a small sample adapter (SSA), and a mobile number 34 from the SSA spindle set.

[0077] In an embodiment, a composition of the present disclosure is topically applied to deliver a pharmaceutically effective level of a TRPV3 inhibitor (e.g., KM-001) to the epidermis. In an embodiment, a composition of the present disclosure is topically applied to deliver a pharmaceutically effective level of a TRPV3 inhibitor (e.g., KM-001) to one or more of the suprabasal layers of the epidermis (e.g., keratinized envelope, stratum granulosum, and stratum spinosum, and upper dermis). In an embodiment, topical application of a composition of the present disclosure provides penetration of the TRPV3 inhibitor to all suprabasal layers of the epidermis. In embodiments, topical administration of a composition of the present disclosure provides a local concentration of a TRPV3 inhibitor (e.g., KM-001) of about 60 μg / g to about 160 mg / g, for example, 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 or about 160 mg / g, including all ranges between any of these values.

[0078] Following topical administration of a composition of the present disclosure, the local concentration of a TRPV3 inhibitor (e.g., KM-001) in the dermis ranges from about 1.5 wt % to 16 wt % of the total amount of KM-001 in the skin, as measured by the IVPT method described herein, including about 1.5 wt %, about 2.0 wt %, about 2.5 wt %, about 3.0 wt %, about 3.5 wt %, about 4.0 wt %, about 4.5 wt %, about 5.0 wt %, about 5.5 wt %, about 6.0 wt %, about 6.5 wt %, about 7.0 wt %, about 7.5 ... %, about 5 wt %, about 7.0 wt %, about 7.5 wt %, about 8.0 wt %, about 8.5 wt %, about 9.0 wt %, about 9.5 wt %, about 10.0 wt %, about 10.5 wt %, about 11.0 wt %, about 11.5 wt %, about 12.0 wt %, about 12.5 wt %, about 13.0 wt %, about 13.5 wt %, about 14.0 wt %, about 14.5 wt %, about 15.0 wt %, about 15.5 wt % or about 16.0 wt %, including all ranges between any of these values, as measured using the IVPT method described herein.

[0079] In an embodiment, topical application to the skin of a patient in need thereof allows about 0.05% to about 20% by weight of KM-001 in the form of an applied composition to penetrate into the stratum corneum, epidermis or dermis, for example, about 0.05%, about 0.1%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, 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 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8 ...%. %, about 8.0 wt %, about 8.5 wt %, about 9.0 wt %, about 9.5 wt %, about 10.0 wt %, about 10.5 wt %, about 11.0 wt %, about 11.5 wt %, about 12.0 wt %, about 12.5 wt %, about 13.0 wt %, about 13.5 wt %, about 14.0 wt %, about 14.5 wt %, about 15.0 wt %, about 15.5 wt %, about 16.0 wt %, about 16.5 wt %, about 17.0 wt %, about 17.5 wt %, about 18.0 wt %, about 18.5 wt %, 19.0 wt %, about 19.5 wt %, or about 20.0 wt %, including any value or range therebetween. In an embodiment, topical application to the skin of a patient in need thereof allows about 1 wt % to about 10 wt % of KM-001 in the form of an applied composition to penetrate into the stratum corneum as measured by IVPT. In an embodiment, topical application to the skin of a patient in need thereof allows about 0.2 wt % to about 8 wt % of KM-001 in the form of an applied composition to penetrate into the epidermis as measured by IVPT. In an embodiment, topical application to the skin of a patient in need thereof allows about 0.05 wt % to about 3 wt % of KM-001 in the form of an applied composition to penetrate into the dermis as measured by IVPT.

[0080] In an embodiment, the cream is topically applied to the skin of a patient in need thereof so that about 50 μg / g to about 6000 μg / g of KM-001 in the form of an applied composition at about 0.2 wt % to about 3 wt % (e.g., about 0.3 wt % or about 1 wt %) in the skin penetrates throughout the skin section, for example, 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 300 μg / g, about 350 μg / g, about 400 μg / g, about 4 50μg / 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 900μg / g, about 950μg / g, about 1000μg / g, about 1100μg / g, about 1200μg / g, about 1300μg / g, about 1400μg / g, about 1500μg / g, about 1600μg / g, about 1700μg / g, about 1800μg / g, about 1900μg / g, about 2000μg / g, about 2100μg / g g, about 2200 μg / g, about 2300 μg / g, about 2400 μg / g, about 2500 μg / g, about 2600 μg / g, about 2700 μg / g, about 2800 μg / g, about 2900 μg / g, about 3000 μg / g, about 3100 μg / g, about 3200 μg / g, about 3300 μg / g, about 3400 μg / g, about 3500 μg / g, about 3600 μg / g, about 3700 μg / g, about 3800 μg / g, about 3900 μg / g, about 4000 μg / g, about 4100 μg / g, about 4200 μg / g, about 43 g / 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, as measured by (matrix-assisted laser desorption / ionization) MALDI. In embodiments, topical application of the cream to the skin of a patient in need thereof causes about 50 μg / g to about 6000 μg / g of KM-001 present in the skin as 1 wt % of the applied composition to penetrate throughout the skin section as measured by MALDI.In an embodiment, the cream is topically applied to the skin of a patient in need so that about 2000 μg / g to about 3000 μg / g of KM-001 presented in the form of 1% by weight of the composition is permeated throughout the skin section, as measured by MALDI. In an embodiment, the cream is topically applied to the skin of a patient in need so that about 2000 μg / g to about 6000 μg / g of KM-001 presented in the form of 1% w / w of the composition is permeated into all layers of the epidermis (particularly the epidermis layer on the basal surface), as measured by MALDI. In an embodiment, the cream is topically applied to the skin of a patient in need so that about 500 μg / g to about 800 μg / g of KM-001 presented in the form of 1% by weight of the composition is permeated into the dermis, as measured by MALDI. In embodiments, the cream is topically applied to the skin of a patient in need thereof to allow penetration into the dermis to achieve a dermal concentration of KM-001 that is 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 6.5%, about 7.0%, about 7.5 ... %, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about In embodiments, topical application of the cream to the skin of a patient in need thereof causes about 50 μg / g to about 1200 μg / g of KM-001 present in the skin as 1 wt % of the applied composition to penetrate into the hair follicles as measured by MALDI.

[0081] 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 a cream containing 1 wt % KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm2 (For example, about 410cm 2 、Approx. 420cm 2 、Approx. 430cm 2 、Approx. 440cm 2 、Approx. 450cm 2 、Approx. 460cm 2 、Approx. 470cm 2 、Approx. 480cm 2 、Approx. 490cm 2 、About 500cm 2 、About 510cm 2 、About 520cm 2 、About 530cm 2 、About 540cm 2 、About 550cm 2 、About 560cm 2 、About 570cm 2 、About 580cm 2 、About 590cm 2 or about 600cm 2, including any value or range therebetween) provides about 50 μg / g to about 6000 μg / g of KM-001 in one or more skin layers, for example, 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 300 μg / g, about 350 μg / g, about 400 μg / g, about 450 μg / g, about 500 μg / g, about 550 μg / g, about 600 μg / g, about 650 μg / g. / g, about 700μg / g, about 750μg / g, about 800μg / g, about 850μg / g, about 900μg / g, about 950μg / g, about 1000μg / g, about 1100μg / g, about 1200μg / g, about 1300μg / g, about 1400μg / g, about 1500μg / g, about 1600μg / g, about 1700μg / g, about 1800μg / g, about 1900μg / g, about 2000μg / g, about 2100μg / g, about 2200μg / g, about 2300μg / g, about 240 0μg / g, about 2500μg / g, about 2600μg / g, about 2700μg / g, about 2800μg / g, about 2900μg / g, about 3000μg / g, about 3100μg / 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 4200μg / g, about 4300μg / g, about 4400 , 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, as measured by (matrix-assisted laser desorption / ionization) MALDI. In an embodiment, about 3 grams of a cream comprising 1 wt % KM-001 is topically applied to about 500 cm 2 The skin provides about 50 μg / g to about 6000 μg / g of KM-001 in one or more skin layers as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0082] In an embodiment, about 2 grams to about 4 grams of a cream comprising 1% by weight KM-001 is topically applied to about 400 cm of a patient in need thereof.2 To about 600cm 2 The skin provides about 2000 μg / g to about 6000 μg / g of KM-001 in the epidermis as measured by (matrix-assisted laser desorption / ionization) MALDI. In an embodiment, about 3 grams of a cream containing 1 wt % KM-001 is topically applied to about 500 cm of a patient in need thereof. 2 The skin provides about 2000 μg / g to about 6000 μg / g of KM-001 in the epidermis as measured by (matrix-assisted laser desorption / ionization) MALDI. In an embodiment, about 2 grams to about 4 grams of a cream containing 1 wt % KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The present invention provides about 2000 μg / g to about 6000 μg / g of KM-001 in the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum, or a combination thereof, 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 topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provides about 500 μg / g to about 800 μg / g of KM-001 in the dermis, as measured by MALDI. In an embodiment, about 3 grams of a cream containing 1 wt % KM-001 is topically applied to about 500 cm of a patient in need thereof. 2 The skin provides about 500 μg / g to about 800 μg / g of KM-001 in the dermis, as measured by MALDI. In an embodiment, about 2 grams to about 4 grams of a cream containing 1% by weight KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 of the skin to provide a concentration of KM-001 in the dermis equivalent to about 1% to about 16% of KM-001 in the epidermis (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 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.0%, about 8.5 ... %, 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), as measured by MALDI. In an embodiment, about 2 grams to about 4 grams of a cream comprising 1 wt % KM-001 is topically applied to about 400 cm of a patient in need thereof. 2To about 600cm 2 The skin provides about 100 μg / g to about 3500 μg / g of KM-001 in the subcutaneous tissue as measured by MALDI. In an embodiment, about 2 grams to about 4 grams of a cream containing 1% by weight KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin of WT AQUA® provides about 50 μg / g to about 1200 μg / g of KM-001 in the hair follicles as measured by MALDI.

[0083] As is well known, the skin is an effective barrier, so the active agent in the topical composition must be in a dissolved state and small enough to penetrate. If the active agent crystallizes or precipitates from the composition before (or during) application, the available dose of the active agent will be reduced. Therefore, it is critical to select solvents and other components / excipients of the composition that maintain the solubility (and chemical stability) of the active agent (e.g., KM-001) during transportation, storage, and use.

[0084] In an embodiment, the induction time of a sample comprising 100 pbw oil phase and 1 pbw KM-001 is at least 500 minutes, as measured by RapidOxy test using 3 to 5 g sample at 120°C, 700 kPa initial pressure and 2% ΔP. In an embodiment, the cream meets the A criteria of European Pharmacopoeia 5.1.3 after storage for 1 year at 25°C ± 2°C and 60% relative humidity ± 5% relative humidity. In an embodiment, the cream meets the A criteria of European Pharmacopoeia 5.1.3 after storage for 6 months at 40°C ± 2°C and 75% relative humidity ± 5% relative humidity. In an embodiment, the cream meets the A criteria of USP 5.1.3 after storage for 6 months at 40°C ± 2°C and 75% relative humidity ± 5% relative humidity. <51> In an embodiment, the solubility of KM-001 in the oil phase is from about 10 wt % to about 15 wt % at 10°C to 30°C.

[0085] In embodiments, the compositions of the present disclosure facilitate delivery of a TRPV3 inhibitor to the intended layer of the skin to treat various dermatological conditions (e.g., skin conditions and / or pruritus as described herein) while minimizing systemic exposure to the TRPV3 inhibitor. Systemic exposure is undesirable because it will increase the likelihood of off-target effects, which may affect the tolerability or safety of the composition. In addition, any TRPV3 inhibitor that is systemically distributed will not be available in the target tissue (i.e., skin) to treat the intended skin condition and / or pruritus. The compositions of the present disclosure have low systemic exposure levels, as measured by the maximum plasma concentration (C max) and the area under the plasma drug concentration-time curve (AUC) value. For example, the C of the composition of the present disclosure on TRPV3 inhibitors (e.g., KM-001) in humans max A value of less than about 40 ng / mL (measured after 28 days in a patient treated topically with a daily dose of a TRPV3 inhibitor of about 0.4 mg / kg*day). In an embodiment, C after 28 days maxThe values ​​ranged 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 8.0 ng / mL, about ng / mL, about 8.5ng / mL, about 9.0ng / mL, about 9.5ng / mL, about 10.0ng / mL, about 10.5ng / mL, about 11.0ng / mL, about 11.5ng / mL, about 12.0ng / mL, about 12.5ng / mL, about 13.0ng / mL, about 13.5ng / mL, about 14.0ng / mL, about 14.5ng / mL, about 15.0ng / mL, about 15.5ng / mL, about 16.0ng / mL, about 16.5ng / mL, about 17.0ng / mL, about 17.5ng / mL, about 18.0ng / mL, about 18.5ng / mL, about 19.0ng / mL, about 19.5 ng / mL, about 20.0 ng / mL, about 20.5 ng / mL, about 21.0 ng / mL, about 21.5 ng / mL, about 22.0 ng / mL, about 22.5 ng / mL, about 23.0 ng / mL, about 23.5 ng / mL, about 24.0 ng / mL, about 24.5 ng / mL, about 25.0 ng / mL, about 25.5 ng / mL, about 26.0 ng / mL, about 26.5 ng / mL, about 27.0 ng / mL, about 27.5 ng / mL, about 28.0 ng / mL, about 28.5 ng / mL, about 29.0 ng / mL, about 29.5 ng / mL, about 30.0 ng / mL, about 30.5 ng / mL, about 31.0 ng / mL, about 31.5 ng / mL, about 32.0 ng / mL, about 32.5 ng / mL, about 33.0 ng / mL, about 33.5 ng / mL, about 34.0 ng / mL, about 34.5 ng / mL, about 35.0 ng / mL, about 35.5 ng / mL, about 36.0 ng / mL, about 36.5 ng / mL, about 37.0 ng / mL, about 37.5 ng / mL, about 38.0 ng / mL, about 38.5 ng / mL, about 39.0 ng / mL, about 39.5 ng / mL, or about 40.0 ng / mL, including all ranges between any of these values.In embodiments, topical administration of a composition of the present disclosure (e.g., a cream) provides a maximum plasma concentration (C) of KM-001 of less than about 40 ng / mL. max ).

[0086] In embodiments, the AUC of a TRPV3 inhibitor (e.g., KM-001) (measured after 28 days in patients treated topically with a daily dose of a TRPV3 inhibitor of about 0.4 mg / kg*day) is less than about 500 ng / mL*h. In embodiments, the AUC of a TRPV3 inhibitor measured under such conditions ranges from undetectable to about 1 ng / mL*h, about 5 ng / mL*h, about 10 ng / mL*h, about 15 ng / mL*h, about 20 ng / mL*h, about 25 ng / mL*h, about 30 ng / mL*h, about 35 ng / mL*h, about 40 ng / mL*h, about 45 ng / mL*h, about 50 ng / mL*h, about 55 ng / mL*h, about 60 ng / mL*h, about 65 ng / mL*h, About 70ng / mL*h, about 75ng / mL*h, about 80ng / mL*h, about 85ng / mL*h, about 90ng / mL*h, about 95ng / mL*h, about 100ng / mL*h, about 150ng / mL*h, about 200ng / mL*h, about 250ng / mL*h, about 300ng / mL*h, about 350ng / mL*h, about 400ng / mL*h, about 450ng / mL*h, or about 500ng / mL*h, including all ranges between any of these values. In embodiments, topical administration provides an area under the plasma drug concentration-time curve (AUC) of KM-001 of less than about 500ng / mL*h.

[0087] Methods for treating skin disorders and pruritus

[0088] Compositions of the present disclosure comprising about 0.2% by weight to about 2% by weight (particularly comprising about 0.3% by weight or about 1.0% by weight in embodiments) of a TRPV3 inhibitor (e.g., KM-001) may be applied at least once a day to an area of ​​the patient's skin affected by a skin disorder and / or pruritus. In some embodiments, the compositions of the present disclosure as 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, noon and evening), or four times a day or more. 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 degree of clinical response. For example, the frequency of application of a composition having a higher TRPV3 inhibitor composition (e.g., about 1.0% by weight KM-001) may be lower than a composition having a lower TRPV3 inhibitor concentration (e.g., about 0.3% by weight KM-001). Likewise, if the severity of the skin disorder and / or pruritus is low, the frequency or concentration of administration of the TRPV3 inhibitor may be reduced. In embodiments, the compositions of the invention may be administered prophylactically, e.g., to a patient susceptible to a skin disorder, in order to delay or prevent the development of symptoms of a dermatological condition (e.g., keratotic lesions and / or pruritus).

[0089] As discussed herein, the amount of the compositions of the present disclosure applied per day can vary based on the severity of the disease, the surface area of ​​the patient's affected skin, and the frequency of application.

[0090] In embodiments, a suitable dosage of a TRPV3 inhibitor (eg, KM-001) of a composition of the present disclosure may be expressed as the amount of TRPV3 inhibitor (eg, KM-001) per kg of patient body weight administered per day. Expressed in this way, suitable daily dosage ranges for a TRPV3 inhibitor (e.g., KM-001) are from about 0.1 to about 1 mg / kg / day, including 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 0.55 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.

[0091] In an embodiment, a suitable dosage of a TRPV3 inhibitor (e.g., KM-001) of a composition of the present disclosure may be expressed as per cm per day. 2 The amount of TRPV3 inhibitor (eg, KM-001) applied to the skin. Expressed in this way, a suitable daily dose range of a TRPV3 inhibitor (eg, KM-001) is about 10 μg / cm 2 / day to about 1000 μg / cm 2 / day, including about 10 μg / cm 2 / day, about 20μg / cm 2 / day, about 30μg / cm 2 / day, about 40μg / cm 2 / day, about 50μg / cm 2 / day, about 60μg / cm 2 / day, about 70μg / cm 2 / day, about 80μg / cm 2 / day, about 90μg / cm 2 / day, about 100μg / cm 2 / day, about 150μg / cm 2 / day, about 200μg / cm 2 / day, about 250μg / cm 2 / day, about 300μg / cm 2 / day, about 350μg / cm 2 / day, about 400μg / cm 2 / day, about 450μg / cm 2 / day, about 500μg / cm 2 / day, about 550μg / cm 2 / day, about 600μg / cm 2 / day, about 650μg / cm 2 / day, about 700μg / cm 2 / day, about 750μg / cm 2 / day, about 800μg / cm 2 / day, about 850μg / cm 2 / day, about 900μg / cm 2 / day, about 950μg / cm 2 / day or about 1000 μg / cm 2 / day, including all ranges between any of these values.

[0092] The compositions of the present disclosure can be applied within a limited time period (e.g., 1, 2, 3, 4 or more weeks) until the patient's dermatological symptoms and / or pruritus subside or are sufficiently treated to allow at least temporary cessation of treatment. In some embodiments, the compositions of the present disclosure can be applied indefinitely to patients with chronic dermatological symptoms or pruritus. In an embodiment, the dosage of the TRPV3 inhibitor (e.g., KM-001) applied can be adjusted to provide an appropriate maintenance dose to prevent the recurrence of dermatological symptoms and / or pruritus. Dose adjustment can 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 topical compositions, or some combination of these adjustments. Therefore, in order to reduce the daily dose of the TRPV3 inhibitor (e.g., KM-001), the patient can switch to a topical composition with a lower TRPV3 inhibitor concentration, apply the topical composition less, apply a smaller amount of topical composition, or some combination of these methods. Similarly, the daily dose of a TRPV3 inhibitor (eg, KM-001) can be increased by switching to a topical composition with a higher TRPV3 inhibitor concentration, applying the topical composition more frequently, applying a larger amount of the topical composition, or some combination of these methods.

[0093] In embodiments, the present disclosure provides methods for treating various dermatological conditions described herein, as well as for treating symptoms such as pruritus associated with (e.g., caused by or manifested by) such dermatological conditions.

[0094] The compositions and methods of the present disclosure are effective in alleviating the symptoms of various dermatological conditions described herein, such as reducing the size and severity of dermatological lesions. For example, the reduction of symptoms can be measured using the Investigator's Global Assessment (IGA) of disease severity, using the IGA score sheet shown in Table 9 in Example 6.

[0095] The compositions of the present disclosure comprising at least one TRPV3 inhibitor described herein (e.g., KM-001) are suitable for treating various skin disorders. For example, skin disorders that can be treated 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, depending on whether the keratosis is hereditary or acquired, and the clinical features of the keratosis: diffuse keratosis affects most of the palms and soles; focal keratosis mainly affects pressure sites; and punctate keratosis causes tiny lumps to appear on the palms and soles. In most cases, the abnormal skin involves only the palms and soles (non-transgradient palmoplantar keratosis), but sometimes it also extends to the tops of the hands and feet (transgradient).

[0096] Specific types of keratosis that may be treated by the compositions and methods of the present disclosure include, but are not limited to, diffuse hereditary palmoplantar keratosis (e.g., Unna-Thost type (autosomal dominant), Vorner type (autosomal dominant), Mal deMeleda type (autosomal dominant or recessive), Huriez syndrome (autosomal dominant), Olmsted syndrome (unknown inheritance pattern), Vohwinkel syndrome (autosomal dominant), PPK with sensorineural hearing loss (mitochondrial inheritance), Bart-Pumphrey syndrome (autosomal dominant), hidrotic ectodermal dysplasia (autosomal dominant), Papillon-Lefevre syndrome (autosomal dominant), syndrome (autosomal recessive), palmoplantar keratoderma long island type (autosomal recessive), and diffuse palmoplantar keratoderma with villous and arrhythmic cardiomyopathy (autosomal recessive); focal hereditary palmoplantar keratoderma (eg, palmoplantar keratoderma striate / plaque type (autosomal dominant), hereditary painful corpus callosum (autosomal dominant), Howel-Evans syndrome (autosomal recessive), and hereditary painful corpus callosum (autosomal dominant). syndrome) or callosity (autosomal dominant), Richner-Hanhart syndrome (autosomal recessive), pachyonychia congenita (autosomal dominant), and striated palmoplantar keratoderma with villous and dilated cardiomyopathy (autosomal recessive); punctate palmoplantar keratoderma (e.g., punctate keratoderma (autosomal dominant), filiform keratoderma (autosomal dominant), marginal keratoderma (acrokeratoelastoidosis, autosomal dominant). Keratodermas that can be treated by the compositions and methods of the present disclosure also include acquired palmoplantar keratoderma, which can be focal or diffuse. Such acquired keratodermas may be associated with a variety of different skin and internal conditions, such as inflammatory skin conditions (e.g., eczema or psoriasis), infections, drugs and toxins, internal cancers, systemic inflammatory diseases, blood circulation problems, or sun damage.

[0097] Ichthyosis is another class of skin disorders that can be treated by the compositions and methods of the present disclosure. Ichthyosis refers to a group of relatively rare skin disorders characterized by the presence of excessive amounts of dry surface scales that continue to dry, thicken, and give the skin a "fish-scaly" appearance. Ichthyosis is considered a keratinization or keratinization disorder and is due to abnormalities in epidermal differentiation or metabolism.

[0098] Ichthyosis can be classified based on clinical presentation, genetic presentation, and histological findings. There are at least 20 different types of ichthyosis. Some types are inherited at birth, others are acquired in adulthood. Inherited forms of ichthyosis may be congenital or have a delayed onset. Ichthyosis vulgaris has autosomal dominant inheritance, meaning the abnormal gene is inherited from both parents. Penetrance is 90%, and onset is delayed until at least three months of age. Recessive X-linked ichthyosis primarily affects males, who have a single X chromosome with the abnormal gene. Females are usually protected by having a normal second X chromosome. Onset may be congenital or delayed by up to six months. In autosomal recessive congenital ichthyosis, one abnormal gene is inherited from each parent. Congenital ichthyosis erythroderma (CIE) is a variant of autosomal recessive congenital ichthyosis (ARCI), a rare epidermal disorder characterized by the presence of fine white scales on a background of generalized erythematous skin. Keratotic ichthyosis occurs in both recessive and dominant forms and is present at birth with a collodion membrane. Harlequin ichthyosis is a rare and severe ichthyosis in which hard, thickened armor-like skin covering the entire body is present from birth. Harlequin ichthyosis is also known as harlequin ichthyosis and ugly fetus. Lamellar ichthyosis is a rare genetic condition. Babies affected by lamellar ichthyosis are usually born with a shiny, waxy layer of skin (called a collodion membrane) that usually falls off within the first two weeks of life. The skin under the collodion membrane is red and scaly. Epidermolytic ichthyosis (EI) is a rare, genetic skin disorder. It becomes apparent at birth or shortly after birth with redness, scaling, and severe blistering of the skin. Hyperkeratosis develops over a period of months and worsens over time. Blister formation decreases but may still occur after trauma to the skin or during the summer. The skin will itch, smell, and become easily infected. Other features can include decreased sweating; nail abnormalities; and in severe cases, growth failure. Superficial epidermolytic ichthyosis (SEI), formerly known as Siemens bullous ichthyosis (IBS), is a rare keratinization disorder with superficial peeling. Despite the hyperkeratosis, the skin is abnormally fragile and has a tendency to shed the outer layer of the epidermis, resulting in localized bare areas. Netherton syndrome (Netherton syndrome) is a rare genetic disorder characterized by scaling of the skin, hair abnormalities, increased susceptibility to atopic eczema (a skin condition that can cause dryness, redness and scaling of the skin), elevated IgE levels, and other associated symptoms. Netherton syndrome is inherited as an autosomal recessive trait. Pachyonychia congenita (PC) is a group of rare autosomal dominant skin disorders caused by mutations in one of five different keratin genes. Pachyonychia congenita is often associated with thickened toenails, plantar keratosis, and pain in the soles of the feet.

[0099] Other types of ichthyosis that may be treated by the compositions and methods of the present disclosure include, but are not limited to, Chanarin-Dorfman syndrome (neutral lipid storage disease), CHILD syndrome (unilateral hemiplegia), Conradi-Hunermann syndrome (X-linked dominant chondrodysplasia punctata), Darier disease, epidermal nevi (elevated ichthyosis, linear epidermal nevus), epidermolytic hyperkeratosis (EHK), erythematous keratosis variabilis (EKV), Giroux-Barbeau syndrome, Hailey-Hailey disease (benign familial pemphigus), elevated ichthyosis Curth-Macklin type, acanthosis alopecia pilaris, KID syndrome (keratitis, ichthyosis, deafness), multiple sulfatase deficiency, desquamative skin syndrome, pityriasis rubra pilaris (PRP), Refsum's disease ( disease) (phytanic acid storage disease), Rud's syndrome, Sjogren-Larsson syndrome, and Tay's syndrome (trichothiodystrophy, IBIDS syndrome).

[0100] In embodiments, the compositions and methods of the present disclosure may be used to treat keratosis, lichen simplex chronicus, pruritic conditions, and ichthyosis. Specific keratosis that may be treated by the compositions and methods of the present disclosure include Mal de Meleda-type keratosis, Olmsted syndrome, Papillon-Lefevre syndrome, palmoplantar keratosis longissima type, pachyonychia congenita, and palmoplantar keratosis punctata. Specific ichthyosis that may be treated by the compositions and methods of the present disclosure include recessive X-linked ichthyosis and harlequin ichthyosis.

[0101] The compositions and methods of the present disclosure may also be used to treat pruritus or itching. Pruritus or itching may be defined as an unpleasant sensation in the skin that causes the urge to scratch. It is a specific feature of many skin diseases and an unusual sign of some systemic diseases. Pruritus may be localized or systemic and may occur as an acute or chronic condition. Itching that persists for more than 6 weeks is referred to as chronic pruritus.

[0102] Itch or pruritus that manifests as a symptom or component of various conditions (e.g., atopic eczema, dermatitis herpetiformis, lichen simplex chronicus, and prurigo nodularis) can also be treated by the compositions and methods of the present invention. These conditions are rarely diagnosed in the absence of pruritus / itching. Chronic pruritus associated with the following dermatological conditions can also be treated by the compositions and methods of the present disclosure, including (but not limited to) dermatitis herpetiformis, dermatomyositis, pemphigoid, Sjögren's syndrome ( Pruritus associated with infections and infestations: arthropod reactions, fungal dermatoses, folliculitis, impetigo and other bacterial infections, insect bites, pediculosis, scabies, viral; Pruritus associated with inflammation: sebum deficiency (dry skin), including aging and senile pruritus, atopic eczema, contact dermatitis (irritant, allergic), drug reactions, "invisible skin diseases", lichen planus, lichen simplex chronicus, mastocytosis (urticaria pigmentosa), miliaria, psoriasis, scars, urticaria; Pruritus associated with tumors: cutaneous T-cell lymphoma or mycosis fungoides (especially Sézary syndrome), cutaneous B-cell lymphoma, cutaneous leukemia; Pruritus associated with pregnancy: pemphigoid gestationis, polymorphic eruption of pregnancy, and pruritus gravidarum. Select systemic causes of chronic pruritus treatable by the compositions and methods of the present disclosure may include: endocrine and metabolic diseases, such as chronic renal failure, diabetes (which may be localized to the scalp), hyperthyroidism, hypothyroidism, liver disease (with or without cholestasis), malabsorption, perimenopausal pruritus; infectious diseases, such as helminthiasis, HIV infection, parasitic diseases; neoplastic and blood diseases, 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 conditions, such as pruritus gravidarum (with or without cholestasis); induced by drugs, such as allopurinol, amiodarone, angiotensin converting enzyme inhibitors, estrogens, hydrochlorothiazide, hydroxyethylcellulose, opioids, simvastatin. Other causes of chronic pruritus may be due to neurological diseases (abscesses, infarctions, multiple sclerosis, back pain paresthesia, tumors) or psychiatric diseases (anxiety disorders, depression, obsessive-compulsive disorder).

[0103] In embodiments, the compositions and methods of the present disclosure are suitable and effective for treating pruritus or itching, either alone or as a therapy for skin disorders such as keratosis or lichen simplex chronicus and their associated pruritus symptoms.

[0104] Numbered implementation plan

[0105] 1. A cream comprising:

[0106]

[0107] aqueous phase; and

[0108] oil phase,

[0109] The concentration of KM-001 is about 0.1 wt % to about 5.6 wt %.

[0110] 2. The cream of embodiment 1, wherein the concentration of KM-001 is about 0.2 wt % to about 3 wt %.

[0111] 3. The cream according to embodiment 1 or 2, wherein the concentration of KM-001 is about 0.3 wt %.

[0112] 4. The cream according to embodiment 1 or 2, wherein the concentration of KM-001 is about 1% by weight.

[0113] 5. The cream of any one of embodiments 1 to 4, wherein the pH of the cream is from about 4 to about 6.

[0114] 6. The cream of any one of embodiments 1 to 5, wherein the pH of the cream is from about 4.5 to about 5.5.

[0115] 7. A cream according to any one of embodiments 1 to 6, wherein the cream comprises:

[0116] (a) from about 20% to about 40% by weight of said oil phase; and

[0117] (b) from about 60% to about 80% by weight of said aqueous phase.

[0118] 8. A cream as described in any one of embodiments 1 to 7, wherein the oil phase comprises triglycerides, C 13-21 Fatty alcohol or mixtures thereof.

[0119] 9. The cream of embodiment 8, wherein the concentration of triglycerides is from about 9% to about 13% by weight.

[0120] 10. The cream of embodiment 8 or 9, wherein the concentration of triglycerides is about 11% by weight.

[0121] 11. The cream of any one of embodiments 8 to 10, wherein the triglyceride is a medium chain triglyceride (MCT).

[0122] 12. The cream of embodiment 11, wherein the MCT is caprylic capric triglyceride.

[0123] 13. A cream as described in any one of embodiments 8 to 12, wherein C 13-21 The concentration of the fatty alcohol is from about 10 wt % to about 14 wt %.

[0124] 14. A cream as described in any one of embodiments 8 to 13, wherein the C 13-21 The concentration of fatty alcohol was about 12% by weight.

[0125] 15. A cream as described in any one of embodiments 8 to 14, wherein the C 13-21 The fatty alcohol was octyldodecanol.

[0126] 16. A cream as described in any one of embodiments 1 to 15, wherein the oil phase

[0127] Does not contain propylene glycol stearyl ether.

[0128] 17. The cream of any one of embodiments 1 to 16, wherein the cream further comprises an antioxidant, a preservative, a viscosity modifier, a pH adjuster, or a mixture thereof.

[0129] 18. The cream of embodiment 17, wherein the antioxidant is propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene, or a mixture thereof.

[0130] 19. The cream of embodiment 18, wherein the antioxidant is a mixture of propyl gallate and BHA.

[0131] 20. The cream of embodiment 19, wherein the concentration of propyl gallate is from about 0.02 wt % to about 0.08 wt %, and the concentration of BHA is from about 0.05 wt % to about 0.2 wt %.

[0132] 21. The cream of embodiment 20, wherein the cream comprises about 0.05 wt % propyl gallate and about 0.1 wt % BHA.

[0133] 22. The cream of embodiment 17, wherein the concentration of the preservative is from about 0.05 wt % to about 4 wt %.

[0134] 23. The cream of embodiment 22, wherein the preservative is a glycol ether, a phenol ether, a benzoate, or a mixture thereof.

[0135] 24. The cream of embodiment 23, wherein the preservative is about 0.05% to about 0.4% by weight phenoxyethanol, about 0.5% to about 2% by weight sodium benzoate, or a mixture thereof.

[0136] 25. The cream of embodiment 17, wherein the viscosity modifier is a copolymer of acrylamide and sodium acryloyldimethyltaurate, polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof.

[0137] 26. The cream of embodiment 25, wherein the viscosity modifier is about 1.5 wt % to about 5 wt % of a copolymer of acrylamide and sodium acryloyldimethyltaurate, polyoxyethylene sorbitan monooleate, sorbitan oleate, or a mixture thereof dispersed in isohexadecane.

[0138] 27. The cream of embodiment 17, wherein the pH adjuster is 10% citric acid.

[0139] 28. The cream of any one of the preceding embodiments, wherein the cream further comprises glycerin, propylene glycol, or a mixture thereof.

[0140] 29. The cream of any one of the preceding embodiments, wherein the cream has a viscosity of at least about 15,000 mPa·s as measured using rotational viscometry at 25°C.

[0141] 30. The cream of embodiment 29, wherein the cream has a viscosity of about 15,000 mPa·s to about 75,000 mPa·s as measured at 25°C using rotational viscometry.

[0142] 31. The cream of embodiment 29, wherein the cream has a viscosity of about 19,500 mPa·s to about 45,200 mPa·s as measured using rotational viscometry at 25°C.

[0143] 32. The cream of any one of the preceding embodiments, wherein the cream is an oil-in-water emulsion.

[0144] 33. The cream of embodiment 32, wherein the average diameter of the globules of the emulsion is less than about 13 μm.

[0145] 34. The cream of embodiment 32, wherein the average diameter of the globules of the emulsion is less than about 10 μm.

[0146] 35. A cream as described in any one of the preceding embodiments, wherein the aqueous phase is a gel at about 2°C to about 40°C.

[0147] 36. The cream of embodiment 1, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm 2 To about 600cm 2The skin provides about 50 μg / g to about 6000 μg / g of KM-001 in one or more skin layers as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0148] 36A. A cream as described in embodiment 36, wherein about 3 grams of the cream containing 1% by weight of KM-001 is topically applied to about 500 cm 2 The skin provides about 50 μg / g to about 6000 μg / g of KM-001 in one or more skin layers, as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0149] 37. The cream of embodiment 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt % KM-001 is topically applied to about 400 cm 2 To about 600cm 2 The skin provides about 2000 μg / g to about 6000 μg / g of KM-001 in the epidermis as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0150] 38. The cream of embodiment 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm 2 To about 600cm 2 The skin provides about 2000 μg / g to about 6000 μg / g of KM-001 in the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum, or a combination thereof, as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0151] 39. The cream of embodiment 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm 2 To about 600cm 2 The skin provided about 500 μg / g to about 800 μg / g of KM-001 in the dermis as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0152] 40. The cream of embodiment 1, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provided a concentration of KM-001 in the dermis equivalent to about 1% to about 16% of the KM-001 in the epidermis, as measured by MALDI.

[0153] 41. The cream of embodiment 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm2 To about 600cm 2 The skin provides about 100 μg / g to about 3500 μg / g of KM-001 in the subcutaneous tissue as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0154] 42. The cream of embodiment 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt % KM-001 is topically applied to about 400 cm 2 To about 600cm 2 The skin of Agilent Technologies provides about 50 μg / g to about 1200 μg / g of KM-001 in the hair follicles as measured by (matrix-assisted laser desorption / ionization) MALDI.

[0155] 43. A cream as described in any of the preceding embodiments, wherein topical application to the skin of a patient in need thereof causes about 0.05% to about 20% by weight of KM-001 present in the form of an applied composition to penetrate into the stratum corneum, epidermis or dermis in the skin as measured by an in vitro permeation test (IVPT).

[0156] 44. The cream of embodiment 43, wherein topical application to the skin of a patient in need thereof causes about 1 wt % to about 10 wt % of KM-001 present in the applied composition to penetrate into the stratum corneum as measured by IVPT.

[0157] 45. The cream of embodiment 43, wherein topical administration to the skin of a patient in need thereof causes about 0.2% to about 8% by weight of KM-001 present in the applied composition to penetrate into the epidermis as measured by IVPT.

[0158] 46. ​​The cream of embodiment 43, wherein topical administration to the skin of a patient in need thereof causes about 0.05% to about 3% by weight of KM-001 present in the applied composition to penetrate into the dermis as measured by IVPT.

[0159] 47. A cream as described in any of the preceding embodiments, wherein the topical application provides a maximum plasma concentration (C 20 of KM-001) of less than about 40 ng / mL. max ).

[0160] 48. The cream of any one of the preceding embodiments, wherein the topical administration provides an area under the plasma drug concentration-time curve (AUC) of KM-001 of less than about 500 ng / mL*h.

[0161] 49. A method of treating a skin disorder or pruritus, the method comprising topically applying to the skin of a patient in need thereof a therapeutically effective amount of KM-001 in any one of the compositions of the preceding claims.

[0162] 50. The method of embodiment 49, wherein the KM-001 is administered at a daily dose of about 0.5 g to about 5 g.

[0163] 51. The method of embodiment 49 or 50, wherein the therapeutically effective amount of KM-001 is 20 μg / cm 2 / day to about 150 μg / cm 2 / sky.

[0164] 52. The method of any one of embodiments 49 to 51, wherein the KM-001 is administered at a dose of about 0.015 mg / kg / day to about 0.5 mg / kg / day.

[0165] 53. The method of any one of embodiments 49 to 52, wherein the maximum plasma concentration (C max ) is less than about 40 ng / mL.

[0166] 54. The method of any one of embodiments 49 to 53, wherein the area under the plasma drug concentration-time curve (AUC) is less than about 500 ng / mL*h.

[0167] 55. The method of any one of embodiments 49 to 54, wherein the skin disorder is keratosis, lichen simplex chronicus, pruritus, or ichthyosis.

[0168] 56. The method of embodiment 55, wherein the skin disorder is a keratosis selected from the group consisting of Mal de Meleda type keratosis, Olmsted syndrome, Papillon-Lefevre syndrome, palmoplantar keratosis, palmoplantar keratosis Long Island type, pachyonychia congenita, and punctate keratosis; and an ichthyosis selected from the group consisting of recessive X-linked ichthyosis and harlequin ichthyosis.

[0169] 57. The method of embodiment 56, wherein the skin disorder is palmoplantar keratoderma.

[0170] 58. The method of embodiment 57, wherein the palmoplantar keratoderma is palmoplantar keratoderma punctata or pachyonychia congenita.

[0171] 59. The method of any one of embodiments 49 to 58, wherein the topical administration reduces the severity of the skin condition by at least 1 IGA scale grade.

[0172] 60. The method of any one of embodiments 49 to 59, wherein the pruritus is keratosis-associated pruritus.

[0173] 61. The method of any one of embodiments 49 to 59, wherein the pruritus is pruritus associated with lichen simplex chronicus.

[0174] 62. The method of any one of embodiments 49 to 61, wherein the topical administration reduces the severity of the pruritus by at least 1 PP-NRS scale grade.

[0175] 63. The method of embodiment 62, wherein the severity of the pruritus is reduced by about 1 to about 10 PP-NRS scale grades.

[0176] 64. The method of any one of embodiments 49 to 63, wherein the composition is administered twice daily.

[0177] 65. The method of embodiment 64, wherein the composition is topically applied once in the morning and once in the evening.

[0178] 66. The method of any one of embodiments 49 to 65, wherein the composition is topically administered for about 20 to 40 days.

[0179] 67. The method of any one of embodiments 49 to 66, wherein the composition is topically administered for about 28 days.

[0180] 68. The method of any one of embodiments 49 to 67, wherein the composition is topically applied to the suprabasal layer of the epidermis.

[0181] 69. The method of embodiment 68, wherein the suprabasal layer of the epidermis is the keratinized envelope, the stratum granulosum and the stratum spinosum, the upper dermis, or a combination thereof.

[0182] 70. The method of embodiment 69, wherein the suprabasal layers of the epidermis are the keratinized envelope, stratum granulosum and spinosum, and the upper dermis.

[0183] 71. The method of any one of embodiments 68 to 70, wherein the local concentration of KM-001 in the suprabasal layer of the epidermis after application of the composition is from about 60 μg / g to about 160 mg / g.

[0184] 72. The method of any one of claims 68 to 70, wherein the local concentration of KM-001 in the upper dermis ranges from about 1.5% to about 16% by weight of the total amount of KM-001 in the skin.

[0185] Example

[0186] Example 1: Ointment and cream type emulsion formulations

[0187] KM-001 is relatively soluble in triglycerides and fatty alcohols. Solubility studies have shown that an oil phase containing about 11 wt% medium chain triglycerides and 12 wt% octyldodecanol allows complete and effective dissolution of 1 wt% KM-001 without any risk of recrystallization and provides a physically stable emulsion. The ointment composition was formulated as shown in Table 1 below:

[0188] Table 1: PEG-based ointment (200293.0600)

[0189]

[0190]

[0191] The cream emulsion was found to have improved tolerability compared to the PEG-based ointment composition. In addition, the cream composition does not require heating during formulation (PEG-based ointments require heating), which improves the stability of KM-001. Examples of three cream emulsions are shown in Table 2 below.

[0192] Table 2: Cream type lotion

[0193]

[0194]

[0195] *Alternative Names: Copolymer of Acrylamide and Sodium Acryloyldimethyl Taurate, Isohexadecane, Polysorbate 80, Sorbitan Oleate; Acrylamide / Sodium Acryloyldimethyl Taurate Copolymer (and) Isohexadecane (and) Polysorbate 80

[0196] The 200293.0435, 200293.0440 and 200293.0600 formulations were tested using an in vitro skin permeation test (IVPT) using stratified abdominal human skin having a thickness of approximately 0.5 mm. The skin samples (approximately 2 cm 2 ) were 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, RH 48.13 ± 16.1%. The cells were dosed with 5 mg / cm 2 Skin samples were tested with ointment and cream emulsion compositions wherein receptor fluid samples were collected at specified time points.

[0197] The samples were then prepared for subsequent chromatographic separation on an HPLC column and mass spectrometric detection. The LC-MS / MS conditions are summarized below.

[0198] Chromatographic column: Phenomenex: Kinetex C18 (2.6μm, 50x 2.1mm)

[0199] Mobile phase A: 1000mL water + 0.1% formic acid

[0200] Mobile phase B: 1000 mL acetonitrile + 0.1% formic acid

[0201] Retention time: KM-001 (about 0.91min) and KM-001-D4 (about 0.90min)

[0202] Gradient composition Time (min) A(％) B(％) Flow rate (μL / min) initial 45 55 500 1.00 5 95 500 2.00 5 95 500 2.01 45 55 500 4.00 45 55 500

[0203] Mass transitions (m / z): KM-001 (417.279>274.700; dwell 150 ms) and KM-001-D4 (421.286>278.800; dwell 150 ms).

[0204] The comparative permeation data of KM-001 from ointment and cream emulsion into skin layers such as stratum corneum, epidermis and dermis are shown below:

[0205] Table 3: IVPT results: Accumulation of KM-001 in the skin layer

[0206]

[0207] Advanced emulsions 200293.0435 and 200293.0440 were developed which have several advantages over the initial PEG-based ointment and are highlighted below.

[0208] Emulsions 200293.0435 and 200293.0440 are classified as creams. These compositions utilize a lipophilic excipient as the primary solvent for KM-001. The concentration of the lipophilic solvent enables KM-001 to be dissolved at concentrations comparable to PEG-based ointments, but provides the potential for enhanced local tolerance while also meeting regulatory and drug product acceptance. The lipophilic solvents used in 200293.0435 and 200293.0440 generally exhibit enhanced local tolerance compared to polar solvents used in PEG-based ointments (e.g., Transcutol HP, propylene carbonate, propylene glycol-1.2, and super refined PEG 400).

[0209] Formulations 200293.0435 and 200293.0440 are able to dissolve the target amount of KM-001 while using propylene glycol at a concentration that is 1 / 3 of that of PEG-based ointments. This enables the beneficial effects of PG, such as solubility of KM-001 and adequate skin delivery of KM-001, to be retained while reducing potential local tolerance issues that may be encountered with higher concentrations of glycols and other polar solvents.

[0210] Emulsions 200293.0435 and 200293.0440 also enable the use of water as a vehicle, which is considered advantageous from a tolerability perspective when compared to anhydrous and polar solvent loaded PEG ointments.

[0211] The polymeric viscosity modifier Sepioneo P600 stabilizes the emulsion without the need for additional surfactants, such as those used in PEG-based ointments (Tween 85). This is also considered advantageous from a topical tolerability perspective.

[0212] The cream formulation possesses significant sensory benefits compared to PEG-based ointments. The advanced cream prototype provides a non-greasy and very pleasant texture that encourages and enhances patient acceptance of the treatment.

[0213] The cream formulation uses a cold process that supports the chemical stability of KM-001. The PEG ointment process requires heat to melt certain components. From a scale-up perspective, the cold process can provide advantages.

[0214] Formulas 200293.0435 and 200293.0440 contain pharmaceutical grade excipients that conform to the United States Pharmacopoeia (USP) or / and the European Pharmacopoeia (Ph. Eur.) or are listed in FDA IID. All raw materials in the emulsions are used at concentrations that are at or below those in FDA-approved topical products.

[0215] In vitro skin permeation testing (IVPT) showed improved delivery of KM-001 to the epidermis and dermis for the cream formulation compared to the PEG-ointment formulation (see Table 3). These results were obtained using a solvent system in an emulsion that provides a local tolerability advantage over PEG-based ointments.

[0216] Example 2: Evaluation of formulations containing KM-001 in a minipig animal model

[0217] The PEG-based ointment described in Table 1 was found to have unstable physical properties as it becomes granular and hardens over time. In addition, some excipients are not currently approved by appropriate regulatory agencies (e.g., U.S. FDA) for use in human drug products. Therefore, it is desirable to develop a more stable formulation with pharmaceutically acceptable excipients that has improved toxicity and skin irritation.

[0218] Minipigs (Sus domesticus) are considered one of the leading animal species for translational research, surgical models, and procedural training, and are increasingly being used as an alternative to dogs or monkeys as a non-rodent species of choice in preclinical toxicology testing of drugs. The use of pigs in this setting has unique advantages because they share similar anatomical and physiological characteristics with humans in terms of the cardiovascular, urinary, skin, and digestive systems [Swindle MM (ed.), Swine as Models in Biomedical Research and Toxicology Testing, Veterinary Pathology, Vol. 49, No. 2, March 2012, pp. 344-356].

[0219] As described below, four preparations were evaluated in miniature pigs: 200293.0435 and 200293.0438, and placebo versions of these preparations, without KM-001. Miniature pigs were kept under a 12-hour light / dark cycle. The pig house environment was controlled by an HVAC system (heating, ventilation and air conditioning), with a temperature range of 16°C to 27°C, a relative humidity of 30% to 70%, and sufficient fresh air circulation. The test cream (KM-001 and placebo) was applied twice a day (except on weekends, when the preparation was applied once a day), and 3g of preparation was applied per area per pig for 14 days.

[0220] One day prior to testing with the cream containing KM-001, pigs received a prophylactic loading dose of the antibiotics 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., for blood sampling).

[0221] Procedure: Apply KM-001 cream to the animal's back 25 x 20cm (500cm 2 ) on the shaved area of ​​the pig's skin. Cover the tested skin area. Use approximately 3 g per area per pig per treatment. Repeat treatment twice a day for 14 days.

[0222] Blood samples were collected at time 0 (baseline), 0.5 hours, 1 hour, 2 hours, 6 hours and 24 hours after application of the cream composition containing KM-001. Blood samples were also collected at time 0 (baseline), 0.5 hours, 1 hour, 2 hours, 6 hours and 24 hours after 14 days of application of the cream containing KM-001. For comparison purposes, blood samples were also obtained from animals administered a placebo cream after 14 days of testing.

[0223] On the scheduled termination day, four skin biopsies were collected from the treatment area of ​​each animal via a 4 mm puncture. In each group, three biopsies were snap frozen and one was fixed with PFA 4% for paraffin embedding. Full-thickness punch biopsies were obtained from three random dorsal sites on Day 3 (end of the last day of treatment) for evaluation. After several days of cleaning (rinsing), an additional dorsal skin biopsy was obtained to evaluate potential clearance. Biopsies were obtained from each animal and snap frozen without the use of tissue fixation or embedding agents (e.g., OCT or paraffin).

[0224] All animals were subjected to the Draize test twice daily when the cream formulation was applied (before and approximately 6 hours after each application). The Draize scoring system used is provided in Table 4 below.

[0225] Table 4: Draize scoring system

[0226]

[0227] On the last day of the test, 4 skin biopsies were obtained from each test animal (placebo and KM-001 formulations). These skin samples were evaluated using quantitative mass spectrometry imaging (MALDI MSI) to obtain KM-001 biodistribution data, KM-001 penetration curves, and absolute quantification of KM-001 in miniature pig skin biopsy samples, thereby allowing comparison of two different KM-001 cream formulations (200293.0435 (F3) and 200293.0438 (F4)). Nine (9) miniature pig biopsies (3 tissues treated with formulation F3, 3 tissues treated with formulation F4, and 3 tissues treated with placebo cream) were evaluated. The results are provided in Table 5 below.

[0228] Table 5: KM-001 quantification (μg / g) obtained by MALDI imaging in control and treated minipig skin tissue sections

[0229]

[0230]

[0231] MALDI imaging was performed by the following method. Minipig skin samples were sectioned at a thickness of 10 μm at a temperature of -21°C using a cryostat (HM 360, Microm). Minipig skin sections were collected on Superfrost slides for MSI acquisition and H&E (hematoxylin and eosin) staining, and then placed in a desiccator for 15 minutes when not used immediately and then stored at -80°C. A dilution series of KM-001 was prepared in water / methanol 50 / 50 (v / v). Each point was spotted on an untreated minipig skin tissue section provided by ImaBiotech (1 μL / drop of deposit). The slide was then dried under vacuum for 15 minutes. A 40 mg / mL DHB MALDI matrix (in methanol / water + 1% TFA, 7:3 (v / v)) spiked with 5 μM KM-001-d4 was selected for optimal detection of KM-001. This matrix was sprayed with an automated sprayer system (TM-Sprayer, HTX Imaging) on ​​a KM-001 dilution series spotted on untreated minipig control skin sections and study samples provided by ImaBiotech. MALDI-FTICR acquisition global parameters:

[0232] -Mode: CASI

[0233] -Ionization: Positive

[0234] -Mass range: 417 ± 15 Da for KM-001 and KM-001-d4 analysis

[0235] -Laser frequency: 2000Hz

[0236] - Spatial resolution: 200 μm for the calibration range of KM-001; 50 μm for placebo and treated human skin tissue sections.

[0237] -Collection area:

[0238] For the calibration range of KM-001, each standard sediment (17 concentrations) was imaged individually.

[0239] For the samples, whole miniature pig skin tissue sections have been imaged by mass spectrometry imaging, and all MSI acquisitions were performed at a data reduction ratio of 0.95. Data reduction is required because MALDI generates a large amount of data when imaging an area.

[0240] All MSI acquisitions used the same MALDI method and the same mass spectrometer.

[0241] Nine (9) MALDI imaging acquisitions with a spatial resolution of 50 μm were performed using the CASI method in positive ion mode to image the KM-001 drug and its associated internal standard (KM-001-d4) in six (6) treated tissues. Permeation profiles of KM-001 were constructed based on distribution and absolute quantification. A lower limit of quantification (LLOQ) of 6.8 μg / g tissue and an upper limit of quantification (ULOQ) of 804.0 μg / g tissue were evaluated, respectively. KM-001 was primarily distributed in the epidermis with higher exposures (ULOQ–extrapolated values ​​for samples treated with F3 formulation ranged between 67.3 μg / g and 5.7 mg / g, and extrapolated values ​​for samples treated with F4 formulation ranged between 2.6 and 147.3 mg / g). Permeation was observed in all suprabasal layers of the epidermis, including the stratum granulosum, and stratum spinosum (in Figure 1-4 indicated by yellow arrows).

[0242] Penetration in the dermis was limited but significant (15.9% of the signal in the epidermis was found in the dermis for the F3 formulation sample; 1.5% for the F4 formulation sample). The subcutaneous tissue showed some exposure (mean exposure of 117 μg / g for the 200293.0435 formulation sample and 3.5 mg / g for the 200293.0438 formulation sample). On average (n=3), the skin penetration of KM-001 F4 formulation treatment group 4 appeared slightly deeper (600 μm vs. 400 μm) compared to the F3 formulation treatment group.

[0243] As a comparison, the same study was performed when a formulation based on KM-001 ointment was used (formulation 200293.0600). Imaging of the 0.3% KM-001 ointment and 1% KM-001 ointment treated groups showed limited penetration, primarily in the epidermis. Exposure of the uppermost layers of the epidermis was comparable to the F3 and F4 formulations, but for samples treated with the 200293.0600 ointment formulation, no penetration of the lower layers of the epidermis was detected and no skin penetration was observed.

[0244] The skin distribution of KM-001 in pig biopsies was evaluated in miniature pigs topically treated with a PEG-ointment containing 200293.0600 1% w / w KM-001. MSI data showed high exposure of the upper epidermis to KM-001, low exposure of the dermis, and limited exposure of the subcutaneous tissue. While the epidermis showed fairly uniform exposure, the subcutaneous tissue was very heterogeneously exposed to KM-001 along the epidermis, which was concentrated in specific areas. A calibration curve was obtained with a lower limit of quantification (LLOQ) of 4.8 μg / g tissue and an upper limit of quantification of 1052 μg / g.

[0245] The concentration of KM-001 in the epidermis showed an important variability [132–1104 μg / g] with a mean of 541 μg / g. In the dermis, the concentration was much lower, about 4 μg / g, close to the limit of quantification. In the subcutaneous tissue area, the mean concentration was 18 μg / g.

[0246] Finally, when the entire section was considered – the closest approach to homogenization followed by LCMS / MS – the average concentration of KM-001 was determined to be 26 μg / g.

[0247] Table 6: MALDI imaging ( Figure 5 ) Quantification of KM-001 obtained in control and treated pig skin tissue sections (μg / g):

[0248]

[0249] Therefore, compared with the KM-001 ointment-based formulation (200293.0600), the KM-001 cream-based formulations (F3 and F4) showed excellent skin penetration characteristics 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) in the epidermis compared to 541 μg / g (PEG-ointment); 539.3 μg / g (F3) and 882 μg / g (F4) in the dermis compared to 4 μg / g (PEG-ointment)).

[0250] Example 3: Mouse C57BL / 6J Model (Oral Administration)

[0251] The efficacy of KM-001 was evaluated in an acetone-ether-water (AEW)-induced male C57BL / 6J mouse pruritus model, which was induced by applying a 1:1 mixture of acetone / ether and water to the cheeks of the animals for treatment every day. KM-001 (10 mg / kg, 1 mg / kg, 0.1 mg / kg, and 0.01 mg / kg) was orally administered to 20 mice. The amount of time spent scratching and the number of episodes within 20 minutes were recorded by an observer. Blood and skin samples were collected at 0, 0.5 hours, 1 hour, and 1.5 hours after administration.

[0252] Topical application of AEW twice daily for 5 days significantly increased the duration and number of spontaneous scratching episodes in C57 BL / 6J mice. Oral treatment with KM-001 (0.1 mg / kg) significantly reduced the duration and number of scratching episodes (scratching time p < 0.001, scratching episodes p < 0.01). There was a trend toward reduced duration and number of scratching episodes with KM-001 (0.01 mg / kg) treatment. In animals treated with 0.1 mg / kg KM-001, a maximum plasma concentration of 1.34 ng / mL was detected at 0.5 hours after dosing (C max ). In animals treated with 0.01 mg / kg, KM-001 was not detected in plasma. The results of this study suggest that KM-001 (0.1 mg / kg) has a potent anti-pruritic effect in the AEW-induced dry skin pruritus model in mice.

[0253] Example 4: Mouse DS-Nh Model (Local Administration)

[0254] DS-Nh mice housed under conventional conditions spontaneously develop dermatitis and skin abnormalities characterized by hyperkeratosis, reduced proliferation of basal keratinocytes, differentiation defects, and keratinization of skin appendages. DS / Nh mice treated with KM-001 1% and 0.3% ointment (25 μg / cheek, one side of each mouse) twice a day for 14 consecutive days (25 mg ointment / cheek, one side of each mouse) showed no compound-related toxicity. At baseline, significant scratching behavior was observed in all mice. Treatment with vehicle and positive control 0.1% tacrolimus only slightly affected this behavior (reductions of 10% and 20%, respectively). Compared with untreated controls, treatment with KM-001 0.3% ointment resulted in a reduction of >40% in scratching on day 14, and KM-001 1% ointment resulted in a reduction of >80% in scratching. Changes in scratching behavior on day 14 compared to day 0 (before the first application of experimental or control ointment) are shown in Figure 2. Figure 6 shown.

[0255] 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 the control mice showed characteristic pathology such as epidermal thickening, abnormalities in the structure of the epidermal layer, and fusion and keratinization of the skin appendages. After two weeks of treatment, only about 30% of the mice in the vehicle-treated group showed some form of normalization of skin pathology, while 0.1% tacrolimus treatment resulted in partial normalization in 40% of the mice. In contrast, both KM-001 ointment-treated groups showed significant improvements in skin histology, with about 70% of the mice showing normalization ( Figure 8). Animals treated with KM-001 1% ointment achieved a 70% improvement mark with complete normalization of the skin, including restoration of hair follicles and sweat glands.

[0256] Example 5: Systemic exposure to KM-001 (topical application)

[0257] I: As part of toxicity studies in miniature pigs and rats, blood concentrations of KM-001 were evaluated using validated analytical methods. In miniature pigs, administration of 4.5 mg KM-001 / kg / day resulted in C max The C value of human systemic exposure was estimated based on the linear extrapolation of the PK data of minipigs after 13 weeks of skin application and taking into account the lower clinical dose (based on mg / kg). max The total body concentrations of 1% hydroxyethyl ester and 1% hydroxyethyl ester were approximately 1.3 ng / mL (0.3% cream) and 4 ng / mL (1% cream), and the AUC was approximately 10 ng / mL*h (0.3%) and 32 ng / mL*h (1%) (Table 5). In a 28-day oral repeated dose toxicity study in rats, the NOAEL was 10 mg / kg / day for systemic C max The systemic exposure level in rats provided approximately 242 times the estimated human systemic exposure after topical administration. max and for AUC, the safety margin would correspond to 836-fold (0.3%) and 261-fold (1%).

[0258]

[0259] e Assumed body surface area (BSA) treated: 10–60 cm 2 .

[0260] f Treatment BSA: 500–600 cm 2 .

[0261] II: The toxicokinetic profile of 0.3% w / w and 1% w / w KM-001 cream in minipigs after 2 weeks of twice daily dermal application, as well as the recovery from any treatment-related effects during a 1-week recovery period, was evaluated. Each test article was applied to the relevant group by topical application of 3 grams twice daily (6 hours apart). Two additional groups were treated in the same manner with either the control KM-001 cream placebo or the reference KM-001 1% PEG ointment.

[0262] In control animals, no detectable amount of KM-001 was found after a single and 14-day application of KM-001 cream placebo. After the first dose (Day 1), detectable amounts of KM-001 were measured in the plasma of animals treated with the test or reference articles, which were comparable to or slightly above the lower limit of quantification.

[0263] On day 14, all minipigs were systemically exposed to KM-001 after repeated skin treatment with the test or reference article. Males and females treated with KM-001 0.3% cream (test article 1) and males and females receiving KM-001 1% PEG ointment (reference article) were similarly exposed to KM-001, while females treated with KM-001 1% cream (test article 2) appeared to be slightly more exposed than males. However, it should be noted that animals receiving KM-001 1% cream were more exposed than animals receiving the reference article containing the same concentration of KM-001. The KM-001 exposure of animals treated with test articles 1 and 2 increased in a fairly proportional manner with dose. After 14 days of twice daily skin application, plasma levels of KM-001 were still detectable 24 hours after treatment. Due to the behavior of plasma concentrations along the last measured time point, it is not possible to estimate the elimination phase of the test article in a reliable manner.

[0264]

[0265] Example 6: Treatment of punctate keratosis and pachyonychia congenita

[0266] Patients with type 1 punctate palmoplantar keratoderma or congenital pachyonychia were treated with 0.3% or 1% KM-001 cream in the affected skin area, twice a day for 84 consecutive days. Before treatment with the composition of the present invention, and then after treatment with the composition of the present invention for a limited time period and dosing regimen, the tolerability and efficacy of the KM-001 composition (measured by the improvement of the appearance of the lesions) were evaluated using the IGA scoring method described below and in Table 9. At a given time point, the IGA score was selected using the specified descriptor that best describes the overall appearance of the patient's lesions. All features under the morphological description are not necessarily present. When assessing the severity of the disease, epidermal exfoliation (i.e., skin abrasions or injuries caused by the patient's own scratching, scratching, rubbing, etc.) is generally not considered. One or more grades (e.g., 1, 2, 3 or 4 grades) of the IGA score change indicate an improvement in the patient's condition, or alternatively, a reduction in the severity of the disease. After treatment with the composition of the present invention, the composition and method of the present invention reduce the severity of the disease by at least 1 grade in the IGA score. An example of improvement in the affected foot area in a patient with pachyonychia congenita is shown in Fig. 12A -D.

[0267] Table 9: IGA Scoring

[0268]

[0269] Example 7: Treatment of pruritus in patients with lichen simplex chronicus

[0270] Patients with pruritus caused by lichen simplex chronicus (LSC) were treated with 0.3% or 1% KM-001 cream or a negative control cream without KM-001. LSC lesions (lesions covering at least 0.5% of the patient's body skin area (BSA) and up to 2% BSA) were treated with KM-001 or a control cream. Itch was assessed using the Peak Pruritus-Numerical Rating Scale (PP-NRS; patients assessed the level of pruritus during the first 24 hours using a 0-10 scale, with 0 being no itch and 10 being the worst itch imaginable).

[0271] After at least 28 days of treatment, patients treated with the compositions of the present disclosure showed improvement in LSC lesions, as indicated by an improvement (reduction) in the IGA score by comparing the appearance of lesions before and after treatment in individual patients. The mean IGA score of patients treated with the KM-001 composition according to the present disclosure was statistically significantly lower than the IGA score of patients treated with the control formulation without KM-001.

[0272] After at least 28 days of treatment, the PP-NRS scores before and after treatment in individual patients were compared, and patients treated with the composition of the present disclosure showed an improvement in the level of pruritus. The mean PP-NRS score of patients treated with the KM-001 composition according to the present disclosure was statistically significantly reduced on the PP-NRS scale, such as by 4 or more points, compared to the PP-NRS scores of patients treated with a control formulation not containing KM-001.

[0273] Example 8: Batch Formulation

[0274] The amount per unit of each component in an exemplary batch formulation of 1% KM-001 cream is shown below.

[0275]

[0276]

[0277] Example 9: Saturated solubility of KM-001 in selected solvent mixtures

[0278] Saturation solubility was determined at room temperature (RT) using a shake flask method with excess API. Equilibrium was assumed to be reached after 24 hours, and excess solids were separated by ultrafiltration prior to dilution and quantification. Saturation solubility studies were quantified for KM-001 using a qualified UPLC-UV analytical method.

[0279] The saturated solubility of KM-001 in the solvent mixture is summarized in Table 10. Images of the samples and their corresponding vehicles after storage at 25 °C for 24 h are presented in Fig.11A -B.

[0280] Table 10. Saturated solubility of KM-001 in solvent mixtures determined by UPLC-UV

[0281]

[0282]

[0283] M1, M13 and M14 were designed for emulsion (cream-gel) concepts, while M2, M3, M6 and M10 were designed to simulate petrolatum-based ointments. Mineral oil was used as a replacement for petrolatum and other hydrocarbons constituting the semi-solid (e.g., petrolatum) or solid (e.g., wax) components of the ointment. Blends containing Kollicream OD (octyldodecanol) or Arlamol E showed higher saturation solubility for KM-001. Model ointment blends containing "light mineral oil" showed lower saturation solubility. The results show that loading doses of up to 1% are theoretically possible in emulsion and ointment concepts. As Fig.11A and 11B As shown, the mixture with higher saturation solubility value of KM-001 displayed a more intense yellow color, which was attributed to the API.

[0284] Example 10: Evaluation of Antioxidant Blends with Model Oil Phase

[0285] Antioxidant blends were screened for efficacy using the RapidOxy instrument. The RapidOxy method is based on the principle of O2 consumption during an oxidation reaction. RapidOxy applies elevated pressure at elevated temperatures to accelerate the oxidation process and measures the O2 consumption as a change in partial pressure. The induction time or induction period is defined as the time required to achieve a certain drop in O2 partial pressure ( Fig.10 ). A typical RapidOxy test protocol is described in Table 11.

[0286] Table 11. Typical RapidOxy test protocol

[0287]

[0288] The RapidOxy method was used to evaluate the protective effects of pharmaceutical antioxidants on individual oils and model oil phases before and after incorporation of KM-001. Individual antioxidants (butylated hydroxytoluene [butylated hydroxytoluene BHT], butylated hydroxyanisole [butylated hydroxyanisole, BHA] and propyl gallate]) and antioxidant combinations with established synergistic effects were also evaluated. Antioxidant combination #1 (AO1) incorporated 0.1% w / w butylated hydroxytoluene (butylated hydroxytoluene BHT) plus 0.1% w / w butylated hydroxyanisole (butylated hydroxyanisole, BHA). Antioxidant combination #2 (AO2) incorporated 0.1% w / w BHA plus 0.05% w / w propyl gallate.

[0289] The RapidOxy study highlighted the oxidative sensitivity of some excipients, vehicle mixtures, KM-001, and the protective effects of various antioxidants. The results are summarized in Table 12.

[0290] The data show that Arlamol E is more sensitive to oxidation than Miglyol, and when 1% KM-001 is added, the induction time of both excipients is shortened. Therefore, Arlamol E (rather than the more stable Miglyol) is used as a solvent model sensitive to oxidation to evaluate the effects of single antioxidants and antioxidant mixtures. The oxidation sensitivity of KM-001 was tested at 1% w / w in all experiments. The addition of KM-001 to Arlamol E resulted in a significant shortening of the induction time, which demonstrates the oxidation sensitivity of KM-001. The same trend was also observed after adding 1% KM-001 to a mixture of Miglyol and RapOxM5 vehicles. Compared with BHT 0.1%, BHA 0.1% is more effective as a single antioxidant, and when used alone, propyl gallate is the most effective antioxidant.

[0291] The antioxidant combination AO2 (0.1% w / w BHA plus 0.05 w / w propyl gallate) produced a longer induction time, indicating that this antioxidant system is more effective than AO1 (0.1% w / w BHT + 0.1% w / w BHA) and the single antioxidants. The effectiveness of the AO2 antioxidant mixture was further confirmed in experiments using the RapOxM5 vehicle mixture supplemented with 1% KM-001.

[0292] Studying the oxidative sensitivity of the vehicle mixtures revealed that certain vehicle mixtures were more reactive to oxygen, namely, RapOxM3, RapOxM4, and RapOxM6 vehicles exhibited significantly shorter induction times than RapOxM1, RapOxM2, and RapOxM5.

[0293] Conclusion: Screening of antioxidant combinations in a model system using the RapidOxy approach showed that mixture AO2 (BHA 0.1%, propyl gallate 0.05%) provided the most effective protection for both oils and actives.

[0294] Table 12. Oxidative sensitivity screening of excipients, vehicle mixture, KM-001 and protective effects of various antioxidants

[0295]

[0296]

[0297] Example 11: Evaluation of Preservative Efficacy of Candidate Antimicrobial Preservative Systems

[0298] Preservative Efficacy Screening Test (PET) was performed on samples stored at RT for one month.The cream gel concept prototype ID and composition are presented in Table 13 and the petrolatum based ointment prototype ID and composition are presented in Table 14.

[0299] Two different antimicrobial preservative systems were evaluated for 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 prototypes did not include an antimicrobial preservative because they are anhydrous systems and therefore could theoretically have self-preserving properties.

[0300] Table 13: Composition of cream-gel prototypes selected for preservative efficacy testing (PET)

[0301]

[0302]

[0303] Table 14: Composition of ointment prototypes selected for preservative efficacy testing (PET)

[0304]

[0305]

[0306] PET was performed according to the procedures described in the various chapters of Eur Ph. and USP. The results obtained were evaluated according to the acceptance criteria specified in the European Pharmacopoeia 5.1.3 Test criteria for topical products provided in Table 15. The relevant acceptance criteria were Ph. Eur. Criteria A for the usual cases of preparations for dermatological use.

[0307] Table 15: Ph.Eur.5.1.3 Acceptance criteria for preservative efficacy testing of dermatological preparations

[0308]

[0309] NI: There was no increase in the number of viable microorganisms compared to the previous reading.

[0310] The PET screening results for the cream-gel concept prototype are presented in Table 16 and the PET screening results for the petrolatum-based ointment prototype are presented in Table 17.

[0311] Table 16: Log reduction compared to inoculum - 28 day results for cream-gel prototypes

[0312]

[0313] (No bacterial data on days 2 and 7)

[0314] Table 17. Log reduction compared to inoculum - 28 day results for the petrolatum based ointment concept.

[0315]

[0316] (No bacterial data on days 2 and 7).

[0317] The BP200293.0435 and BP200293.0440 prototypes of the cream-gel concept showed encouraging PET results after 1 month storage at RT, so they were further evaluated after 3 months stability under accelerated storage conditions (40°C). According to Ph.Eur.5.1.3 Acceptance Criteria A for Dermatological Preparations and USP <51> The efficacy of the antimicrobial preservative system (i.e., 0.2% sodium benzoate + 1% phenoxyethanol) of these samples was evaluated according to the acceptance criteria for topical products specified in (Table 18).

[0318] Table 18: USP <51> Acceptance criteria for preservative efficacy testing for topical products

[0319]

[0320] "No increase" in counts was defined as 0.5 log10 units more NMT than the value to which it was compared.

[0321] The PET results for the BP200293.0435 and BP200293.0440 prototype samples stored under accelerated conditions for 3 months are presented in Tables 19 and 20.

[0322] Table 19: According to USP <51> , Log reduction compared to inoculum - 28 day results for cream-gel formulations 200293.0435 and 200293.0440.

[0323]

[0324] Table 20: Log reduction compared to inoculum according to Ph. Eur. (5.1.3.) - 28 day results for cream-gel formulations 200293.0435 and 200293.0440.

[0325]

[0326] Both formulations, BP200293.0435 and BP200293.0440, passed USP acceptance criteria and Ph. Eur. Standard A. These tests validated the preservative system efficacy data generated at 1 month stability at RT and showed that 0.2% sodium benzoate + 1% phenoxyethanol is a suitable antimicrobial preservative system for BP200293.0435 and BP200293.0440 formulations.

Claims

1. A cream comprising: aqueous phase; and oil phase, The concentration of KM-001 is about 0.1 wt % to about 5.6 wt %.

2. The cream of claim 1, wherein the concentration of KM-001 is about 0.2 wt% to about 3 wt%.

3. The cream of claim 1 or 2, wherein the concentration of KM-001 is about 0.3 wt%.

4. The cream of claim 1 or 2, wherein the concentration of KM-001 is about 1 wt%.

5. The cream of any one of claims 1 to 4, wherein the pH of the cream is from about 4 to about 6.

6. The cream of any one of claims 1 to 5, wherein the pH of the cream is from about 4.5 to about 5.

5.

7. A cream according to any one of claims 1 to 6, wherein the cream comprises: (a) from about 20% to about 40% by weight of said oil phase; and (b) from about 60% to about 80% by weight of said aqueous phase.

8. The cream according to any one of claims 1 to 7, wherein the oil phase comprises triglycerides, C 13-21 Fatty alcohol or mixtures thereof.

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

10. A cream as claimed in claim 8 or 9, wherein the concentration of triglycerides is about 11% by weight.

11. The cream of any one of claims 8 to 10, wherein the triglyceride is a medium chain triglyceride (MCT).

12. The cream of claim 11, wherein the MCT is caprylic capric triglyceride.

13. A cream as claimed in any one of claims 8 to 12, wherein C 13-21 The concentration of the fatty alcohol is from about 10 wt % to about 14 wt %.

14. The cream of any one of claims 8 to 13, wherein the C 13-21 The concentration of fatty alcohol was about 12% by weight.

15. The cream of any one of claims 8 to 14, wherein the C 13-21 The fatty alcohol was octyldodecanol.

16. The cream according to any one of claims 1 to 15, wherein the oil phase does not contain polyoxypropylene stearyl ether.

17. The cream of any one of claims 1 to 16, wherein the cream further comprises an antioxidant, a preservative, a viscosity modifier, a pH adjuster, or a mixture thereof.

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

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

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

21. The cream of claim 20, wherein the cream comprises about 0.05 wt% propyl gallate and about 0.1 wt% BHA.

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

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

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

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

27. The cream of claim 17, wherein the pH adjuster is 10% citric acid.

28. A cream as claimed in any preceding claim, wherein the cream further comprises glycerol, propylene glycol or a mixture thereof.

29. A cream as claimed in any preceding claim, wherein the cream has a viscosity of at least about 15,000 mPa-s as measured using rotational viscometry at 25°C.

30. The cream of claim 29, wherein the cream has a viscosity of about 15,000 mPa·s to about 75,000 mPa·s as measured at 25°C using rotational viscometry.

31. The cream of claim 29, wherein the cream has a viscosity of about 19,500 mPa·s to about 45,200 mPa·s as measured at 25°C using rotational viscometry.

32. A cream as claimed in any preceding claim, wherein the cream is an oil-in-water emulsion.

33. The cream of claim 32, wherein the average diameter of the globules of the emulsion is less than about 13 μm.

34. The cream of claim 33, wherein the average diameter of the globules of the emulsion is less than about 10 μm.

35. A cream as claimed in any preceding claim wherein the aqueous phase is a gel at about 2°C to about 40°C.

36. The cream of claim 1, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provides from about 50 μg / g to about 6000 μg / g of KM-001 in one or more skin layers as measured by matrix-assisted laser desorption / ionization (MALDI).

37. The cream of claim 36, wherein about 3 grams of the cream comprising 1 wt% KM-001 is topically applied to about 500 cm of a patient in need thereof. 2 The skin provides from about 50 μg / g to about 6000 μg / g of KM-001 in one or more skin layers as measured by MALDI.

38. The cream of claim 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provided about 2000 μg / g to about 6000 μg / g of KM-001 in the epidermis as measured by MALDI.

39. The cream of claim 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provides about 2000 μg / g to about 6000 μg / g of KM-001 in the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum, or a combination thereof, as measured by MALDI.

40. The cream of claim 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provided about 500 μg / g to about 800 μg / g of KM-001 in the dermis as measured by MALDI.

41. The cream of claim 1, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provided a concentration of KM-001 in the dermis equivalent to about 1% to about 16% of KM-001 in the epidermis, as measured by MALDI.

42. The cream of claim 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin provides about 100 μg / g to about 3500 μg / g of KM-001 in the subcutaneous tissue as measured by MALDI.

43. The cream of claim 36, wherein about 2 grams to about 4 grams of the cream comprising 1 wt% KM-001 is topically applied to about 400 cm of a patient in need thereof. 2 To about 600cm 2 The skin of WT AQUA® provides about 50 μg / g to about 1200 μg / g of KM-001 in the hair follicles as measured by MALDI.

44. A cream as claimed in any of the preceding claims, wherein topical application to the skin of a patient in need thereof causes about 0.05% to about 20% by weight of KM-001 present in the applied composition to penetrate into the stratum corneum, epidermis or dermis as measured by an in vitro penetration test (IVPT).

45. The cream of claim 44, wherein topical application to the skin of a patient in need thereof causes about 1% to about 10% by weight of KM-001 present in the applied composition to penetrate into the stratum corneum as measured by IVPT.

46. ​​The cream of claim 44, wherein topical application to the skin of a patient in need thereof causes about 0.2% to about 8% by weight of KM-001 present in the applied composition to penetrate into the epidermis as measured by IVPT.

47. The cream of claim 44, wherein topical application to the skin of a patient in need thereof results in penetration of about 0.05% to about 3% by weight of KM-001 in the applied composition into the dermis as measured by IVPT.

48. A cream as claimed in any one of the preceding claims, wherein the topical application provides a maximum plasma concentration (C 20 of KM-001) of less than about 40 ng / mL. max ).

49. The cream of any of the preceding claims, wherein the topical administration provides an area under the plasma drug concentration-time curve (AUC) of KM-001 of less than about 500 ng / mL*h.

50. A method of treating a skin disorder or pruritus comprising topically applying to the skin of a patient in need thereof a therapeutically effective amount of a composition according to any one of the preceding claims.

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