Nootkatone for the treatment of pruritus

Abstract

The present disclosure generally relates to compounds, compositions, and methods for treating pruritus using a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt, or a derivative thereof. Methods of formulating and using the compositions are also provided. Provided herein are methods of treating pain in a subject in need thereof. The methods include administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt, or a derivative thereof to the subject. In some embodiments, the compositions have less than about 5% (w / w) of other components naturally present in nootkatone-containing sources. In other embodiments, the nootkatone in the compositions has a purity of at least about 95% (w / w). In some variations, the compositions comprise nootkatone.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 430,325, filed December 5, 2022, U.S. Provisional Patent Application No. 63 / 478,666, filed January 5, 2023, U.S. Provisional Patent Application No. 63 / 478,668, filed January 5, 2023, U.S. Provisional Patent Application No. 63 / 478,669, filed January 5, 2023, U.S. Provisional Patent Application No. 63 / 478,670, filed January 5, 2023, and U.S. Provisional Patent Application No. 63 / 478,671, filed January 5, 2023, the contents of each of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present disclosure relates generally to nootkatones, compositions, and methods for treating various diseases and conditions, and more specifically to treating pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy. [Background technology]

[0003] The skin is the first line of defense against external insults; without this defense, underlying tissues and organs are susceptible to damage. For example, the skin maintains a relatively water-impermeable barrier between the organism and its external environment to prevent dehydration. Furthermore, the skin plays an important role in a person's appearance. In general, most people desire younger, healthier-looking skin. And for some of these people, the appearance of signs of skin aging, such as thinning skin, wrinkles, and age spots, is a compelling reminder of their loss of youth. As a result, treating the signs of skin aging has become a burgeoning business in our youth-obsessed society. Treatments range from cosmetic creams and moisturizers to various forms of cosmetic surgery.

[0004] Numerous agents, both natural and synthetic, are known for use in skin care compositions that are commercially available for the treatment of various skin conditions, particularly those associated with one or more diseases and conditions, such as pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy.

[0005] Pain is a defense mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness, or in which patients would benefit from pain suppression. Various forms of pain include, but are not limited to, chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, and idiopathic pain.

[0006] Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): pp. 681-688). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to nerves and pain caused by individual nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Individual nerve damage manifestations include post-amputation pain, postoperative nerve injury pain, and nerve entrapment injury (e.g., neuropathic back pain).

[0007] Abdominal pain is a common and complex health problem worldwide, affecting individual well-being. This pain can range from mild to severe and is often due to a variety of conditions, including gastrointestinal disorders (e.g., irritable bowel syndrome and celiac disease), inflammation (e.g., inflammatory bowel disease), and reproductive system problems (e.g., endometriosis). Symptoms often include nausea, abdominal bloating, and changes in bowel habits, and pain can occur in different abdominal regions.

[0008] Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by recurrent abdominal pain associated with bowel movements and changes in the frequency or pattern of stool. Symptoms often include abdominal pain, bloating, and a feeling of fullness, and in severe cases, these symptoms can significantly reduce quality of life.

[0009] Celiac disease is a genetic autoimmune disorder caused by gluten ingestion. Celiac disease increases intestinal permeability and initiates an inflammatory response due to gluten breakdown products. The disease is characterized by chronic inflammation of the small intestine, potentially leading to villous atrophy and causing symptoms such as abdominal pain, malabsorption, diarrhea, abdominal distension, and nausea.

[0010] Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a group of chronic inflammatory bowel diseases that are more common in developed countries. Ulcerative colitis affects the colon, which can extend from the terminal ileum to the anus. During relapses, ulcerative colitis often causes painful, bloody diarrhea, fever, and weight loss. Treatment primarily focuses on controlling inflammation, often using expensive monoclonal antibody therapy.

[0011] Endometriosis affects 10-15% of women of reproductive age and is characterized by the growth of uterine tissue outside the uterus, typically in the ovaries. This tissue responds to menstrual cycle hormones, causing inflammation and pain. Symptoms include painful menstruation, painful intercourse, and chronic abdominal pain, which do not always correlate with the severity of the condition. Some women with extensive endometriosis may be asymptomatic, while those with milder forms may experience severe pain.

[0012] Pruritus is a localized or generalized itchy condition that is a common and distressing symptom in various diseases. Although it usually occurs on the skin, it can also occur in extracutaneous sites, such as mucous membranes. It is a frequent symptom of localized skin disorders caused by hypersensitivity reactions (such as allergic reactions to insect bites or environmental allergens), urticaria, fungal and bacterial dermatoses, ectoparasitic infections, and hemorrhoids. It can also be a symptom caused by systemic diseases, including hypothyroidism, thyrotoxicosis, mucocandidiasis in diabetes, and Hodgkin's disease (see, for example, Herndon, JH Jr., Int. J. Derm. 14, 465-484 (1975); Winkelmann, RK, Med. Clin. N. Am. 66, 1119-1133 (1982)). Many systemic diseases and skin disorders are associated with persistent or recurrent attacks of pruritus. Although the clinical importance of pruritus is undeniable, effective treatment is limited by currently available therapies.

[0013] Eczema is a chronic disease that causes inflammation, redness, and irritation of the skin. Atopic dermatitis is the most common form of eczema. The cause of eczema, including atopic dermatitis, remains unknown. Atopic dermatitis has become a major global public health problem, affecting 1% to 20% of people worldwide. The prevalence of atopic dermatitis is approximately 1% to 3% in adults and approximately 10% to 20% in children. Atopic dermatitis is the most common form of eczema in children. Since the 1960s, the prevalence of atopic dermatitis has increased more than threefold. The reason for this increase in prevalence remains unclear (Lee, JH, et al. A Comprehensive Review of the Treatment of Atopic Eczema, Allergy Asthma Immunol. Res., 2016 8(3), 181-190). Atopic dermatitis is a global public health concern and carries a significant economic burden. Furthermore, atopic dermatitis affects the quality of life of not only the sufferer but also their family. Eczema, including atopic dermatitis, remains a challenging condition for physicians and patients.

[0014] Psoriasis is a clinically heterogeneous, lifelong skin disease that manifests in multiple forms, including plaque, flexural, guttate, pustular, or psoriasiform. An estimated 60 million people worldwide have psoriasis. In 2014, the World Health Organization recognized psoriasis as a serious noncommunicable disease, highlighting the devastation associated with misdiagnosis, inappropriate treatment, and stigma. The Global Burden of Disease Study estimated that psoriasis accounted for 5.6 million all-age disability-adjusted life years (DALYs) in 2016, at least three times the number associated with inflammatory bowel disease (Raharja, A., et al. Psoriasis: a brief overview. Clin Med (Lond). 2021 May;21(3):170-173).

[0015] Diabetes causes several skin-related complications, ranging from diabetic dermopathy, diabetic blisters (diabetic bullae / bullosis diabeticorum), diabetic peripheral neuropathy (DPN), xerosis (dry skin), ichthyosis-like skin changes, a tendency to develop fungal infections in the feet, acanthosis nigricans, diabetes-related pruritus, and nerve damage (diabetic neuropathy). Diabetic dermopathy, commonly referred to as shin spots, is characterized by light brown or reddish, oval, or round, slightly sunken, scaly patches, most frequently appearing on the shins. Diabetic blisters are blister-like lesions that spontaneously occur on the feet and hands of diabetic patients. These blisters may or may not show scarring or atrophy. Xerosis refers to abnormally dry skin with scaling, cracks, or a rough texture, most frequently appearing on the feet. Ichthyosis-like skin changes (fish scale skin) are exemplified by large, bilateral areas of dryness and scaling, especially on the hands and feet. Acanthosis nigricans is a common skin pigmentation disorder characterized by dark patches of skin with a thick, velvety texture. Affected skin may be itchy and odorous. Diabetic peripheral neuropathy (DPN) is nerve damage caused by chronic hyperglycemia and diabetes. DPN leads to numbness, loss of sensation, and sometimes pain in the feet, legs, or hands. Diabetes-related pruritus is more likely to occur in diabetic patients with dry skin or diabetic neuropathy and is often localized to the scalp, ankles, feet, trunk, or genitals. Given the significant clinical implications, healthcare providers need to be aware of risk factors and develop appropriate management strategies for skin complications in diabetes. Thus, there is a continuing need in the art for compounds, compositions, and methods for treating pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy, along with a variety of other diseases and conditions. [Prior art documents] [Non-patent literature]

[0016] [Non-Patent Document 1] Dieleman,JP,et al.,Incidence rates and treatment of neuropathic pain conditions in the general population.Pain,2008.137(3):p.681-8 [Non-patent document 2] Herndon, J. H. Jr., Int. J. Derm. 14, 465-484 (1975) [Non-patent document 3] Winkelmann, RK, Med. Clins. N. Am. 66, 1119-1133 (1982) [Non-patent document 4] Lee,JH,et al.A Comprehensive Review of the Treatment of Atopic Eczema,Allergy Asthma Immunol.Res.,2016 8(3),181-190 [Non-patent document 5] Raharja,A.,et al.Psoriasis:a brief overview.Clin Med(Lond).2021 May;21(3):170-173 Summary of the Invention [Means for solving the problem]

[0017] Provided herein are methods for treating pain in a subject in need thereof. The methods include administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt, or a derivative thereof to the subject. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present in the nootkatone-containing source. In other embodiments, the nootkatone in the composition has a purity of at least about 95% (w / w). In some variations, the composition comprises nootkatone.

[0018] Provided herein are methods for treating pruritus in a subject in need thereof. The methods include administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt, or a derivative thereof to the subject. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present in the nootkatone-containing source. In other embodiments, the nootkatone in the composition has a purity of at least about 95% (w / w). In some variations, the composition comprises nootkatone.

[0019] Provided herein are methods for treating atopic dermatitis or psoriasis in a subject in need thereof. The methods include administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt, or a derivative thereof to the subject. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present in the nootkatone-containing source. In other embodiments, the nootkatone in the composition has a purity of at least about 95% (w / w). In some variations, the composition comprises nootkatone.

[0020] Provided herein are methods for treating diabetic skin disorders or diabetic peripheral neuropathy in a subject in need thereof. The methods include administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt, or a derivative thereof to the subject. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present in the nootkatone-containing source. In other embodiments, the nootkatone in the composition has a purity of at least about 95% (w / w). In some variations, the composition comprises nootkatone.

[0021] Provided herein are methods for improving the appearance of skin in a subject in need thereof. The methods include administering a therapeutically effective amount of nootkatone, a dermatologically acceptable salt, or a derivative thereof to the subject. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present in the nootkatone-containing source. In other embodiments, the nootkatone in the composition has a purity of at least about 95% (w / w). In some variations, the composition comprises nootkatone.

[0022] Nootkatone and pharmaceutically acceptable compositions thereof are useful for treating or reducing the severity of various diseases, disorders, or conditions, including, but not limited to, pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy. In various embodiments, nootkatone and pharmaceutically acceptable compositions are inhibitors or modulators of one or more of the following therapeutic targets: voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB. Thus, nootkatone and pharmaceutically acceptable compositions thereof are useful for treating or reducing the severity of various diseases, disorders, or conditions described herein. [Brief explanation of the drawings]

[0023] [Figure 1A] This shows the blocking effect of nootkatone in mouse dorsal root ganglia (DRG) via neuronal depolarization. 100 μM nootkatone blocked neuronal depolarization in capsaicin / transient receptor potential vanilloid subfamily member 1 (TRPV1)-negative neurons in mice. [Figure 1B]This shows the blocking effect of nootkatone in mouse dorsal root ganglia (DRG) via neuronal depolarization. 100 μM nootkatone blocked neuronal depolarization in capsaicin / transient receptor potential vanilloid subfamily member 1 (TRPV1)-negative neurons in mice.

[0024] [Figure 2] Transient responses to 30 mM KCl in human DRG are shown (vehicle vs. nootkatone effect to 30 mM KCl).

[0025] [Figure 3] A and B show naughtokatone-mediated neuronal depolarization in human DRG. Naughtokatone was applied at 30 μM (first application) and 100 μM (second application) to observe its effect on electrical field stimulation (EFS)-induced neuronal depolarization / activity.

[0026] [Figure 4] 1 is a graphic representation of the effects of nootkatone in an in vivo formalin-induced pain mouse model.

[0027] [Figure 5] Figure 1 shows that nootkatone alleviated acute pain in both phases (phase 1 and phase 2) in an in vivo formalin-induced mouse model. [Figure 6] Figure 1 shows that nootkatone alleviated acute pain in both phases (phase 1 and phase 2) in an in vivo formalin-induced mouse model.

[0028] [Figure 7] 1 shows the efficacy of topical application of nootkatone in a mouse acute pain model using the tail flick test.

[0029] [Figure 8]1 shows that oral administration of nootkatone at 30 mpk alleviated chloroquine-induced scratching / itch in mice.

[0030] [Figure 9] 1 shows that topical administration of nootkatone at 10% alleviated chloroquine-induced scratching / itching in mice.

[0031] [Figure 10] 1 shows that PO nootkatone at 100 mg / Kg alleviated BAM8-22-induced scratching / itch in mice.

[0032] [Figure 11] 1 shows a graphical representation of the topical application of nootkatone in the MC903-induced mouse atopic dermatitis model.

[0033] [Figure 12] The effect of topical application of nootkatone in an imiquimod (IMQ)-induced mouse model of psoriasis is shown. Nootkatone slightly but significantly reduced cumulative PASI readout on days 1-6.

[0034] [Figure 13] Figure 1 shows the effect of topical application of nootkatone in an imiquimod (IMQ)-induced mouse model of psoriasis. Nootkatone slightly but significantly reduced cumulative PASI readout at day 6.

[0035] [Figure 14] 1 shows the study design for the effect of nootkatone on DSS-induced locomotor activity.

[0036] [Figure 15] A, B, C, D, E, and F are graphical representations showing the effect of nootkatone on DSS-induced locomotor activity.

[0037] [Figure 16]1 shows the study design for the effect of nootkatone on visceral pain in a mouse DSS-induced colitis model.

[0038] [Figure 17-1] A, B, C, and D are graphical representations showing the effect of nootkatone on visceral pain in a mouse DSS-induced colitis model. [Figure 17-2] E, F, G, H, and I are graphical representations showing the effect of nootkatone on visceral pain in a mouse DSS-induced colitis model.

[0039] [Figure 18] 1 shows the study design for the effect of nootkatone on visceral pain in a mouse TNBS-induced colitis model.

[0040] [Figure 19-1] A, B, C, and D are graphical representations showing the effect of nootkatone on visceral pain in a mouse TNBS-induced colitis model. [Figure 19-2] E, F, G, H, I, and J are graphical representations showing the effect of nootkatone on visceral pain in a mouse TNBS-induced colitis model. DETAILED DESCRIPTION OF THE INVENTION

[0041] Provided herein are compounds, compositions, and methods for treating, reducing, or ameliorating pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy in a subject in need thereof.

[0042] Nootkatone is a sesquiterpenoid and has the chemical structure shown below. [ka]

[0043] Nootkatone is a naturally occurring compound that can be found in many plants (e.g., Nardostachys jatamansi), citrus fruits (e.g., grapefruit (Citrus paradisi)), and the Alaska yellow cedar tree (Chamaecyparis nootkatensis). Nootkatone was first isolated from the heartwood of the Alaska yellow cedar tree (Erdtman, H., Hirose, Y., 1962. The chemistry of the natural order Cupressales. 46. The structure of nootkatone. Acta Chem. Scand. 16(6), 1311-1314.). Nootkatone can be obtained by extraction and purification from natural sources (Kelsey, RG, et al., 2015. Volatile terpenoids and tropolones in heartwood extracts of yellow cedar, Monterey cypress, and their hybrid Leyland cypress. Ann. For. Sci. 72, 349-355.), as well as by total synthesis (Marshall, JA, Ruden, RA, 1971. Stereoselective total synthesis of racemic nootkatone. J. Org. Chem. 36(4), 594-596.) and biosynthesis (Sowden, RJ, et al., 2005. Biotransformation of the sesquiterpene (+)-valencene by cytochrome P450cam and P450BM-3. Org. Biomol. Chem. 3(1), 57-64.).

[0044] In various embodiments, nootkatone may be synthesized, isolated, and purified from a product mixture obtained in a host engineered to express enzymes in the nootkatone biosynthetic pathway, or from a product mixture obtainable from a naturally occurring source, such as a citrus plant. In some embodiments, nootkatone may also refer to a mixture of compounds containing or enriched for the nootkatone compound, such as from an engineered host, such as a microorganism, or isolated from or derived from a plant extract. In other embodiments, nootkatone may further refer to derivatives and analogs thereof. For example, nootkatone compounds contemplated for use herein may be obtained in vivo by expressing one or more enzymes involved in the nootkatone biosynthetic pathway in recombinant yeast, or in vitro using isolated and purified enzymes involved in the nootkatone biosynthetic pathway (such as those described in U.S. Patent Application Publication Nos. 2015 / 0007368 and 2012 / 0246767, which are incorporated by reference in their entireties).

[0045] In certain embodiments, nootkatone is derived from the oxidation of valencene obtained by fermentation, such as by a microorganism possessing one or more valencene synthases and / or other molecules that catalyze the formation of valencene. It will be understood that nootkatone can be formed as part of a combination of compounds derived from the oxidation of a valencene-containing fermentation product obtained by culturing a microorganism possessing one or more valencene synthases and / or other molecules that catalyze the formation of valencene. This combination can be purified to maximize the percentage of nootkatone relative to other compounds.

[0046] As used herein, reference to an "extract" generally refers to a plant extract containing material derived from any species within the specified genus, unless a specific species is identified. Unless otherwise specified, any part of the plant may be used to obtain the extract used in the composition, including, but not limited to, roots, stems, rhizomes, leaves, flowers, fruits, and / or extracts of these parts. Plant extracts may be commercially obtained from a variety of sources. Furthermore, suitable plant extracts can be obtained by using any conventional extraction method, including, but not limited to, one or more of the methods further described below.

[0047] Plant extracts can be obtained via conventional extraction methods understood in the art, such as water (e.g., steam) extraction or solvent (e.g., alcohol) extraction. The compositions of the present disclosure are not limited to a particular extraction method, and extraction is not necessary, as suitable extracts (e.g., standardized extracts) are readily available from numerous commercial suppliers. Exemplary extraction methods are described below.

[0048] To obtain an extract, polar solvents (such as alcohols (e.g., methanol, ethanol, butylene glycol)), ethers (e.g., ethyl ether), ketones (e.g., acetone), esters (e.g., ethyl acetate), water, or mixtures thereof can be used as solvents. Certain extracts can also be obtained by further extracting the extract from a polar solvent with a non-polar solvent. Suitable non-polar solvents include, but are not limited to, ethyl acetate, hexane, dichloromethane, chloroform, or mixtures thereof. There are various extraction methods that can be used to obtain an extract suitable for the composition. Such methods include, but are not limited to, the extraction method disclosed in U.S. Pat. No. 7,897,184, which is incorporated herein by reference in its entirety.

[0049] Details of the therapeutic methods and compositions, including dosages, dosing regimens, and kits therefor, are described in further detail below.

[0050] Pharmaceutically / dermatologically acceptable salts and compositions As described herein, nootkatone is provided as an inhibitor or modulator of one or more of the following therapeutic targets: voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB. In conjunction with or independent of this inhibitory or modulatory activity, nootkatone is useful for treating diseases, disorders, and conditions, including, but not limited to, pruritus, chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain. Furthermore, in conjunction with or independent of this inhibitory or modulatory activity, nootkatone is useful for treating diseases, disorders, and conditions, including, but not limited to, atopic dermatitis or psoriasis. Furthermore, in conjunction with or independent of this inhibitory or modulating activity, nootkatone is useful for treating diseases, disorders, and conditions, including, but not limited to, diabetic skin disorders or diabetic peripheral neuropathy. Accordingly, in another aspect of the present disclosure, pharmaceutically acceptable compositions are provided, which comprise nootkatone as described herein and optionally include a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, such compositions optionally further comprise one or more additional therapeutic agents.

[0051] It will also be understood that nootkatone of the present disclosure may exist in a therapeutic free form or, where appropriate, as a pharmaceutically acceptable derivative thereof. In accordance with the present disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, ester, salt of such an ester, hydrate, stereoisomer, or any other adduct or derivative capable of directly or indirectly providing nootkatone, or a metabolite or residue thereof, as otherwise described herein, upon administration to a subject in need thereof.

[0052] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" refers to any non-toxic salt or ester salt of nootkatone of the present disclosure that, upon administration to a recipient, is capable of directly or indirectly providing nootkatone or an inhibitory active metabolite or inhibitory active residue thereof. As used herein, the term "inhibitorily active metabolite or inhibitory active residue thereof" means that the metabolite or residue thereof is also an inhibitor or modulator of one or more of the therapeutic targets.

[0053] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference in its entirety. Pharmaceutically acceptable salts of nootkatone of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4

[0023] The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of nootkatone disclosed herein. Such quaternization may result in water or oil-soluble or dispersible products. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0054] As used herein, a pharmaceutically acceptable composition of the present disclosure additionally comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, as appropriate for the particular dosage form desired, including, as used herein, any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the nootropics of the present disclosure, such as by imparting any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated within the scope of the present disclosure.Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool, sugars (such as lactose, glucose, and sucrose); starches (such as corn starch and potato starch); cellulose and its derivatives (sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; pharmaceutical excipients (such as cocoa butter and suppository wax); oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); glycols; such as propylene glycol or polyethylene glycol; esters (such as ethyl oleate and ethyl laurate); agar; buffers (such as magnesium hydroxide and aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer, as well as other non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate); in addition, coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0055] In another aspect, the disclosure features a pharmaceutical composition that includes nootkatone and a pharmaceutically acceptable carrier.

[0056] In another aspect, the disclosure features a pharmaceutical composition including a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0057] The nootkatone or pharmaceutically acceptable salt thereof used in the administered composition may be obtained from any commercially available source or by any method or technique known in the art. For example, in some variations, nootkatone may be isolated from natural sources. In other variations, nootkatone may be synthesized according to any method known in the art.

[0058] In various embodiments, the composition comprises nootkatone or a pharmaceutically acceptable salt thereof, and optionally consists essentially of nootkatone or a pharmaceutically acceptable salt thereof. As used herein, the phrase "consisting essentially of" generally includes the elements / ingredients specifically recited for a particular embodiment. Furthermore, the phrase "consisting essentially of" generally includes and allows for the presence of additional or optional elements / ingredients that do not materially affect the basic and / or novel characteristics of that particular embodiment. In certain embodiments, "consisting essentially of" allows for the presence of ≦10 weight percent (wt%), ≦5 wt%, or ≦1 wt% of additional or optional ingredients, based on the total weight of the composition.

[0059] In various embodiments, the composition includes one or more pharmaceutically acceptable excipients that are inactive ingredients. Examples of inactive ingredients include, but are not limited to, pharmaceutical excipients, such as diluents and binders, granulating agents, glidants (or flow aids), fillers, lubricants, preservatives, stabilizers, coatings, disintegrants, flavors, dyes, preservatives, solvents (e.g., alcohol), and combinations thereof. When utilized to form a composition, the inactive ingredient(s) can be used in various amounts and combined with nootkatone or a pharmaceutically acceptable salt thereof to form a composition suitable for topical application to human or animal skin. It will further be understood that the amount of active ingredient described herein may be normalized to 100 parts by weight of the composition to account for the presence of inactive ingredients, if utilized.

[0060] Optionally, the composition may contain one or more additional components (such as additives).Suitable additives include, but are not limited to, those understood in the art, including humectants, emollients, emulsifiers, surfactants, oils, extracts, skin protectants, disinfectants, preservatives, drugs and active pharmaceutical ingredients, analgesic compounds, anti-neuralgia compounds, antioxidants, blood circulation promoters, antidepressant compounds, anti-anxiety compounds, anti-stress compounds, sunscreens, insect repellents, preservatives, scrubbing agents, fragrances, colorants, fillers, solvents, vehicles, carriers, other types of additives known to those skilled in the art, and combinations thereof.Such additives can be used alone or in combination.Generally, optional additives can be any type used in pharmaceuticals, dietary supplements, personal care products, and cosmetics.

[0061] Examples of such carrier ingredients are oils, fats, waxes, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, fragrances, dyes, lower alkanols, and the like. If desired, additional ingredients (e.g., anti-inflammatory agents, antibacterial agents, antifungal agents, disinfectants, vitamins, sunscreens, antibiotics, skin whitening agents, healing promoters / fibroblast proliferation compounds, neuromuscular blocking agents, sunscreens, or other anti-acne agents) can be included in the composition.

[0062] Examples of oils as carrier agents include fats and oils (such as olive oil and hydrogenated oils); waxes (such as beeswax and lanolin); hydrocarbons (such as liquid paraffin, ceresin, and squalene); fatty acids (such as stearic acid and oleic acid); alcohols (such as cetyl alcohol, stearyl alcohol, lanolin alcohol, and hexadecanol); and esters (such as isopropyl myristate, isopropyl palmitate, and butyl stearate). Examples of surfactants as carrier agents may include anionic surfactants (such as sodium stearate, sodium cetyl sulfate, polyoxyethylene lauryl ether phosphate, sodium N-acyl glutamate, etc.); cationic surfactants (such as stearyl dimethylbenzyl ammonium chloride and stearyl trimethyl ammonium chloride); amphoteric surfactants (such as alkylaminoethyl glycine hydrochloride solution and lecithin); and nonionic surfactants (such as glyceryl monostearate, sorbitan monostearate, sucrose fatty acid esters, propylene glycol monostearate, polyoxyethylene oleyl ether, polyethylene glycol monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene coconut fatty acid monoethanol arnide, polyoxypropylene glycol (such as materials sold under the trademark "Pluronic®"), polyoxyethylene castor oil, and polyoxyethylene lanolin). Examples of humectants as carriers include glycerin, 1,3-butylene glycol, and propylene glycol; examples of lower alcohols include ethanol and isopropanol; and examples of thickeners include xanthan gum, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, and sodium carboxymethyl cellulose.Examples of antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, citric acid, ethoxyquin, alpha-lipoic acid, vitamin C, vitamin E, coenzyme Q-10, and idebenone. Plant antioxidants include carotenoids (such as lycopene); flavonoids (such as silymarin (milk thistle), silybin, silydianin, and silychristin); soy (isoflavins), grape seed extract; and polyphenols (such as green tea extract, rosmarinic acid (rosemary), hypericin (St. John's wort), oleuropein (olive leaf), curcurmin (turmeric root), tetrahydrocurcumin, and pycogenol (marine bark)). Examples of anti-inflammatory agents include anti-inflammatory plant substances such as allantoin, aloe vera, ginkgo biloba, and green tea (also considered an antioxidant). Examples of skin bleaching agents include hydroquinone or kojic acid. Examples of healing promoters / fibroblast proliferation compounds include copper peptides or palmitoyl-pentapetide (pal-KTTKS). Examples of neuromuscular blocking agents include acetyl hexapeptide 3 (argircline) or dimethylaminoethanol. Examples of chelating agents include edetate disodium and ethanehydroxydiphosphate. Examples of buffers as carrier agents include citric acid, sodium citrate, boric acid, borax, and disodium hydrogen phosphate, and examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, dehydroacetic acid, salicylic acid, and benzoic acid.

[0063] As used herein, "emollient" refers to a material used to prevent or relieve dryness and protect the skin. A wide variety of suitable emollients are known and may be used herein. See, for example, Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972) and U.S. Pat. No. 4,919,934 to Deckner et al., issued April 24, 1990, both of which are incorporated herein by reference in their entireties. Exemplary compositions containing emollients according to various aspects of the present disclosure may include any ingredients suitably adapted to provide moisture retention, reduced transepidermal water loss (TEWL), smooth feel, softness, increased substantivity, and / or the like. Furthermore, exemplary emollient compositions may be used to soften or smooth the skin by reducing roughness, cracking, irritation, and / or the like.

[0064] It is understood that certain components or additives may be classified under different terms in the art, and simply because a component or additive is classified under such a term does not mean that it is limited to that function. When utilized, the additive(s) may be present in the composition in various amounts. Additional components for optional use in the composition are described in U.S. Patent No. 5,747,006 to Dornoff et al., U.S. Patent Nos. 5,980,904, 6,994,874, 7,060,304, 7,247,321, and 7,364,759 to Leverett et al., and U.S. Publication No. 2017 / 0252293 to Brumbaugh et al., the disclosures of which are incorporated herein by reference in their entireties.

[0065] The composition can be prepared using various methods. For example, the active ingredients of the composition and one or more optional inactive substances can be mixed or blended and compressed or compounded using various methods known in the art. The composition of the present disclosure is not limited to a specific order of manufacturing steps or manufacturing method.

[0066] The composition may be in various forms. Examples of suitable forms include solids, gels, and liquids. For example, the composition may be formulated for application to the skin of a subject as a gel, cream, lotion, shampoo, conditioner, dry shampoo, pomade, mousse, powder, or foam. In another example, the composition may be formulated for spraying onto the skin of a subject. The composition may be formulated to be sprayed as either an aerosol spray or a pump spray. In yet another example, the composition may be formulated for application using a pre-moistened wet paper towel. In another example, the composition may be formulated as a solid that is rubbed onto the skin of a subject. In another example, the composition may be formulated for delivery via a patch that adheres to the skin of a subject.

[0067] The composition may comprise at least about 0.375% w / w, at least about 0.75% w / w, at least about 1% w / w, at least about 1.5% w / w, at least about 3% w / w, at least 4% w / w, at least 5% w / w, at least 6% w / w, at least 7% w / w, at least 8% w / w, at least 9% w / w, at least 10% w / w, at least 11% w / w, at least 12% w / w, at least 13% w / w, at least 14% w / w, at least 15% w / w, at least 16% w / w, at least 17% w / w, at least 18% w / w, at least 19% w / w, at least 20% w / w, or more of nootkatone or a pharmaceutically acceptable salt thereof. In certain variations, the composition comprises about 0.375% w / w, about 0.75% w / w, about 1% w / w, about 1.5% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, or more of nootkatone or a pharmaceutically acceptable salt thereof.

[0068] In certain variations, the composition comprises from about 0.1% to about 20% w / w, from about 0.1% to about 15% w / w, from about 0.1% to about 5% w / w, from about 0.1% to about 3% w / w, from about 0.1% to about 1.5% w / w, from about 0.1% to about 1% w / w, from about 0.1% to about 0.75% w / w, from about 0.1% to about 0.375% w / w, from about 0.375% to about 5% w / w, from about 0.375% to about 3% w / w, from about 0.375% to about 1.5% w / w, from about 0.375% to about 1% w / w, from about 0.375% to about 0.75% w / w, The composition comprises 0.75% to about 5% w / w, about 0.75% to about 3% w / w, about 0.75% to about 1.5% w / w, about 0.75% to about 1% w / w, about 1% to about 5% w / w, about 1% to about 3% w / w, about 1% to about 1.5% w / w, about 1.5% to about 5% w / w, about 1.5% to about 3% w / w, about 3% to about 5% w / w, about 1% to about 15% w / w, about 2% to about 10% w / w, about 4% to about 8% w / w, about 5% to about 15% w / w, or about 8% to about 12% w / w of nootkatone or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the composition comprises less than about 50% w / w, less than about 40% w / w, less than about 30% w / w, less than about 25% w / w, less than about 20% w / w, less than about 15% w / w, less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2% w / w, less than about 1% w / w, less than about 0.5% w / w, less than about 0.25% w / w, less than about 0.1% w / w, less than about 0.05% w / w, less than about 0.01% w / w, or less than about 0.001% w / w of other components naturally occurring in the nootkatone-containing source. In one variation, the composition has no detectable amounts of other components naturally occurring in the nootkatone-containing source. In one embodiment, the weight of components in the composition other than nootkatone that are naturally present in the nootkatone-containing source is less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% of the total weight of any nootkatone in the composition.

[0070] In other embodiments, the nootkatone or pharmaceutically acceptable salt thereof present in the composition has a purity of at least about 50% w / w, at least about 60% w / w, at least about 70% w / w, at least about 75% w / w, at least about 80% w / w, at least about 90% w / w, at least about 95% w / w, at least about 96% w / w, at least about 97% w / w, at least about 98% w / w, at least about 99% w / w, at least about 99.9% w / w, at least about 99.99% w / w, or at least about 99.999% w / w, or a purity of about 100% w / w.

[0071] In some variations, the composition comprises (i) nootkatone or a pharmaceutically acceptable salt thereof, and (ii) one or more additional sesquiterpenoids. In some variations, the composition comprises a sesquiterpenoid mixture, wherein at least one sesquiterpenoid is nootkatone or a pharmaceutically acceptable salt thereof.

[0072] In various embodiments, the composition is in the form of a gel or cream. In these and other embodiments, the composition comprises nootkatone and pharmaceutically / cosmetically acceptable excipients. "Pharmaceutically / cosmetically acceptable excipient(s)" are ingredients added to the composition in addition to the active ingredient, nootkatone. Excipients may be added to facilitate manufacturing, enhance stability, enhance product characteristics, enhance skin penetration, enhance patient acceptability, enhance release of the active ingredient, and the like. Pharmaceutically / cosmetically acceptable excipient(s) include, but are not limited to, one or more emulsifiers, gelling agents, preservatives, chelating agents, viscosity modifiers, antioxidants, surfactants, emollients, opacifiers, skin conditioners, fragrances, colorants, fillers, moisturizers, pH adjusters, acidifiers, solvents, vehicles, oily vehicles, suspending agents, dispersing agents, and any other excipients known in the art for formulating pharmaceutically / cosmetically acceptable compositions. According to the present disclosure, certain excipients may serve multiple roles in the composition, for example, they may act as both a preservative and a pH adjuster.

[0073] In some embodiments, the composition comprises nootkatone or a pharmaceutically acceptable salt thereof formulated in petrolatum. In some variations, the composition consists essentially of nootkatone or a pharmaceutically acceptable salt thereof and petrolatum. In one particular variation, the composition consists of nootkatone or a pharmaceutically acceptable salt thereof and petrolatum.

[0074] In certain embodiments, nootkatone or a pharmaceutically acceptable salt thereof and (ii) one or more additional sesquiterpenoids and / or excipients may be formulated as an aqueous gel-based composition. In these and other embodiments, the composition comprises nootkatone or a pharmaceutically acceptable salt thereof formulated in an aqueous gel-based composition. In some variations, the composition consists essentially of nootkatone or a pharmaceutically acceptable salt thereof and one or more aqueous gel-based excipients. In certain variations, the composition consists of nootkatone or a pharmaceutically acceptable salt thereof and one or more aqueous gel-based excipients.

[0075] It is contemplated herein that the gel-based composition may contain an active ingredient (e.g., nootkatone), a gelling agent, a pH adjuster, a solvent, an antioxidant, a preservative, or a combination thereof. The active ingredient may be present in the composition in an amount of about 0.1 wt.% to about 50 wt.%, about 1 wt.% to about 40 wt.%, about 1 wt.% to about 30 wt.%, about 1 wt.% to about 20 wt.%, or about 2 wt.% to about 10 wt.%, based on the total weight of the composition. In some embodiments, the active ingredient may be present in the gel-based composition in an amount greater than 0.1 wt.%, greater than 0.5 wt.%, greater than 1 wt.%, greater than 3 wt.%, or greater than 4 wt.%, based on the total weight of the composition.

[0076] The gelling agent may be present in the gel base in an amount of about 0.1 wt.% to about 10 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.5 wt.% to about 3 wt.%, or about 0.5 wt.% to about 2 wt.%, based on the total weight of the composition. In some embodiments, the gelling agent may be present in the gel base composition in an amount greater than 0.1 wt.%, greater than 0.2 wt.%, greater than 0.3 wt.%, greater than 0.4 wt.%, or greater than 0.5 wt.%, based on the total weight of the composition.

[0077] The solvent may be present in the gel base composition in an amount of about 50 wt.% to about 99.9 wt.%, about 70 wt.% to about 99 wt.%, about 80 wt.% to about 99 wt.%, or about 90 wt.% to about 95 wt.%, based on the total weight of the composition. In some embodiments, the gelling agent may be present in the gel base composition in an amount greater than 50 wt.%, greater than 60 wt.%, greater than 70 wt.%, greater than 80 wt.%, or greater than 90 wt.%, based on the total weight of the composition.

[0078] The preservative may be provided in any amount known in the art, hi some embodiments, the preservative is present in the gel base composition in an amount of about 0.001 wt.% to about 3 wt.%, about 0.01 wt.% to about 1 wt.%, about 0.01 wt.% to about 0.50 wt.%, or about 0.15 wt.% to about 0.25 wt.%. In some embodiments, the preservative is present in the gel base composition in an amount greater than 0.01%, greater than 0.02%, greater than 0.03%, greater than 0.04%, greater than 0.05%, greater than 0.06%, greater than 0.07%, greater than 0.08%, greater than 0.09%, greater than 0.1%, greater than 0.11%, greater than 0.12%, greater than 0.13%, greater than 0.14%, greater than 0.16%, greater than 0.16%, greater than 0.17%, or greater than 0.18% by weight of the total gel base composition.

[0079] The pH adjuster may be present in the composition in an amount of about 0.1 wt.% to about 10 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.5 wt.% to about 3 wt.%, or about 0.5 wt.% to about 2 wt.%, based on the total weight of the composition. In some embodiments, the gelling agent may be present in the gel base composition in an amount greater than 0.1 wt.%, greater than 0.2 wt.%, greater than 0.3 wt.%, greater than 0.4 wt.%, or greater than 0.5 wt.%, based on the total weight of the composition.

[0080] The antioxidant may be provided in any suitable amount, hi some embodiments, the antioxidant is present in the gel base composition in an amount of about 0.001 wt.% to about 3 wt.%, about 0.01 wt.% to about 1 wt.%, about 0.01 wt.% to about 0.50 wt.%, or about 0.05 wt.% to about 0.15 wt.%. In some embodiments, the antioxidant is present in the gel base composition in an amount greater than 0.01%, greater than 0.015%, greater than 0.02%, greater than 0.025%, greater than 0.03%, greater than 0.035%, greater than 0.04%, greater than 0.045%, greater than 0.05%, greater than 0.055%, greater than 0.06%, greater than 0.065%, greater than 0.07%, greater than 0.075%, greater than 0.08%, greater than 0.085%, greater than 0.09%, or greater than 0.095% by weight of the gel base composition.

[0081] In other embodiments, nootkatone or a pharmaceutically acceptable salt thereof and (ii) one or more additional sesquiterpenoids and / or excipients may be formulated as a cream-based composition. In these and other embodiments, the composition comprises nootkatone or a pharmaceutically acceptable salt thereof formulated in a cream-based composition. In some variations, the composition consists essentially of nootkatone or a pharmaceutically acceptable salt thereof and one or more excipients of the cream-based composition. In one particular variation, the composition consists of nootkatone or a pharmaceutically acceptable salt thereof and one or more excipients of the cream-based composition.

[0082] It is contemplated herein that the cream-based composition may contain an active ingredient (e.g., nootkatone), an emulsifier, an emollient, a solvent, an antioxidant, a preservative, or a combination thereof. The active ingredient may be present in the composition in an amount of about 0.1 wt.% to about 50 wt.%, about 1 wt.% to about 40 wt.%, about 1 wt.% to about 30 wt.%, about 1 wt.% to about 20 wt.%, or about 2 wt.% to about 10 wt.%, based on the total weight of the composition. In some embodiments, the active ingredient may be present in the cream-based composition in an amount greater than 0.1 wt.%, greater than 0.5 wt.%, greater than 1 wt.%, greater than 3 wt.%, or greater than 4 wt.%, based on the total weight of the composition.

[0083] The emulsifier may be present in the cream base in an amount of from about 0.1 wt.% to about 50 wt.%, from about 1 wt.% to about 25 wt.%, from about 2 wt.% to about 20 wt.%, or from about 8 wt.% to about 12 wt.%, based on the total weight of the composition. In some embodiments, the emulsifier may be present in the cream base composition in an amount greater than 0.1 wt.%, greater than 1 wt.%, greater than 5 wt.%, greater than 6 wt.%, or greater than 8 wt.%, based on the total weight of the composition.

[0084] The emollient may be present in the cream base in an amount of from about 0.1 wt.% to about 50 wt.%, from about 1 wt.% to about 25 wt.%, from about 2 wt.% to about 20 wt.%, or from about 8 wt.% to about 12 wt.%, based on the total weight of the composition. In some embodiments, the emollient may be present in the cream base composition in an amount greater than 0.1 wt.%, greater than 1 wt.%, greater than 5 wt.%, greater than 6 wt.%, or greater than 8 wt.%, based on the total weight of the composition.

[0085] The solvent may be present in the cream base composition in an amount of about 40 wt.% to about 99.9 wt.%, about 50 wt.% to about 90 wt.%, about 60 wt.% to about 85 wt.%, or about 70 wt.% to about 80 wt.%, based on the total weight of the composition. In some embodiments, the gelling agent may be present in the cream base composition in an amount greater than 40 wt.%, greater than 50 wt.%, greater than 60 wt.%, greater than 65 wt.%, or greater than 70 wt.%, based on the total weight of the composition.

[0086] The preservative may be provided in any amount known in the art, hi some embodiments, the preservative is present in the cream base composition in an amount of about 0.001 wt.% to about 3 wt.%, about 0.01 wt.% to about 1 wt.%, about 0.01 wt.% to about 0.50 wt.%, or about 0.20 wt.% to about 0.30 wt.%. In some embodiments, the preservative is present in the cream base composition in an amount greater than 0.01%, greater than 0.02%, greater than 0.03%, greater than 0.04%, greater than 0.05%, greater than 0.06%, greater than 0.07%, greater than 0.08%, greater than 0.09%, greater than 0.1%, greater than 0.11%, greater than 0.12%, greater than 0.13%, greater than 0.14%, greater than 0.16%, greater than 0.16%, greater than 0.17%, or greater than 0.18% by weight of the total cream base composition.

[0087] The antioxidant may be provided in any suitable amount, hi some embodiments, the antioxidant is present in the gel base composition in an amount of about 0.001 wt.% to about 3 wt.%, about 0.01 wt.% to about 1 wt.%, about 0.01 wt.% to about 0.50 wt.%, or about 0.05 wt.% to about 0.15 wt.%. In some embodiments, the antioxidant is present in the gel base composition in an amount greater than 0.01%, greater than 0.015%, greater than 0.02%, greater than 0.025%, greater than 0.03%, greater than 0.035%, greater than 0.04%, greater than 0.045%, greater than 0.05%, greater than 0.055%, greater than 0.06%, greater than 0.065%, greater than 0.07%, greater than 0.075%, greater than 0.08%, greater than 0.085%, greater than 0.09%, or greater than 0.095% by weight of the gel base composition.

[0088] As introduced above, it is contemplated herein that the gel-based or cream-based compositions may include an active ingredient (e.g., nootkatone), a gelling agent, an emulsifier, an emollient, a pH adjuster, a solvent, an antioxidant, a preservative, or a combination thereof.

[0089] Gelling agents that can be used in the composition include polysaccharides (carrageenan, alginate), proteins (gelatin), cellulose derivatives (hydroxypropyl cellulose, hydroxyethyl cellulose), acrylic acid polymers (carbomer, Carbopol), clays (bentonite, hectorite), polyacrylamides (Sepigel 305), hydrocarbon gels (polybutene, hydrogenated polydecene), silica (hydrophobic fumed silica, silica silylate), fatty acid derivatives (12-hydroxystearic acid, ethylene glycol monostearate), amide derivatives (stearic acid diethanolamide, stearic acid amide MEA), wax esters (beeswax, candelilla wax), fatty alcohols (cetyl alcohol, stearyl alcohol), or combinations thereof. The gelling agent can be made from a carboxyvinyl polymer (such as carbomer). Non-limiting examples of carbomers include Carbopol 981, Carbopol ETD2020, Carbopol 980, Carbopol Ultrez 10, Pemulen TR1, hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer (such as Sepineo™ Derm), acrylamide / sodium acryloyldimethyl taurate copolymer / isohexadecane, polysorbate 80 (such as Sepineo™ P600 or Simulgel™ 600), or combinations thereof. Other gelling agents may be made from cellulose derivatives (such as, for example, hydroxypropylmethylcellulose or hydroxyethylcellulose), xanthan gum, aluminum / magnesium silicate (such as Veegum K or Veegum Ultra), guar gum, polyacrylamide (such as polyacrylamide / C13-14 isoparaffin / laureth-7 mixture), acrylamide, AMPS copolymer dispersion 40% / isohexadecane, modified starch (such as structure Solanace), or combinations thereof. In an exemplary embodiment, the gelling agent comprises a carbomer (such as Carbopol Ultrez 10).

[0090] The pH adjuster may include an organic acid, an inorganic base (neutralizing base), a buffer system, or a combination thereof. Non-limiting examples of suitable organic acids include citric acid, lactic acid, acetic acid, or a combination thereof. Non-limiting examples of inorganic bases include sodium hydroxide (NaOH), potassium hydroxide (KOH), ammonium hydroxide, or a combination thereof. Non-limiting examples of suitable buffer systems include citric acid / monosodium citrate (citrate buffer), acetic acid / sodium acetate (acetate buffer), phosphate buffer, or a combination thereof. In an exemplary embodiment, the pH adjuster includes an inorganic base (such as NaOH).

[0091] A variety of solvents can be utilized in the composition, each imparting distinct properties and functionality (e.g., penetration enhancement, preservation, emulsification, etc.). The broad chemistry of solvents suitable for cosmetic gels includes water, alcohols (e.g., ethanol or isopropyl alcohol), ethers (e.g., diethylene glycol monoethyl ether, diethyl ether, or ethoxydiglycol), esters (e.g., ethyl acetate, isopropyl myristate), hydrocarbons (e.g., mineral oil, isododecane), glycols (e.g., diethylene glycol, propylene glycol, or butylene glycol), and silicones (e.g., dimethicone or cyclopentasiloxane). These solvents impart a wide range of properties, including volatility, polarity, permeability, spreadability, solubility, evaporation rate, and texture, allowing formulators to select the most suitable solvent(s) based on the desired properties of the gel- or cream-based composition. In exemplary embodiments, the solvents include water, alcohols (e.g., ethanol), ethers (e.g., diethylene glycol monoethyl ether), glycols (e.g., propylene glycol), and esters (e.g., isopropyl myristate). In various embodiments, glycols may also function as emulsifiers or preservatives. In many embodiments, ethers may also function as hydrophobic oils. In various embodiments, esters may also function as penetration enhancers.

[0092] The embodiments are not limited by the number or type of preservatives used in the compositions described herein. For example, preservatives useful in the embodiments include, but are not limited to, pentylene glycol, ethylenediaminetetraacetic acid (EDTA) and its salts, chlorhexidine and its diacetate, dihydrochloride, digluconate derivatives, 1,1,1-trichloro-2-methyl-2-propanol, parachlorometaxylenol, polyhexamethylene biguanide hydrochloride, dehydroacetic acid, diazolidinyl urea, 2,4-dichlorobenzyl alcohol, 4,4-dimethyl-1,3-oxazolidine, formaldehyde, glutaraldehyde, dimethylidantoin, imidazolidinyl urea, 5-chloro-2-methyl-4-isothiazolin-3-one, ortho-phenylphenol, benzyl alcohol, benzoic acid and its salts, 4-hydroxybenzoic acid and its methyl- , ethyl-, propyl-, isopropyl-, butyl-, isobutyl-esters (parabens), methylparaben, propylparaben, isopropylparaben, isobutylparaben, butylparaben, ethylparaben, triclosan, 2-phenoxyethanol, phenylmercuric acetate, quaternium-15, methyl salicylate, salicylic acid and its salts, sorbic acid and its salts, iodopropanyl butylcarbamate, calcium sorbate, zinc pyrithione, 5-bromo-S-nitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol, sulfites, bisulfites, and benzalkonium chloride, phenoxyethanol, 2-phenoxyethanol, chloroxylenol, diazolidinyl urea, and combinations thereof. In an exemplary embodiment, the composition includes methylparaben, propylparaben, or a combination thereof.

[0093] A variety of antioxidants can be utilized in the compositions. Examples of suitable antioxidants include, but are not limited to, amino acids (such as glycine, histidine, tyrosine, tryptophan, and derivatives thereof), imidazoles (such as urocanic acid and derivatives thereof), peptides (such as D,L-carnosine, D-carnosine, L-carnosine, and derivatives thereof (such as anserine)), carotenoids, carotenes (such as α-carotone, β-carotene, lycopene, and derivatives thereof), chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof (dihydrolipoic acid), and the like. acid), aurothioglycose, propylthiouracil and other thiols (thioredoxin, glutathione, cysteine, cystine, cystamine, and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, α-linoleyl, cholesteryl, and glyceryl esters and salts thereof), dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides, and salts), sulfoximine compounds (buthionine sulfoximine, phosphatidylcholine ... cysteine ​​sulfoximine, buthionine sulfone, penta-, hexa-, hepta-thionine sulfoximine, etc.), unsaturated fatty acids and their derivatives (alpha-linolenic acid, linoleic acid, oleic acid, folic acid, and their derivatives, etc.), ubiquinone and ubiquinol and their derivatives, vitamin C and its derivatives (ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate, etc.), tocopheral and derivatives (vitamin E acetate ester, etc.), vitamin A and derivatives (vitamin A palmitate ester, etc.), vitamin B and its derivatives, coniferyl benzoate from benzoin resin, rutinic acidAntioxidants include uric acid and its derivatives, α-glycosyl rutin, ferulic acid, furfurylidene glucitol, carnosine, butylated hydroxytoluene, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, superoxide dismutase, zinc and its derivatives (e.g., ZnO, ZnSO), selenium and its derivatives (e.g., selenium methionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide), and the like. In certain embodiments, the one or more antioxidants may include vitamin B, nordihydroguaiaretic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, erythorbic acid, sodium erythorbate, ascorbyl palmitate, and ascorbyl stearate. In an exemplary embodiment, the antioxidant includes BHT.

[0094] In some embodiments, the composition may include an emulsifying agent or emulsifier. The emulsifier can be provided to adjust the properties (such as density, viscosity, melting point, and / or droplet size) of the cream base composition, and in some embodiments, the emulsifier may increase the stability of the cream base composition. Various emulsions suitable for the embodiments described herein and methods for preparing such emulsions are well known in the art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., USA, which is incorporated herein by reference in its entirety. The compositions of various embodiments may include any emulsifier or combination of emulsifiers. For example, in some embodiments, the cream base composition may be a common oil-in-water emulsion or water-in-oil emulsion containing nootkatone and water or one or more common oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, soybean oil, mineral oil, sesame oil, etc.). In other embodiments, the cream base composition may include one or more emulsifiers, such as mixtures of cetyl (C16) and stearyl (C18) fatty alcohols with anionic emulsifiers, sesquioleic acid esters (such as sorbitan sesquioleate or polyglyceryl-2-sesquioleate), ethoxylated esters of derivatives of natural oils (such as polyethoxylated esters of hydrogenated castor oil), silicone emulsifiers (such as silicone polyols), anionic emulsifiers, fatty acid soaps (such as stearic acid fatty acid sulfates such as potassium and sodium cetostearyl sulfate), ethoxylated fatty alcohols, sorbitan esters, ethoxylated sorbitan esters, ethoxylated fatty acid esters (such as ethoxylated stearic acid, ethoxylated monoglycerides, ethoxylated diglycerides, and ethoxylated triglycerides), nonionic self-emulsifying waxes, ethoxylated fatty acids, methyl glucose esters (such as polyglycerol-3 methyl glucose distearate), and mixtures thereof.In an exemplary embodiment, the emulsifier can be a mixture of cetyl (C16) and stearyl (C18) fatty alcohols and anionic emulsifiers, commercially available from BASF under the trade name Kolliphor CSA.

[0095] The cream base composition of various embodiments may include any chelating agent or combination of chelating agents. Examples of chelating agents useful in various embodiments include, but are not limited to, alanine, sodium polyphosphate, sodium metaphosphate, citric acid, phosphoric acid, tartaric acid, ethylenediaminetetraacetic acid (edetate, EDTA) and derivatives and salts thereof, dihydroxyethylglycine, and mixtures thereof. In certain embodiments, the chelating agent may be EDTA or edetate disodium dihydrate.

[0096] In some embodiments, the cream base composition may include one or more viscosity modifiers. Viscosity modifiers in such embodiments may generally include, for example, high molecular weight compounds such as carboxyvinyl polymers, carboxymethylcellulose, polyvinylpyrrolidone, hydroxyethylcellulose, methylcellulose, natural gums (such as gelatin and tragacanth gum), and various alcohols (such as polyvinyl alcohol). In other embodiments, the viscosity modifier may include ethanol or isopropyl alcohol. In some embodiments, the viscosity modifier may be a high molecular weight saturated or unsaturated fatty alcohol, such as, but not limited to, carbitol, lauryl alcohol, myristyl alcohol, cetyl alcohol, isocetyl alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, erucyl alcohol, 2-octyldodecanyl alcohol, cetearyl alcohol, lanolin alcohol, and the like; in certain embodiments, the viscosity modifier may be oleyl alcohol.

[0097] In some embodiments, the cream base compositions described herein may contain one or more surfactants. Such embodiments are not limited by the type of surfactant used. For example, in some embodiments, the one or more surfactants may be anionic surfactants, such as alkyl sulfates, alkyl ether sulfates, alkyl sulfonates, alkylaryl sulfonates, alkyl succinates, alkyl sulfosuccinates, alkoyl sarcosinates (N-alkoyl sarcosinates), acyltaurates, acyl isethionates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, α-olefin sulfonates, and alkali metal and alkaline earth metal, ammonium, and triethanolamine salts thereof. Such alkyl ether sulfates, alkyl ether phosphates, and alkyl ether carboxylates may have 1 to 10 ethylene oxide or propylene oxide units per molecule, and in some embodiments, 1 to 3 ethylene oxide units. More specific examples include, but are not limited to, sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate, ammonium lauryl ether sulfate, sodium lauryl sarcosinate, sodium oleyl succinate, ammonium lauryl sulfosuccinate, sodium dodecylbenzenesulfonate, and triethanolamine dodecylbenzenesulfonate. In other embodiments, one or more surfactants may be amphoteric surfactants, such as alkyl betaines, alkylamidopropyl betaines, alkyl sulfobetaines, alkyl glucinates, alkyl carboxyglucinates, alkyl amphoacetates or α-propionates, alkyl amphodiacetates, or α-dipropionates, and more specifically, cocodimethylsulfopropyl betaine, lauryl betaine, cocamidopropyl betaine, or sodium cocoamphopropionate.

[0098] In certain embodiments, one or more surfactants can be nonionic surfactants, such as the reaction products of aliphatic alcohols or alkylphenols having 6 to 20 carbon atoms in the linear or branched alkyl chain with ethylene oxide and / or propylene oxide, where the alkylene oxide can be in an amount of from about 6 moles to about 60 moles per mole of alcohol. In certain embodiments, nonionic surfactants may include alkylamine oxides, mono- and dialkylalkanolamides, fatty acid esters of polyethylene glycols, ethoxylated fatty acid amides, saturated fatty alcohols reacted with ethylene oxide, alkyl polyglycosides, and sorbitan ether esters, and in some embodiments, nonionic surfactants include ceteareth-2, ceteareth-3, ceteareth-4, ceteareth-5, ceteareth-6, ceteareth-7, ceteareth-8, ceteareth-9, ceteareth-10, ceteareth-11, ceteareth-12, ceteareth-13, ceteareth-14, ceteareth-15, ceteareth-16, ceteareth-17, ceteareth-18, ceteareth-19, ceteareth-20, ceteareth-21, ceteareth-22, ceteareth-23, ceteareth-24, ceteareth-25, ceteareth-26, ceteareth-27, ceteareth-28, ceteareth-29, ceteareth-30, ceteareth-31, ceteareth-32, ceteareth-33, ceteareth-34, ceteareth-35, ceteareth-36, ceteareth-37, ceteareth-38, ceteareth-39, ceteareth-40, ceteareth-41, ceteareth-42, ceteareth-43, ceteareth-44, ceteareth-45, ceteareth-46, ceteareth-47, ceteareth-48, ceteareth-49, cetea Ceteareth-16, ceteareth-17, ceteareth-18, ceteareth-20, ceteareth-22, ceteareth-23, ceteareth-24, ceteareth-25, ceteareth-27, ceteareth-28, ceteareth-29, ceteareth-30, ceteareth-33, ceteareth-34, ceteareth-40, ceteareth-50, ceteareth-55, ceteareth-60, ceteareth-80, ceteareth-100, and the like or combinations thereof, or can be combinations of one or more ceteareths with fatty acid alcohols such as stearyl alcohol, oleyl alcohol, linoleyl alcohol, arachidyl alcohol, cetyl alcohol, and the like. In certain embodiments, the one or more surfactants may be commercially available ceteareth containing surfactants such as CREMOPHOR EL®, CREMOPHOR A-6®, CREMPHOR A-25®, or combinations thereof.

[0099] In some embodiments, cream-based composition can comprise one or more emollients.Generally, the function of emollients is to allow cream-based composition, and thus active agent, to remain on the skin surface or in the stratum corneum.Emollients are well known in the art and are described, for example, in International Cosmetic Ingredient Dictionary, Eighth Edition, 2000 (this document is incorporated herein by reference in its entirety). In certain embodiments, the one or more emollients may be white petrolatum, fatty acid esters, fatty alcohols, or combinations thereof, including, but not limited to, diisopropyl adipate, oleyl alcohol, lanolin, isopropyl myristate, isopropyl palmitate, caprylic / capric triglyceride, cetyl lactate, cetyl palmitate, hydrogenated castor oil, glyceryl esters, hydroxycetyl isostearate, hydroxycetyl phosphate, isopropyl isostearate, isostearyl isostearate, diisopropyl sebacate, polyoxypropylene(5) poloxyethylene(20) cetyl ether (PPG-5-Ceteth-20), 2-ethylhexyl isononoate, 2-ethylhexyl stearate, C12-C16 fatty alcohols, C12-C16 fatty alcohol lactate, isopropyl lanolate In some embodiments, the one or more emollients may be a combination of fatty alcohols, including fatty alcohols such as 2-ethyl-hexyl salicylate, 2-ethyl-hexyl salicylate, and mixtures thereof.In certain embodiments, the one or more emollients are selected from the group consisting of a blend of cetyl fatty alcohol and stearyl fatty alcohol, isopropyl myristate, 1-hexadecanol, acetylated lanolin, behenosyl dimethicone, C12-15 alkyl benzoate, cetearyl octanoate, cocoglycerides, dimethicone dicaprylate / dicaprate copolyol, dimethiconol, dioctyl adipate, glyceryl stearate, isocetyl alcohol, isohexadecane, isopentyl cyclohexanone, isopropyl palmitate, lauryl lactate, mineral oil, methoxy peg-22 / dodecyl glycol copolymer, myristyl lactate, octyldodecyl neopentanoate, octyl cocoate, octyl palmitate, octyl stearate, octyldodecyl neopentanoate, polyglyceryl-4 isosterate. isosterate), polyoxyl 40 stearate, polyoxymethylene urea, potassium sorbate, propylene glycol, propylene glycol isoceta-3 acetate, and propylene glycol myristyl ether acetate. In an exemplary embodiment, the emollient comprises white petrolatum, a mixture of cetyl and stearyl fatty alcohols, isopropyl myristate, or a combination thereof.

[0100] In certain embodiments, the cream base composition may include one or more opacifying agents. Opacifying agents impart color or whiteness to compositions that would otherwise be clear or have an undesirable color. In some embodiments, ingredients such as emollients, surfactants, and / or emulsifiers may provide sufficient opacity. In other embodiments, one or more additional opacifying agents may be provided in the cream base composition. Opacifying agents are well known in the art and include, but are not limited to, higher fatty alcohols (such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol, arachidyl alcohol, and behenyl alcohol), solid esters (such as cetyl palmitate, glyceryl laurate, and stearamide MEA-stearate), high molecular weight fatty amides and alkanolamides, and various fatty acid derivatives (such as propylene glycol and polyethylene glycol esters). In other embodiments, the opacifying agent may include inorganic materials such as magnesium aluminum silicate, zinc oxide, titanium dioxide, or other sunscreens.

[0101] In some embodiments, the cream-based composition may contain one or more skin conditioners. Skin conditioners are generally ingredients that can improve moisture retention in the skin, slow the evaporation of moisture from the skin, and cause skin plasticization / softening. Common skin conditioners include, for example, mineral oil, petrolatum, fatty alcohols, lanolin and its derivatives, fatty acids, glycolic fatty acids, sugars, glycerin, propylene glycol, sorbitol, and polyethylene glycol, vitamins, and herbal derivatives. Additional skin conditioners can be found in the CTFA Cosmetic Ingredient Handbook, 1st Ed., 1988, which is incorporated herein by reference in its entirety. In some embodiments, the one or more skin conditioners may include, but are not limited to, moisturizers such as fructose, glucose, glycerin, propylene glycol, glycereth-26, mannitol and urea, pyrrolidone carboxylic acid, hydrolyzed lecithin, cocobetaine, cysteine ​​hydrochloride, glutamine, polyoxypropylene(15) polyoxyethylene (PPG-15), sodium gluconate, potassium aspartate, oleyl betaine, thiamine hydrochloride, sodium laureth sulfate, sodium hyaluronate, hydrolyzed proteins, hydrolyzed keratin, amino acids, amine oxides, water-soluble derivatives of vitamins A, E, and D, amino-functional silicones, ethoxylated glycerin, alpha-hydroxy acids and their salts, water-soluble fatty oil derivatives (such as PEG-24 hydrogenated lanolin, almond oil, grape seed oil, and castor oil); many other water-soluble skin conditioners described, and mixtures thereof. In certain embodiments, the skin conditioner may include lanolin or lanolin derivatives, caprylic / capric triglyceride, diisopropyl adipate, and combinations thereof.

[0102] In certain embodiments, the cream base composition comprises an oil phase, an aqueous phase, and nootkatone. The oil phase may be present in an amount of about 5 wt.% to about 50 wt.%, alternatively about 10 wt.% to about 45 wt.%, alternatively about 15 wt.% to about 40 wt.%, or alternatively about 20 wt.% to about 30 wt.%. The aqueous phase may be present in an amount of about 10 wt.% to about 70 wt.%, alternatively about 20 wt.% to about 60 wt.%, alternatively about 25 wt.% to about 55 wt.%, or alternatively about 30 wt.% to about 45 wt.%. Nootkatone (or an isomer thereof) may be present in an amount of from about 0.1 wt.% to about 30 wt.%, alternatively, from about 1 wt.% to about 20 wt.%, alternatively, from about 1 wt.% to about 10 wt.%.

[0103] In these and other embodiments, the oil phase comprises one or more emulsifiers and / or emollients, such as a mixture of cetyl (C16) fatty alcohol and stearyl (C18) fatty alcohol, as well as anionic emulsifiers, isopropyl myristate, white petrolatum, or combinations thereof. The aqueous phase comprises water. The cream-based composition may further comprise an additional emulsifier (such as diethylene glycol monoethyl ether). The cream-based formulation may further comprise an antioxidant (such as BHT). The cream-based composition may further comprise a preservative (such as methylparaben, propylparaben, or a combination thereof).

[0104] Uses of the compounds and pharmaceutically acceptable salts and compositions Nootkatone and pharmaceutically acceptable compositions are useful for treating or reducing the severity of various diseases, disorders, or conditions, including, but not limited to, pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy. In various embodiments, nootkatone and pharmaceutically acceptable compositions are inhibitors or modulators of one or more of the following therapeutic targets: voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB. Thus, nootkatone and pharmaceutically acceptable compositions are useful for treating or reducing the severity of various diseases, disorders, or conditions described herein.

[0105] In various embodiments, the terms "inhibit" and "modulate" are used interchangeably to refer to an agent that reduces or suppresses a biological activity (e.g., abrogating the activity of an ion channel such as NaV1.7). NaV1.7 inhibitors include inhibitors having any combination of the structural and / or functional properties disclosed herein.

[0106] In certain embodiments, nootkatone or a pharmaceutically acceptable salt thereof has an IC of less than 50 micromolar (μM), optionally less than 40 μM, optionally less than 30 μM, optionally less than 20 μM, optionally less than 10 μM, or optionally less than 1 μM. 50 Alternatively, nootkatone or a pharmaceutically acceptable salt thereof has an IC50 of about 0.01 μM to about 100 μM, optionally about 0.1 μM to about 75 μM, optionally about 1 μM to about 50 μM, optionally about 1 μM to about 25 μM, or optionally about 1 μM to about 10 μM. 50 to inhibit or modulate one or more of the therapeutic targets.

[0107] In some embodiments, "treating" or "treatment" refers to curative or disease-modifying treatment, including treatment of patients at risk of or suspected of having a disease, as well as treatment of patients who are ill or have been diagnosed with a disease or medical condition, and "treating" or "treatment" includes suppression of clinical recurrence. In these and other embodiments, "treating" or "treatment" refers to obtaining a beneficial or desired result (e.g., a clinical result) in a subject, including (1) alleviating one or more symptoms caused by or associated with a disease, disorder, or condition; (2) reducing the severity of a disease, disorder, or condition; (3) delaying or halting the onset or progression of one or more symptoms caused by or associated with a disease, disorder, or condition (e.g., stabilizing a disease, disorder, or condition); and (4) alleviating a disease (e.g., by causing regression of one or more clinical symptoms) (e.g., improving a disease state, enhancing the effect of another pharmaceutical agent, slowing or halting the progression of a disease, and / or improving quality of life).

[0108] In some embodiments, the method includes administering nootkatone or a pharmaceutically acceptable salt thereof to a subject in a pharmaceutical excipient to form a composition. The composition may contain 10-500 mg, 10-800 mg, 20-1,000 mg, 30-1,200 mg, 50-1,500 mg, or 100-2,000 mg, or more of nootkatone or a pharmaceutically acceptable salt thereof in a single dosage unit. Consequently, preferred oral single dosage units (or recommended daily intakes) are 20-200 mg, 40-400 mg, 60-600 mg, 80-800 mg, 100-1,000 mg, or 200-2,000 mg, or in some cases even greater.

[0109] As used herein, the term "administering" a pharmaceutical composition or drug refers to both direct and indirect administration of a pharmaceutical composition or drug, where direct administration of a pharmaceutical composition or drug is typically performed by a healthcare professional (e.g., a doctor, a nurse, etc.), and indirect administration includes providing or making the pharmaceutical composition or drug available to a healthcare professional for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.).

[0110] In some variations, the method includes administering to a subject nootkatone or a pharmaceutically acceptable salt thereof in an excipient formulation (such as petrolatum, a gel-based formulation, or a cream-based formulation) to form a composition comprising at least about 0.375% w / w, at least about 0.75% w / w, at least about 1% w / w, at least about 1.5% w / w, at least about 3% w / w, at least 4% w / w, at least 5% w / w, at least 6% w / w, at least 7% w / w, at least 8% w / w, at least 9% w / w, at least 10% w / w, at least 11% w / w, at least 12% w / w, at least 13% w / w, at least 14% w / w, at least 15% w / w, at least 16% w / w, at least 17% w / w, at least 18% w / w, at least 19% w / w, at least 20% w / w, or more of nootkatone or a pharmaceutically acceptable salt thereof. In certain variations, the composition comprises about 0.375%, about 0.75%, about 1%, about 1.5%, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20%, or more of nootkatone or a pharmaceutically acceptable salt thereof.

[0111] In various embodiments, the amount of the composition administered to a subject is measured in square centimeters (cm 2The composition is based on the amount of nootkatone or a pharmaceutically acceptable salt thereof in milligrams (mg) per area of ​​skin at 0.01 mg / cm. 2 (skin cm 2 (mg of notekatone per cm), at least 0.02 mg / cm 2 , at least 0.03 mg / cm 2 , at least 0.04 mg / cm 2 , at least 0.05 mg / cm 2 , at least 0.06 mg / cm 2 , at least 0.07 mg / cm 2 , at least 0.08 mg / cm 2 , at least 0.09 mg / cm 2 , at least 0.1 mg / cm 2 , at least 0.12 mg / cm 2 , at least 0.14 mg / cm 2 , at least 0.16 mg / cm 2 , at least 0.18 mg / cm 2 , at least 0.2 mg / cm 2 , at least 0.22 mg / cm 2 , at least 0.24 mg / cm 2 , at least 0.26 mg / cm 2 , at least 0.28 mg / cm 2 , at least 0.3 mg / cm 2 , at least 0.32 mg / cm 2 , at least 0.34 mg / cm 2 , at least 0.36 mg / cm 2 , at least 0.38 mg / cm 2 , at least 0.4 mg / cm 2 The composition may be administered to a subject in an amount of about 0.01 mg / cm or more. 2 ~about 0.4mg / cm 2 , about 0.05mg / cm 2 ~about 0.3mg / cm 2 , about 0.1mg / cm 2 ~about 3mg / cm 2 , or about 0.15 mg / cm 2 ~about 0.25mg / cm 2can be administered to a subject in an amount of

[0112] The composition may be applied daily, several times a day, or in any suitable regimen as needed to achieve the desired results. In the methods of the present disclosure, the frequency of administration (e.g., topical application) may depend on several factors, including the severity of the condition (such as pain, itching, or symptoms thereof) or the desired level of symptom relief. Generally, the regimen involves application of the composition once or twice a day, including a morning administration and / or an afternoon administration. The amount and / or frequency of application of the composition may depend on several factors, including the desired level of result and the particular composition. In some embodiments, the composition is administered once a day. In other embodiments, the composition is administered twice a day. In yet other embodiments, the composition is administered three times a day. In yet other embodiments, the composition is administered four times a day. However, it will be understood that the composition may be administered more than four times a day.

[0113] In some variations, the composition is administered for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 24 weeks, at least about 32 weeks, at least about 40 weeks, at least about 48 weeks, or at least about 1 year. In certain variations, the composition is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 24 weeks, about 32 weeks, about 40 weeks, about 48 weeks, or about 1 year. In one variation, the composition is administered for about 1 week to about 1 year, about 4 weeks to about 8 weeks, about 4 weeks to about 12 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 32 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 48 weeks, or about 4 weeks to about 1 year.

[0114] Nootkatone, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, can be administered as described herein. In some embodiments, the composition is administered topically to a subject. In other embodiments, the composition is administered orally.

[0115] In another aspect, the disclosure features a method of inhibiting a therapeutic target in a subject (such as at least one of voltage-gated sodium channels (NaV), kappa opiate receptors (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB), the method includes administering nootkatone, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject. In various embodiments, nootkatone does not inhibit NaV1.5. In some embodiments, the phrase "does not inhibit," with respect to NaV1.5, refers to a condition in which nootkatone, or a pharmaceutically acceptable salt thereof, inhibits NaV1.5 with an IC50 of greater than 100 micromolar (μM). 50 This means that NaV1.5 is inhibited.

[0116] pain In yet another aspect, the disclosure features a method of treating or reducing the severity of chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain in a subject, the method includes administering an effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone, or a pharmaceutically acceptable salt thereof.

[0117] In yet another aspect, the disclosure features a method of treating or reducing the severity of intestinal or abdominal pain in a subject, where the intestinal or abdominal pain includes irritable bowel syndrome (IBS) pain, celiac disease pain, inflammatory bowel disease (IBD) pain (such as Crohn's disease pain or ulcerative colitis pain), endometriosis pain, or interstitial cystitis pain, the method includes administering an effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone. Other non-limiting examples of diseases or conditions that can lead to bowel or abdominal pain include acute cholecystitis, lactose intolerance, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), small intestinal bacterial overgrowth (SIBO), hiatal hernia, intestinal parasites such as giardiasis, food poisoning, constipation, irritable bowel syndrome (IBS), gastroenteritis (both viral and bacterial), various forms of colitis (such as ischemic colitis), pancreatic cancer, liver cancer, colon cancer, stomach cancer, pelvic inflammatory disease (PID), ovarian torsion, kidney infection (pyelonephritis), abdominal migraine, abdominal pain, and ulcerative colitis. These conditions include aneurysms, adhesions (bands of scar tissue in the abdomen), Meckel's diverticulum, Zollinger-Ellison syndrome, intussusception (common in children), Hirschsprung's disease (in children), porphyria, appendicitis (neutropenic enteritis), gastroesophageal reflux disease (GERD), gastritis, peptic ulcer disease, celiac disease, food intolerances or allergies, gallstones, pancreatitis, liver disease (including hepatitis), kidney stones, urinary tract infections (UTIS), diverticulitis, appendicitis, endometriosis, ovarian cysts, ectopic pregnancy, hernias, intestinal obstructions, and mesenteric ischemia. Each of these conditions can present with a variety of symptoms, making accurate diagnosis essential for effective treatment.

[0118] In yet another aspect, the disclosure features a method of treating or lessening the severity of neuropathic pain in a subject, including postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; post-spinal cord injury pain, idiopathic small fiber neuropathy, small fiber neuropathy, or trigeminal autonomic cephalopathy, the method comprising administering an effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0119] In yet another aspect, the disclosure features a method of treating or reducing the severity of musculoskeletal pain in a subject, where the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, heat pain, or dental pain, the method includes administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0120] In yet another aspect, the disclosure features a method of treating or reducing the severity of inflammatory pain in a subject, where the inflammatory pain includes rheumatoid arthritis pain or vulvodynia, the method includes administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0121] In yet another aspect, the disclosure features a method of treating or lessening the severity of idiopathic pain in a subject, where the idiopathic pain includes fibromyalgia pain, the method includes administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0122] In yet another aspect, the disclosure features a method in which a subject is treated with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0123] In another aspect, the disclosure features a method of inhibiting a therapeutic target in a subject (such as at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB), the method includes administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone to the subject. In various embodiments, nootkatone does not inhibit NaV1.5.

[0124] In another aspect, the disclosure features a method of inhibiting a therapeutic target in a biological sample (such as at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB), the method includes contacting the biological sample with a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone. In various embodiments, nootkatone does not inhibit NaV1.5.

[0125] In another aspect, the present disclosure provides a method for treating acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, status epilepticus, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatic nerve pain, and the like. The present invention features a method of treating or lessening the severity of nootkatone, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders in a subject, the method comprising administering an effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0126] In another aspect, the present disclosure provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy. -;Hereditary sensory neuropathies;Peripheral nerve injury;Painful neuromas;Ectopic proximal and distal discharges;Radiopathy;Chemotherapy-induced neuropathic pain;Radiation therapy-induced neuropathic pain;Post-mastectomy pain;Central pain;Spinal cord injury pain;Post-stroke pain;Thalamic pain;Complex regional pain syndrome;Phantom limb pain;Intractable pain;Acute pain, acute postoperative pain;Acute musculoskeletal pain;Arthral pain;Mechanical low back pain;Neck pain;Tendonitis;Injury / exercise pain;Acute visceral pain;Pyelonephritis;Appendicitis;Cholecystitis;Intestinal Obstruction; Hernia; Chest pain, cardiac pain; Pelvic pain, renal colic pain, acute obstetric pain, labor pain; Caesarean section pain; Acute inflammatory, febrile, and traumatic pain; Acute intermittent pain, endometriosis; Acute shingles pain; Sickle cell anemia; Acute pancreatitis; Breakthrough pain; Orofacial pain; Sinusitis pain; Toothache; Multiple sclerosis (MS) pain; Pain in depression; Leprosy pain; Behcet's disease pain; Adiposity; Phlebitis pain; Guillain-Barré pain; Painful legs and moving toes syndrome; Haglund syndrome; Erythromelalgia The present invention features a method for treating or reducing the severity of pain; Fabry disease pain; bladder and genitourinary disorders; urinary incontinence; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) types I and II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain in a subject, the method comprising administering an effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0127] In another aspect, the disclosure features a method of treating neuropathic pain or reducing its severity in a subject, the method comprising administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In one aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, post-spinal cord injury pain, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic cephalgia.

[0128] In some embodiments, a "therapeutically effective amount" refers to an amount that is effective in treating a disease when administered to a subject; for example, a therapeutically effective amount can be an amount sufficient to treat pain. A therapeutically effective amount can be determined empirically.

[0129] In some embodiments, the composition is administered orally, vaginally, rectally, or via inhalation to a subject suffering from pain or one or more symptoms of pain.In another embodiment, the composition is administered orally, vaginally, rectally, or via inhalation to a subject who is expected to suffer from pain or who is expected to have one or more symptoms of pain, but who may not yet suffer from pain or one or more symptoms of pain.

[0130] In some embodiments, the composition is administered to at least a portion of the body, and the subject may be suffering from pain or one or more symptoms of pain. In some embodiments, the composition is administered to at least a portion of the subject's hand, arm, limb, face and neck, or trunk, and the subject may be suffering from pain or one or more symptoms of pain. In another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be suffering from pain or one or more symptoms of pain. In yet another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be expected to suffer from pain or to have one or more symptoms of pain, but may not yet be suffering from pain or one or more symptoms of pain.

[0131] In one aspect, a method for reducing pain in a subject is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In some embodiments, pain is rated on a 0-10 point Likert scale, with 0 corresponding to no pain and 10 corresponding to the worst pain imaginable. In some embodiments, pain is assessed based on the subject's experience over the past 24 hours. In some embodiments, pain is assessed 7 days, 14 days, 21 days, or 28 days after initiation of administration of the composition. In some embodiments, the method comprises reducing the assessed pain by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from the subject's baseline assessment of pain prior to administration of the composition. In some embodiments, the method comprises reducing pain by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of pain in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce assessed pain by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from a baseline assessment of pain in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce pain by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of pain in the subject prior to administration of the composition. In various embodiments, pain is assessed based on the IBS Symptom Severity Scale, the Brief Pain Questionnaire, the Visceral Sensitivity Index, the Pain Numerical Rating Scale (P-NRS), the Illness Impact Profile, the Pain Disability Index, the Pain Catastrophizing Scale, the McGill Pain Questionnaire, or a combination thereof. In certain embodiments, pain is assessed based on the Pain Numerical Rating Scale (P-NRS), as described herein.

[0132] In some variations of the foregoing, the subject has been formally or clinically diagnosed as having pain.

[0133] Itching In some aspects, a method of treating pruritus in a subject in need thereof is provided, the method comprising administering to the subject a composition comprising a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0134] In the context of this disclosure, the term "pruritus" is intended to be interchangeable with the term "itch" and defines the well-known sensory state associated with the desire to scratch. The sensory state associated with itch is distinct from that of pain, although itch and pain can be caused by a variety of chemical, mechanical, thermal, or electrical stimuli. Itch and pain differ in that (1) itch, unlike pain, can only be elicited from the superficial layers of the skin, mucous membranes, and conjunctiva, and (2) itch and pain do not usually occur simultaneously in the same skin region. For example, applying histamine to the skin produces itch but not pain. Furthermore, itch and pain are treated by different pharmacological principles in that itch is considered insensitive to opiate and nonsteroidal anti-inflammatory drug (NSAID) treatments, both of which are effective in treating pain. Finally, itch originates solely in the skin, while pain originates from deeper structures. The pruritus may be localized to various well-defined skin areas (such as the skin of the ankles, wrists, lips, hands, chest, and the like) or may be generalized pruritus that is not localized to a particular part of the skin.

[0135] Pruritus, regardless of its nature or the extent to which inflammation or hypersensitivity reactions are part of the pathology, can be associated with numerous dermatological disorders, including, but not limited to, acne vulgaris, alopecia, asteatotic eczema, atopic dermatitis, melanoma, drug-induced skin reactions, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, lichen simplex chronicus, lichen planus, pemphigus, pemphigoid, actinic dermatitis, pityriasis rosea, pyoderma gangrenosum, dyshidrotic eczema, psoriasis, prurigo nodularis, rosacea, scabies, seborrheic dermatitis, seborrhea, scleroderma, Sjogren's disease, stasis dermatitis, subacute cutaneous lupus erythematosus, photodermatitis, vitiligo, and urticaria.

[0136] Dermatological causes of pruritus are often associated with hypersensitivity or allergic reactions in the skin, such as type I or type IV allergic reactions. Thus, pruritus can be associated with atopic dermatitis and its various types (atopic dermatitis, hand eczema, infantile eczema, childhood eczema, adult eczema, keratosis pilaris, ichthyosis vulgaris, hand and foot dermatitis, keratoconus, dyshidrotic eczema, discoid eczema, nummular eczema) and allergic contact reactions, such as contact dermatitis and its various types (allergic contact dermatitis, irritant contact dermatitis, and overtreatment dermatitis).

[0137] In some aspects, the disclosure provides a method of treating pruritus in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of nootkatone, optionally wherein (a) the composition has less than about 5% w / w of other components naturally occurring in nootkatone-containing sources, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b). The subject is a human, cat, dog, or horse. The composition is administered topically. The composition has less than about 1% w / w of other components naturally occurring in nootkatone-containing sources, and the nootkatone in the composition has a purity of at least about 99% w / w. The composition further comprises petrolatum. The composition comprises about 1.5% to about 10% w / w of nootkatone and is administered once or twice daily. The composition is administered for at least 12 weeks. Additionally, administration of the composition to a subject reduces pruritus after a predetermined period of time, as determined according to the pruritus itch numerical rating scale (I-NRS).

[0138] In one aspect, the disclosure provides a method of treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, the method comprising administering to the subject a therapeutically effective amount of a composition comprising nootkatone, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB; and optionally, (a) the composition has less than about 5% w / w of other components naturally present in a nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0139] In one aspect, the present disclosure provides a pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in a method of treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0140] In one aspect, the disclosure provides use of nootkatone, or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for use in treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0141] In some embodiments, the administered composition is a personal care product. In one variation, the administered composition is a cosmetic, a pharmaceutical, or both. In one particular variation, the administered composition meets U.S. Food and Drug Administration regulations, including the requirements governing cosmetics, pharmaceuticals, or both.

[0142] In some variations, the methods provided herein alleviate, slow, or halt the onset or progression of one or more symptoms caused by or associated with pruritus. In other variations, the methods provided herein reduce the intensity of or alleviate pruritus by causing regression of one or more symptoms. In various embodiments, nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone may be effective in treating a variety of conditions associated with several types of pruritus classified by Twycros et al. (Quart. J. Med. 2003;96:7-26), which is incorporated by reference in its entirety: pruriceptive (those related to the skin, e.g., scabies), neuropathic (those resulting from lesions of afferent pathways in the nervous system, e.g., peripheral neuritis, brain tumors), neurogenic (those resulting from centrally acting mediators that do not damage the central nervous system, e.g., opioid peptides in cholestatic disorders), and psychogenic.

[0143] In some embodiments, a "therapeutically effective amount" also refers to an amount that is effective in treating a disease when administered to a subject; for example, a therapeutically effective amount can be an amount sufficient to treat pruritus. A therapeutically effective amount can be confirmed empirically.

[0144] In some embodiments, the composition is administered to at least a portion of the body, and the subject may be suffering from pruritus or one or more symptoms of pruritus. In some embodiments, the composition is administered to at least a portion of the subject's hand, arm, limb, face and neck, or trunk, and the subject may be suffering from pruritus or one or more symptoms of pruritus. In another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be suffering from pruritus or one or more symptoms of pruritus. In yet another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be expected to suffer from pruritus or to have one or more symptoms of pruritus, but may not yet be suffering from pruritus or one or more symptoms of pruritus. In some embodiments, pruritus is assessed based on the Itch Numerical Rating Scale (I-NRS), as described herein.

[0145] In some variations of the foregoing, the subject has been formally or clinically diagnosed as having pruritus.

[0146] Atopic dermatitis In some aspects, a method of treating eczema in a subject in need thereof is provided, the method comprising administering to the subject a composition comprising a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0147] In some variations, the eczema is atopic dermatitis. Atopic dermatitis is a condition in which the skin of an affected subject becomes red and itchy. Atopic dermatitis can be chronic and may flare up periodically. Symptoms of atopic dermatitis can include, for example, dry skin; itching; red to brownish-gray patches; small bumps (which may ooze fluid and / or crust when scratched), scaly skin, and sensitive skin due to scratching. Subjects with atopic dermatitis may also have other conditions (such as asthma or hay fever). Atopic dermatitis can affect children, adolescents, and adults.

[0148] In some variations, the compositions herein are used to treat eczema (including, for example, atopic dermatitis) in humans and other animals with naturally occurring eczema.

[0149] In some embodiments, the administered composition is a personal care product. In one variation, the administered composition is a cosmetic, a pharmaceutical, or both. In one particular variation, the administered composition meets U.S. Food and Drug Administration regulations, including the requirements governing cosmetics, pharmaceuticals, or both.

[0150] In some variations, the methods provided herein alleviate, slow, or halt the onset or progression of one or more symptoms caused by or associated with eczema (including, for example, atopic dermatitis). In other variations, the methods provided herein reduce the severity of or alleviate eczema by causing regression of one or more symptoms.

[0151] In some embodiments, a "therapeutically effective amount" refers to an amount that is effective in treating a disease when administered to a subject; for example, a therapeutically effective amount may be an amount sufficient to treat eczema (including, for example, atopic dermatitis). A therapeutically effective amount may be confirmed empirically.

[0152] In some embodiments, the composition is administered to at least a portion of the body, and the subject may be suffering from eczema or one or more symptoms of eczema. In some embodiments, the composition is administered to at least a portion of the subject's hands, arms, limbs, face and neck, or trunk, and the subject may be suffering from eczema or one or more symptoms of eczema. In another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be suffering from eczema or one or more symptoms of eczema. In yet another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be expected to suffer from eczema or to have one or more symptoms of eczema, but may not yet suffer from eczema or one or more symptoms of eczema.

[0153] In some variations, the composition is administered to a subject with mild to severe eczema (e.g., atopic dermatitis). In some variations, the composition is administered to a subject with mild to moderate eczema (e.g., including atopic dermatitis). In one particular variation, eczema (e.g., including atopic dermatitis) affects about 5% to about 20% of the subject's total body surface area, excluding the face, scalp, axillae, and intertriginous areas.

[0154] In some embodiments, administration of the composition to a subject reduces redness, average lesion size, itching, or pain caused by eczema (including, e.g., atopic dermatitis), or improves the overall complexion of areas affected by eczema, or any combination of the foregoing.

[0155] In one aspect, a method for reducing redness in a subject suffering from eczema is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In a variation of the foregoing aspect, the method reduces redness in a subject suffering from atopic dermatitis. In some embodiments, redness is rated on a scale of 0 to 10, with 0 corresponding to no redness and 10 corresponding to the worst redness imaginable. In some embodiments, the method comprises reducing redness by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from baseline redness in the subject assessed prior to administration of the composition. In some embodiments, the method comprises reducing redness by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline redness in the subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce redness by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from baseline redness in a subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce redness by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline redness in a subject assessed prior to administration of the composition.

[0156] In one aspect, a method of reducing the severity of eczema in a subject suffering from eczema is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In a variation of the foregoing aspect, the method reduces the severity of atopic dermatitis in a subject suffering from atopic dermatitis. In some embodiments, severity is assessed on a 0-4 point scale, with 0 corresponding to clear and 4 corresponding to severe. In some embodiments, severity is assessed based on one or more criteria selected from the group consisting of erythema, induration or papule formation, and weeping or crusting. In some embodiments, severity is assessed on a 0-4 point Investigator Global Assessment (IGA) scale detailed in Table 5 herein. In some embodiments, severity is assessed on a 0-4 point Participant Global Assessment (PGA) scale detailed in Table 5 herein. In some embodiments of the foregoing, the severity of the eczema is assessed using an Eczema Area and Severity Index (EASI) score of 0 to 72, as detailed in Table 5 herein. In some embodiments, the method comprises reducing the severity by about 4 points, about 3 points, about 2 points, or about 1 point on the IGA scale from baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprises reducing the severity by about 4 points, about 3 points, about 2 points, or about 1 point on the PGA scale from baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprises reducing the severity by about 72 points, about 64 points, about 56 points, about 48 points, about 40 points, about 32 points, about 24 points, about 26 points, or about 8 points on the EASI scale from baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprises reducing severity by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce severity by about 4 points, about 3 points, about 2 points, or about 1 point on the IGA scale from baseline severity in the subject assessed prior to administration of the composition.In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce severity by about 4 points, about 3 points, about 2 points, or about 1 point on the PGA scale from baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce severity by about 72 points, about 64 points, about 56 points, about 48 points, about 40 points, about 32 points, about 24 points, about 26 points, or about 8 points on the EASI scale from baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce severity by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline severity in the subject assessed prior to administration of the composition.

[0157] In one aspect, a method of improving the appearance of skin in a subject suffering from eczema is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In a variation of the foregoing aspect, the method improves the appearance of skin in a subject suffering from atopic dermatitis. In some embodiments, the improvement in skin appearance is assessed by the subject suffering from atopic dermatitis. In some embodiments, the improvement in skin appearance is measured on a 1-7 point Global Image Change (GIC) scale as set forth in Table 8 herein. In some embodiments, the method results in skin that is very much improved, very much improved, minimally improved, or unchanged in appearance compared to the skin's appearance immediately prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to result in skin that is very much improved, very much improved, minimally improved, or unchanged in appearance compared to the skin's appearance immediately prior to administration of the composition.

[0158] In one aspect, a method of reducing the severity of target lesions in a subject suffering from eczema is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In a variation of the foregoing aspect, the method reduces the severity of target lesions in a subject suffering from atopic dermatitis. In some embodiments, the severity of the target lesions is assessed based on one or more criteria selected from the group consisting of erythema, edema or papulation, weeping or crusting, excoriation, lichenification, and dryness. In some embodiments, the target lesions are at least 10 cm 2 It has an area of

[0159] In one aspect, a method of reducing average lesion size in a subject suffering from eczema is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In a variation of the foregoing aspect, the method reduces average lesion size in a subject suffering from atopic dermatitis. In some embodiments, the method comprises reducing the average lesion size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% from the baseline average lesion size in the subject measured before administration of the composition. In some embodiments, the methods involve administering the composition for a period of time sufficient to reduce average lesion size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% from a baseline average lesion size in the subject measured prior to administration of the composition.

[0160] In one aspect, a method for reducing itch in a subject suffering from eczema is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In a variation of the foregoing aspect, the method reduces itch in a subject suffering from atopic dermatitis. In some embodiments, itch is rated on a 0-10 point Likert scale, with 0 corresponding to no itch and 10 corresponding to the worst itch imaginable. In some embodiments, itch is assessed based on the subject's experience over the past 24 hours. In some embodiments, itch is assessed 7, 14, 21, or 28 days after initiation of administration of the composition. In some embodiments, the method comprises reducing itch assessment by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from the subject's baseline assessment of itch prior to administration of the composition. In some embodiments, the method comprises reducing itch by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of itch in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce assessed itch by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from a baseline assessment of itch in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce itch by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of itch in the subject prior to administration of the composition.

[0161] In one aspect, a method for reducing pain in a subject suffering from eczema is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In a variation of the foregoing aspect, the method reduces pain in a subject suffering from atopic dermatitis. In some embodiments, pain is rated on a 0-10 point Likert scale, with 0 corresponding to no pain and 10 corresponding to the worst pain imaginable. In some embodiments, pain is assessed based on the subject's experience over the past 24 hours. In some embodiments, pain is assessed 7, 14, 21, or 28 days after initiation of administration of the composition. In some embodiments, the method comprises reducing the assessed pain by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from the subject's baseline assessment of pain prior to administration of the composition. In some embodiments, the method comprises reducing pain by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of pain in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce assessed pain by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from a baseline assessment of pain in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce pain by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of pain in the subject prior to administration of the composition.

[0162] In some variations of the foregoing, the subject has been formally or clinically diagnosed with eczema (including, for example, atopic dermatitis).

[0163] psoriasis In some embodiments, the composition is administered to at least a portion of the body, and the subject may be suffering from psoriasis or one or more symptoms of psoriasis. In some embodiments, the composition is administered to at least a portion of the subject's hands, arms, limbs, face and neck, or trunk, and the subject may be suffering from psoriasis or one or more symptoms of psoriasis. In another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be suffering from psoriasis or one or more symptoms of psoriasis. In yet another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be suspected of having psoriasis or one or more symptoms of psoriasis, but may not yet be suffering from psoriasis or one or more symptoms of psoriasis.

[0164] In some embodiments, the subject has mild to moderate psoriasis. In some embodiments, psoriasis affects about 3% to about 15% of the subject's total body surface area, excluding the face, scalp, hands, or soles of the feet. In some embodiments, the psoriasis is plaque psoriasis. In some embodiments, the psoriasis is flexural psoriasis. In some embodiments, the psoriasis is guttate psoriasis. In some embodiments, the psoriasis is pustular psoriasis. In some embodiments, the psoriasis is erythrodermic psoriasis.

[0165] In some embodiments, administration of the composition to a subject reduces itching, redness, scaling, burning, stinging, cracking, scaling, or pain, or a combination thereof, caused by psoriasis.

[0166] In one aspect, a method of reducing redness in a subject suffering from psoriasis is provided, the method comprising administering to the subject any of the compositions described herein. In some embodiments, redness is rated on a scale of 0 to 5, with 0 corresponding to no redness and 5 corresponding to very severe redness. In some embodiments, the method comprises reducing redness by about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from baseline redness in the subject assessed prior to administration of the composition. In some embodiments, the method comprises reducing redness by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline redness in the subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce redness by about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from baseline redness in the subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce redness by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline redness in a subject assessed prior to administration of the composition.

[0167] In one aspect, a method of reducing the severity of target lesions caused by psoriasis in a subject is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In some embodiments, the severity of the target lesions is assessed based on one or more criteria selected from the group consisting of erythema, edema / papulation, weeping / crusting, peeling, lichenification, and dryness. In some embodiments, the target lesions are assessed based on one or more criteria selected from the group consisting of Physician's Global Assessment (PGA), Itchy-Red Numerical Rating Scale (I-NRS), and Patient Global Assessment (PGIC) described herein in Table 11. In some embodiments, the target lesions are at least 10 cm 2 It has an area of

[0168] In one aspect, a method for reducing average lesion size caused by psoriasis in a subject is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In some embodiments, the method comprises reducing the average lesion size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% from the baseline average lesion size in the subject measured prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce the average lesion size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% from the baseline average lesion size in the subject measured prior to administration of the composition.

[0169] In one aspect, a method of reducing the severity of psoriasis in a subject suffering from psoriasis is provided, the method comprising administering any of the compositions described herein to the subject. In some embodiments, the severity of psoriasis in the subject is assessed on a 0-4 point scale, with 0 corresponding to clear and 4 corresponding to severe. In some embodiments, the severity of psoriasis is assessed based on one or more criteria selected from the group consisting of erythema, edema / papulation, weeping / crusting, peeling, lichenification, and dryness. In some embodiments, the severity of psoriasis is assessed on a 0-4 point Physician's Global Assessment (PGA) scale detailed in Table 9 herein. In some embodiments, the method comprises reducing the severity of psoriasis by about 4 points, about 3 points, about 2 points, or about 1 point from the baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprises reducing severity by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline severity in a subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce the severity of psoriasis by about 4 points, about 3 points, about 2 points, or about 1 point from baseline severity in a subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce severity by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline severity in a subject assessed prior to administration of the composition.

[0170] In one aspect, a method of reducing the severity of psoriasis in a subject suffering from psoriasis is provided, the method comprising administering to the subject any of the compositions described herein. In some embodiments, the severity of psoriasis is assessed on the Psoriasis Area and Severity Index (PASI) scale, which ranges from 0 to 72 points, and the severity of erythema, induration, and scaling is assessed on a scale of 0 to 4 points for the head and neck, upper limbs, lower limbs, and trunk, respectively; the sum of the scores for each body region is multiplied by a weighting factor of 0.1 for the head, 0.2 for the upper limbs, 0.3 for the trunk, or 0.4 for the lower limbs; and each weighted score is multiplied by a score of 0 to 6 based on the percent surface area of ​​the body region affected by psoriasis (no effect = score 0, 1-9% = score 1, 10-29% = score 2, 30-49% = score 3, 50-69% = score 4, 70-89% = score 5, and 90-100% = score 6), and the resulting scores are summed to arrive at a total score on the PASI scale. In some embodiments, the method comprises reducing psoriasis severity, as assessed by PASI, by about 72 points, about 64 points, about 56 points, about 48 points, about 40 points, about 32 points, about 24 points, about 26 points, or about 8 points from baseline severity in a subject assessed prior to administration of the composition. In some embodiments, the method comprises reducing severity, as assessed by the PASI scale, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline severity in a subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce psoriasis severity, as assessed by PASI, by about 72 points, about 64 points, about 56 points, about 48 points, about 40 points, about 32 points, about 24 points, about 26 points, or about 8 points from baseline severity in a subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce severity as assessed by the PASI scale by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from baseline severity in the subject assessed prior to administration of the composition.

[0171] In one aspect, a method of reducing total body surface area (BSA) affected by psoriasis is provided, the method comprising administering any of the compositions described herein to a subject. In some embodiments, the method comprises reducing the total BSA affected by psoriasis by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% compared to a baseline total BSA affected by psoriasis in a subject assessed prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce the total BSA affected by psoriasis by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% compared to a baseline total BSA affected by psoriasis in a subject assessed prior to administration of the composition.

[0172] In one aspect, a method for reducing average plaque size in a subject suffering from psoriasis is provided, the method comprising administering any of the compositions described herein to the subject. In some embodiments, the method comprises reducing the average plaque size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% from the baseline average plaque size in the subject measured before administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce the average plaque size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% from the baseline average plaque size in the subject measured before administration of the composition.

[0173] In one aspect, a method of reducing itch (or itching) in a subject suffering from psoriasis is provided, the method comprising administering to the subject any of the compositions described herein. In some embodiments, itch is rated on a 0-10 point Likert scale, with 0 corresponding to no itch and 10 corresponding to the worst itch imaginable. In some embodiments, itch is assessed based on the subject's experience over the past 24 hours. In some embodiments, itch is assessed 7, 14, 21, or 28 days after initiation of administration of the composition. In some embodiments, the method comprises reducing assessed itch by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from the subject's baseline assessment of itch prior to administration of the composition. In some embodiments, the method comprises reducing itch by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of itch in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce assessed itch by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from a baseline assessment of itch in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce itch by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of itch in the subject prior to administration of the composition.

[0174] In one aspect, a method for reducing pain in a subject suffering from psoriasis is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In some embodiments, pain is rated on a 0-10 point Likert scale, with 0 corresponding to no pain and 10 corresponding to the worst pain imaginable. In some embodiments, pain is assessed based on the subject's experience over the past 24 hours. In some embodiments, pain is assessed 7, 14, 21, or 28 days after initiation of administration of the composition. In some embodiments, the method comprises reducing the assessed pain by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from the subject's baseline pain rating prior to administration of the composition. In some embodiments, the method comprises reducing pain by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of pain in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce assessed pain by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from a baseline assessment of pain in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to reduce pain by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% from a baseline assessment of pain in the subject prior to administration of the composition.

[0175] In one aspect, a method of improving the appearance of the skin in a subject suffering from psoriasis is provided, the method comprising administering to the subject any of the compositions or pharmaceutical compositions comprising nootkatone described herein. In some embodiments, the improvement in skin appearance is assessed by the subject suffering from psoriasis. In some embodiments, the improvement in skin appearance is measured using the Patient Global Impression Change (PGIC) scale of 1 to 7, as set forth in Table 11 herein. In some embodiments, the method results in skin that is very much improved, very much improved, minimally improved, or unchanged in appearance compared to the appearance of the skin immediately prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to result in skin that is very much improved, very much improved, minimally improved, or unchanged in appearance compared to the appearance of the skin immediately prior to administration of the composition.

[0176] In some variations of the foregoing, the subject has been formally or clinically diagnosed as having psoriasis.

[0177] In some aspects, the disclosure features a method of treating psoriasis in a subject in need thereof, the method including administering to the subject a composition including a therapeutically effective amount of nootkatone, where optionally (a) the composition has less than about 5% w / w of other components naturally occurring in nootkatone-containing sources, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b). The subject is a human, cat, dog, or horse. The composition is administered topically. The composition has less than about 1% w / w of other components naturally occurring in nootkatone-containing sources, and the nootkatone in the composition has a purity of at least about 99% w / w. The composition further includes petrolatum. The composition includes about 1.5% to about 10% w / w of nootkatone. The composition is administered once or twice daily for at least 12 weeks.

[0178] Improved skin appearance Nootkatone and dermatologically acceptable compositions are useful for improving the appearance of skin (e.g., skin exhibiting one or more diseases, disorders, or conditions), including, but not limited to, pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy. The phrase "improving the appearance of skin" includes, but is not limited to, clearing the skin or reducing mild residual discoloration, and reducing erythema, induration, papulation, edema, exfoliation, lichenification, weeping / crusting, redness, or a combination thereof. In various embodiments, nootkatone and dermatologically acceptable compositions are functionalized cosmetic compositions that improve skin elasticity, skin tension, prevent skin dryness, exhibit skin-improving effects (e.g., wrinkle reduction, skin lightening), reduce skin inflammation, skin lesions, and combinations thereof. In various embodiments, the prevention, improvement, or treatment of skin conditions provides skin lubrication, skin exfoliation, reduced skin redness, reduced skin inflammation, reduced skin flushing, reduced skin dryness, improved skin radiance, improved skin tone, improved skin clarity, improved skin firmness, improved skin tautness, improved skin elasticity, and / or improved overall skin appearance. In various embodiments, nootkatone and dermatologically acceptable compositions are inhibitors or modulators of one or more of the following therapeutic targets: voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB. Accordingly, nootkatone and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of various diseases, disorders, or conditions described herein.

[0179] In various embodiments, the terms "inhibit" and "modulate" are used interchangeably to refer to an agent that reduces or suppresses a biological activity (e.g., abrogating the activity of an ion channel such as NaV1.7). NaV1.7 inhibitors include inhibitors having any combination of the structural and / or functional properties disclosed herein.

[0180] In certain embodiments, nootkatone or a dermatologically acceptable salt thereof has an IC of less than 50 micromolar (μM), optionally less than 40 μM, optionally less than 30 μM, optionally less than 20 μM, optionally less than 10 μM, or optionally less than 1 μM. 50 Alternatively, nootkatone or a dermatologically acceptable salt thereof has an IC50 of about 0.01 μM to about 100 μM, optionally about 0.1 μM to about 75 μM, optionally about 1 μM to about 50 μM, optionally about 1 μM to about 25 μM, or optionally about 1 μM to about 10 μM. 50 to inhibit or modulate one or more of the therapeutic targets.

[0181] In some embodiments, the method includes administering nootkatone or a dermatologically acceptable salt thereof to a subject in a pharmaceutical excipient to form a composition. The composition may contain 10-500 mg, 10-800 mg, 20-1,000 mg, 30-1,200 mg, 50-1,500 mg, or 100-2,000 mg, or more of nootkatone or a dermatologically acceptable salt thereof in a single dosage unit. Consequently, preferred oral single dosage units (or recommended daily intakes) are 20-200 mg, 40-400 mg, 60-600 mg, 80-800 mg, 100-1,000 mg, or 200-2,000 mg, or in some cases even greater.

[0182] As used herein, the term "administering" a cosmetic composition or drug refers to both direct administration and indirect administration of a cosmetic composition or drug, where direct administration of a cosmetic composition or drug is typically performed by a medical professional (e.g., a doctor, a nurse, etc.), and indirect administration includes providing the cosmetic composition or drug to a medical professional or making the cosmetic composition or drug available to a medical professional for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.).

[0183] In some aspects, methods of improving the appearance of skin in a subject in need thereof are provided, the methods comprising administering to the subject a composition comprising a therapeutically effective amount of nootkatone, a dermatologically acceptable salt thereof, or a cosmetic composition of nootkatone. In some embodiments, the skin exhibits pain, pruritus, symptoms of atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy.

[0184] In various embodiments, the method of use can also be referred to as a cosmetic method for improving the appearance of the skin of a subject with skin imperfections. Specifically, the composition is useful and can be used to improve the appearance of the skin of a subject with skin imperfections. The subject is typically a human being and can be of various ages. The composition is not limited to a specific subject or a specific location on the skin of the subject. For example, a person can apply the composition to their face, neck, arms, hands, chest, torso, legs, feet, etc., or any combination thereof.

[0185] In some embodiments, the composition is administered to at least a portion of the body, and the subject may be suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy, or one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy. In some embodiments, the composition is administered to at least a portion of the hand, arm, limb, face and neck, or trunk, and the subject may be suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy, or one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy. In another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy, or may be suffering from one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy. In yet another embodiment, the composition is administered to at least a portion of the entire body, and the subject may be expected to suffer from pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy, or may be expected to have one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy, but may not yet be suffering from psoriasis, or one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy.

[0186] In one aspect, a method for improving the appearance of skin in a subject suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy is provided, the method comprising administering to the subject any of the compositions comprising nootkatone or cosmetic compositions described herein. In some embodiments, the improvement in skin appearance is assessed by the subject suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy. In some embodiments, the improvement in skin appearance is measured using the Patient Global Impression Change (PGIC) scale of 1 to 7, as set forth in Table 8 herein. In some embodiments, the method results in skin that is very much improved, very much improved, minimally improved, or unchanged in appearance compared to the skin's appearance immediately prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period sufficient to result in skin that is very much improved, very much improved, minimally improved, or unchanged in appearance compared to the skin's appearance immediately prior to administration of the composition.

[0187] In some variations of the foregoing, the subject has been formally or clinically diagnosed with pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disorders, or diabetic peripheral neuropathy.

[0188] Pharmaceutical / cosmetic manufacturing In one aspect, the disclosure provides use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in inhibiting a therapeutic target (such as at least one of voltage-gated sodium channels (NaV), kappa opiate receptors (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB). In various embodiments, nootkatone does not inhibit NaV1.5.

[0189] In yet another aspect, the disclosure provides for the use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain in a subject.

[0190] In yet another aspect, the disclosure provides a use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating or reducing the severity of intestinal or abdominal pain in a subject, wherein the intestinal or abdominal pain comprises irritable bowel syndrome (IBS) pain, celiac disease pain, inflammatory bowel disease (IBD) pain (such as Crohn's disease pain or ulcerative colitis pain), endometriosis pain, or interstitial cystitis pain.

[0191] In yet another aspect, the disclosure provides a use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain includes post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; post-spinal cord injury pain, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic neuropathy.

[0192] In yet another aspect, the present disclosure provides a use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject, wherein musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, heat pain, or dental pain.

[0193] In yet another aspect, the present disclosure provides a use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating inflammatory pain or reducing its severity in a subject, wherein inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0194] In yet another aspect, the present disclosure provides for the use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating or reducing the severity of idiopathic pain in a subject, wherein idiopathic pain includes fibromyalgia pain.

[0195] In yet another aspect, the disclosure provides for the use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament in combination with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with nootkatone or the pharmaceutical composition.

[0196] In another aspect, the disclosure provides a use of nootkatone or a pharmaceutical composition as described herein for the manufacture of a medicament for use in treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, status epilepticus, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal dysmotility.

[0197] In another aspect, the present disclosure provides a method for treating femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tousen-Neuropathic Neuropathy. Neuropathies; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom limb pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury / exercise pain; acute visceral pain; pyelonephritis; appendix Inflammation; Cholecystitis; Intestinal obstruction; Hernia; Chest pain, cardiac pain; Pelvic pain, renal colic pain, acute obstetric pain, labor pain; Caesarean section pain; Acute inflammatory, febrile, and traumatic pain; Acute intermittent pain, endometriosis; Acute shingles pain; Sickle cell anemia; Acute pancreatitis; Breakthrough pain; Orofacial pain; Sinusitis pain; Toothache; Multiple sclerosis (MS) pain; Pain in depression; Leprosy pain; Behcet's disease pain; Adiposity; Phlebitis pain; Guillain-Barré pain; Sore legs and moving toes syndrome; Hugging The present invention provides the use of nootkatone or a pharmaceutical composition as described herein for the manufacture of a medicament for use in treating or reducing the severity of: bladder and genitourinary disorders; urinary incontinence; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) types I and II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0198] In yet another aspect, the present disclosure provides use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain. In one aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, post-spinal cord injury pain, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic headache.

[0199] In yet another aspect, the present disclosure provides a use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating or reducing the severity of pruritus in a subject.

[0200] In yet another aspect, the present disclosure provides a use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating or reducing the severity of atopic dermatitis or psoriasis in a subject.

[0201] In yet another aspect, the present disclosure provides a use of nootkatone or a pharmaceutical composition described herein for the manufacture of a medicament for use in treating or reducing the severity of diabetic skin disorders or diabetic peripheral neuropathy in a subject.

[0202] In yet another aspect, the present disclosure provides use of nootkatone or a cosmetic composition described herein for the manufacture of a cosmetic product for use in improving the appearance of skin.

[0203] Embodiments of the present disclosure also include methods for preparing the above compositions, for example, by conventional mixing and the like. For example, in some embodiments, nootkatone may be combined with any combination of the above ingredients in purified water using conventional mixing, and after a stable emulsion is formed, the pH and viscosity may be adjusted using known methods to achieve a cream with an appropriate pH. In other embodiments, various combinations of ingredients may be combined in purified water by conventional mixing, and then nootkatone may be added to the mixture. The pH, viscosity, opacity, and / or density may be adjusted to achieve a cosmetically acceptable cream.

[0204] Administration of Pharmaceutically Acceptable Salts and Compositions In certain embodiments of the present disclosure, an "effective amount" of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition is an amount effective to treat or lessen the severity of one or more of pruritus, chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain.

[0205] Nootkatone and compositions, according to the methods of the present disclosure, may be administered in any amount and using any route of administration effective for treating or reducing the severity of one or more of the pain or non-pain disorders described herein. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the infection, the particular drug, its mode of administration, and the like. Nootkatone may be formulated in dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form," as used herein, refers to a physically discrete pharmaceutical unit appropriate for the subject to be treated. However, it will be understood that the total daily usage of nootkatone and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the particular compound used; duration of treatment; drugs used in combination or concomitantly with the particular compound used, and similar factors well known in the medical arts. The term "subject" or "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.

[0206] The pharmaceutically acceptable compositions of the present disclosure may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powder, ointment, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. The phrases "parenteral administration" and "parenterally administered," as used herein, mean modes of administration other than intradigestive and topical administration (usually by injection), and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. In certain embodiments, nootkatone of the present disclosure may be administered orally or parenterally at dosage levels of from about 0.01 mg / kg of the subject's body weight / day to about 100 mg / kg of the subject's body weight / day, from about 0.01 mg / kg of the subject's body weight / day to about 50 mg / kg of the subject's body weight / day, optionally from about 1 mg / kg of the subject's body weight / day to about 25 mg / kg of the subject's body weight / day, one or more times daily to achieve the desired therapeutic effect.

[0207] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to nootkatone, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof). In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfuming agents.

[0208] In addition to nootkatone, the suspension may also contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0209] Sterols (such as cholesterol) are known to complex with cyclodextrins. Thus, in certain embodiments, when the inhibitor is a steroidal alkaloid, the inhibitor may be formulated with a cyclodextrin (such as α-, β-, and γ-cyclodextrin, dimethyl-β-cyclodextrin, and 2-hydroxypropyl-β-cyclodextrin).

[0210] Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated using suitable dispersing or wetting agents and suspending agents according to the knowledge of the art. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents (e.g., solutions in 1,3-butanediol, etc.). Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic monodiglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

[0211] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, by autoclaving, or by including a sterilizing agent in a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use. In various embodiments, the first part of the formulation (e.g., nootkatone) can be sterilized by filtration, and the second part (e.g., pharmaceutical excipients) can be sterilized by autoclaving.

[0212] To prolong the effect of nootkatone, it is often desirable to slow its absorption from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. Consequently, the rate of absorption of nootkatone depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending nootkatone in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of nootkatone in biodegradable polymers (such as polylactide-polyglycolide). Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by encapsulating nootkatone in liposomes or microemulsions that are compatible with body tissues.

[0213] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, nootkatone is mixed with at least one inert pharmaceutically acceptable excipient or carrier, which may be sodium citrate or dicalcium phosphate and / or a) fillers or extenders (such as starch, lactose, sucrose, glucose, mannitol, and silicic acid), b) binders (such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), c) humectants (such as glycerol), d) disintegrants (agar, Examples of additives include: calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate), e) solution flow retardants (such as paraffin), f) absorption accelerators (such as quaternary ammonium compounds), g) wetting agents (such as cetyl alcohol and glycerol monostearate), h) adsorbents (such as kaolin and bentonite clay), and i) lubricants (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0214] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using pharmaceutical excipients such as lactose or milk sugar, high molecular weight polyethylene glycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using pharmaceutical excipients such as lactose or milk sugar, high molecular weight polyethylene glycols, and the like.

[0215] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine.

[0216] Tablets and other solid dosage forms (such as dragees, capsules, pills, and granules) of the pharmaceutical compositions of the present invention can optionally be scored or prepared with coatings and shells (such as enteric coatings and other coatings well known in the pharmaceutical formulation art). They can also be formulated to delay or control the release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to achieve the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by including a sterilizing agent in a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be of a composition that releases the active ingredient(s) only, or selectively, in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0217] Formulations of the pharmaceutical compositions of the present disclosure for rectal, vaginal, or urethral administration may be present as suppositories, which may be prepared by mixing one or more compounds with one or more suitable non-irritating pharmaceutical excipients or carriers (e.g., including cocoa butter, polyethylene glycol, a suppository wax, or a salicylate), which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release nootkatone.

[0218] Alternatively or additionally, the compositions may be formulated for delivery via a catheter, stent, wire, or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0219] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0220] Nootkatone may also be in microencapsulated form containing one or more of the above-mentioned pharmaceutical excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, nootkatone may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition such that the release of the active ingredient(s) occurs only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0221] Dosage forms for the topical or transdermal administration of nootkatone include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Nootkatone may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0222] Ointments, pastes, creams, and gels may contain, in addition to nootkatone, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0223] Powders and sprays can contain, in addition to nootkatone, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0224] Transdermal patches have the added advantage of controlled delivery of nootkatone to the body. Such dosage forms can be made by dissolving or dispersing nootkatone in a suitable medium. Absorption enhancers can also be used to increase the flux of nootkatone across the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing nootkatone in a polymer matrix or gel.

[0225] Ophthalmic formulations, eye ointments, eye drops, and ear drops are also contemplated as being within the scope of this disclosure. Pharmaceutical compositions suitable for parenteral administration comprise one or more compounds in combination with one or more pharmaceutically acceptable sterile, isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders (which may contain antioxidants, buffers, bacterial growth inhibitors, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents) that can be reconstituted into sterile injectable solutions or dispersions immediately before use.

[0226] Examples of suitable aqueous and non-aqueous carriers that can be used in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). The proper fluidity can be maintained, for example, by using coating materials (such as lecithin), by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0227] Such compositions may also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the compositions. Furthermore, prolonged absorption of injectable pharmaceutical forms can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0228] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injection in order to prolong the effect of drugs.This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility.As a result, the absorption rate of a drug depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0229] When nootkatone is administered to humans and animals as a pharmaceutical, it may be given by itself or as a pharmaceutical composition containing the active ingredient (e.g., 0.1 to 99.5% (more preferably, 0.5 to 90%)) in combination with a pharmaceutically acceptable carrier.

[0230] The addition of nootkatone to animal feed is preferably accomplished by preparing a suitable feed premix containing an effective amount of nootkatone and including the premix in the complete ration.

[0231] Alternatively, intermediate concentrates or feed supplements containing the active ingredient can be blended into the feed. Methods for preparing and administering such feed premixes and complete rations are described in reference works (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, USA, 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., USA, 1977).

[0232] Introduction methods can also be provided by rechargeable or biodegradable devices. Recently, various sustained-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs (including proteinaceous biopharmaceuticals). Various biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of nootkatone at specific target sites.

[0233] Actual dosage levels of the active ingredient in the pharmaceutical compositions may be varied to provide an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient.

[0234] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound or its ester, salt, or amide employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0235] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start dosages of nootkatone used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0236] Generally, a suitable daily dose of nootkatone will be the amount of nootkatone that is the lowest therapeutically effective dose. Such an effective dose will generally depend on the factors described above. Generally, intravenous, intracerebroventricular, and subcutaneous doses of nootkatone for a patient will range from about 0.0001 to about 100 mg / kg body weight / day.

[0237] If desired, the effective daily dose of nootkatone may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.

[0238] The patient receiving this treatment may be any animal in need, including primates in general, particularly humans, as well as other mammals (such as horses, cattle, pigs, and sheep), as well as poultry and pets.

[0239] Nootkatone can be administered neat or in a mixture with a pharmaceutically acceptable and / or sterile carrier, and can also be administered in conjunction with other antimicrobial agents (such as penicillins, cephalosporins, aminoglycosides, and glycopeptides). Thus, combination therapy includes sequential, simultaneous, and separate administration of nootkatone in such a manner that the therapeutic effect of what is administered first is still detectable when the subsequent treatment is administered.

[0240] The present disclosure contemplates formulating the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Additionally, the present disclosure contemplates administration via any of the aforementioned routes of administration. One of skill in the art can select an appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated.

[0241] The activity of nootkatones utilized in this disclosure as inhibitors of therapeutic targets may be assayed according to the methods generally described in the Examples herein or according to methods available to one of skill in the art.

[0242] Additional therapeutic agents It will also be understood that the nootkatone and pharmaceutically acceptable compositions of the present disclosure can be used in combination therapy, i.e., nootkatone and pharmaceutically acceptable compositions can be administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures. The particular combination of therapies (therapeutics or procedures) to use in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It will also be understood that the treatments used can achieve a desired effect for the same disorder (e.g., a compound of the present invention can be administered simultaneously with another agent used to treat the same disorder), or the treatments can achieve a different effect (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease or condition being treated." For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles (such as etodolac, indomethacin, sulindac, tolmetin, etc.); naphthylalkanones (such as nabumetone); oxicams (such as piroxicam); para-aminophenol derivatives (such as acetaminophen); propionic acids (such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin, etc.); salicylates (such as aspirin, choline magnesium trisalicylate, diflunisal, etc.; fenamic acids (meclofenamic acid, mefenamic acid, etc.); and pyrazoles (phenylbutazone, etc.); or opioid (narcotic) agonists (codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine, etc.). Additionally, non-drug analgesic approaches may be utilized in conjunction with the administration of one or more compounds of the present disclosure.For example, anesthetic approaches (intraspinal injection, nerve blockade), neurosurgical approaches (neuroablation of CNS pathways), neurostimulatory approaches (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy approaches (physical therapy, orthotic devices, diathermy), or psychological approaches (cognitive methods - hypnosis, biofeedback, or behavioral methods) may also be used. Additional suitable therapeutic agents or approaches are generally described in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website at www.fda.gov (the entire contents of which are incorporated herein by reference).

[0243] In another embodiment, the additional suitable therapeutic agent is selected from the following: (1) an opioid analgesic (e.g., morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, or pentazocine). (2) nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulfasalazine, (3) barbiturates (e.g., amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental); (4) sedative benzodiazepines (e.g., chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, , oxazepam, temazepam, or triazolam; (5) sedating histamine (H1) antagonists (e.g., diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine); (6) sedatives (such as glutethimide, meprobamate, methaqualone, or dichloralphenazone); (7) muscle relaxants (e.g., baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine);(8) NMDA receptor antagonists (e.g., dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®) (a combination formulation of morphine and dextromethorphan), topiramate, neramexane, or perzinfotel (NR2B antagonists, e.g., ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1- (9) alpha-adrenergic agonists (e.g., doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline; (10) tricyclic antidepressants (e.g., desipramine, imipramine, amitriptyline, or nortriptyline); (11) anticonvulsants (e.g., carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproate);(12) Tachykinin (NK) antagonists, specifically NK-3, NK-2, or NK-1 antagonists (e.g., (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3 -(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S)); (13) muscarinic antagonists (e.g., oxybutynin, tolterodine, propiverine, tropsium chloride, chloride), darifenacin, solifenacin, temiverine, and ipratropium; (14) COX-2 selective inhibitors (e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib); (15) coal tar analgesics, specifically, paracetamol; (16) neuroleptics (droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, and atropine). Lipiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclineltant, Miraxion®, or sarizotan; (17) vanilloid receptor agonists (e.g., resiniferatoxin or cibamide) or antagonists (e.g., capsazepine, GRC-15300);(18) beta-adrenergic agonists (e.g., propranolol); (19) local anesthetics (e.g., mexiletine); (20) corticosteroids (e.g., dexamethasone); (21) 5-HT receptor agonists or antagonists, specifically, 5-HT1B / 1D agonists (e.g., eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan); (22) 5-HT2A receptor antagonists (R(+)-alpha-(2,3-dimethoxyphenyl) -1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907), etc.; (23) cholinergic (nicotinic) analgesics (such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine); (24) Tramadol®, tramadol ER (Ultram ER®), tapentadol ER (Nucynta®);(25) PDE5 inhibitor (5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indoline) 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide, etc.;(26) Alpha-2-delta ligands (gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[alpha], 3[alpha], 5[alpha])(3-amino-methyl-bicyclo[3.2.0]hepta- 3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hepta -6-yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5 -methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, etc.; (27) cannabinoids (e.g., KHK-6188); (28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonists; (29) serotonin reuptake; inhibitors (such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone); (3 0) noradrenaline (norepinephrine) reuptake inhibitors (such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan®)), particularly selective noradrenaline reuptake inhibitors (such as reboxetine, specifically (S,S)-reboxetine); (3 1) serotonin-norepinephrine dual reuptake inhibitors (venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine); (32) inducible nitric oxide synthase (iNOS) inhibitors (S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, etc.); in, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile;2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide, etc.; (33) acetylcholinesterase inhibitors (donepezil, etc.); (34) prostaglandin E2 subtype 4 (EP4) antagonists (N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide, or 4-[(15)-1-({[5-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide, etc.); (35) leukotriene B4 antagonists (1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057), or DPC-11870, etc.); (36) 5-lipoxygenase inhibitors (zileuton, 6-[(3- Fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504), etc.; (37) sodium channel blockers (lidocaine, lidocaine + tetracaine cream (ZRS-201), or eslicarbazepine acetate, etc.); (38) NaV1.7 blockers (XEN-402, etc. and WO2011 / 140425; WO2012 / 106499);(39) NaV1.8 blockers (such as those disclosed in WO2012 / 112743; WO2012 / 125613, or PCT / US2013 / 21535 (the entire contents of each application are incorporated herein by reference)); (40) NaV1.7 and NaV1.8 combined blockers (such as DSP-2230 or BL-1021); (41) 5-HT3 antagonists (such as ondansetron); (42) TP RV1 receptor agonists (such as capsaicin (NeurogesX®, Qutenza®); and pharmaceutically acceptable salts and solvates thereof); (43) nicotinic receptor antagonists (such as varenicline); (44) N-type calcium channel antagonists (such as Z-160); (45) nerve growth factor antagonists (such as tanezumab); (46) endopeptidase stimulators (such as senrebotase); and (47) angiotensin II antagonists (such as EMA-401).

[0244] In one embodiment, the additional suitable therapeutic agent is selected from V-116517, pregabalin, controlled-release pregabalin, ezogabine (Potiga®), ketamine / amitriptyline topical cream (Amiket®), AVP-923, perampanel (E-2007), ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (carisbamate), BMS-954561, or ARC-4558.

[0245] The amount of additional therapeutic agent present in the compositions of the present disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent, and will range from about 10% to about 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0246] Nootkatone or a pharmaceutically acceptable composition thereof can also be included in compositions for coating implantable medical devices (such as prostheses, artificial valves, vascular grafts, stents, and catheters). Accordingly, in another aspect, the present disclosure includes compositions for coating such implantable devices, comprising nootkatone as generally described above and belonging to the classes and subclasses herein, and a carrier suitable for coating such implantable devices. In yet another aspect, the present disclosure includes such implantable devices coated with a composition comprising nootkatone as generally described above and belonging to the classes and subclasses herein, and a carrier suitable for coating such implantable devices. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof to impart controlled release characteristics in the composition.

[0247] Another aspect of the present disclosure relates to inhibiting therapeutic target activity in a biological sample or subject, the method comprising administering nootkatone or a composition comprising nootkatone to the subject or contacting the biological sample with nootkatone or a composition comprising nootkatone. The term "biological sample," as used herein, includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0248] Inhibition of therapeutic target activity in biological samples is useful for a variety of purposes known to those of skill in the art, including, but not limited to, the study of therapeutic targets in biological and pathological phenomena and the comparative evaluation of new therapeutic target inhibitors.

[0249] In some embodiments, the present disclosure relates to a kit comprising a composition and specific instructions describing how to use the composition to treat or prevent pain or pruritus in a subject in need thereof.

[0250] Reference herein to a value or parameter modified by "about" includes (and describes) embodiments directed to the value or parameter itself. For example, a description of "about X" includes a description of "X." In some embodiments, the term "about," when used in connection with a measurement or to modify a value, unit, constant, or range of values, refers to a variation of + / - 10%, 5%, 2%, or 1%.

[0251] References herein to "between" two values ​​or parameters include (and describe) embodiments that include those two values ​​or parameters themselves. For example, a description that refers to "between x and y" includes a description of "x" itself and "y" itself.

[0252] Aspects of various embodiments of the present disclosure Aspect 1 Embodiment 1.1: A method of treating or preventing pruritus in a subject in need thereof, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; and optionally (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0253] Embodiment 1.2: The method of embodiment 1.1, wherein the subject is a human.

[0254] Embodiment 1.3: The method of embodiment 1.1, wherein the subject is a cat, dog, or horse.

[0255] Embodiment 1.4: The method of any one of Embodiments 1.1 to 1.3, wherein the composition is administered topically.

[0256] Aspect 1.5: The method of any one of Aspects 1.1 to 1.4, wherein the composition has less than about 1% w / w of other components naturally occurring in a nootkatone-containing source, and wherein the nootkatone in the composition has a purity of at least about 99% w / w.

[0257] Embodiment 1.6: The method of any one of Embodiments 1.1 to 1.5, wherein the composition further comprises an emulsifier.

[0258] Embodiment 1.7: The method of any one of Embodiments 1.1 to 1.5, wherein the composition further comprises a gelling agent.

[0259] Embodiment 1.8: The method of any one of Embodiments 1.1 to 1.7, wherein the composition comprises nootkatone.

[0260] Embodiment 1.9: The method of any one of Embodiments 1.1 to 1.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0261] Embodiment 1.10: The method of any one of Embodiments 1.1 to 1.9, wherein the composition comprises at least 5% w / w nootkatone.

[0262] Embodiment 1.11: The method of any one of Embodiments 1.1 to 1.8, wherein the composition comprises about 1.5% to about 10% w / w of nootkatone.

[0263] Embodiment 1.12: The method of any one of Embodiments 1.1 to 1.11, wherein the composition is administered once or twice daily.

[0264] Embodiment 1.13: The method of any one of Embodiments 1.1 to 1.12, wherein the composition is administered for at least 12 weeks.

[0265] Embodiment 1.14: The method of any one of Embodiments 1.1 to 1.13, wherein said administering said composition to said subject reduces itch after a predetermined time period, as determined according to an Itch Numerical Rating Scale (I-NRS).

[0266] Embodiment 1.15: The method of any one of Embodiments 1.1 to 1.13, wherein administering the composition to the subject reduces pruritus after a predetermined time period, as evidenced by a reduction in atopic dermatitis, as determined according to the Patient Oriented Eczema Measure (POEM).

[0267] Embodiment 1.16: A method of treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB; Optionally, (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0268] Aspect 1.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in a method of treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0269] Aspect 1.18: Use of nootkatone, or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for use in treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0270] Aspect 1.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in the treatment of pruritus, wherein said nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0271] Aspect 1.20: Nootkatone in a method for treating pruritus, said method comprising: 1. The method of claim 1, further comprising topically administering to the skin of a subject in need thereof a therapeutically effective amount of nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0272] Aspect 1.21: The method of Aspect 1.20, wherein said therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0273] Embodiment 1.22: The method of Embodiment 1.21, wherein said topical administration comprises topically administering an amount sufficient to reduce the intensity of pruritus, thereby alleviating pruritus by causing regression of one or more symptoms related to pruritus.

[0274] Aspect 2 Embodiment 2.1: A method of treating or preventing psoriasis in a subject in need thereof, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; and optionally (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0275] Embodiment 2.2: The method of embodiment 2.1, wherein the subject is a human.

[0276] Embodiment 2.3: The method of embodiment 2.1, wherein the subject is a cat, dog, or horse.

[0277] Embodiment 2.4: The method of any one of Embodiments 2.1 to 2.3, wherein the composition is administered topically.

[0278] Aspect 2.5: The method of any one of Aspects 2.1 to 2.4, wherein the composition has less than about 1% w / w of other components naturally occurring in the nootkatone-containing source, and wherein the nootkatone in the composition has a purity of at least about 99% w / w.

[0279] Embodiment 2.6: The method of any one of Embodiments 2.1 to 2.5, wherein the composition further comprises an emulsifier.

[0280] Embodiment 2.7: The method of any one of Embodiments 2.1 to 2.5, wherein the composition further comprises a gelling agent.

[0281] Embodiment 2.8: The method of any one of Embodiments 2.1 to 2.7, wherein the composition comprises nootkatone.

[0282] Embodiment 2.9: The method of any one of Embodiments 2.1 to 2.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0283] Embodiment 2.10: The method of any one of Embodiments 2.1 to 2.9, wherein the composition comprises at least 5% w / w nootkatone.

[0284] Embodiment 2.11: The method of any one of Embodiments 2.1 to 2.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0285] Embodiment 2.12: The method of any one of Embodiments 2.1 to 2.11, wherein the composition is administered once or twice daily.

[0286] Embodiment 2.13: The method of any one of Embodiments 2.1 to 2.12, wherein the composition is administered for at least 12 weeks.

[0287] Embodiment 2.14: The method of any one of Embodiments 2.1 to 2.13, wherein administering the composition to the subject reduces psoriasis after a predetermined time, as determined according to the Psoriasis Area and Severity Index (PASI), Target Lesion Severity Score (TLSS), or a combination thereof.

[0288] Embodiment 2.15: The method of any one of Embodiments 2.1 to 2.13, wherein administering the composition to the subject reduces psoriasis after a predetermined time period, as evidenced by a reduction in pruritus, as determined according to an Itch Numerical Rating Scale (I-NRS).

[0289] Embodiment 2.16: A method of treating or preventing psoriasis in a subject by inhibiting or modulating a therapeutic target, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB; Optionally, (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0290] Aspect 2.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in a method of treating or preventing psoriasis in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0291] Aspect 2.18: Use of nootkatone, or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for use in treating or preventing psoriasis in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-kB.

[0292] Aspect 2.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in the treatment of psoriasis, wherein said nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0293] Aspect 2.20: Nootkatone in a method for treating psoriasis, said method comprising: 1. The method of claim 1, further comprising topically administering to the skin of a subject in need thereof a therapeutically effective amount of nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0294] Aspect 2.21: The method of Aspect 2.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0295] Embodiment 2.22: The method of Embodiment 2.21, wherein said topical administration comprises topically administering an amount sufficient to reduce the severity of psoriasis and alleviate psoriasis by causing regression of one or more symptoms associated with psoriasis.

[0296] Aspect 3 Aspect 3.1: A method of treating or preventing atopic dermatitis in a subject in need thereof, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; and optionally (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0297] Embodiment 3.2: The method of embodiment 3.1, wherein the subject is a human.

[0298] Embodiment 3.3: The method of embodiment 3.1, wherein the subject is a cat, dog, or horse.

[0299] Embodiment 3.4: The method of any one of Embodiments 3.1 to 3.3, wherein the composition is administered topically.

[0300] Embodiment 3.5: The method of any one of Embodiments 3.1 to 3.4, wherein the composition has less than about 1% w / w of other components naturally occurring in the nootkatone-containing source, and wherein the nootkatone in the composition has a purity of at least about 99% w / w.

[0301] Embodiment 3.6: The method of any one of Embodiments 3.1 to 3.5, wherein the composition further comprises an emulsifier.

[0302] Embodiment 3.7: The method of any one of Embodiments 3.1 to 3.5, wherein the composition further comprises a gelling agent.

[0303] Embodiment 3.8: The method of any one of Embodiments 3.1 to 3.7, wherein the composition comprises nootkatone.

[0304] Embodiment 3.9: The method of any one of Embodiments 3.1 to 3.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0305] Embodiment 3.10: The method of any one of Embodiments 3.1 to 3.9, wherein the composition comprises at least 5% w / w nootkatone.

[0306] Embodiment 3.11: The method of any one of Embodiments 3.1 to 3.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0307] Embodiment 3.12: The method of any one of Embodiments 3.1 to 3.11, wherein the composition is administered once or twice daily.

[0308] Embodiment 3.13: The method of any one of Embodiments 3.1 to 3.12, wherein the composition is administered for at least 12 weeks.

[0309] Embodiment 3.14: The method of any one of Embodiments 3.1 to 3.13, wherein administering the composition to the subject reduces atopic dermatitis after a predetermined time, as determined according to a Patient Oriented Eczema Scale (POEM), a Target Lesion Severity Score (TLSS), or a combination thereof.

[0310] Embodiment 3.15: The method of any one of Embodiments 3.1 to 3.13, wherein administering the composition to the subject reduces atopic dermatitis after a predetermined time period, as evidenced by reduced pruritus, as determined according to the Itch Numerical Rating Scale (I-NRS).

[0311] Embodiment 3.16: A method of treating or preventing atopic dermatitis in a subject by inhibiting or modulating a therapeutic target, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB; Optionally, (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0312] Aspect 3.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in a method of treating or preventing atopic dermatitis in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0313] Aspect 3.18: Use of nootkatone, or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for use in treating or preventing atopic dermatitis in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0314] Aspect 3.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in the treatment of atopic dermatitis, wherein said nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0315] Aspect 3.20: Nootkatone in a method of treating atopic dermatitis, said method comprising: 1. The method of claim 1, further comprising topically administering to the skin of a subject in need thereof a therapeutically effective amount of nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0316] Aspect 3.21: The method of Aspect 3.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0317] Embodiment 3.22: The method of embodiment 3.21, wherein said topical administration comprises topically administering an amount sufficient to reduce the severity of atopic dermatitis, thereby alleviating atopic dermatitis by causing regression of one or more symptoms associated with atopic dermatitis.

[0318] Aspect 4 Aspect 4.1: A method of treating or preventing diabetic skin disorders or diabetic peripheral neuropathy in a subject in need thereof, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; and optionally (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0319] Embodiment 4.2: The method of embodiment 4.1, wherein the subject is a human.

[0320] Embodiment 4.3: The method of embodiment 4.1, wherein the subject is a cat, dog, or horse.

[0321] Embodiment 4.4: The method of any one of Embodiments 4.1 to 4.3, wherein the composition is administered topically.

[0322] Embodiment 4.5: The method of any one of Embodiments 4.1 to 4.4, wherein the composition has less than about 1% w / w of other components naturally occurring in the nootkatone-containing source, and wherein the nootkatone in the composition has a purity of at least about 99% w / w.

[0323] Embodiment 4.6: The method of any one of embodiments 4.1 to 4.5, wherein the composition further comprises an emulsifier.

[0324] Embodiment 4.7: The method of any one of embodiments 4.1 to 4.5, wherein the composition further comprises a gelling agent.

[0325] Embodiment 4.8: The method of any one of Embodiments 4.1 to 4.7, wherein the composition comprises nootkatone.

[0326] Embodiment 4.9: The method of any one of Embodiments 4.1 to 4.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0327] Embodiment 4.10: The method of any one of Embodiments 4.1 to 4.9, wherein the composition comprises at least 5% w / w nootkatone.

[0328] Embodiment 4.11: The method of any one of Embodiments 4.1 to 4.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0329] Embodiment 4.12: The method of any one of Embodiments 4.1 to 4.11, wherein the composition is administered once or twice daily.

[0330] Embodiment 4.13: The method of any one of Embodiments 4.1 to 4.12, wherein the composition is administered for at least 12 weeks.

[0331] Embodiment 4.14: The method of any one of Embodiments 4.1 to 4.13, wherein said administering said composition to said subject reduces diabetic skin disorders or diabetic peripheral neuropathy after a predetermined time period, as determined according to Target Lesion Severity Score (TLSS).

[0332] Embodiment 4.15: The method of any one of Embodiments 4.1 to 4.13, wherein said administering said composition to said subject reduces diabetic skin disorders or diabetic peripheral neuropathy as evidenced by a reduction in pruritus after a predetermined time period, as determined according to an Itch Numerical Rating Scale (I-NRS).

[0333] Embodiment 4.16: A method of treating or preventing diabetic skin disorders or diabetic peripheral neuropathy in a subject by inhibiting or modulating a therapeutic target, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB; Optionally, (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0334] Aspect 4.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in a method of treating or preventing diabetic skin disorders or diabetic peripheral neuropathy in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0335] Aspect 4.18: Use of nootkatone, or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for use in treating or preventing diabetic skin disorders or diabetic peripheral neuropathy in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0336] Aspect 4.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in the treatment of diabetic skin disorders or diabetic peripheral neuropathy, wherein said nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0337] Aspect 4.20: Nootkatone in a method for treating diabetic dermopathy or diabetic peripheral neuropathy, said method comprising: 1. The method of claim 1, further comprising topically administering to the skin of a subject in need thereof a therapeutically effective amount of nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0338] Aspect 4.21: The method of Aspect 4.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0339] Embodiment 4.22: The method of Embodiment 4.21, wherein said topical administration comprises topically administering an amount sufficient to reduce the severity of the diabetic dermopathy or diabetic peripheral neuropathy, thereby alleviating the diabetic dermopathy or diabetic peripheral neuropathy by causing regression of one or more symptoms associated with the diabetic dermopathy or diabetic peripheral neuropathy.

[0340] Aspect 5 Aspect 5.1: A method for improving the appearance of skin in a subject in need thereof, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; and optionally (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0341] Embodiment 5.2: The method of embodiment 5.1, wherein the subject is a human.

[0342] Embodiment 5.3: The method of embodiment 5.1, wherein the subject is a cat, dog, or horse.

[0343] Embodiment 5.4: The method of any one of Embodiments 5.1 to 5.3, wherein the composition is administered topically.

[0344] Embodiment 5.5: The method of any one of Embodiments 5.1 to 5.4, wherein the composition has less than about 1% w / w of other components naturally occurring in a nootkatone-containing source, and wherein the nootkatone in the composition has a purity of at least about 99% w / w.

[0345] Embodiment 5.6: The method of any one of embodiments 5.1 to 5.5, wherein the composition further comprises an emulsifier.

[0346] Embodiment 5.7: The method of any one of embodiments 5.1 to 5.5, wherein the composition further comprises a gelling agent.

[0347] Embodiment 5.8: The method of any one of Embodiments 5.1 to 5.7, wherein the composition comprises nootkatone.

[0348] Embodiment 5.9: The method of any one of embodiments 5.1 to 5.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0349] Embodiment 5.10: The method of any one of Embodiments 5.1 to 5.9, wherein the composition comprises at least 5% w / w nootkatone.

[0350] Embodiment 5.11: The method of any one of Embodiments 5.1 to 5.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0351] Embodiment 5.12: The method of any one of Embodiments 5.1 to 5.11, wherein the composition is administered once or twice daily.

[0352] Embodiment 5.13: The method of any one of Embodiments 5.1 to 5.12, wherein the composition is administered for at least 12 weeks.

[0353] Embodiment 5.14: The method of any one of Embodiments 5.1 to 5.13, wherein administering the composition to the subject improves the appearance of the skin after a predetermined time, as determined according to Redness Numerical Rating Scale (R-NRS), Patient Global Impression Change (P-GIC), EuroQol 5-item (EQ-5D), or a combination thereof.

[0354] Embodiment 5.15: The administering of the composition to the subject comprises: a reduction in atopic dermatitis over a defined period of time as determined according to the Patient Oriented Eczema Scale (POEM), Target Lesion Severity Score (TLSS), or a combination thereof; a reduction in diabetic dermopathy or diabetic peripheral neuropathy over a defined period of time as determined according to the Target Lesion Severity Score (TLSS), or The method of any one of embodiments 5.1-5.13, wherein the method improves the appearance of the skin, as evidenced by both a reduction in atopic dermatitis and a reduction in diabetic dermopathy or diabetic peripheral neuropathy.

[0355] Embodiment 5.16: A method for improving skin appearance in a subject by inhibiting or modulating a therapeutic target, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB; Optionally, (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0356] Aspect 5.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in a method for improving skin appearance in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0357] Aspect 5.18: Use of nootkatone, or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for use in improving the appearance of skin in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0358] Aspect 5.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in improving the appearance of skin, wherein said nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0359] Aspect 5.20: A nootkatone in a method for improving the appearance of skin, said method comprising: 1. The method of claim 1, further comprising topically administering to the skin of a subject in need thereof a therapeutically effective amount of nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0360] Aspect 5.21: The method of Aspect 5.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0361] Embodiment 5.22: The method of embodiment 5.21, wherein said topical administration comprises topically administering an amount sufficient to improve the appearance of the skin, thereby improving the appearance of the skin by causing regression of one or more symptoms related to skin imperfections.

[0362] Aspect 6 Aspect 6.1: A method of treating or preventing intestinal or abdominal pain in a subject in need thereof, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; and optionally (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0363] Embodiment 6.2: The method of embodiment 6.1, wherein the subject is a human.

[0364] Embodiment 6.3: The method of embodiment 6.1, wherein the subject is a cat, dog, or horse.

[0365] Embodiment 6.4: The method of any one of Embodiments 6.1 to 6.3, wherein the composition is administered orally.

[0366] Embodiment 6.5: The method of any one of Embodiments 6.1 to 6.4, wherein the composition has less than about 1% w / w of other components naturally present in the nootkatone-containing source, and wherein the nootkatone in the composition has a purity of at least about 99% w / w.

[0367] Embodiment 6.6: The method of any one of embodiments 6.1 to 6.5, wherein the composition is in the form of a tablet or pill.

[0368] Embodiment 6.7: The method of any one of embodiments 6.1 to 6.5, wherein said intestinal pain or said abdominal pain is a symptom of inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), or a combination thereof.

[0369] Embodiment 6.8: The method of any one of Embodiments 6.1 to 6.7, wherein the composition comprises nootkatone.

[0370] Embodiment 6.9: The method of any one of Embodiments 6.1 to 6.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0371] Embodiment 6.10: The method of any one of Embodiments 6.1 to 6.9, wherein the composition comprises at least 5% w / w nootkatone.

[0372] Embodiment 6.11: The method of any one of Embodiments 6.1 to 6.8, wherein the composition comprises about 1.5% to about 10% w / w of nootkatone.

[0373] Embodiment 6.12: The method of any one of Embodiments 6.1 to 6.11, wherein the composition is administered once or twice daily.

[0374] Embodiment 6.13: The method of any one of Embodiments 6.1 to 6.12, wherein the composition is administered for at least 12 weeks.

[0375] Embodiment 6.14: The method of any one of Embodiments 6.1 to 6.13, wherein administering the composition to the subject reduces pain after a predetermined time, as determined according to the IBS Symptom Severity Scale, Brief Pain Questionnaire, Visceral Sensitivity Index, Pain Numerical Rating Scale (P-NRS), Illness Impact Profile, Pain Disability Index, Pain Catastrophizing Scale, McGill Pain Questionnaire, or a combination thereof.

[0376] Embodiment 6.15: The method of embodiment 6.14, wherein administering the composition to the subject reduces intestinal or abdominal pain after a predetermined time, as determined according to a Pain Numerical Rating Scale (P-NRS).

[0377] Embodiment 6.16: A method of treating or preventing intestinal or abdominal pain in a subject by inhibiting or modulating a therapeutic target, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB; Optionally, (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0378] Aspect 6.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in a method for treating or preventing intestinal or abdominal pain in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0379] Aspect 6.18: Use of nootkatone, or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for use in treating or preventing intestinal or abdominal pain in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0380] Aspect 6.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in the treatment of intestinal or abdominal pain, wherein said nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0381] Aspect 6.20: Nootkatone in a method for treating intestinal or abdominal pain, said method comprising: 1. The method of claim 1, further comprising topically administering to the skin of a subject in need thereof a therapeutically effective amount of nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0382] Aspect 6.21: The method of Aspect 6.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

[0383] Embodiment 6.22: The method of embodiment 6.21, wherein the local administration comprises locally administering an amount sufficient to reduce the severity of intestinal or abdominal pain, thereby alleviating the intestinal or abdominal pain by causing a regression of one or more symptoms related to the intestinal or abdominal pain. [Example]

[0384] The subject matter of the present disclosure will be better understood with reference to the following examples, which are offered by way of illustration of the present disclosure, and not by way of limitation. The following examples are included to demonstrate various embodiments contemplated herein. Those of skill in the art will understand that the procedures disclosed in the examples that follow represent procedures discovered by the inventor(s) to work well in the practice of the invention, and therefore can be considered to constitute preferred modes of practice thereof. However, those of skill in the art will understand, in light of the present disclosure, that many changes can be made in the specific embodiments disclosed without departing from the spirit and scope of the invention and still obtain like or similar results. All percentages are by weight, and all measurements are made at 23° C. unless otherwise specified.

[0385] Example 1 Exemplary aqueous gel-based compositions containing nootkatone An exemplary formulation (Exemplary Comp. I) and a comparative formulation (Comparative Comp. I) of an aqueous gel-based composition were formed according to the methods described herein. Table 1 below shows the exemplary and comparative formulations of the aqueous gel-based composition. [Table 1] The gelling agent may be a carbomer commercially available under the trade name Carbopol Ultrez 10. Solvent II can be diethylene glycol monoethyl ether, commercially available under the trade name Transcutol P.

[0386] Example 2 Exemplary Cream-Based Compositions Comprising Nootkatone An exemplary formulation of a cream-based composition (Exemplary Comp. II) and a comparative formulation (Comparative Comp. II) were formed according to the methods described herein. Table 2 below shows the exemplary and comparative formulations of the cream-based composition. [Table 2] The emulsifier may be a mixture of cetyl (C16) and stearyl (C18) fatty alcohols commercially available under the trade name Kolliphor CS A. Solvent II can be diethylene glycol monoethyl ether, commercially available under the trade name Transcutol P.

[0387] Example 3 A 14-week study to evaluate the use of the compound in humans with atopic dermatitis A 14-week, placebo-controlled, double-blind study is being conducted to evaluate the safety and tolerability of a topical cream (exemplary Comp. II) for reducing atopic dermatitis.

[0388] Participants self-report mild to moderate atopic dermatitis, which is confirmed by photographs by the investigator at screening. Participants with current or past history of other comorbid skin conditions (e.g., psoriasis) that would interfere with the evaluation of the efficacy of the exemplary Comp. II will be excluded from the study at the investigator's discretion.

[0389] During the trial, patients will topically apply a formulation containing nootkatone (the "test product") according to the study procedures and study questionnaires and assessments set forth below.

[0390] Test Procedure Upon initial eligibility, participants will receive an email containing study participation information, including instructions for completing study assessments, if required. These study assessments can be accessed via the Chloe mobile app, available for Apple iOS and Android® devices. Participant actions are as follows:

[0391] Screening Period (3 weeks; maximum -21 days): - Complete informed consent -Complete basic personal information, medical history, and concomitant medications - Mild to moderate severity of AD as confirmed by the investigator Participants will take photos of their skin using Chloe The investigator will review the images to determine the severity. -Eligibility verification and registration

[0392] Randomization and Shipping Period (Day 0 + up to 2 weeks): -Randomize to one of two groups: ○Illustrative Comp. II ○Comp.II for comparison -Provide a preferred shipping address for the topical test product / placebo cream and study supplies - Shipment and collection of topical test product / placebo cream and study supplies to participant's home -Participants will enter the baseline period upon receiving their shipment

[0393] Baseline Period (Days 1-7): Day 1: -Complete the Patient Oriented Eczema Scale (POEM) -Target lesion photography / Target Lesion Severity Score (TLSS) The investigator will identify target lesions from photographs taken at screening to confirm AD. Participants will use Chloe to take photos of target lesions. Investigators will complete the Target Lesion Severity Score (TLSS) using photographs -Start using a wrist-worn electronic device that tracks nighttime scratching behavior while you sleep every day: -Complete the Itch-NRS (average itch and worst itch) -Continued nightly use of a wrist-worn electronic device that tracks nighttime scratching behavior during sleep for up to 7 days

[0394] Topical test product / placebo use period (days 8-35): every day: - Initiate application of topical test product / placebo Apply topical test product / placebo cream twice daily to affected skin, particularly target lesions -Complete test product compliance questionnaire -Adverse Event Questionnaire: Itch-NRS (average itch and worst itch) completed -Adverse event survey: Nightly use of a wearable device that tracks nighttime scratching behavior will continue until day 35

[0395] At the end of each week (days 14, 21, 28, and 35): - Visual reporting of adverse events; photography of target lesions / Target Lesion Severity Score (TLSS) Participants will use Chloe to take photos of target lesions. Investigators will complete the Target Lesion Severity Score (TLSS) using photographs -Skin Appearance Questions: Patient Global Impression Change (P-GIC) - Complete questionnaires regarding any additional adverse events / reactions associated with study product / placebo use

[0396] At the end of the topical test product / placebo cream use period (Day 35): -Complete the Patient Oriented Eczema Scale (POEM) -Complete an experience survey

[0397] Open-label extension period (Days 36-63): -Optional open-label use of exemplary Comp. II -Participants who request an extension will receive a shipment of product. - Chloe to report any adverse reactions / events associated with product use at any time -Continued nightly use of a wrist-worn electronic device that tracks nocturnal scratching behavior during sleep through day 63

[0398] End of open-label extension period (day 63) -Complete test product compliance questionnaire -Complete the Skin Appearance Questionnaire: Patient Global Impression Change (P-GIC)

[0399] Test Questionnaire and Assessment Itch Numerical Rating Scale: The Itch Numerical Rating Scale (NRS) is a brief self-report measure of itch severity. Average and worst itch over the past 24 hours are assessed daily using a 10-point Numerical Rating Scale (NRS). Additionally, objective behavioral data are collected nightly using a wearable device equipped with an application that tracks nighttime scratching behavior and synchronizes data to participants' smartphones.

[0400] Patient-Oriented Eczema Scale (POEM): The POEM is a validated patient-administered questionnaire to assess the symptoms and monitor the severity of atopic dermatitis. It is a seven-question assessment with a maximum score of 28 that translates into eczema severity. It is administered at baseline and at the end of the topical test product / placebo use period.

[0401] Patient Global Impression Change (P-GIC): The Patient Global Impression Change (P-GIC) is a 7-point Likert scale reflecting the participant's assessment of the overall improvement in skin appearance. It is administered daily throughout the course of topical test product / placebo use.

[0402] Target Lesion Severity Score (TLSS): The Target Lesion Severity Score (TLSS) is an investigator-completed scale that assesses the severity of AD lesions based on erythema, induration, papulation, lichenification, weeping / crusting, and scaling. Each of the five characteristics is rated on a 4-point scale, with a maximum TLSS score of 15. It is completed by the investigator using photographs of target lesions taken by the participant at baseline and at the end of each application week.

[0403] Adverse Event Survey: At the end of each week during the topical test product / placebo use period, participants will be asked about any additional unpleasant experiences in an objective manner, such as, "Have you had any unusual symptoms or problems since the last week?"

[0404] Experience Survey: The experience survey consists of questions regarding product use, likelihood of continued use, product preferences, and experiences related to the application, testing tools, and testing in general.

[0405] Table 3 below shows the alignment of the various assessments described above with the treatment of various conditions or diseases. [Table 3]

[0406] Example 4 To investigate the safety, skin tolerability, and efficacy of exemplary Comp. II in improving skin appearance in individuals, including those with diabetic peripheral neuropathy and diabetic skin disorders. A multicenter, double-blind, randomized, vehicle-controlled, single-dose study of the exemplary Comp. II and vehicle cream (Comparative Comp. II) will be conducted to evaluate the safety, skin tolerability, and efficacy of nootkatone compared to vehicle. During the study, the exemplary Comp. II or Comparative Comp. II will be applied twice daily for 8 weeks. The study will include 60 male and female patients over the age of 18 who have diabetic peripheral neuropathy (DPN) and meet the inclusion / exclusion criteria.

[0407] Study and treatment duration: approximately 13 weeks (4 weeks screening, 8 weeks application, and 1 week follow-up).

[0408] Study objectives and endpoints related to safety, tolerability, and improvement of skin appearance: [Table 4]

[0409] Cosmetic Test Product and Administration Mode Study: Participants will be randomized to receive one of the following test products as described below: -Exemplary Comp. II -Comp.II for comparison

[0410] Mode of administration: The exemplary Comp. II cream and comparative Comp. II cream will be applied topically twice daily to DPN-affected areas for 8 weeks. Participants will be instructed to apply the test product to all DPN-affected areas (skin imperfections) (including those that have healed) and any new skin imperfections (DPN lesions) that may appear during the 8-week application period. At baseline, a lesion that represents the participant's overall DPN condition and will be treated with the cosmetic test product will be selected as the target lesion. This lesion will be identified and measured at each subsequent visit during the application period and documented in the participant's study record.

[0411] Test criteria evaluation: Safety rating: Adverse Effects (AEs) and Serious Adverse Effects (SAEs) ·Skin tolerability (erythema, edema, burning / stinging, pain, itching) Investigator assessment of skin appearance: ·TLSS (Target Lesion Severity Score): [Table 5] Other measures: photography of target lesions. Statistical Methods: Appropriate statistical methods are used to validate the test results provided herein.

[0412] Table 6 below shows the alignment of the various assessments described above with the treatment of various conditions or diseases. [Table 6]

[0413] Example 5 A four-week trial to evaluate the use of the compound in humans suffering from pain A 4-week, vehicle-controlled, double-blind trial is conducted to evaluate the safety and tolerability of a topical cream for reducing pain.

[0414] During the trial, patients will topically apply a formulation containing nootkatone ("test product") to the treatment area(s) twice daily (once in the morning and once in the afternoon) for four weeks. Subjects will be instructed to gently cleanse the treatment area immediately prior to application of the test product. However, skin should be allowed to dry thoroughly before application. Participants will use the dosing guidelines shown in Table 7 below when applying the test product. [Table 7]

[0415] The test products used in the clinical trial have various concentrations of nootkatone formulated in petrolatum: 0.375% w / w (exemplary Comp. III), 0.75% w / w (exemplary Comp. IV), 1.5% w / w (exemplary Comp. V), and 3% w / w (exemplary Comp. VI). The vehicle test product contains petrolatum but no nootkatone (comparative Comp. III).

[0416] In the clinical trial, each participant will use the test product for four weeks, with assessments at baseline before starting test product use, and at 7, 14, 21, and 28 days after use. Assessments will be conducted visually via self-report questionnaires and photographs of the atopic dermatitis-affected areas treated with the test product at each assessment time point. Photographs will be scored by one or more board-certified dermatologists according to standard photography guidelines provided to participants.

[0417] At each evaluation time point, participants will be evaluated according to the primary and secondary endpoints shown in Tables 8 and 9 below: [Table 8] [Table 9]

[0418] Table 10 below shows the alignment of the various assessments described above with the treatment of various conditions or diseases. [Table 10]

[0419] Example 6 A four-week study to evaluate the use of the compound in humans with atopic dermatitis A 4-week, vehicle-controlled, double-blind trial will be conducted to evaluate the safety and tolerability of a topical cream for reducing atopic dermatitis.

[0420] Participants must have a clinical diagnosis of mild to moderate atopic dermatitis according to the Hanifin and Rajka criteria, affecting 5% to 20% (inclusive) of the total body surface area, excluding the face, scalp, axillae, and intertriginous regions. Patients with confounding skin conditions (e.g., psoriasis, rosacea, erythroderma, or ichthyosis (other than ichthyosis vulgaris)) will be excluded from the trial.

[0421] During the trial, patients will topically apply a formulation containing nootkatone ("test product") to the treatment area(s) twice daily (once in the morning and once in the afternoon) for four weeks. Subjects will be instructed to gently cleanse the treatment area immediately prior to application of the test product. However, skin should be allowed to dry thoroughly before application. Participants will use the dosing guidelines shown in Table 11 below when applying the test product. [Table 11]

[0422] Exemplary test products used in the clinical trial have various concentrations of nootkatone formulated in petrolatum: 0.375% w / w (Exemplary Comp. III), 0.75% w / w (Exemplary Comp. IV), 1.5% w / w (Exemplary Comp. V), and 3% w / w (Exemplary Comp. VI). The vehicle test product contains petrolatum but no nootkatone (Comparative Comp. III).

[0423] In the clinical trial, each participant will use the test product for four weeks, with assessments at baseline before starting test product use, and at 7, 14, 21, and 28 days after use. Assessments will be conducted visually via self-report questionnaires and photographs of the atopic dermatitis-affected areas treated with the test product at each assessment time point. Photographs will be scored by one or more board-certified dermatologists according to standard photography guidelines provided to participants.

[0424] At each evaluation time point, participants will be evaluated according to the primary and secondary endpoints shown in Tables 12 and 13 below: [Table 12] [Table 13]

[0425] Table 14 below shows the alignment of the various assessments described above with the treatment of various conditions or diseases. [Table 14-1]

[0426] Example 7 Studies to evaluate the use of compounds in humans with psoriasis A 4-week, vehicle-controlled, double-blind trial is conducted to evaluate the safety and tolerability of a topical cream for reducing psoriasis.

[0427] Participants must have a clinical diagnosis of mild to moderate plaque psoriasis affecting 3% to 15% (inclusive) of their total body surface area, excluding the face, scalp, hands, or soles of the feet. Participants with confounding skin conditions (e.g., atopic dermatitis, rosacea, erythroderma, or ichthyosis (other than ichthyosis vulgaris)) will be excluded from the trial.

[0428] During the trial, participants will topically apply a formulation containing nootkatone ("test product") to the treatment area(s) twice daily (once in the morning and once in the afternoon) for four weeks. Participants will be instructed to gently cleanse the treatment area immediately prior to application of the test product. However, skin should be allowed to dry thoroughly before application. Participants will use the dosing guidelines shown in Table 15 below when applying the test product. [Table 15]

[0429] Exemplary test products used in the clinical trial have various concentrations of nootkatone formulated in petrolatum: 0.375% w / w (Exemplary Comp. III), 0.75% w / w (Exemplary Comp. IV), 1.5% w / w (Exemplary Comp. V), and 3% w / w (Exemplary Comp. VI). The vehicle test product contains petrolatum but no nootkatone (Comparative Comp. III).

[0430] In the clinical trial, each participant will use the test product for four weeks, and two site visits will be conducted for each participant's assessment, including a baseline assessment immediately before starting test product use, and an assessment four weeks after test product use. During each visit, patients will be assessed for Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA), redness, target lesion assessment, Itch Numerical Rating Scale (I-NRS), Pain Numerical Rating Scale (P-NRS), and any adverse events. During the four-week assessment, participants will also be asked to provide a Patient Global Assessment (PGIC).

[0431] The Psoriasis Area and Severity Index is derived by separately assessing the severity of erythema, induration, and scaling on a 0-4 scale for the head and neck, upper and lower extremities, and trunk. A score is assigned to each symptom on each body region separately. The sum of the scores for each body region is then multiplied by a weighting factor of 0.1 for the head, 0.2 for the upper extremities, 0.3 for the trunk, or 0.4 for the lower extremities. The resulting weighted score is then multiplied by a score ranging from 0 to 6 based on the percent surface area of ​​the body region affected by psoriasis (no impact = score 0, 1-9% = score 1, 10-29% = score 2, 30-49% = score 3, 50-69% = score 4, 70-89% = score 5, and 90-100% = score 6). The resulting scores are then summed to derive a total score on the PASI scale.

[0432] Physician Global Assessment (PGA) is an overall psoriasis severity rating on a scale of 0 to 4 assessed during a clinic visit. Table 16 below shows the criteria for each PGA grade. [Table 16]

[0433] The investigator and participant will independently assess and rate the severity of skin redness according to the criteria shown in Table 17 below. [Table 17]

[0434] Measurements of approximately 10 cm at baseline 2 One of the above target lesions will be selected per subject. The target lesion must be representative of the subject's condition and must not be located on the hands, feet, or genitals. Photographs of the target lesion will be taken from two perspectives (close-up and close-up of the body area). Target lesions will be assessed individually for PGA, redness (investigator and subject), pruritus NRS, and Patient Global Identification Change (PGIC). Additional assessments will be made for the following individual scales: erythema, edema / papulation, oozing / crusting, excoriation, lichenification, and dryness.

[0435] The Itch Numerical Rating Scale (I-NRS) is a daily patient-reported measure (24-hour recall) of worst level of itch intensity. Subjects rate their skin itch severity by selecting a number from 0 (no itch) to 10 (worst imaginable itch) that best represents their worst level of itch in the past 24 hours.

[0436] The Pain Numerical Rating Scale (P-NRS) is a daily patient-reported measure (24-hour recall) of worst level of itch intensity. Subjects rate their skin pain severity by selecting the number from 0 (no pain) to 10 (worst imaginable pain) that best represents their worst level of pain in the past 24 hours.

[0437] The Patient Global Perception of Change (PGIC) is a global rating on a scale of 1 to 7 assessed during a clinic visit. Subjects are asked, "Please tell us your perception of the improvement you have experienced in the appearance and feel of your skin since starting to use the study product." Table 18 below shows the PGIC grades. [Table 18]

[0438] Table 14 below shows the alignment of the various assessments described above with the treatment of various conditions or diseases. [Table 14-2]

[0439] Example 8 The methods used in this study were adapted from the scientific literature to maximize reliability and reproducibility. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Assays were performed under the conditions described below. Where indicated, IC 50 Values ​​were determined by non-linear least squares regression analysis using MathIQ™ (ID Business Solutions Ltd., UK), as shown in Table 19 below. [Table 19]

[0440] Example 9 The methods used in this study were adapted from the scientific literature to maximize reliability and reproducibility. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Assays were performed under the conditions described below. Where indicated, IC 50 Values ​​were determined by non-linear least squares regression analysis using MathIQ™ (ID Business Solutions Ltd., UK), as shown in Table 20 below. [Table 20]

[0441] Sodium channel Site 2 (Nav site 2) was evaluated using the following parameters: -Source: Wistar rat brain (cerebellum removed) -Media: 1.0% DMSO Incubation time / temperature: 60 minutes at 37°C Incubation buffer: 50 mM HEPES, 50 mM Tris-HCl (pH 7.4), 130 mM choline chloride, 5.4 mM KCl, 0.8 mM MgCl2, 5.5 mM glucose, 40 μg / ml LqTX -Kd: 0.052 μM -Ligand: 5.0nM [ 3 H]Batrachotoxinin -Non-specific ligand: 100 μM veratridine -Specific binding: 77% -Quantification method: Radioligand binding -Bmax: 0.7 pmol / mg protein

[0442] Neuronal nitric oxide synthase (nNOS) was assessed using the following parameters: -Source: Cerebellum of Wistar rats -Substrate: 20.0 nM [3H]L-arginine -Media: 1.0% DMSO Pre-incubation time / temperature: 15 minutes at 25°C Incubation time / temperature: 10 minutes at 25°C Incubation buffer: 50 mM HEPES (pH 7.4), 1 mM EDTA, 1 mM NADPH, 1.25 mM CaCl2.2H2O, 1 mM DTT, 10 μg / ml calmodulin -Quantification method: [3H]citrulline quantification

[0443] The following parameters were used to assess opiate kappa (OP2, KOP): -Source: Human recombinant HEK-293 cells -Media: 1.0% DMSO Pre-incubation time / temperature: 15 minutes at 25°C Incubation time / temperature: 60 minutes at 25°C Incubation buffer: 50 mM Tris-HCl (pH 7.4) -Kd: 0.4 nM Ligand: 0.6 nM [3H]diprenorphine -Non-specific ligand: 10.0 μM naloxone -Specific binding: 90% -Quantification method: Radioligand binding -Bmax: 1.10 pmol / mg protein

[0444] The following parameters were used to evaluate sigma σ1: -Source: Human Jurkat cells -Media: 1.0% DMSO Incubation time / temperature: 2 hours at 37°C Incubation buffer: 50 mM Tris-HCl (pH 8.0) -Kd: 16.0 nM -Ligand: 15.0 nM [3H]pentazocine -Non-specific ligand: 10.0 μM haloperidol -Specific binding: 90% -Quantification method: Radioligand binding -Bmax: 1.08 pmol / mg protein

[0445] Adenosine A3 was assessed using the following parameters: -Source: Human recombinant CHO-K1 cells -Media: 1.0% DMSO Incubation time / temperature: 60 minutes at 25°C Incubation buffer: 25 mM HEPES (pH 7.4), 5 mM MgCl2, 1 mM CaCl2, 0.1% BSA -Kd: 5.90nM -Ligand: 0.5nM 125 I]AB-MECA Non-specific ligand: 1.0 μM IB-MECA -Specific binding: 83% -Quantification method: Radioligand binding -Bmax: 1.08 pmol / mg protein

[0446] The prostanoid EP2 was evaluated using the following parameters: -Source: Human recombinant HEK-293 cells -Media: 1.0% DMSO Incubation time / temperature: 2 hours at 25°C Incubation buffer: 10 mM MES (pH 6.0), 1 mM EDTA, 10 mM MgCl -Kd: 3.10 nM -Ligand: 4.0nM [ 3 H]prostaglandin E2 (PGE2) -Non-specific ligand: 10.0 μM prostaglandin E2 (PGE2) -Specific binding: 80% -Quantification method: Radioligand binding -Bmax: 1.40 pmol / mg protein

[0447] The norepinephrine transporter (NET) was assessed using the following parameters: -Source: Human recombinant MDCK cells -Media: 1.0% DMSO Incubation time / temperature: 3 hours at 4°C Incubation buffer: 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 1 μM leupeptin, 10 μM PMSF -Kd: 0.024 μM -Ligand: 0.2nM 125 I]RTI-55 -Nonspecific ligand: 10.0 μM desipramine -Specific binding: 75% -Quantification method: Radioligand binding -Bmax: 2.50 pmol / mg protein

[0448] Example 10 Nootkatone inhibits intrinsic dorsal root ganglion (DRG) firing in mice and humans Dorsal root ganglion neurons sense danger in the periphery and relay messages to the central nervous system (CNS). Pruritogenic substances released by skin and immune cells can directly activate specific neurons. Nootkatone has been shown to inhibit intrinsic dorsal root ganglion (DRG) firing in mice and humans. Using specific markers to identify specific neuronal subtypes in mouse DRG (i.e., calcitonin gene-related peptide (CGRP) for peptidergic neurons and isolectin B4 (IB4) for nonpeptidergic neurons), nootkatone demonstrated a dose-dependent blockade of neuronal depolarization in nonpeptidergic mouse DRG.

[0449] Mouse DRG excision and cell culture: Mouse DRG Excision: All procedures in this study were performed in accordance with the rules and regulations of the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Wild-type adult mice were euthanized using CO2 and thoroughly sprayed with 70% (vol / vol) ethanol immediately before DRG excision. All procedures described below were performed under sterile conditions. Euthanized mice were decapitated, and the dorsal skin was incised along the midline from the neck to the tail. Skin was removed from the entire dorsal surface of the body. The forelimbs were pinned, and the spinal column was transected transversely at the last rib to ensure collection of only lumbar DRGs and not thoracic DRGs. Two linear longitudinal incisions were made from the spinal incision to the tail, penetrating adjacent tissue on either side of the spinal column. The spinal column was then hemisected horizontally to the tail, ensuring severance of the vertebrae on both sides of the spinal column. The dorsal half of the spinal column was lifted, and then, if the cut was made correctly (neither too high nor too low along the dorsal-ventral midline), the DRGs became visible as white (partially translucent) bulbs along both sides of the spinal column. Each ganglion was removed by grasping the distal extension of the DRG behind and just below the bulb using precision forceps. Direct pinching of the DRG bulb was avoided to minimize damage to any neurons. All lumbar DRGs were removed. The distal and proximal extensions arising from the DRGs were removed with Vannas-type iris scissors, and the DRGs were then placed in a Petri dish containing cold Hank's balanced salt solution (HBSS).

[0450] Mouse DRG cell culture and calcium assay methodology: Lumbar mouse DRG neurons were isolated, dissociated, and plated on poly-D-lysine-coated plates for 24 hours. Mouse DRG neurons were incubated with Fura-2-acetoxymethyl ester (Fura-2-AM) dye for at least 1 hour before experimental data collection. 30 mM K + Mouse DRG neurons were depolarized by applying potassium (K) at 6-minute intervals, and calcium influx due to membrane depolarization was observed. +) application served as a control. Nootkatone was tested at concentrations of 10 μM, 30 μM, and 100 μM as follows: after the first three control K applications, nootkatone was applied sequentially at the concentrations listed above. Each concentration of nootkatone was followed by a series of K applications to observe inhibition and reversibility. Four minutes after the last K application, 100 μM allyl isothiocyanate (AITC) was applied, incubated for 60 seconds, and then removed by washing. Six minutes after allyl isothiocyanate (AITC) application, 500 nM capsaicin was applied and monitored for 2 minutes. In mouse DRGs, 100 μM nootkatone blocked neuronal depolarization in capsaicin / transient receptor potential vanilloid subfamily member 1 (TRPV1)-negative neurons, as shown in Figures 1A and 1B.

[0451] Human DRG Cell Culture and DRG Calcium Assay Methodology: Human DRG neurons were extracted from a 32-year-old Hispanic male and dissociated for calcium imaging assays. Below is a summary of the human DRG cell culture, DRG calcium assay, and analysis. i. Loading of Fluo-8 acetoxymethyl ester (Fluo-8 AM) Fluo-8 dye into human DRG neuron cultures. ii. Electric field stimulation (EFS). iii. A high voltage was set to activate 70-80% of neurons via action potential (AP) depolarization but not to activate voltage-gated calcium channels by direct depolarization. 1. Baseline (vehicle, 5 min). Application of high-voltage electric field stimulation (10 pulses). 2. Addition of test substance (nootkatone) at a predetermined concentration (5 min). Application of high-voltage electric field stimulation (10 pulses). 3. Addition of test substance (nootkatone) at a predetermined concentration (5 min). Application of high-voltage electric field stimulation (10 pulses). 4.Continued application of the test substance (nootkaton). 5. Addition of test article (nootkatone) + 30 mM KCl. 6. Addition of 200 nM capsaicin.

[0452] Human DRG calcium assay analysis: Below are the subsequent steps for a human DRG calcium assay experiment and subsequent data analysis. 1. Measurement of EFS activity per neuron a. Number of calcium steps before and after addition of nootkatone. b. Amplitude of the first calcium step before and after addition of nootkatone. c. Cumulative calcium transient amplitude before and after addition of nootkatone. 2. Measurement of KCl-responsive neurons. a KCl-induced neuronal amplitude. 3. Number and percentage of responsive neurons per experimental condition (i.e., nootkatone concentration).

[0453] Nootkatone was applied at 100 μM to observe its effect on KCl-induced neuronal depolarization / activity. + Neurons were depolarized / activated using EFS and electric field stimulation. Figure 2 shows the transient response to KCl in human DRG. Nootkatone was applied at 30 μM (first application) and 100 μM (second application) to observe its effect on EFS-induced neuronal depolarization / activity (shown in Figures 3A and 3B).

[0454] In human DRG, 100 μM nootkatone blocked neuronal depolarization in capsaicin / TRPV1-positive neurons. Because TRPV1 neurons are involved in both itch and pain in humans, species differences in capsaicin / TRPV1 activity imply greater efficacy of nootkatone in both of these indications.

[0455] Example 11 Efficacy of nootkatone in an in vivo formalin-induced pain mouse model The rodent formalin-induced pain model is widely used as an acute and rapid in vivo screening test to evaluate the potential analgesic effects of novel compounds. This model encompasses inflammatory, neurogenic, and central nociceptive mechanisms. Injecting a 2.7% formalin solution into the surface of the hindpaw of mice or rats allows for the modeling of both acute and persistent pain using a single chemical within a relatively limited timeframe. This model induces a biphasic nociceptive behavioral response, with the early phase thought to result from direct activation of small primary afferent nerves and the late phase thought to result from sensitization of central nervous system neurons within the dorsal horn (which is involved in neuropathic pain).

[0456] Experimental protocol for the rodent formalin-induced pain model: The effect of nootkatone on formalin-induced nociception in male C57BL / 6 mice was assessed as follows. Male C57BL / 6 mice were treated with nootkatone (3 mg / kg / 10 mL; po, 10 mg / kg / 10 mL; po, 30 mg / kg / 10 mL; po, 100 mg / kg / 10 mL; po, and 300 mg / kg / 10 mL; po) for 3 days. On the third day, mice were injected intraplantarly with formalin (2.7% in saline, 50 μl / mouse) 1 hour after treatment. On the day of intraplantar formalin injection, positive control mice were treated with gabapentin (100 mpk, i.p.) and formalin was injected 30 minutes after gabapentin treatment. Nociceptive responses (duration of paw licking and biting behavior (seconds)) were recorded from 0 to 40 minutes after formalin injection (shown in Figure 4). Nociceptive responses from 0 to 5 minutes after formalin injection were considered Phase 1 (shown in Figure 5), and responses from 16 to 40 minutes were considered Phase 2 (shown in Figure 6). Nootkatone showed good results in both Phase 1 and Phase 2 studies.

[0457] Example 12 Topical application of nootkatone alleviated acute pain in mice This study was conducted to evaluate the efficacy of nootkatone in male C57BL / 6 mice using the tail flick test. Mice were acclimatized 1 day and before the start of the experiment in a mouse holder. At the time of the experiment, mice were gently restrained in the mouse holder and the middle third of their tails were placed over a radiant heat source (Ugo Basile, Varese, Italy) with infrared intensity set at 25%. The latency to withdrawal from the heat source (tail flick) was measured with an accuracy of 0.1 seconds. The stimulation was stopped upon tail withdrawal, and the latency to tail flip was automatically recorded, with a cutoff time of 10 seconds. The average time of three measurements before topical administration of the compound was used as the baseline latency. The baseline tail flick latency of the mice was recorded, and then nootkatone (at concentrations ranging from 1.5%, 3%, and 6%) was applied topically to the tails of the mice. The tail flick latency was recorded at 15 minutes, 30 minutes, 1 hour, 1.5 hours, and 2 hours after application. Positive control mice received 3% lidocaine emulsion and tail flick latencies were recorded at 15 minutes, 30 minutes, 1 hour, 1.5 hours, and 2 hours after application.

[0458] Overall tail-flip latency was the average of three measurements taken at least 1 min apart.

[0459] The maximum possible effect (MPE%) was calculated using the following formula:

number

[0460] The positive control, 3% lidocaine, showed significant effects at all time points tested. The negative control animals showed no effect at all time points tested. Compared to the negative control, topical administration of nootkatone showed significant effects at all time points tested in a dose-dependent manner (shown in Figure 7).

[0461] Example 13 Effect of nootkatone (oral and topical administration) on chloroquine-induced scratching / itch in rodent models Oral nootkatone alleviated chloroquine-induced scratching / itching in mice: Chloroquine (an antimalarial drug) induces a sharp, stinging, itch-like sensation in mice. Male ICR mice weighing 23±3 g were divided into six groups (n=8 / treatment group) as follows: Group 1 was a negative control (no treatment or chloroquine), Group 2 was vehicle-treated (10 mL / kg PO) + chloroquine (5 mg / kg SC), Group 3 was diphenhydramine (60 mg / kg PO) + chloroquine (5 mg / kg SC), Group 4 was nootkatone (10 mg / kg PO) + chloroquine (5 mg / kg SC), Group 5 was nootkatone (30 mg / kg PO) + chloroquine (5 mg / kg SC), and Group 6 was nootkatone (100 mg / kg PO) + chloroquine (5 mg / kg SC). All animals, except for mice in Group 1, which received vehicle instead of subcutaneous chloroquine (SC), received a subcutaneous injection of 5 mg / kg chloroquine at a volume of 10 mL / kg using a 27-gauge needle in the rostral back. Vehicle or test substance (nootkatone) was administered once by oral gavage (PO) 60 minutes before chloroquine injection. Vehicle for diphenhydramine: water; vehicle for Treatment Group 1: Tween® 80:0.5% MC (0.5:99.5, v / v). After injection of the prurigen, the number of scratching behaviors was recorded by visual observation for 30 minutes. Only scratches at the injection site were counted (other areas such as the ears and face were excluded). Immediately after the scratching test, blood was collected by cardiac puncture from all eight animals in the test substance (nootkatone) groups (Groups 4–6, n = 25). Collected blood was placed into lithium heparin-coated tubes, gently mixed, kept on ice, and centrifuged at 2,500 x g for 15 minutes at 4°C within 1 hour of collection. Plasma was then collected and frozen at -70°C or below until shipment for further testing. As shown in Figure 8, oral administration of nootkatone at 30 mpk alleviated chloroquine-induced scratching / itching in mice.

[0462] Topical nootkatone alleviated chloroquine-induced scratching / itching in mice: Male ICR mice weighing 23±3 g were used. The study was divided into two sessions, separated by 2-3 days. Except for Group 1 mice, which received vehicle instead of subcutaneous chloroquine (SC), all animals received a subcutaneous injection of 5 mg / kg chloroquine at a volume of 10 mL / kg using a 27-gauge needle. Vehicle or test article (nootkatone) was applied topically (TOP) once around the chloroquine injection site 60 minutes before chloroquine injection. Diphenhydramine, the positive control, was administered once by oral gavage (PO) 60 minutes before chloroquine injection. Chloroquine vehicle: 0.9% NaCl; diphenhydramine vehicle: 5% DMSO / 2% Tween® 80; TA1 vehicle: TBD. After injection of the prurigen, the number of scratching behaviors was recorded by visual observation for 30 minutes (three intervals of 10 minutes each). Only scratching behaviors at the injection site were counted (other sites such as the ears and face were excluded). 10% topical nootkatone alleviated chloroquine-induced scratching / itching in mice (shown in Figure 9). The efficacy of 10% topical nootkatone was found to be better than clobestasol (a steroid) and ruxolitinib (a commercially available JAK1-2 inhibitor).

[0463] Example 14 Effect of nootkatone on bovine adrenal medulla (BAM) 8-22-induced itch in a rodent model BALB / c mice were divided into six groups (n=8 / treatment group) as follows: Group 1 was a negative control (no treatment or chloroquine), Group 2 was vehicle-treated (10 mL / kg PO) + BAM8-22 (150 μg / animal, SC), Group 3 was cyproheptadine (3 mg / kg PO) + BAM8-22 (150 μg / animal, SC), Group 4 was nootkatone (10 mg / kg PO) + BAM8-22 (150 μg / animal, SC), Group 5 was nootkatone (30 mg / kg PO) + BAM8-22 (150 μg / animal, SC), and Group 6 was nootkatone (100 mg / kg PO) + BAM8-22 (150 μg / animal, SC). All animals, except for Group 1 mice, which received vehicle instead of BAM8-22 subcutaneously (SC), received a subcutaneous injection of 150 μg / animal BAM8-22 in a volume of 50 μL using a 27-gauge needle on the rostral back. Vehicle or test substance was administered once by oral gavage (PO) 60 minutes prior to BAM8-22 injection. Vehicle for BAM8-22: 0.9% NaCl; vehicle for cyproheptadine: 2% Tween® 80; vehicle for Treatment Group 1: Tween® 80: 0.5% MC (400 cPs) in saline (0.5:99.5, v:v). After injection of the prurigen, the number of scratching behaviors was recorded by visual observation for 30 minutes. Only scratches at the injection site were counted (other areas such as the ears and face were excluded). Nootkatone at 100 mg / Kg PO alleviated BAM8-22-induced scratching / itch in mice (shown in Figure 10).

[0464] Example 15 Topical nootkatone formulation in the MC903 mouse model of atopic dermatitis MC903, a low-calcium analog of vitamin D3, induces cutaneous and systemic atopic dermatitis / eczema-like inflammation. Topical application of MC903 to the ear induces skin inflammation and other AD-like phenotypes in C57BL / 6J wild-type (WT) mice. This treatment increases ear skin thickening, a surrogate marker of ear skin inflammation.

[0465] During the first week of MC903 treatment, only minor changes in ear appearance were visible, such as redness, dryness, swelling, and hypervascularity. These changes were clearly observed from the fifth day of MC903 treatment and worsened over time, especially during the last few days of the experiment.

[0466] Experimental Protocol: Eight- to nine-week-old female C57BL / 6 mice were used in the study. All mice were acclimated before handling. Mice were housed in microisolator cages and maintained under specific pathogen-free conditions. All procedures were performed under appropriate institutional animal care guidelines. MC903 (2 nmol / 20 μL, dissolved in 100% ethanol) was applied topically (TOP) to the right ear daily for 14 consecutive days from days 1 to 14 for all animals except for Group 1 (sham) animals. MC903 was applied 1 hour after the test article (nootkatone at 3% and 10% concentrations) from days 7 to 14. 20 μL of ethanol (no antigen) was applied daily to the right ear for 14 consecutive days from days 1 to 14 for Group 1 (sham) animals. The petrolatum vehicle and test article (nootkatone) were applied twice daily (BID) TOP at 6-hour intervals for 8 consecutive days (1 hour before MC903 challenge) from days 7 to 14. The reference compound (clobetasol) (0.01 mg / ear) was administered topically once daily (TOP) for 8 consecutive days (1 hour before MC903 challenge) from days 7 to 14.

[0467] Female C57BL / 6 mice were randomly assigned to the following treatment groups: 1. Sham: No MC903, no treatment (negative control) 2. Medium: MC903 treatment and Vaseline medium 3. 0.05% clobetasol 4. 1.5% ruxolitinib (Groups 3 and 4 served as the positive control and comparison standard) 5. 3% Notekatone in Vaseline medium 6. 10% Notekatone in Vaseline medium MC903 treatment was performed on days 1 to 14. Clobetasol treatment, ruxolitinib treatment, and nootkatone treatment were performed on days 7 to 14. Treatment was administered 1 hour before MC903 challenge. Scratching behavior was recorded for 60 minutes immediately after MC903 challenge. Clobestasol (a steroid) and ruxolitinib (a JAK1-2 inhibitor) were used as positive controls. As shown in Figure 11, 3% nootkatone was more effective than clobestasol (a steroid) and ruxolitinib (a JAK1-2 inhibitor). 3% nootkatone demonstrated robust efficacy against scratching behavior on day 7.

[0468] Example 16 Effect of nootkatone on imiquimod (IMQ)-induced psoriasis in a mouse model Experimental Protocol: Female Balb / c mice aged 10-12 weeks were used in the study. All mice were acclimated before handling. Mice were housed in microisolator cages and maintained under specific pathogen-free conditions. During this period, mice were observed daily for clinical signs. Mice exhibiting any abnormalities or health disorders or poor physical condition were excluded from the study. All procedures were performed under appropriate animal care facility guidelines. On day 1, mice were randomized based on the thickness of the dorsal skin pinch and body weight. Hair on the backs of mice was removed using hair removal cream and clippers.

[0469] Table 21 below shows the study design. [Table 21]

[0470] Nootkatone in petrolatum gel at concentrations ranging from 2.5% to 10% was applied topically in the IMQ psoriasis model, with an additional pruritus readout. Imiquimod (5%) was applied: 47 mg to the back skin and 15.5 mg to the right ear, once daily for 5 days (4 hours after treatment).

[0471] The main test parameters are given below. > Day 1, 2, 3, 4, 5, and 6 parameters: ■Weight ■ Thickness of pinched back skin and ear ■ Psoriasis Area and Severity Index (PASI) ■ One-hour scratch test on days 1, 4, and 6 >Histopathology (back skin and right ear) > Bioanalysis (optional): 4 hours after topical application of test compound on Day 6 (optional) > Gene expression analysis of biomarkers (optional)

[0472] Nootkatone produced small but significant reductions in several psoriasis readouts (e.g., cumulative PASI, back redness + thickness + scaling score + ear redness + thickness + scaling score, 0-24, as shown in Figures 12 and 13). In this study, the effect was observed primarily at the later time point(s).

[0473] Example 17 Effect of nootkatone on DSS-induced locomotor activity in mice Dextran sulfate sodium (DSS)-induced locomotor activity refers to changes in motor patterns observed after administration of DSS, a compound commonly used to induce colitis in experimental models. Assessment of locomotor activity after DSS administration is essential for understanding the behavioral manifestations of DSS-induced colitis. During the assessment, the following activities were monitored: walking time, distance traveled, resting time, duration of stay in the center square, number of entries into the center square, and wall rearing behavior. Open field test analysis was performed using the BehaviorCloud platform. Decreased locomotor activity often indicates discomfort or disease-related fatigue, while increased activity may suggest agitation or compensatory behavior. These locomotor responses to DSS are valuable for elucidating the peripheral and central effects of colitis and the efficacy of therapeutic interventions. The mouse model was prepared as shown in Figure 14. The results of the assessment are shown in Figures 15A-F.

[0474] Disease control mice showed a significant decrease in locomotor activity (distance traveled, walking time, and resting time) compared with vehicle controls. Compared with vehicle, DSS groups showed a significant decrease in distance traveled and walking time, while resting time was significantly increased. Nootkatone at 100 mg / kg and 300 mg / kg tended to improve locomotor activity compared with disease control mice. Zone activity analysis (duration of time spent in the center of the square and number of entries into the center of the square) showed greater anxiety in DSS mice compared with vehicle controls, while nootkatone-treated mice showed improved exploratory behavior. DSS mice showed a significant decrease in exploratory behavior compared with control mice (rearing on the chamber wall), while mice treated with 300 mg / kg nootkatone showed an increase in exploratory behavior compared with DSS mice.

[0475] Example 18 Effect of nootkatone on visceral pain in a mouse model of DSS-induced colitis This study aimed to explore the mechanisms of visceral pain in a murine DSS (dextran sulfate sodium)-induced colitis model, a method commonly used to mimic inflammatory bowel disease (IBD) in an experimental setting. The primary focus of this study was to understand pain pathways and their regulation in the context of IBD. To achieve this, the study quantified inflammation and its systemic impact using a combination of disease activity index (DAI) scoring and exposure analysis in both plasma and colon tissue. DAI scoring, a comprehensive measure that considers weight loss, stool consistency, and bleeding, provided a reliable measure of colitis severity. Simultaneously, exposure analysis in plasma and colon tissue assessed the presence and concentrations of inflammatory markers, cytokines, and other biochemical indicators of inflammation. This dual approach ensured a thorough understanding of the inflammatory process at both the local and systemic levels.

[0476] Behavioral parameters, specifically the von Frey pain response and capsaicin-induced pain response, were essential components of the study to assess sensory and pain aspects in the mouse model. The von Frey test, which involves applying a calibrated filament to measure mechanical pain sensitivity, was useful for assessing changes in pain perception due to colitis. In contrast, the capsaicin-induced pain response test, which involves administering capsaicin (a compound known to induce pain and mimic inflammatory pain in humans) and observing the pain response, provided insight into nociceptive pathways and pain modulation in the context of colitis. These behavioral tests were essential for correlating the degree of inflammation with the severity of pain, thereby contributing to a deeper understanding of visceral pain mechanisms in the context of IBD. The mouse model was prepared as shown in Figure 16. The results of the von Frey assay are shown in Figures 17A-17D. The results of the capsaicin-induced visceral pain assay are shown in Figures 17E-17I.

[0477] Von Frey assays were performed using two methods: the up-down method using 0.008 g, 0.02 g, and 0.16 g filaments and nociceptive scoring. Nootkatone demonstrated dose-dependent antihyperalgesic effects in both methods. Nootkatone at 300 mg / kg BID demonstrated significant antihyperalgesic activity in the up-down assay.

[0478] The DSS group showed the highest nociceptive behavior after capsaicin instillation into the colon. Nootkatone treatment showed a clear dose-dependent reduction in nociceptive behavior. Abdominal licking and pushing behavior after capsaicin instillation was reduced in the treated group. Abdominal contractions were not observed. Stretching behavior was mixed with rearing behavior and was therefore not considered in the overall response summary. Nootkatone reduced all nociceptive responses in a dose-dependent manner.

[0479] Example 19 Effect of nootkatone on visceral pain in a TNBS-induced colitis model in mice This study aimed to explore the mechanisms of visceral pain in a murine TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced colitis model, a method commonly used to mimic inflammatory bowel disease (IBD) in an experimental setting. The primary focus of this study was to understand pain pathways and their regulation in the context of IBD. To achieve this, the study quantified inflammation and its systemic effects using a combination of disease activity index (DAI) scoring and exposure analysis in both plasma and colon tissue. DAI scoring, a comprehensive measure that considers weight loss, stool consistency, and bleeding, provided a reliable measure of colitis severity. Simultaneously, exposure analysis in plasma and colon tissue assessed the presence and concentrations of inflammatory markers, cytokines, and other biochemical indicators of inflammation. This dual approach ensured a thorough understanding of the inflammatory process at both the local and systemic levels.

[0480] Behavioral parameters, specifically the von Frey pain response and capsaicin-induced pain response, were essential components of the study to assess sensory and pain aspects in the mouse model. The von Frey test, which involves applying a calibrated filament to measure mechanical pain sensitivity, was useful for assessing changes in pain perception due to colitis. In contrast, the capsaicin-induced pain response test, which involves administering capsaicin (a compound known to induce pain and mimic inflammatory pain in humans) and observing the pain response, provided insight into nociceptive pathways and pain modulation in the context of colitis. These behavioral tests were essential for correlating the degree of inflammation with the severity of pain, thereby contributing to a deeper understanding of visceral pain mechanisms in the context of IBD. The mouse model was prepared as shown in Figure 18. The results of the von Frey assay are shown in Figures 19A-19D. The results of the capsaicin-induced visceral pain assay are shown in Figures 19E-19J.

[0481] Von Frey analysis was performed using two methods (up-down method using 0.008 g, 0.02 g, and 0.16 g filaments and nociceptive scoring). Nootkatone demonstrated a dose-dependent antihyperalgesic effect in both methods. Nootkatone at 300 mg / kg BID demonstrated significant antihyperalgesic activity in both methods.

[0482] After intracolonic capsaicin infusion, mice with TNBS-induced colitis exhibited severe visceral pain, as evidenced by the mice freezing for most of the time. While freezing, the mice also exhibited minimal but varied spontaneous pain behaviors. Nootkatone significantly and dose-dependently reduced freezing behavior.

Claims

1. 1. A method of treating or preventing pruritus in a subject in need thereof, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt thereof; and optionally (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone or pharmaceutically acceptable salt thereof in the composition has a purity of at least about 95% w / w, or both (a) and (b).

2. The method of claim 1 , wherein the subject is a human.

3. 10. The method of claim 1, wherein the subject is a cat, dog, or horse.

4. The method of any one of claims 1 to 3, wherein the composition is administered topically.

5. 5. The method of any one of claims 1 to 4, wherein the composition has less than about 1% w / w of other components naturally occurring in a nootkatone-containing source, and wherein the nootkatone or pharmaceutically acceptable salt thereof in the composition has a purity of at least about 99% w / w.

6. The method of any one of claims 1 to 5, wherein the composition further comprises an emulsifier.

7. The method of any one of claims 1 to 5, wherein the composition further comprises a gelling agent.

8. The method of any one of claims 1 to 7, wherein the composition comprises nootkatone.

9. 9. The method of claim 8, wherein the composition comprises at least 1.5% w / w nootkatone.

10. 9. The method of claim 8, wherein the composition comprises at least 5% w / w nootkatone.

11. 9. The method of claim 8, wherein the composition comprises from about 1.5% to about 10% w / w of nootkatone.

12. The method of any one of claims 1 to 11, wherein the composition is administered once or twice daily.

13. The method of any one of claims 1 to 12, wherein the composition is administered for at least 12 weeks.

14. 14. The method of claims 1-13, wherein said administering said composition to said subject reduces itch after a predetermined time period, as determined according to the Itch Numerical Rating Scale (I-NRS).

15. 14. The method of any one of claims 1-13, wherein said administering said composition to said subject reduces pruritus over a period of time, evidenced by a reduction in atopic dermatitis, as determined according to the Patient Oriented Eczema Measure (POEM).

16. 1. A method of treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, said method comprising: administering to said subject a composition comprising a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt thereof; wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB; Optionally, (a) the composition has less than about 5% w / w of other components naturally occurring in the nootkatone-containing source, or (b) the nootkatone or pharmaceutically acceptable salt thereof in the composition has a purity of at least about 95% w / w, or both (a) and (b).

17. 1. A pharmaceutical composition comprising nootkatone or a pharmaceutically acceptable salt thereof for use in a method for treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

18. 1. Use of nootkatone, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

19. 1. Nootkatone or a pharmaceutically acceptable salt thereof for use in the treatment of pruritus, wherein said nootkatone or a pharmaceutically acceptable salt thereof is administered topically, subcutaneously, or orally.

20. 1. Nootkatone in a method for treating pruritus, said method comprising:

1. A method for treating pruritus comprising topically administering to the skin of a subject in need of treatment a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to modulate the amount or activity of a therapeutic target.

21. 21. The method of claim 20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, erythroid transcription factor 2 (NFE2), and NF-κB.

22. 22. The method of claim 21, wherein the topical administration comprises topically administering an amount sufficient to reduce the intensity of pruritus and relieve pruritus by causing regression of one or more symptoms related to pruritus.

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