Nootkatone for the treatment of pruritus

Abstract

The present disclosure relates generally to compounds, compositions, and methods for treating pruritus using a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt or derivative thereof. Methods of formulating and using the compositions are also provided.

Description

NOOTKATONE FOR THE TREATMENT OF PRURITUSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority and benefit of U.S. Provisional Patent Application No. 63 / 430,325 filed on December 5, 2022; U.S. Provisional Patent Application No. 63 / 478,666 filed on January 5, 2023; U.S. Provisional Patent Application No. 63 / 478,668 filed on January 5, 2023; U.S. Provisional Patent Application No. 63 / 478,669 filed on January 5, 2023; U.S. Provisional Patent Application No. 63 / 478,670 filed on January 5, 2023; and U.S. Provisional Patent Application No. 63 / 478,671 filed on January 5, 2023. The contents of each of these applications are incorporated herein by reference in their entirety for all purposes.TECHNICAL FIELD

[0002] The present disclosure relates generally to nootkatone, compositions, and methods for treating a variety of diseases and conditions, and more specifically, to treating pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy.BACKGROUND

[0003] Skin is the first line of defense against environmental insults that would otherwise damage sensitive underlying tissue and organs. For example, skin maintains a relatively water- impermeable barrier between an organism and its environment to prevent dehydration. Additionally, skin plays a key role in a person's physical appearance. Generally, most people desire to have younger, healthy looking skin. And to some of these people, the tell-tale signs of skin aging such as thinning skin, wrinkles, and age spots are an undesirable reminder of the disappearance of youth. As a result, treating the signs of aging in skin has become a booming business in youth-conscious societies. 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 marketed to treat various skin conditions, especially 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 protective mechanism that allows healthy animals to avoid tissue damage and to prevent further damage to injured tissue. Nonetheless there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain. Various forms of pain include, but are not limited to, chronic pain, gut 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 an injury to the sensory nerves (Dieleman, J. P., et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): p. 681-8). Neuropathic pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve and pain caused by a discrete nerve injury. The metabolic neuropathies include post herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injuries indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries, such as neuropathic back pain.

[0007] Abdominal pain is a common and complex health issue globally, affecting individuals' well-being. This pain, which can range from mild to severe, often results from various conditions such as 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, bloating, and altered bowel habits, and the pain may occur in different abdominal areas.

[0008] Irritable bowel syndrome (IBS), a chronic gastrointestinal disorder, is marked by recurrent abdominal pain linked to bowel movements, and changes in stool frequency or form. Symptoms often include abdominal pain, bloating and distension, and it can significantly reduce life quality in severe cases.

[0009] Celiac disease, a genetic autoimmune disorder, is triggered by gluten consumption. It increases intestinal permeability, allowing gluten-breakdown products to initiate an inflammatory response. This disease is marked by chronic inflammation of the small intestine, potentially leading to villi atrophy, and causes symptoms like abdominal pain, malabsorption, diarrhea, bloating, and nausea.

[0010] Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a group of chronic inflammatory intestinal diseases more common in developed countries.Ulcerative colitis affects the colon and can range from the distal ileum to the anus. It often causes painful, bloody diarrhea, fever, and weight loss during flare-ups. Treatment mainly focuses on controlling inflammation, often using costly monoclonal antibody therapies.

[0011] Endometriosis, affecting 10-15% of women in their reproductive years, is characterized by uterine tissue growth outside the uterus, commonly in the ovaries. This tissue responds to menstrual cycle hormones, causing inflammation and pain. Symptoms include painful menstruation, pain during intercourse, and chronic abdominal pain, and they don't always correlate with the severity of the condition. Some women with extensive endometriosis may not experience symptoms, while those with milder forms can have severe pain.

[0012] Pruritus is a condition involving localized or general itching that is a common and distressing symptom in a variety of diseases. Although usually occurring in the skin, pruritus can also occur in non-cutaneous sites such as mucous membranes. Pruritus is a frequent manifestation of localized skin disorders caused by hypersensitivity reactions such as allergic reactions to insect bites or to environmental allergens, urticaria, dermatoses of fungal and bacterial origins, ectoparasite infections, and hemorrhoids. Pruritus may also be a symptom caused by systemic diseases, including, for example, hypothyroidism, thyrotoxicosis, mucocandiasis in diabetes mellitus, and Hodgkin's disease, (see, for example, Herndon, J. H. Jr., Int. J. Derm. 14, 465-484 (1975); Winkelmann, R. K„ Med. Clins. N. Am. 66, 1119-1133 (1982). Many systemic diseases and skin disorders are accompanied by bouts of persistent or recurrent pruritus. The clinical importance of pruritus is irrefutable but effective treatment has been limited by current available treatments.

[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 causes of eczema, including atopic dermatitis, remain unclear. Atopic dermatitis is a major global public health problem, affecting l%-20% of people worldwide. The prevalence of atopic dermatitis in adults is about l%-3%, and 10%-20%, in children. Atopic dermatitis is the most common form of eczema in childhood. Since 1960s, the prevalence of atopic dermatitis has increased more than 3-fold. The reasons for the rising prevalence are as yet unclear (Lee, J. H., et al. A Comprehensive Review of the Treatment of Atopic Eczema, Allergy Asthma Immunol. Res., 2016 8(3), 181- 190). Atopic dermatitis is a worldwide public health concern with significant financial burden. In addition, atopic dermatitis affects the quality of life of families as well as those affectedthemselves. Eczema, including atopic dermatitis, remains a challenging condition for physicians and patients.

[0014] Psoriasis is a clinically heterogeneous lifelong skin disease that presents in multiple forms such as plaque, flexural, guttate, pustular or erythrodermic. An estimated 60 million people have psoriasis worldwide. In 2014, the World Health Organization recognized psoriasis as a serious non-communicable disease and highlighted the distress related to misdiagnosis, inadequate treatment and stigmatization of this disease. 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-fold that of inflammatory bowel disease (Raharja, A., et al. Psoriasis: a brief overview. Clin Med (Land). 2021 May; 21(3): 170-173.).

[0015] Diabetes mellitus causes several skin related complications ranging from diabetic dermopathy, diabetic blisters (diabetic bullae / bullosis diabeticorum), diabetic peripheral neuropathy (DPN), xerosis (skin dryness), ichthyosiform skin changes, feet propensity to develop fungal infections, acanthosis nigricans, diabetes-associated pruritus to nerve damage (diabetic neuropathy). Diabetic dermopathy, commonly referred to as shin spots is characterized by light brown or reddish, oval or round, slightly indented scaly patches most often appearing on the shins. Diabetic blisters are blister-like lesions spontaneously occurring 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 presented on the feet areas. Ichthyosiform 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. The affected areas skin may also itch or have an odor. Diabetic peripheral neuropathy (DPN) is nerve damage caused by chronically high blood sugar and diabetes. DPN leads to numbness, loss of sensation, and sometimes pain in feet, legs, or hands. Diabetes-associated pruritus is more likely in patients with diabetes who have dry skin or diabetic neuropathy and is often localized to include the scalp, ankles, feet, trunk, or genitalia. With significant clinical implications, healthcare providers need to be aware of the risk factors to devise appropriate management strategies for skin complications in diabetes.

[0016] Accordingly, there is an ongoing need in the art for compounds, compositions and methods for treating pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy, along with a variety of other diseases and conditions.BRIEF SUMMARY

[0017] A method of treating pain in a subject in need thereof is provided herein. The method comprises administering to the subject a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt or derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components that are naturally occurring in a 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] A method of treating pruritus in a subject in need thereof is provided herein. The method comprises administering to the subject a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt or derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components that are naturally occurring in a 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] A method of treating atopic dermatitis or psoriasis in a subject in need thereof is provided herein. The method comprises administering to the subject a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt or derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components that are naturally occurring in a 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] A method of treating diabetic dermopathy or diabetic peripheral neuropathy in a subject in need thereof is provided herein. The method comprises administering to the subject a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt or derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components that are naturally occurring in a 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] A method for improving the appearance of skin in a subject in need thereof is provided herein. The method comprises administering to the subject a therapeutically effective amount of nootkatone, a dermatologically acceptable salt or derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components that arenaturally occurring in a 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 its pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB and thus are useful for treating or lessening the severity of the variety of diseases, disorders, or conditions described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIGS. 1A and IB show the blocking effect of nootkatone in mouse dorsal root ganglia (DRGs) via neuronal depolarization. 100 pM nootkatone blocked neuronal depolarization in capsaicin / transient receptor potential vanilloid subfamily member 1 (TRPV1) negative neurons in mice.

[0024] FIG. 2 illustrates the transient response to 30mM KC1 in human DRGs (Vehicle v / s nootkatone effect on 30mM KC1).

[0025] FIGS. 3A and 3B illustrate nootkatone mediated neuronal depolarization in human DRGs. Nootkatone was applied at 30uM (first application) and lOOuM (second application) to observe its effect on Electrical field stimulation (EFS) induced neuronal depolarization / activity.

[0026] FIG. 4 is a graphical representation of the effect of nootkatone in in-vivo formalin induced pain mice model.

[0027] FIG. 5 and FIG.6 represent that nootkatone relieved acute pain in both phases (Phase- 1 and Phase-2 in in-vivo formalin induced mouse model.

[0028] FIG. 7 illustrates the efficacy of nootkatone topical application in mouse acute pain model using tail flick test.

[0029] FIG. 8 illustrates that 30mpk oral administration of nootkatone relieved chloroquine-induced scratching / itching in mice.

[0030] FIG. 9 illustrates that 10% topical administration of nootkatone relieved chloroquine-induced scratching / itching in mice.

[0031] FIG. 10 illustrates that lOOmg / Kg, PO nootkatone relieved BAM8-22-induced scratching / itching in mice.

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

[0033] FIG. 12 illustrates the effect of the topical application of nootkatone in imiquimod (IMQ)-induced psoriasis mouse model. Nootkatone caused a slight but significant decrease in cumulative PASI readout from days 1 to 6.

[0034] FIG. 13 illustrates the effect of the topical application of nootkatone in imiquimod (IMQ)-induced psoriasis mouse model. Nootkatone caused a slight but significant decrease in cumulative PASI readout on day 6.

[0035] FIG. 14 illustrates a study design for the effect of nootkatone on DSS-induced locomotor activity.

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

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

[0038] FIGS. 17A, 17B, 17C, 17D, 17E, 17F, 17G, 17H, and 171 are graphical representations illustrating the effect of nootkatone on visceral pain in a mouse model of DSS- induced colitis.

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

[0040] FIGS. 19A, 19B, 19C, 19D, 19E, 19F, 19G, 19H, 191, and 19J are graphical representations illustrating the effect of nootkatone on visceral pain in a mouse model of TNBS-induced colitis.DETAILED DESCRIPTION

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

[0042] Nootkatone is a sesquiterpenoid, and has the chemical structure shown below:Nootkatone

[0043] Nootkatone is a naturally-occurring compound that can be found in many plants, such as Nardostachys jatamansi. citrus fruits such as grapefruit (Citrus paradisi), and in Alaskan yellow cedar trees (Chamaecyparis nootkatensis). Nootkatone was first isolated from the heartwood of the Alaskan 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 may be obtained by extraction and purification from natural sources (Kelsey, R.G., et al., 2015. Volatile terpenoids and tropolones in heartwood extracts of yellowcedar, Monterey cypress, and their hybrid Leyland cypress. Ann. For. Sci. 72, 349-355.), as well as by total synthesis (Marshall, J.A., Ruden, R.A., 1971. Stereoselective total synthesis of racemic nootkatone. J. Org. Chem. 36 (4), 594-596.), and biosynthesis (Sowden, R.J., 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 mixture of products produced in a host modified to express enzymes of the nootkatone biosynthetic pathway or that can be produced from naturally occurring sources, such as citrus plants. In some embodiments, nootkatone may also refer to a mixture of chemical compoundscontaining or enriched for the nootkatone compound and derived from a modified host, such as a microorganism, or isolated or derived from plant extracts. In other embodiments, nootkatone may further refer to derivatives and analogs thereof. For example, the nootkatone compound contemplated for use herein may be produced in vivo through expression of one or more enzymes involved in the nootkatone biosynthetic pathway in a recombinant yeast or in vitro using isolated, 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 entirety.

[0045] In certain embodiments, nootkatone is derived from oxidation of valencene that was produced by fermentation, such as by microorganisms harboring one or more valencene synthases and / or other molecules that catalyze formation of valencene. It is to be appreciated that nootkatone may be formed as a portion of a combination of chemical compounds derived from oxidation of a valencene-containing fermentation product produced by culturing microorganisms harboring one or more valencene synthases and / or other molecules that catalyze formation of valencene. This combination can be purified to maximize the percent of nootkatone relative to other chemical compounds.

[0046] As used herein, reference to “extract” generally refers to an extract of a plant containing material from any species within the identified genus, unless the particular species is identified. Unless otherwise identified, any part of the plant may be used to obtain the extract used in the composition including, but not limited to, the root, stem, rhizome, leaf, flower, fruit, and / or extracts of these parts. The plant extract may be commercially obtained from various resources. In addition, suitable plant extracts can be obtained by using any conventional extraction technique including, but not limited to, one or more techniques described further below.

[0047] The plant extracts can be obtained via conventional extraction methods understood in the art, such as by water (e.g., steam) extraction or by solvent (e.g, alcohol) extraction. The composition of this disclosure is not limited to a particular extraction method, nor is extraction required since suitable extracts (e.g, standardized extracts) are readily available from a number of commercial suppliers. Exemplary extraction methods are described below.

[0048] To obtain an extract, a polar solvent such as an alcohol (e.g., methanol, ethanol, butylene glycol), an ether (e.g, ethyl ether), a ketone (e.g., acetone), an ester (e.g., ethylacetate), water, or mixtures thereof, can be used as a solvent. Certain extracts can be also obtained by further extracting the extract from the 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 a variety of extraction methods that may be used to produce extracts suitable for the composition. These methods Include, but are not limited to, the extraction methods disclosed in U.S. Pat. No. 7,897,184, which is hereby incorporated by reference in its entirety.

[0049] The details of the treatment methods and compositions are described in further detail below, including the doses, dosing regimens and kits for the same.Pharmaceutically / Dermatologically Acceptable Salts and Compositions

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

[0051] It will also be appreciated that nootkatone of the disclosure can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, hydrates,stereoisomers, or any other adduct or derivative which upon administration to a subject in need is capable of providing, directly or indirectly, nootkatone as otherwise described herein, or a metabolite or residue thereof.

[0052] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of nootkatone of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, nootkatone or an inhibitory active metabolite or residue thereof. As used herein, the term “inhibitory active metabolite or residue thereof’ means that a 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. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference in its entirety. Pharmaceutically acceptable salts of nootkatone of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-4 alkyl)4 salts. This disclosure also envisions the quatemization of any basic nitrogen-containing groups of nootkatone disclosed herein. Water or oil-soluble or dispersable products may be obtainedby such quatemization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0054] As described herein, the pharmaceutically acceptable compositions of the disclosure additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. 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 the preparation thereof. Except insofar as any conventional carrier medium is incompatible with nootkatone of the disclosure, such as by producing 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 to be within the scope of this disclosure. Some examples of materials which 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, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coatingagents, 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 comprising nootkatone and a pharmaceutically acceptable carrier.

[0056] In another aspect, the disclosure features a pharmaceutical composition comprising 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 a pharmaceutically acceptable salt thereof used in the compositions administered may be obtained from any commercially available sources, or any methods or techniques known in the art. For example, in some variations, the nootkatone may be isolated from a natural source. In other variations, the nootkatone may be synthesized according to any methods known in the art.

[0058] In various embodiments, the composition includes 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 encompasses the specifically recited elements / components for a particular embodiment. Further, the phrase “consisting essentially of’ generally encompasses and allows for the presence of additional or optional elements / components that do not materially impact the basic and / or novel characteristics of that particular embodiment. In certain embodiments, “consisting essentially of’ allows for the presence of <10, <5, or <1, weight percent (wt. %) of additional or optional components based on the total weight of the composition.

[0059] In various embodiments, the composition includes one or more pharmaceutically acceptable additives that are inactive ingredients. Examples of inactive ingredients include, but are not limited to, excipients, such as diluents and binders, granulating agents, glidants (or flow aids), fillers, lubricants, preservatives, stabilizers, coatings, disintegrants, fragrances, pigments, preservatives, solvents (e.g, alcohols), and combinations thereof. If utilized to form the 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 that is suitable for topical application to human or animal skin. It is to be further appreciated that the amounts of actives described herein can be normalized with respect to 100 parts by weight of the composition to account for the presence of inactive ingredients (if utilized).

[0060] Optionally, the composition may include one or more additional components such as additives. Suitable additives include those understood in the art, including but not limited to, moisturizers, emollients, emulsifiers, surfactants, oils, extracts, skin protectants, disinfectants, antiseptics, drugs and drug substances, analgesic compounds, anti-neuralgic compound, anti-oxidants, blood circulation promoters, antidepressant compounds, anti-anxiety compounds, anti-stress compounds, sunscreens, insect repellants, preservatives, exfoliants, fragrances, colors, fillers, solvents, vehicles, carriers, other types of additives known to those of skill in the art, and combinations thereof. Such additives may be utilized alone or in combination. In general, the optional additives may be of any type used in pharmaceuticals, nutraceuticals, personal care products and cosmetic products.

[0061] Examples of such carrier components are oils, fats, waxes, surfactants, humectants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dyestuffs, lower alkanols, and the like. If desired, further ingredients may be incorporated in the compositions, e.g., anti-inflammatory agents, antibacterials, antifungals, disinfectants, vitamins, sunscreens, antibiotics, skin bleaching agents, healing enhancers / fibroblast proliferation compounds, neuromuscular blocking agents, sunscreens, or other anti-acne agents.

[0062] Examples of oils as a carrier agent comprises 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. As examples of surfactants as carrier agents, there may be cited anionic surfactants such as sodium stearate, sodium cetylsulfate, polyoxyethylene laurylether phosphate, sodium N-acyl glutamate; cationic surfactants such as stearyldimethylbenzylammonium chloride and stearyltrimethylammonium chloride; ampholytic surfactants such as alkylaminoethylglycine hydrocloride solutions and lecithin; and nonionic surfactants such as glycerin monostearate, sorbitan monostearate, sucrose fatty acid esters, propylene glycol monostearate, polyoxyethylene oleylether, polyethylene glycol monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene coconut fatty acid monoethanolamide, polyoxypropylene glycol (such as the materials sold under the trademark “Pluronic”), polyoxyethylene castor oil, and polyoxyethylene lanolin. Examples of humectants as carrier agents include glycerin, 1,3-butylene glycol, and propylene glycol; examples of loweralcohols include ethanol and isopropanol; examples of thickening agents include xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol and, sodium carboxymethyl cellulose. Examples of antioxidants comprise butylated hydroxy toluene, butylated hydroxyanisole, propyl gallate, citric acid, ethoxyquin, alpha lipoic acid, vitamin C, vitamin E, co-enzyme Q-10, and idebenone; botanical anti-oxidants include carotenoids such as lycopene; flavonoids such as silymarin (milk thistle), silybin, silydianin, silychristine; soybeans (isoflavins), grape seed extract; polyphenols such as green tea extract, rosmarinic acid (rosemary), hypercin (Saint John's wort), oleuropein (olive leal), curcurmin (tumeric root), tetrahydrocurcumin, and pycogenol (marine bark pine). Examples of anti-inflammatory agents include anti-inflammatory botanicals such as allantoin, aloe vera, ginkgo biloba, green tea (also considered an antioxidant). Examples of skin bleaching agents are hydroquinone or kojic acid. Examnples of healing enhancers / fibroblast proliferation compounds include copper peptides or palmitoyl-pentapetide (pal-KTTKS). Examples of neuromuscular blocking agents such as acetyl hexapeptide 3 (argircline) or dimethylaminoethanol. Examples of chelating agents include disodium edetate and ethanehydroxy diphosphate. Examples of buffers as carrier agents comprise citric acid, sodium citrate, boric acid, borax, and disodium hydrogen phosphate; and examples of preservatives are methyl parahydroxybenzoate, ethyl parahydroxybenzoate, dehydroacetic acid, salicylic acid and benzoic acid.

[0063] As used herein, "emollient" refers to materials used for the prevention or relief of dryness, as well as for the protection of the skin. A wide variety of suitable emollients are known and can be used herein. See e.g., 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 Apr. 24, 1990, both of which are incorporated herein by reference in their entirety. A representative composition comprising the emollient in accordance with various aspects of the present disclosure may comprise any components that are suitably adapted for providing moisture retention, reduction of transepidermal water loss (TEWL), smooth feel, softness, increased substantivity, and / or the like. Additionally, representative emollient compositions may be employed to soften or smooth the skin by reducing roughness, cracking, irritation, and / or the like.

[0064] It is to be appreciated that certain components or additives may be classified under different terms of art and just because a component or additive is classified under such a term does not mean that they are limited to that function. If utilized, the additive or additives maybe present in the composition in various amounts. Additional ingredients for optional use in the composition are described in U.S. Pat. No. 5,747,006 to Domoff et al., U.S. Pat. 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 hereby incorporated by reference in their entirety.

[0065] The composition can be prepared using various methods. For example, actives of the composition, and optionally one or more inactives, can be mixed or blended and compressed or compounded utilizing various techniques understood in the art. The composition of this disclosure is not limited to a particular order of manufacturing steps or method of manufacture.

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

[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 even 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 even more of nootkatone, or a pharmaceutically acceptable salt thereof.

[0068] In certain variations, the composition comprises between about 0.1% and about 20% w / w, between about 0.1% and about 15% w / w, between about 0.1% and about 5% w / w, between about 0.1% and about 3% w / w, between about 0.1% and about 1.5% w / w, between about 0.1% and about 1% w / w, between about 0.1% and about 0.75% w / w, between about 0.1% and about 0.375% w / w, between about 0.375% and about 5% w / w, between about 0.375% and about 3% w / w, between about 0.375% and about 1.5% w / w, between about 0.375% and about 1% w / w, between about 0.375% and about 0.75% w / w, between about 0.75% and about 5% w / w, between about 0.75% and about 3% w / w, between about 0.75% and about 1.5% w / w, between about 0.75% and about 1% w / w, between about 1% and about 5% w / w, between about 1% and about 3% w / w, between about 1% and about 1.5% w / w, between about 1.5% and about 5% w / w, between about 1.5% and about 3% w / w, between about 3% and about 5% w / w, between about 1% and about 15% w / w, between about 2% and about 10% w / w, between about 4% and about 8% w / w, between about 5% and about 15% w / w, or between about 8% and 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 that are naturally occurring in a nootkatone-containing source. In one variation, the composition does not have a detectable amount of other components that are naturally occurring in a nootkatone-containing source. In one embodiment, the mass of the components in the composition other than nootkatone that are naturally occurring in a 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% the total mass of any nootkatone in the composition.

[0070] In other embodiments, nootkatone, or a pharmaceutically acceptable salt thereof, is 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 a cream. In these and other embodiments, the composition comprises nootkatone and a pharmaceutically / cosmetically acceptable excipient. “Pharmaceutically / cosmetically acceptable excipient(s)” are components that are added to the composition other than the active ingredient nootkatone. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance skin penetration, enhance patient acceptability, enhance actives release, etc. Pharmaceutically / cosmetically acceptable excipient(s) includes, but not limited to, one or more emulsifiers, gelling agents, preservatives, chelating agents, viscosity modifiers, antioxidants, surfactants, emollients, opacifying agents, skin conditioners, fragrants, colorants, fillers, humectants, pH modifiers, acidifying agents, solvent, vehicles, oily vehicles, suspending agents, dispersing agents, and any other excipient known to the art for formulating pharmaceutically / cosmetically acceptable compositions. According to the present disclosure, a particular excipient may perform multiple roles in the composition, for example, it can act both as a preservative and as a pH modifier.

[0073] In some embodiments, the composition comprises nootkatone, or a pharmaceutically acceptable salt thereof, formulated in petroleum jelly. In some variations, the composition consists essentially of nootkatone, or a pharmaceutically acceptable salt thereof, and petroleum jelly. In certain variations, the composition consists of nootkatone, or a pharmaceutically acceptable salt thereof, and petroleum jelly.

[0074] In certain embodiments, nootkatone, or pharmaceutically acceptable salts thereof; and (ii) one or more additional sequiterpenoids 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 apharmaceutically acceptable salt thereof, and one or more excipients of the aqueous gel-based composition. In certain variations, the composition consists of nootkatone, or a pharmaceutically acceptable salt thereof, and one or more excipients of the aqueous gel-based composition.

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

[0076] The gelling agent may be present in the gel -based in an amount from about 0. 1 wt. % to about 10 wt.%, from about 0. 1 wt.% to about 5 wt.%, from about 0.5 wt.% to about 3 wt.%, or from about 0.5 wt.% to about 2 wt.% based on a total weight of the composition. In some embodiments, the gelling agent may be present in the gel-based 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 a total weight of the composition.

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

[0078] The preservative may be provided in any amount known in the art. In some embodiments, the preservative is present in the gel-based composition in an amount of from about 0.001 wt.% to about 3 wt.%, from about 0.01 wt.% to about 1 wt.%, from about 0.01 wt.% to about 0.50 wt.%, or from about 0.15 wt.% to about 0.25 wt.%. In some embodiments, the preservative is present in the gel -based 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 than0.06%, 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% based on a total weight of the gel-based composition.

[0079] The pH modifier may be present in the gel-based composition in an amount from about 0.1 wt.% to about 10 wt.%, from about 0.1 wt.% to about 5 wt.%, from about 0.5 wt.% to about 3 wt.%, or from about 0.5 wt.% to about 2 wt.% based on a total weight of the composition. In some embodiments, the gelling agent may be present in the gel-based 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 a total weight of the composition.

[0080] The antioxidant may be provided in any suitable amount. In some embodiments, the antioxidant is present in the gel-based composition in an amount of from about 0.001 wt.% to about 3 wt.%, from about 0.01 wt.% to about 1 wt.%, from about 0.01 wt.% to about 0.50 wt.%, or from about 0.05 wt.% to about 0.15 wt.%. In some embodiments, the antioxidant is present in the gel-based 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% based on a total weight of the gel-based composition.

[0081] In other embodiments, nootkatone or pharmaceutically acceptable salts thereof; and (ii) one or more additional sequiterpenoids and / or excipients may be formulated as a creambased 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 certain variations, 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 comprise the active component (e.g., nootkatone), an emulsifier, emollient, a solvent, an antioxidant, a preservative, or combinations thereof. The active component may be present in the compositionin an amount of from about 0.1 wt.% to about 50 wt.%, from about 1 wt.% to about 40 wt.%, from about 1 wt.% to about 30 wt.%, from about 1 wt.% to about 20 wt.%, or from about 2 wt.% to about 10 wt.%, based on a total weight of the composition. In some embodiments, the active component 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 a total weight of the composition.

[0083] The emulsifier may be present in the cream-based in an amount 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 a total weight of the composition. In some embodiments, the emulsifier may be present in the cream-based 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 a total weight of the composition.

[0084] The emollient may be present in the cream-based in an amount 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 a total weight of the composition. In some embodiments, the emollient may be present in the cream-based 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 a total weight of the composition.

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

[0086] The preservative may be provided in any amount known in the art. In some embodiments, the preservative is present in the cream-based composition in an amount of from about 0.001 wt.% to about 3 wt.%, from about 0.01 wt.% to about 1 wt.%, from about 0.01 wt.% to about 0.50 wt.%, or from about 0.20 wt.% to about 0.30 wt.%. In some embodiments, the preservative is present in the cream-based 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%, greaterthan 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% based on a total weight of the cream-based composition.

[0087] The antioxidant may be provided in any suitable amount. In some embodiments, the antioxidant is present in the gel-based composition in an amount of from about 0.001 wt.% to about 3 wt.%, from about 0.01 wt.% to about 1 wt.%, from about 0.01 wt.% to about 0.50 wt.%, or from about 0.05 wt.% to about 0.15 wt.%. In some embodiments, the antioxidant is present in the gel-based 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% based on a total weight of the gel -based composition.

[0088] As introduced above, it is contemplated herein that the gel-based or cream-based composition may comprise the active component (e.g., nootkatone), a gelling agent, an emulsifier, an emollient, a pH modifier, a solvent, an antioxidant, a preservative, or combinations thereof.

[0089] Gelling agents that can be used in the composition, include polysaccharides (carrageenan, alginates), proteins (gelatin), cellulose derivatives (hydroxypropyl cellulose, hydroxyethyl cellulose), acrylic acid polymers (carbomers, Carbopol), clay (bentonite, hectorite), polyacrylamides (Sepigel 305), hydrocarbon gels (polybutene, hydrogenated poly decene), silica (hydrophobic fumed silica, silica silylate), fatty acid derivatives (12- hydroxystearic acid, ethylene glycol monostearate), amide derivatives (stearic acid diethanolamide, stearamide MEA), wax esters (beeswax, candelilla wax), fatty alcohols (cetyl alcohol, stearyl alcohol), or combinations thereof. The gelling agent may be made of carboxyvinyl polymers (such as carbomers). Non-limiting examples of carbomers includes Carbopol 981, Carbopol ETD 2020, Carbopol 980, Carbopol Ultrez 10, Pemulen TRI, Hydroxyethyl Acrylate / Sodium Acryloyldimethyl Taurate Copolymer (such as Sepineo™ Derm), Acrylamide / Sodium acryloyldimethyl taurate copolymer / Isohexadecane, Polysorbate 80 (such as Sepineo™ P 600 or Simulgel™ 600), or combinations thereof. Other gelling agents may be made of cellulose derivatives such as, for example, hydroxypropylmethylcellulose, or hydroxy ethylcellulose, xanthan gums, aluminum / magnesium silicates such as Veegum K orVeegum Ultra, guar gums, polyacrylamides such as the mixture polyacrylamide / C13-14 isoparaffin / laureth-7, acrylamides, AMPS copolymer dispersion 40% / isohexadecane, modified starches such as structure Solanace, or combinations thereof. In exemplary embodiments, the gelling agent comprises a carbomer, such as Carbopol Ultrez 10.

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

[0091] A variety of solvents can be utilized in the composition, each offering distinct properties and functionalities (e.g., penetration enhancement, preservation, emulsification, etc). Broad chemistries of solvents suitable for cosmetic gels include water, alcohols (such as ethanol or isopropyl alcohol), ethers (such as diethylene glycol monoethyl ether, diethyl ether or ethoxydiglycol), esters (such as ethyl acetate, isopropyl myristate), hydrocarbons (such as mineral oil, isododecane), glycols (such as diethylene glycol, propylene glycol, or butylene glycol), and silicones (such as dimethicone or cyclopentasiloxane). These solvents offer a wide range of properties, including volatility, polarity, permeation, spreadability, solubility, evaporation rate, and texture, allowing formulators to select the most suitable solvent(s) based on the desired characteristics of the gel-based or the cream-based composition. In exemplary embodiments, the solvent comprises water, an alcohol such as ethanol, an ether such as diethylene glycol monoethyl ether, a glycol such as propylene glycol, and an ester such as isopropyl myristate. In various embodiments, the glycol may also function as an emulsifier or preservative. In many embodiments, the ether may also function as a hydrophobic oil. In various embodiments, the ester may also function as a penetration enhancer.

[0092] Embodiments are not limited by the number or type of preservatives used in the compositions described herein. For example, preservatives useful in embodiments may include, but are not limited to, pentylene glycol, ethylene diamine tetra acetate (EDTA) and its salts, chlorhexidine and its diacetate, dihydrochloride, digluconate derivatives, 1,1,1 -tri chloro- 2-methyl-2-propanol, parachlorometaxylenol, polyhexamethylenebiguanide hydrochloride,dehydroacetic acid, diazolidinyl urea, 2,4-dichlorobenzyl alcohol, 4,4-dimethyl-l,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, isopropylparabens, isobutylparabens, butylparabens, ethylparaben, trichlosan, 2-phenoxyethanol, phenyl mercuric acetate, quatemium-15, methylsalicylate, salicylic acid and its salts, sorbic acid and its salts, iodopropanyl butylcarbamate, calcium sorbate, zinc pyrithione, 5-bromo-Snitro-l,3-dioxane, 2-bromo-2-nitropropane-l,3-diol, sulfites, bisulfites, and benzalkonium chloride, phenoxyethanol, 2-phenoxyethanol, chloroxylenol, diazolidinyl urea, and combinations thereof. In exemplary embodiments, the composition includes methylparaben, propylparaben, or a combination thereof.

[0093] A variety of antioxidants can be utilized in the composition. 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-camosine, D-camosine, L-camosine and derivatives thereof such as anserine, carotinoids, carotenes such as a-carotone, [3-carotene, lycopene, and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof such as dihydrlipoic acid, aurothioglycose, propylthiouracil and other thiols such as thioredoxin, glutathione, cysteine, cystine, cystamine and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, a-linoleyl, cholesteryl and glyceryl esters and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof such as esters, ethers, peptides, lipids, nucleotides, nucleosides, and salts, sulfoximine compounds such as buthionine sulfoximines, homocysteine sulfoximine, buthionine sulfones, penta-, hexa-, hepta-thionine sulfoximine, unsaturated fatty acids and derivatives thereof such as a-linolenic acid, linoleic acid, oleic acid, folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives thereof such as ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate, tocopherals and derivatives such as vitamin E acetate, vitamin A and derivatives such as vitamin A palmitate, vitamin B and derivatives thereof, coniferyl benzoate of benzoin resin, rutinic acid and derivatives thereof, a- glycosylrutin, ferulic acid, furfurylidene glucitol, camosine, butyl hydroxy toluene, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, superoxide dismutase, zinc and derivatives thereof such as ZnO, ZnSO4, selenium and derivatives thereofsuch as selenium methionine, stilbene and derivatives thereof such as stilbene oxide, transstilbene oxide and the like. In certain embodiments, the one or more antioxidants may include vitamin B, nordihydroguaiaretic acid, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), propyl gallate, erythorbate acid, sodium erythorbate, ascorbir palmitate, and ascorbir stearate. In exemplary embodiments, 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 of the cream-based composition, such as density, viscosity, the melting point, and / or droplet size; and in some embodiments, the emulsifier may increase the stability of the cream-based composition. Various emulsions suitable for embodiments described herein and methods for preparing such emulsions are well known in the art and are described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., USA, which is hereby incorporated by reference in its entirety. The compositions of various embodiments may include any emulsifiers or combination of emulsifiers. For example, in some embodiments, the cream-based composition may be a common oil-in-water or water-in-oil emulsion including nootkatone and water or one or more common oils such as, for example, cottonseed, groundnut, com, germ, olive, castor, soybean, mineral, and sesame oils. In other embodiments, the creambased composition may include one or more emulsifiers, such as, for example, a mixture of cetyl (Cl 6) and stearyl (Cl 8) fatty alcohols and an anionic emulsifier, sesquioleates such as sorbitan sesquioleate or polyglyceryl-2-sesquioleate, ethoxylated esters of derivatives of natural oils such as the poly ethoxylated ester of hydrogenated castor oil, silicone emulsifiers such as silicone polyols, anionic emulsifiers, fatty acid soaps such as potassium stearate and fatty acid sulphates like sodium cetostearyl sulphate, ethoxylated fatty alcohols, sorbitan esters, ethoxylated sorbitan esters, ethoxylated fatty acid esters such as ethoxylated stearates, ethoxylated mono, di-, and triglycerides, non-ionic self-emulsifying waxes, ethoxylated fatty acids, methylglucose esters such as polyglycerol-3 methyl glucose distearate, and mixtures thereof. In exemplary embodiments, the emulsifier may be a mixture of cetyl (Cl 6) and stearyl (Cl 8) fatty alcohols and an anionic emulsifier commercially available from BASF under the trade name Kolliphor CSA.

[0095] The cream-based compositions of various embodiments may include any chelating agent or combination of chelating agents. Examples of the chelating agents useful in various embodiments include, but are not limited to, alanine, sodium polyphosphate, sodiummethaphosphate, citric acid, phosphoric acid, tartaric acid, ethylenediamine tetra acetic acid (Edetate, EDTA) and derivatives and salts thereof, dihydroxyethyl glycine, and mixtures thereof. In particular embodiments, the chelating agent may be EDTA or edetate disodium, dihydrate.

[0096] In some embodiments, the cream-based composition may include one or more viscosity modifiers. The viscosity modifier of such embodiments may generally include a high molecular weight compound such as, for example, carboxyvinyl polymer, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxy ethyl cellulose, methyl cellulose, natural gum 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 and unsaturated fatty alcohol such as, but are 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, and in certain embodiments, the viscosity modifier may be oleyl alcohol.

[0097] In some embodiments, the cream-based compositions described herein may include one or more surfactants. Such embodiments are not limited by type of surfactant used; for example, in some embodiments, the one or more surfactants may be anionic surfactants such as alkyl sulfates, alkylether sulfates, alkylsulfonates, alkylaryl sulfonates, alkyl succinates, alkyl sulfosuccinates, N-alkoylsarcosinates, acyl taurates, acyl isethionates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, a-olefinsulfonates, and the alkali metal and alkaline earth metal salts and ammonium and triethanolamine salts thereof. Such alkyl ether sulfates, alkyl ether phosphates and alkyl ether carboxylates can have between 1 and 10 ethylene oxide or propylene oxide units, and in some embodiments, 1 to 3 ethylene oxide units, per molecule. 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 dodecylbenzene sulfonate, triethanolamine dodecylbenzenesulfonate. In other embodiments, the one or more surfactants may be amphoteric surfactants such as, for example, alkylbetaines, alkylamidopropylbetaines, alkylsulfobetaines, alkylglycinates, alkylcarboxyglycinates, alkylamphoacetates or a-propionates, alkylamphodiacetates or a-dipropionates, and morespecifically, cocodimethylsulfopropylbetaine, lauryl betaine, cocamidopropylbetaine or sodium cocamphopropionate.

[0098] In certain embodiments, the one or more surfactants may be non-ionic surfactants such as, for example, the reaction products of aliphatic alcohols or alkylphenols having 6 to 20 carbon atoms in a linear or branched alkyl chain with ethylene oxide and / or propylene oxide where the alkylene oxide may be from about 6 moles to about 60 moles per mole of alcohol. In particular embodiments, non-ionic surfactants may include alkylamine oxides, mono- and dialkylalkanolamides, fatty acid esters of poly ethylenengly cols, ethoxylated fatty acids amides, saturated fatty acid alcohols reacted with ethylene oxide, alkyl polyglycosides, and sorbitan ether esters, and in some embodiments, the non-ionic surfactant may be 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-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 one or more ceteareth in combination with a fatty acid alcohol 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 a commercially available ceteareth containing surfactants such as CREMOPHOR EL®, CREMOPHOR A-6®, CREMPHOR A-25® or combinations thereof.

[0099] In some embodiments, the cream-based composition may include one or more emollients. Generally, emollients function enable the cream-based composition and by extension the active agent to remain on the skin surface or in the stratum comeum. Emollients are well known in the art and are listed, for example, the International Cosmetic Ingredient Dictionary, Eighth Edition, 2000, which is hereby incorporated by reference in its entirety. In certain embodiments, the one or more emollient may be white petrolatum, fatty esters, fatty alcohols, or combinations thereof including, but not limited to, diisopropyl adipate, oleyl alcohol, lanolin, isopropyl myristate, isopropyl palmitate, caprylic / capric triglycerides, cetyl lactate, cetyl palmitate, hydrogenated castor oil, glyceryl esters, hydroxycetyl isostearate, hydroxy cetyl phosphate, isopropyl isostearate, isostearyl isostearate, diisopropyl sebacate, polyoxypropylene (5) poloxyethylene (20) cetyl ether (PPG-5-Ceteth-20), 2-ethylhexyl isononoate, 2-ethylhexyl stearate, C12 to C16 fatty alcohol, C12 to C16 fatty alcohol lactate,isopropyl lanolate, 2-ethyl-hexyl salicylate, and mixtures thereof. In some embodiments, the one or more emollients may be a combination of fatty alcohols. In certain embodiments, the one or more emollients may be a mixture of cetyl and stearyl fatty alcohols, isopropyl myristate, 1 -hexadecanol, acetylated lanolin, behenocyl dimethicone, Cl 2- 15 alkyl benzoate, cetearyl octanoate, cocoglycerides, dicaprylate / dicaprate dimethicone copolyol, dimethiconol, dioctyl adipate, glyceryl stearate, isocetyl alcohol, isohexadecane, isopentylcyclohexanone, isopropyl palmitate, lauryl lactate, mineral oil, methoxy peg-22 / dodecyl glycol copolymer, myristyl lactate, ocryldodecyl neopentanoate, octyl cocoate, octyl palmitate, octyl stearate, octyldodecyl neopentanoate, polyglyceryl-4 isosterate, polyoxyl 40 stearate, polyoxymethylene urea, potassium sorbate, propylene glycol, propylene glycol isoceth-3 acetate, and propylene glycol myristyl ether acetate. In exemplary embodiments, 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-based composition may include one or more opacifying agents. Opacifying agents provide color or whiteness to a composition that may otherwise be clear of would have an undesirable color. In some embodiments, components such as, for example, emollients, surfactants, and / or emulsifiers may provide sufficient opaqueness. In other embodiments, one or more additional opacifying agents may be provided to the cream-based composition. Opacifying agents are well known in the art and include, but are not limited to, higher fatty alcohols such as cetyl, stearyl, cetostearyl alcohol, arachidyl and behenyl alcohols, solid esters such as cetyl palmitate, glyceryl laurate, 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, opacifying agents may include inorganic materials such as, for example, magnesium aluminum silicate, zinc oxide, titanium dioxide or other sunblocking agents.

[0101] In some embodiments, the cream-based composition may include one or more skin conditioners. Skin conditioners are components that may generally improve moisture retention in the skin, retard evaporation of water from the skin, and cause plasticization / softening of the skin. Common skin conditioners include, for example, mineral oil, petrolatum, aliphatic alcohols, lanolin and its derivatives, fatty acids, glycol fatty acids, sugars, glycerin, propylene glycol, sorbitols, and polyethylene glycols, vitamins and herbal derivatives. Additional skin conditioners can be found in CTFA Cosmetic Ingredient Handbook, 1st Ed., 1988, which is hereby incorporated herein by reference in its entirety. In some embodiments, the one or moreskin conditioners may include, but are not limited to, humectants, such as fructose, glucose, glycerin, propylene glycol, glycereth-26, mannitol and urea, pyrrolidone carboxylic acid, hydrolyzed lecithin, coco-betaine, 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, aminofunctional silicones, ethoxylated glycerin, a-hydroxy acids and salts thereof, water-soluble fatty oil derivatives, such as PEG-24 hydrogenated lanolin, almond oil, grape seed oil and castor oil; numerous other water-soluble skin conditioners listed, and mixtures thereof. In certain embodiments, the skin conditioners may include lanolin or lanolin derivatives, caprylic capric / triglyceride, diisopropyl adipate, and combinations thereof.

[0102] In certain embodiments, the cream-based composition comprises an oil phase, an aqueous phase, and nootkatone. The oil phase may be present in an amount of from about 5 wt.% to 50 wt.%, alternatively from about 10 wt.% to about 45 wt.%, alternatively from about 15 wt.% to about 40 wt.%, or alternatively from 20 wt.% to about 30 wt.%. The aqueous phase may be present in an amount of from about 10 wt.% to 70 wt.%, alternatively from about 20 wt.% to about 60 wt.%, alternatively from about 25 wt.% to about 55 wt.%, or alternatively from 30 wt.% to about 45 wt.%. Nootkatone (or its isomers) 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 (Cl 6) and stearyl (Cl 8) fatty alcohols and an anionic emulsifier, 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.Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[0104] Nootkatone and pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabeticperipheral 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB and thus are useful for treating or lessening the severity of the variety of diseases, disorders, or conditions described herein.

[0105] In various embodiments, the terms “inhibits” and “modulates” are used interchangeably to refer to an agent that decreases or suppresses a biological activity, such as to repress an 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, inhibits or modulated one or more of the therapeutic targets with an ICso less than 50 micromolar (pM), optionally less than 40 pM, optionally less than 30 pM, optionally less than 20 pM, optionally less than 10 pM, or optionally less than 1 pM. Alternatively, nootkatone or a pharmaceutically acceptable salt thereof, inhibits or modulated one or more of the therapeutic targets with an ICso from about 0.01 pM to about 100 pM, optionally from about 0.1 pM to about 75 pM, optionally from about 1 pM to about 50 pM, optionally from about 1 pM to about 25 pM, or optionally from about 1 pM to about 10 pM.

[0107] In some embodiments, “treating” or “treatment” refers to curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. In these and other embodiments, “treating” or “treatment” refers to obtaining beneficial or desired results, for example clinical results, in a subject, including: (1) alleviating one or more symptoms caused by or associated with a disease, disorder, or condition; (2) reducing the extent of the disease, disorder, or condition; (3) slowing or stopping the development or progression of one or more symptoms caused by or associated with the disease, disorder, or condition (for example, stabilizing the disease, disorder, or condition); and (4) relieving the disease, for example, by causing the regression of one or more clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying or stopping the progression of the disease, and / or increasing the quality of life).

[0108] In some embodiments, the method comprises administering to the subject nootkatone, or a pharmaceutically acceptable salt thereof, in an excipient to form a composition. The composition may comprise between 10-500 mg, or between 10-800 mg, or between 20-1,000 mg, or between 30-1,200 mg, or between 50-1,500 mg, or between 100- 2,000 mg or even more of nootkatone, or a pharmaceutically acceptable salt thereof in a single dosage unit. Consequently, preferred oral single dosage units (or recommended daily uptake) will be between 20-200 mg, or between 40-400 mg, or between 60-600 mg, or between 80-800 mg, or between 100-1,000 mg, or between 200-2,000 mg, and in some cases even higher.

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

[0110] In some variations, the method comprises administering to the subject nootkatone, or a pharmaceutically acceptable salt thereof, in an excipient formulation, such as petroleum jelly, the gel-based formulation, or the cream-based formulation, to form a composition. The composition comprises 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 even 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% w / w, or even more of nootkatone or a pharmaceutically acceptable salt thereof.[OHl] In various embodiments, the amount of composition is administered to the subject is based on the amount of nootkatone, or a pharmaceutically acceptable salt thereof, in milligrams (mg) per area of skin in centimeters -squared (cm2). The composition may beadministered to the subject in an amount of at least 0.01 mg / cm2(mg of nootkatone per cm2of skin), at least 0.02 mg / cm2. at least 0.03 mg / cm2. at least 0.04 mg / cm2. at least 0.05 mg / cm2. at least 0.06 mg / cm2. at least 0.07 mg / cm2. at least 0.08 mg / cm2. at least 0.09 mg / cm2. at least 0. 1 mg / cm2. at least 0.12 mg / cm2. at least 0.14 mg / cm2. at least 0.16 mg / cm2at least 0.18 mg / cm2at least 0.2 mg / cm2. at least 0.22 mg / cm2. at least 0.24 mg / cm2. at least 0.26 mg / cm2. at least 0.28 mg / cm2. at least 0.3 mg / cm2. at least 0.32 mg / cm2. at least 0.34 mg / cm2. at least 0.36 mg / cm2. at least 0.3 8mg / cm2. at least 0.4 mg / cm2, or even more. The composition may be administered to the subject in an amount of between about 0.01 mg / cm2and about 0.4 mg / cm2, between about 0.05 mg / cm2and about 0.3 mg / cm2, between about 0.1 mg / cm2and about 3 mg / cm2, or between about 0.15 mg / cm2and about 0.25 mg / cm2.

[0112] The composition may be applied as needed, daily, several times per day or in any suitable regimen such that the desired outcome is achieved. In the method of this disclosure, the frequency of administration (e.g., topical application) can depend on several factors, including the severity of the disease conditions such as pain, pruritus or symptoms of the same or the desired level of relief from the symptoms. Generally, a regimen includes application of the composition once or twice daily to include an administration in the morning and / or an administration in the evening. The amount and / or frequency of application of the composition may depend on several factors, including the level of desired results and the specific composition. In some embodiments, the composition is administered once per day. In other embodiments, the composition is administered twice per day. In still other embodiments, the composition it administered three times per day. In yet other embodiments, the composition is administered four times per day. However, it is to be appreciated that the composition may be administered more than four times per 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 between about 1 week and about 1 year, between about 4 weeks and about 8 weeks, between about 4 weeks and about 12 weeks, between about 4 weeks and about 16 weeks, between about4 weeks and about 24 weeks, between about 4 weeks and about 32 weeks, between about 4 weeks and about 40 weeks, between about 4 weeks and about 48 weeks, or between about 4 weeks and about 1 year.

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

[0115] In another aspect, the disclosure features a method of inhibiting a therapeutic target, such as at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF- KB, in a subject comprising administering to the subject nootkatone or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In various embodiments, nootkatone does not inhibit NaV 1.5. In some embodiments, the phrase “does not inhibit” with regard to NaV 1.5 means that nootkatone, or a pharmaceutically acceptable salt thereof, inhibits NaV 1.5 with an ICso greater than 100 micromolar (pM).Pain

[0116] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of chronic pain, gut or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain comprising 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 lessening the severity in a subject of gut or abdominal pain, wherein gut 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, wherein the method comprises 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 may lead to gut 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 like 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 migraines, abdominal aortic aneurysm, adhesions (bands of scar tissue in the abdomen), meckel's diverticulum, zollinger-ellison syndrome, intussusception (common in children), hirschsprung's disease (in children), porphyria, typhlitis (neutropenic enterocolitis), gastroesophageal reflux disease (gerd), gastritis, peptic ulcers, celiac disease, food intolerances or allergies, gallstones, pancreatitis, liver disease (such as hepatitis), kidney stones, urinary tract infections (utis), diverticulitis, appendicitis, endometriosis, ovarian cysts, ectopic pregnancy, hernia, intestinal obstruction, and mesenteric ischemia. Each of these conditions can present with varying symptoms, making accurate diagnosis crucial for effective treatment.

[0118] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom 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, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia wherein the method comprises 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 lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, bum pain or dental pain wherein the method comprises 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 lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia wherein the method comprises administering a therapeuticallyeffective 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 in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain wherein the method comprises 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 wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to 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, such as at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF- KB, in a subject comprising administering to the subject 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.

[0124] In another aspect, the disclosure features a method of inhibiting a therapeutic target, such as at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF- KB, in a biological sample comprising 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 disclosure features a method of treating or lessening the severity in a subject of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, backpain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility, comprising administering an effective amount of nootkatone, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of nootkatone.

[0126] In another aspect, the disclosure features a method of treating or lessening the severity in a subject of femur 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 headaches; 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; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom 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; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, bum and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitis, or angina-induced pain, 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 or lessening the severity in a subject of neuropathic pain 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 post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom 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, drug therapy 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 cephalalgia.

[0128] In some embodiments, a “therapeutically effective amount” refers to an amount effective, when administered to the subject, to treat a disease, e.g, a therapeutically effective amount may be an amount sufficient to treat pain. The therapeutically effective amount may be ascertained experimentally.

[0129] In some embodiments, the composition is administered orally, vaginally, rectally, or via inhalation, to the 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 the subject that may expect to suffer from pain, or expect one or more symptoms of pain, but 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, where 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 a hand, arm, leg, face and neck, trunk of the subject, where 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 full body, where 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 full body, where the subject may expect to suffer from pain, or expect one or more symptoms of pain, but not yet suffer from pain or one or more symptoms of pain.

[0131] In one aspect, provided is a method of reducing pain in a subject, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceuticalcomposition as described herein. In some embodiments, the pain is assessed on a 0 to 10 point Likert scale, wherein 0 corresponds to no pain, and 10 corresponds to the worst imaginable pain. In some embodiments, the pain is assessed based on the subject’s experience over the past 24 hours. In some embodiments, the pain is assessed at 7 days, 14 days, 21 days, or 28 days following the start 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 a baseline assessment of pain in the subject 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 of time sufficient to reduce 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 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 of time 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, the pain is assessed on the basis of the IBS Symptom Severity Scale, the Brief Pain Inventory, the Visceral Sensitivity Index, the Pain Numeric Rating Scale (P-NRS), the Sickness Impact Profile, the Pain Disability Index, the Pain Catastrophizing Scale, the McGill Pain Questionnaire, or combinations thereof. In certain embodiments, the pain is assessed on the basis of the Pain Numerical Rating Scale (P-NRS), as described herein.

[0132] In some variations of the foregoing, the subject is formally diagnosed or clinically diagnosed with pain.Pruritus

[0133] In some aspects, provided are methods for treating pruritus in a subject in need thereof, 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 the present disclosure, the term “pruritus” is meant to be interchangeable with the term “itch” and defines a well known sensory state associated with the desire to scratch. The sensory state associated with pruritus is different from that of pain although pruritus and pain can be produced by a variety of chemical, mechanical, thermal or electrical stimuli. Itch and pain differ in that (1) itch, unlike pain, can only be evoked from the superficial layers of skin, mucosa, and conjunctiva, and (2) itch and pain usually do not occur simultaneously from the same skin region. For example, the application of histamine to skin produces itch but not pain. Furthermore, itch and pain are treated by different pharmacologically principles in that itch appears to be insensitive to opiate and non-steroidal anti-inflammatory drug (NSAID) treatment, both of which are effective in treating pain. Finally, itch occurs only in the skin; pain arises from deeper structures as well. Pruritus may be localized in various well defined areas of the skin, such as skin of the ankle, wrest, lips, hands, chest and the like, or it might be general pruritus not localized in a particular part of the skin.

[0135] Pruritus may be associated with a plethora of dermatological diseases, irrespective of their nature or to what extent inflammation or hypersensitivity reactions are part of the pathology. Non-limiting examples on such dermatological diseases are: acne vulgaris, alopecia, asteatotic eczema, atopic dermatitis, melanomas, drug-induced skin reactions, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, lichen simplex chronicus, lichen planus, pemphigus, pemphigoid, photodermatoses, pityriasis rosea, pyoderma gangrenosum, pompholyx, psoriasis, prurigo nodularis, rosacea, scabies, seborrheic dermatitis, seborrhea, scleroderma, Sjogren's Disease, stasis dermatitis, subacute cutaneous lupus erythematosus, sunburn, cutaneous manifestations of systemic lupus erythematosus, vitiligo, and urticaria.

[0136] Dermatological causes of pruritus often relates to hypersensitivity reactions in skin or allergic reactions, such a type-I or type-IV allergy reactions in skin. Thus, pruritus may be associated with atopic dermatitis and the various types thereof (atopic dermatitis, hand eczema, infantile eczema, childhood eczema, adult eczema, keratosis pilaris, ichthyosis vulgaris, hand and foot dermatitis, keratoconus, pompholyx, discoid eczema, nummular eczema) and allergic contact reactions, such as with contact dermatitis and the various types thereof (allergic contact dermatitis, irritant contact dermatitis and over-treatment 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 that are naturally occurring 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). The subject is a human, a cat, a dog or a horse. The composition is topically administered. The composition has less than about 1% w / w of other components that are naturally occurring in a nootkatone-containing source, and the nootkatone in the composition has a purity of at least about 99% w / w. The composition further comprises petroleum jelly. The composition comprises between about 1.5% and about 10% w / w of nootkatone and is administered once or twice per day. The composition is administered for at least 12 weeks. Further, administering of the composition to the subject reduces pruritus after a predetermined amount of time as determined in accordance with the pruritus itch numerical rating scale (I-NRS).

[0138] In an 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 composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB; and optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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 an aspect, the disclosure provides a pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or a 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[0140] In an aspect, the disclosure provides a 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[0141] In some embodiments, the composition administered is a personal care product. In one variation, the composition administered is a cosmetic product, a drug product, or both. In certain variations, the composition administered meets US Food and Drug Administration regulations, including requirements defining a cosmetic product, a drug product, or both.

[0142] In some variations, the methods provided herein alleviate, or slow or stop the development or progression of one or more symptoms caused by or associated with pruritus. In other variations, the methods provided herein reduce the extent of pruritus, or relieves pruritus by causing the 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 the treatment of a variety of conditions relevant to multiple types of pruritus as classified by Twycross et al. (Quart. J. Med. 2003; 96:7-26) which is incorporated by reference in its entirety, namely pruritoceptive (cutaneous, e.g., scabies), neuropathic (due to lesions of afferent pathways of the nervous system, e.g, peripheral neuritis, brain tumors), neurogenic (due to centrally acting mediators which do not damage the central nervous system, e.g., opioid peptides of cholestasis) and psychogenic.

[0143] In some embodiments, a “therapeutically effective amount” also refers to an amount effective, when administered to the subject, to treat a disease, e.g, a therapeutically effective amount may be an amount sufficient to treat pruritus. The therapeutically effective amount may be ascertained experimentally.

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

[0145] In some variations of the foregoing, the subject is formally diagnosed or clinically diagnosed with pruritus.Atopic Dermatitis

[0146] In some aspects, provided are methods for treating eczema in a subject in need thereof, 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 that makes the skin of the affected subject red and itchy. The atopic dermatitis may be chronic and can flare periodically. Atopic dermatitis symptoms may include, for example, dry skin; itching; red to brownish-gray patches; small, raised bumps, which may lead fluid and / or crust over when scratched; scaly skin; sensitive skin from scratching. A subject suffering from atopic dermatitis may also experience other conditions, such as asthma or hay fever. Atopic dermatitis may 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 composition administered is a personal care product. In one variation, the composition administered is a cosmetic product, a drug product, or both. In certain variations, the composition administered meets US Food and Drug Administration regulations, including requirements defining a cosmetic product, a drug product, or both.

[0150] In some variations, the methods provided herein alleviate, or slow or stop the development or progression of one or more symptoms caused by or associated with eczema, including for example, atopic dermatitis. In other variations, the methods provided hereinreduces the extent of eczema, or relieves eczema by causing the regression of one or more symptoms.

[0151] In some embodiments, a “therapeutically effective amount” refers to an amount effective, when administered to the subject, to treat a disease, e.g., a therapeutically effective amount may be an amount sufficient to treat eczema, including for example, atopic dermatitis. The therapeutically effective amount may be ascertained experimentally.

[0152] In some embodiments, the composition is administered to at least a portion of the body, where 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 a hand, arm, leg, face and neck, trunk of the subject, where 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 full body, where 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 full body, where the subject may expect to suffer from eczema, or expect one or more symptoms of eczema, but not yet suffer from eczema or one or more symptoms of eczema.

[0153] In some variations, the composition is administered to a subject having mild to severe eczema, including for example, atopic dermatitis. In some variations, the composition is administered to a subject having mild to moderate eczema, including for example, atopic dermatitis. In certain variations, about 5% to about 20% of the total body surface area of the subject, excluding the face, scalp, axillae, and intertriginous areas, is affected by eczema, including for example, atopic dermatitis.

[0154] In some embodiments, the administering of the composition to the subject reduces redness, average lesion size, itching or pain caused by the eczema (including for example, atopic dermatitis), or improves general complexion in areas affected by the eczema, or any combination of the foregoing.

[0155] In one aspect, provided is a method of reducing redness in a subject suffering from eczema, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In one variation of the foregoing aspect, the method reduces redness in a subject suffering from atopic dermatitis. In some embodiments, the redness is assessed on a 0 to 10 point scale, wherein 0 corresponds tono redness, and 10 corresponds to the worst redness imaginable. In some embodiments, the method comprises reducing redness by about 10 points, 9 points, 8 points, 7 points, 6 points, 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from a 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 a 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, 9 points, 8 points, 7 points, 6 points, 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from a 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 a baseline redness in the subject assessed prior to administration of the composition.

[0156] In one aspect, provided is a method of reducing the severity of eczema in a subject suffering from eczema, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In one variation of the foregoing aspect, the method reduces the severity of atopic dermatitis in a subject suffering from atopic dermatitis. In some embodiments, the severity is assessed on a 0 to 4 point scale, wherein 0 corresponds to clear, and 4 corresponds to severe. In some embodiments, the severity is assessed on the basis of one or more criteria selected from the group consisting of erythema, induration or papulation, and oozing or crusting. In some embodiments, the severity is assessed on a 0 to 4 point Investigator Global Assessment (IGA) scale, as detailed in Table 5 herein. In some embodiments, the severity is assessed on a 0 to 4 point Participant Global Assessment (PGA) scale, as detailed in Table 5 herein. In some embodiments of the foregoing, the severity of eczema is assessed on a 0 to 72 point Eczema Area and Severity Index Score (EASI) as detailed in Table 5 herein. In some embodiments, the method comprises reducing severity by about 4 points, about 3 points, about 2 points, or about 1 point on the IGA scale from a baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprises reducing severity by about 4 points, about 3 points, about 2 points, or about 1 point on the PGA scale from a baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprisesreducing 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 a 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 a 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 IGA scale from a 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 a 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 a 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 a baseline severity in the subject assessed prior to administration of the composition.

[0157] In one aspect, provided is a method of improving the appearance of the skin of a subject suffering from eczema, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In one variation of the foregoing aspect, the method improves the appearance the skin of a subject suffering from atopic dermatitis. In some embodiments, the improvement in the appearance of the skin is assessed by the subject suffering from atopic dermatitis. In some embodiments, the improvement of the appearance of the skin is measured on a 1 to 7 point Global Impressions of Change (GIC) scale, as described in Table 8 herein. In some embodiments, the method results in skin that is very much improved, much improved, minimally improved, or not changed in appearance as compared to the appearance of the skin immediately prior to administration of the compositions. In some embodiments, the method comprises administering the composition for a period of time sufficient to result in skin that is very muchimproved, much improved, minimally improved, or not changed in appearance as compared to the appearance of the skin immediately prior to administration of the compositions.

[0158] In one aspect, provided is a method of decreasing the severity of a target lesion in a subject suffering from eczema, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In one variation of the foregoing aspect, the method decreases the severity of a target lesion in a subject suffering from atopic dermatitis. In some embodiments, the severity of the target lesion is assessed on the basis of one or more criteria selected from the group consisting of erythema, edema or papulation, oozing or crusting, excoriation, lichenification, and dryness. In some embodiments, the target lesion has an area of at least 10 cm2.

[0159] In one aspect, provided is a method of decreasing average lesion size in a subject suffering from eczema, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In one variation of the foregoing aspect, the method decreases average lesion size in a subject suffering from atopic dermatitis. In some embodiments, the method comprises reducing 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 subj ect as measured prior to administration of the composition. In some embodiments, the method comprises 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 as measured prior to administration of the composition.

[0160] In one aspect, provided is a method of reducing itching in a subject suffering from eczema, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In one variation of the foregoing aspect, the method reduces itching in a subject suffering from atopic dermatitis. In some embodiments, the itching is assessed on a 0 to 10 point Likert scale, wherein 0 corresponds to no itching, and 10 corresponds to the worst imaginable itch. In some embodiments, the itching is assessed based on the subject’s experience over the past 24 hours. In some embodiments, the itching is assessed at 7 days, 14 days, 21 days, or 28 days followingthe start of administration of the composition. In some embodiments, the method comprises reducing the assessed itching 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 itching in the subject prior to administration of the composition. In some embodiments, the method comprises reducing itching 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 itching in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce the assessed itching 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 itching in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce itching 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 itching in the subject prior to administration of the composition.

[0161] In one aspect, provided is a method of reducing pain in a subject suffering from eczema, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In one variation of the foregoing aspect, the method reduces pain in a subject suffering from atopic dermatitis. In some embodiments, the pain is assessed on a 0 to 10 point Likert scale, wherein 0 corresponds to no pain, and 10 corresponds to the worst imaginable pain. In some embodiments, the pain is assessed based on the subject’s experience over the past 24 hours. In some embodiments, the pain is assessed at 7 days, 14 days, 21 days, or 28 days following the start 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 a baseline assessment of pain in the subject 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 of time sufficient to reduce 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 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 of time 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 is formally diagnosed or clinically diagnosed with eczema, including for example, atopic dermatitis.Psoriasis

[0163] In some embodiments, the composition is administered to at least a portion of the body, where 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 a hand, arm, leg, face and neck, trunk of the subject, where 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 full body, where 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 full body, where the subject may expect to suffer from psoriasis, or expect one or more symptoms of psoriasis, but not yet suffer from psoriasis or one or more symptoms of psoriasis.

[0164] In some embodiments, the subject has mild to moderate psoriasis. In some embodiments, about 3% to about 15% of the total body surface area of the subject, excluding the face, scalp, hands, or soles of feet, is affected by psoriasis. 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, the administering of the composition to the subject reduces itching, redness, scaling, burning, stinging, cracking, flaking, or pain, or a combination thereof, caused by the psoriasis.

[0166] In one aspect, provided is a method of reducing redness in a subject suffering from psoriasis, comprising administering to the subject any of the compositions described herein. Insome embodiments, the redness is assessed on a 0 to 5 point scale, wherein 0 corresponds to no redness, and 5 corresponds 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 a 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 a 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 5 points, about 4 points, about 3 points, about 2 points, or about 1 point from a 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 a baseline redness in the subject assessed prior to administration of the composition.

[0167] In one aspect, provided is a method of decreasing the severity of a target lesion caused by psoriasis in a subject, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In some embodiments, the severity of the target lesion is assessed on the basis of one or more criteria selected from the group consisting of erythema, edema / papulation, oozing / crusts, excoriation, lichenification, and dryness. In some embodiments, the target lesion is assessed on the basis of one or more criteria selected from the group consisting of Physician’s Global Assessment (PGA), Redness, Itch Numerical Rating Scale (I-NRS), and Patient Global Impression of Change (PGIC) as described herein in Table 11. In some embodiments, the target lesion has an area of at least 10 cm2.

[0168] In one aspect, provided is a method of decreasing average lesion size caused by psoriasis in a subject, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In some embodiments, the method comprises reducing 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 as measured prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of timesufficient 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 as measured prior to administration of the composition.

[0169] In one aspect, provided is a method of reducing the severity of psoriasis in a subject suffering from psoriasis, comprising administering to the subject any of the compositions described herein. In some embodiments, the severity of psoriasis in the subject is assessed on a 0 to 4 point scale, wherein 0 corresponds to clear, and 4 corresponds to severe. In some embodiments, the severity of psoriasis is assessed on the basis of one or more criteria selected from the group consisting of erythema, edema / papulation, oozing / crusts, excoriation, lichenification, and dryness. In some embodiments, the severity of psoriasis is assessed on a 0 to 4 point Physician Global Assessment (PGA) scale, as detailed in Table 9 herein. In some embodiments, the method comprises reducing psoriasis severity by about 4 points, about 3 points, about 2 points, or about 1 point from a 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 a 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 psoriasis severity by about 4 points, about 3 points, about 2 points, or about 1 point from a 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 a baseline severity in the subject assessed prior to administration of the composition.

[0170] In one aspect, provided is a method of reducing the severity of psoriasis in a subject suffering from psoriasis, comprising administering to the subject any of the compositions described herein. In some embodiments, the severity of psoriasis is assessed on a 0 to 72 point Psoriasis Area and Severity Index (PASI) scale, wherein the severity of erythema, induration, and desquamation are each assessed on a 0 to 4 point scale for the head and neck, upper limbs, lower limbs, and trunk; the sum of the scores for each body area 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;each of the weighted scores are multiplied by a score of 0 to 6 based on the percent surface area of the body area that is affected by psoriasis (not affected = 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 derive the total score on the PASI scale. In some embodiments, the method comprises reducing psoriasis severity as assessed by the PASI scale 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 a baseline severity in the subject assessed prior to administration of the composition. In some embodiments, the method comprises reducing severity as assessed on 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 a 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 psoriasis severity as assessed on the PASI scale 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 a 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 as assessed on 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 a baseline severity in the subject assessed prior to administration of the composition.

[0171] In one aspect, provided is a method of decreasing the total body surface area (BSA) affected by psoriasis, comprising administering to the subject any of the compositions described herein. 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% relative to a baseline total BSA affected by psoriasis 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 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% relative to a baseline total BSA affected by psoriasis in the subject assessed prior to administration of the composition.

[0172] In one aspect, provided is a method of decreasing average plaque size in a subject suffering from psoriasis, comprising administering to the subject any of the compositionsdescribed herein. In some embodiments, the method comprises reducing 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 a baseline average plaque size in the subject as measured prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce 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 a baseline average plaque size in the subject as measured prior to administration of the composition.

[0173] In one aspect, provided is a method of reducing itching (or pruritus) in a subject suffering from psoriasis, comprising administering to the subject any of the compositions described herein. In some embodiments, the itching is assessed on a 0 to 10 point Likert scale, wherein 0 corresponds to no itching, and 10 corresponds to the worst imaginable itch. In some embodiments, the itching is assessed based on the subject’s experience over the past 24 hours. In some embodiments, the itching is assessed at 7 days, 14 days, 21 days, or 28 days following the start of administration of the composition. In some embodiments, the method comprises reducing the assessed itching 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 itching in the subject prior to administration of the composition. In some embodiments, the method comprises reducing itching 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 itching in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce the assessed itching 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 itching in the subject prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce itching 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 itching in the subject prior to administration of the composition.

[0174] In one aspect, provided is a method of reducing pain in a subject suffering from psoriasis, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In some embodiments, the pain is assessed on a 0 to 10 point Likert scale, wherein 0 corresponds to no pain, and 10 corresponds to the worst imaginable pain. In some embodiments, the pain is assessed based on the subject’s experience over the past 24 hours. In some embodiments, the pain is assessed at 7 days, 14 days, 21 days, or 28 days following the start 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 a baseline assessment of pain in the subject 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 of time sufficient to reduce 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 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 of time 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, provided is a method of improving the appearance of skin of a subject suffering from psoriasis, comprising administering to the subject any of the compositions comprising nootkatone or pharmaceutical composition as described herein. In some embodiments, the improvement in the appearance of the skin is assessed by the subject suffering from psoriasis. In some embodiments, the improvement of the appearance of the skin is measured on a 1 to 7 point Patient Global Impressions of Change (PGIC) scale, as described in Table 11 herein. In some embodiments, the method results in skin that is very much improved, much improved, minimally improved, or not changed in appearance as compared to the appearance of the skin immediately prior to administration of the compositions. In some embodiments, the method comprises administering the composition for a period of time sufficient to result in skin that is very much improved, much improved, minimally improved,or not changed in appearance as compared to the appearance of the skin immediately prior to administration of the compositions.

[0176] In some variations of the foregoing, the subject is formally diagnosed or clinically diagnosed with psoriasis.

[0177] In some aspects, the present disclosure features a method of treating psoriasis 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 that are naturally occurring 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). The subject is a human, a cat, a dog or a horse. The composition is topically administered. The composition has less than about 1% w / w of other components that are naturally occurring in a nootkatone-containing source, and the nootkatone in the composition has a purity of at least about 99% w / w. The composition further comprises petroleum jelly. The composition comprises between about 1.5% and / or about 10% w / w of nootkatone. The composition is administered once or twice per day for at least 12 weeks.Improving the Skin Appearance

[0178] Nootkatone and dermatologically acceptable compositions are useful for improving the appearance of skin, such as skin exhibiting one or more diseases, disorders, or conditions, including, but not limited to, pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy. The phrase “improving the appearance of skin” includes, but is not limited to. skin clearing or reducing minor residual discoloration, as well as reducing erythema, induration, papulation, edema, excoriations, lichenification, oozing / crustin, redness, or combinations thereof. In various embodiments, nootkatone and dermatologically acceptable compositions are functional cosmetic compositions that improve skin elasticity, skin tonicity, prevent dryness of skin, exhibit skin improvement effects such as reduction of wrinkles, skin lightening, reduce cutaneous inflammation, skin lesions and combinations thereof. In various embodiments, the prevention, improvement, or treatment of the skin condition provides skin moisturization, skin exfoliation, skin redness reduction, skin inflammation reduction, skin flushing reduction, skin dryness reduction, enhanced skin radiance, enhanced skin tone, enhanced skin clarity, enhanced skin firmness, enhanced skin tightness, enhanced skin elasticity, and / or enhanced overall skin appearance. In various embodiments, nootkatone anddermatologically acceptable compositions are inhibitors or modulators of one or more of the following therapeutic targets: voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB and thus are useful for treating or lessening the severity of the variety of diseases, disorders, or conditions described herein.

[0179] In various embodiments, the terms “inhibits” and “modulates” are used interchangeably to refer to an agent that decreases or suppresses a biological activity, such as to repress an 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, inhibits or modulated one or more of the therapeutic targets with an ICso less than 50 micromolar (pM), optionally less than 40 pM, optionally less than 30 pM, optionally less than 20 pM, optionally less than 10 pM, or optionally less than 1 pM. Alternatively, nootkatone, or a dermatologically acceptable salt thereof, inhibits or modulated one or more of the therapeutic targets with an ICso from about 0.01 pM to about 100 pM, optionally from about 0.1 pM to about 75 pM, optionally from about 1 pM to about 50 pM, optionally from about 1 pM to about 25 pM, or optionally from about 1 pM to about 10 pM.

[0181] In some embodiments, the method comprises administering to the subject nootkatone, or a dermatologically acceptable salt thereof, in an excipient to form a composition. The composition may comprise between 10-500 mg, or between 10-800 mg, or between 20-1,000 mg, or between 30-1,200 mg, or between 50-1,500 mg, or between 100- 2,000 mg or even more of nootkatone, or a dermatologically acceptable salt thereof in a single dosage unit. Consequently, preferred oral single dosage units (or recommended daily uptake) will be between 20-200 mg, or between 40-400 mg, or between 60-600 mg, or between 80-800 mg, or between 100-1,000 mg, or between 200-2,000 mg, and in some cases even higher.

[0182] As used herein, the term “administering” a cosmetic composition or drug refers to both direct and indirect administration of the cosmetic composition or drug, wherein direct administration of the cosmetic composition or drug is typically performed by a health care professional (e.g., physician, nurse, etc.), and wherein indirect administration includes a step of providing or making available the cosmetic composition or drug to the health careprofessional for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.).

[0183] In some aspects, provided are methods for improving the appearance of skin in a subject in need thereof, 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 symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy.

[0184] In various embodiments, the method of use may also be referred to as a cosmetic method for improving the appearance of skin of a subject with skin imperfections. Specifically, the composition is useful for and may be used for improving the appearance of skin of a subject with skin imperfections. The subject is typically a human and can be of various ages. The composition is not limited to a particular subject or location of skin on the subject. For example, a person may 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, where the subject may be suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy, or one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy. In some embodiments, the composition is administered to at least a portion of a hand, arm, leg, face and neck, trunk of the subject, where the subject may be suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy, or one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy. In another embodiment, the composition is administered to at least a portion of the full body, where the subject may be suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy, or one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy. In yet another embodiment, the composition is administered to at least a portion of the full body, where the subject may expect to suffer from pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy, or expect one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabeticperipheral neuropathy, but not yet suffer from psoriasis or one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy.

[0186] In one aspect, provided is a method of improving the appearance of skin of a subject suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy, comprising administering to the subject any of the compositions comprising nootkatone or cosmetic composition as described herein. In some embodiments, the improvement in the appearance of the skin is assessed by the subject suffering from pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy. In some embodiments, the improvement of the appearance of the skin is measured on a 1 to 7 point Patient Global Impressions of Change (PGIC) scale, as described in Table 8 herein. In some embodiments, the method results in skin that is very much improved, much improved, minimally improved, or not changed in appearance as compared to the appearance of the skin immediately prior to administration of the compositions. In some embodiments, the method comprises administering the composition for a period of time sufficient to result in skin that is very much improved, much improved, minimally improved, or not changed in appearance as compared to the appearance of the skin immediately prior to administration of the compositions.

[0187] In some variations of the foregoing, the subject is formally diagnosed or clinically diagnosed with pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy.Manufacture of Medicaments / Cosmetics

[0188] In one aspect, the disclosure provides the use of nootkatone or 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 receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB. In various embodiments, nootkatone does not inhibit NaV1.5.

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

[0190] In yet another aspect, the disclosure provides the use of nootkatone or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of gut or abdominal pain, wherein gut 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 the use of nootkatone or pharmaceutical composition described herein for the manufacture of a medicament for use in a treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom 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, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral 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 disclosure provides the use of nootkatone or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, bum pain or dental pain.

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

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

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

[0196] In another aspect, the disclosure provides the use of nootkatone or pharmaceutical composition 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 headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

[0197] In another aspect, the disclosure provides the use of nootkatone or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of femur 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 headaches; 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; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom 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; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, bum andtrauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitis, or angina-induced pain.

[0198] In another aspect, the disclosure provides the use of nootkatone or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of neuropathic pain. In one aspect, the neuropathic pain is selected from post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom 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, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

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

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

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

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

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

[0204] In certain embodiments of the disclosure an “effective amount” of nootkatone, a pharmaceutically acceptable salt thereof or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of pruritus, chronic pain, gut or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain.

[0205] Nootkatone and compositions, according to the method of the disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the pain or non-pain diseases recited herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Nootkatone may be formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of nootkatone and compositions of the disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like 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 this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, 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 “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. In certain embodiments, nootkatone of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg and optionally from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain 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, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

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

[0209] It is known that sterols, such as cholesterol, will form complexes with cyclodextrins. Thus, in certain embodiments, where the inhibitor is a steroidal alkaloid, it may be formulated with cyclodextrins, such as a-, [3- and y-cyclodextrin, di methyl -[3 cyclodextrin and 2- hydroxypropyl-P-cyclodextrin.

[0210] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0211] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, by autoclave sterilization, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In various embodiments, a first portion of the formulation may be sterilized by filtration (e.g., nootkatone) and the second portion may be sterilized by autoclave sterilization (e,g, the excipient).

[0212] In order to prolong the effect of nootkatone, it is often desirable to slow the absorption of nootkatone from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of nootkatone then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished 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 upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping 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 such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0214] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can 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 can also be of a composition that they release 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 can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0215] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0216] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, 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-described excipients.

[0217] Formulations of the pharmaceutical compositions of the disclosure for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is 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, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially 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 can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms nootkatone may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other thaninert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release 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 can 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 that may be required.

[0222] The ointments, pastes, creams and gels may contain, in addition to nootkatone, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, 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 providing controlled delivery of nootkatone to the body. Such dosage forms can be made by dissolving or dispersing nootkatone in the proper 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 formulation, eye ointments, eye drops, and eardrops 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 nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants,buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0226] Examples of suitable aqueous and nonaqueous carriers that may be employed in the 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. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0227] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0228] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0229] When nootkatone is administered as a pharmaceutical, to humans and animals, it can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

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

[0231] Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as “Applied Animal Nutrition”, W.H. Freedman and CO., San Francisco, U.S.A., 1969 or “Livestock Feeds and Feeding” O and B books, Corvallis, Ore., U.S.A., 1977).

[0232] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of nootkatone at a particular target site.

[0233] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0234] The selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like 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 could start doses of nootkatone employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0236] In general, a suitable daily dose of nootkatone will be that amount of nootkatone that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon 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 per kilogram of body weight per 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 is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.

[0239] Nootkatone can be administered as such or in admixtures with pharmaceutically acceptable and / or sterile carriers and can also be administered in conjunction with other antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Conjunctive therapy thus includes sequential, simultaneous and separate administration of nootkatone in a way that the therapeutic effects of the first administered one are still detectable when the subsequent therapy is administered.

[0240] The present disclosure contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Furthermore, the present disclosure contemplates administration via any of the foregoing routes of administration. One of skill in the art can select the 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 nootkatone utilized in this disclosure as an inhibitor of the therapeutic targets may be assayed according to methods described generally in the Examples herein, or according to methods available to one of ordinary skill in the art.Additional Therapeutic Agent

[0242] It will also be appreciated that nootkatone and pharmaceutically acceptable compositions of the disclosure can be employed in combination therapies, that is, nootkatone and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desiredtherapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (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: nonopioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such sa Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the disclosure. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods- hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally 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, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0243] In another embodiment, additional appropriate therapeutic agents are 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) a nonsteroidal antiinflammatory drug (NS AID), 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, sulindac, tolmetin or zomepirac; (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental; (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam; (5) a histamine (Hl) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone; (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine; (8) an NMDA receptor antagonist, 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 including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l- piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone; (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7- dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl) quinazoline; (10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline; (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate; (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,ll- tetrahy dro-9-methyl-5 -(4-methy lphenyl)-7H- [1,4] diazocino [2, 1 -g] [ 1 ,7] -naphthyridine-6- 13- dione (TAK-637), 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4- fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]- 2-phenylpiperidine (2S,3S); (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium; (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) a coal-tar analgesic, in particular paracetamol; (16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore,eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan; (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300); (18) a beta-adrenergic such as propranolol; (19) a local anaesthetic such as mexiletine; (20) a corticosteroid such as dexamethasone; (21) a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan; (22) a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907); (23) a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine; (24) Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®); (25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulphonyl)phenyl]-l-methyl-3-n-propyl-l,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',r:6,l]-pyrido[3,4-b]indole- 1, 4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-l-yl-l-sulphonyl)-phenyl]-5- methyl-7-propyl-3H-imidazo[5,l-f|[l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3- pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-l-ylsulphonyl)pyridin-3- yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3- chtoro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]-N-(pyrimi din-2- ylmethyl)pyrimidine-5-carboxamide, 3-(l-methyl-7-oxo-3-propyl-6,7-dihydro-lH- pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4- propoxybenzenesulfonamide; (26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3 -methyl gabapentin, (1 [alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3 S,5R)-3-amino-5-methyl-heptanoic acid, (3 S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3- fluorobenzyl)-proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l- aminomethyl-cyclohexylmethyl)-4H-[l,2,4]oxadiazol-5-one, C-[l-(lH-tetrazol-5-ylmethyl)- cy cl oheptyl] -methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3 S,5R)-3-amino-5-methyl-nonanoic acid, (3 S,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; (27) a cannabinoid such as KHK-6188; (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist; (29) a serotonin reuptakeinhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone; (30) a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine; (31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O- desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine; (32) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l- iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl- L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)- 3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3 S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2- chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3 S)-3-amino-4-hydroxy-l- (5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4- hydroxy-l-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3- chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyldisulfide; (33) an acetylcholinesterase inhibitor such as donepezil; (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-dimethyl-lH- imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid; (35) a leukotriene B4 antagonist; such as l-(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; (36) a 5 -lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4- yl])phenoxy-methyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3- pyridylmethyl)-l,4-benzoquinone (CV-6504); (37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate; (38) an NaV1.7 blocker, such as XEN-402 and such as those disclosed in WO2011 / 140425; WO2012 / 106499; WO2012 / 112743; WO2012 / 125613 or PCT / US2013 / 21535 the entire contents of each application hereby incorporated by reference; (39) an NaV1.8 blocker, suchas those disclosed in WO2008 / 135826 and W02006 / 011050 the entire contents of each application hereby incorporated by reference; (40) a combined NaV1.7 and NaV1.8 blocker, such as DSP-2230 or BL-1021; (41) a 5-HT3 antagonist, such as ondansetron; (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof; (43) a nicotinic receptor antagonist, such as varenicline; (44) an N-type calcium channel antagonist, such as Z-160; (45) a nerve growth factor antagonist, such as tanezumab; (46) an endopeptidase stimulant, such as senrebotase; and (47) an angiotensin II antagonist, such as EMA-401.

[0244] In one embodiment, the additional appropriate therapeutic agents are selected from V-l 16517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine / ami tripty line 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 this 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. The amount of additional therapeutic agent in the presently disclosed compositions will range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0246] Nootkatone or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the disclosure, in another aspect, includes a composition for coating an implantable device comprising nootkatone as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the disclosure includes an implantable device coated with a composition comprising nootkatone as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials 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, polysaccarides,polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[0247] Another aspect of the disclosure relates to inhibiting a therapeutic target activity in a biological sample or a subject, which method comprises administering to the subject, or contacting the biological sample with nootkatone or a composition comprising nootkatone. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof, biopsied material obtained from a mammal or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0248] Inhibition of a therapeutic target activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are 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 that includes the composition and specific instructions that explain how to use the composition for treating or preventing pain or pruritus in a subject in need thereof.

[0250] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of + / - 10%, 5%, 2%, or 1%.

[0251] Reference to “between” two values or parameters herein includes (and describes) embodiments that include those two values or parameters per se. For example, description referring to “between x and y” includes description of “x” and “y” per se.Aspects of the Various Embodiments of the DisclosureAspect 1

[0252] Aspect 1.1 : A method of treating or preventing pruritus in a subj ect in need thereof, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof;optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

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

[0254] Aspect 1.3: The method of aspect 1.1, wherein the subject is a cat, a dog or ahorse.

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

[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 that are naturally occurring in a nootkatone- containing source, and the nootkatone in the composition has a purity of at least about 99% w / w.

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

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

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

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

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

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

[0263] Aspect 1.12: The method of any one of aspects 1.1 to 1.11, wherein the composition is administered once or twice per day.

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

[0265] Aspect 1.14: The method of aspects 1.1 to 1.13, wherein the administering of the composition to the subject reduces pruritus after a predetermined amount of time as determined in accordance with the Itch Numerical Rating Scale (I-NRS).

[0266] Aspect 1.15: The method of any one of aspects 1.1 to 1.13, wherein the administering of the composition to the subject reduces pruritus as evidence by a reduction of atopic dermatitis after a predetermined amount of time as determined in accordance with the Patient Oriented Eczema Measure (POEM).

[0267] Aspect 1.16: 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 composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB; and optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

[0268] Aspect 1.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or a 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

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

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

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

[0273] Aspect 1.22: The method of aspect 1.21, wherein the topical administration comprises topically administering an amount sufficient to reduce the extent of pruritus, and relieves pruritus by causing the regression of one or more symptoms pertaining to pruritus.Aspect 2

[0274] Aspect 2.1: A method of treating or preventing psoriasis in a subject in need thereof, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

[0275] Aspect 2.2: The method of aspect 2.1, wherein the subject is ahuman.

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

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

[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 that are naturally occurring in a nootkatone- containing source, and the nootkatone in the composition has a purity of at least about 99% w / w.

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

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

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

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

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

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

[0285] Aspect 2.12: The method of any one of aspects 2.1 to 2.11, wherein the composition is administered once or twice per day.

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

[0287] Aspect 2.14: The method of aspects 2.1 to 2.13, wherein the administering of the composition to the subject reduces psoriasis after a predetermined amount of time as determined in accordance with the Psoriasis Area and Severity Index (PASI), the Target Lesion Severity Score (TLSS), or a combination thereof.

[0288] Aspect 2.15: The method of any one of aspects 2.1 to 2.13, wherein the administering of the composition to the subject reduces psoriasis as evidence by a reduction of pruritus after a predetermined amount of time as determined in accordance with the Itch Numerical Rating Scale (I-NRS).

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

[0290] Aspect 2.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or a 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 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 the nootkatone or a pharmaceutically acceptable salt or derivative thereof is administered topically, subcutaneously or orally.

[0293] Aspect 2.20: Nootkatone in a method of treatment of psoriasis, the method comprising:topically administering to a skin of a subject in need thereof a therapeutically effective amount of the nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate an 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[0295] Aspect 2.22: The method of aspect 2.21, wherein the topical administration comprises topically administering an amount sufficient to reduce the extent of psoriasis, and relieves psoriasis by causing the regression of one or more symptoms pertaining to psoriasis.Aspect 3

[0296] Aspect 3.1 : A method of treating or preventing atopic dermatitis in a subject in need thereof, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

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

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

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

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

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

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

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

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

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

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

[0307] Aspect 3.12: The method of any one of aspects 3.1 to 3.11, wherein the composition is administered once or twice per day.

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

[0309] Aspect 3.14: The method of aspects 3.1 to 3.13, wherein the administering of the composition to the subject reduces atopic dermatitis after a predetermined amount of time as determined in accordance with the Patient Oriented Eczema Measure (POEM), the Target Lesion Severity Score (TLSS), or a combination thereof.

[0310] Aspect 3.15: The method of any one of aspects 3.1 to 3.13, wherein the administering of the composition to the subject reduces atopic dermatitis as evidence by a reduction of pruritus after a predetermined amount of time as determined in accordance with the Itch Numerical Rating Scale (I-NRS).

[0311] Aspect 3.16: A method of treating or preventing atopic dermatitis in a subject by inhibiting or modulating a therapeutic target, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrinetransporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB; and optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

[0312] Aspect 3.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or a 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

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

[0315] Aspect 3.20: Nootkatone in a method of treatment of atopic dermatitis, the method comprising: topically administering to a skin of a subject in need thereof a therapeutically effective amount of the nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate an 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[0317] Aspect 3.22: The method of aspect 3.21, wherein the topical administration comprises topically administering an amount sufficient to reduce the extent of atopic dermatitis, and relieves atopic dermatitis by causing the regression of one or more symptoms pertaining to atopic dermatitis.Aspect 4

[0318] Aspect 4.1: A method of treating or preventing diabetic dermopathy or diabetic peripheral neuropathy in a subject in need thereof, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

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

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

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

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

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

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

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

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

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

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

[0329] Aspect 4.12: The method of any one of aspects 4.1 to 4.11 , wherein the composition is administered once or twice per day.

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

[0331] Aspect 4.14: The method of aspects 4.1 to 4.13, wherein the administering of the composition to the subject reduces diabetic dermopathy or diabetic peripheral neuropathy after a predetermined amount of time as determined in accordance with the Target Lesion Severity Score (TLSS).

[0332] Aspect 4.15: The method of any one of aspects 4.1 to 4.13, wherein the administering of the composition to the subject reduces diabetic dermopathy or diabetic peripheral neuropathy as evidence by a reduction of pruritus after a predetermined amount of time as determined in accordance with the Itch Numerical Rating Scale (I-NRS).

[0333] Aspect 4.16: A method of treating or preventing diabetic dermopathy or diabetic peripheral neuropathy in a subject by inhibiting or modulating a therapeutic target, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB; and optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

[0334] Aspect 4.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or a derivative thereof, for use in a method of treating or preventing diabetic dermopathy 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[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 dermopathy 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

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

[0337] Aspect 4.20: Nootkatone in a method of treatment of diabetic dermopathy or diabetic peripheral neuropathy, the method comprising: topically administering to a skin of a subject in need thereof a therapeutically effective amount of the nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate an 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[0339] Aspect 4.22: The method of aspect 4.21, wherein the topical administration comprises topically administering an amount sufficient to reduce the extent of diabetic dermopathy or diabetic peripheral neuropathy, and relieves diabetic dermopathy or diabeticperipheral neuropathy by causing the regression of one or more symptoms pertaining to diabetic dermopathy or diabetic peripheral neuropathy.Aspect 5

[0340] Aspect 5.1: A method for improving the appearance of skin in a subject in need thereof, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

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

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

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

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

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

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

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

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

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

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

[0351] Aspect 5.12: The method of any one of aspects 5.1 to 5.11 , wherein the composition is administered once or twice per day.

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

[0353] Aspect 5.14: The method of aspects 5.1 to 5.13, wherein the administering of the composition to the subject improves the appearance of skin after a predetermined amount of time as determined in accordance with the Redness Numeric Rating Scale (R-NRS), Patients’ Global Impression of Change (P-GIC), EuroQol 5 Dimension (EQ-5D), or combinations thereof.

[0354] Aspect 5.15: The method of any one of aspects 5.1 to 5.13, wherein the administering of the composition to the subject improves the appearance of skin as evidence by: a reduction of atopic dermatitis after a predetermined amount of time as determined in accordance with the Patient Oriented Eczema Measure (POEM), the Target Lesion Severity Score (TLSS), or a combination thereof; a reduction of diabetic dermopathy or diabetic peripheral neuropathy after a predetermined amount of time as determined in accordance with the Target Lesion Severity Score (TLSS); or both a reduction of atopic dermatitis and a reduction of diabetic dermopathy or diabetic peripheral neuropathy.

[0355] Aspect 5.16: A method for improving the appearance of skin in a subject by inhibiting or modulating a therapeutic target, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrinetransporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB; and optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

[0356] Aspect 5.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or a derivative thereof, for use in a method for 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

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

[0359] Aspect 5.20: Nootkatone in a method for improving the appearance of skin, the method comprising: topically administering to a skin of a subject in need thereof a therapeutically effective amount of the nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate an 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[0361] Aspect 5.22: The method of aspect 5.21, wherein the topical administration comprises topically administering an amount sufficient to improve the appearance of skin, and improves the appearance of skin by causing the regression of one or more symptoms pertaining to skin imperfections.Aspect 6

[0362] Aspect 6.1: A method of treating or preventing gut or abdominal pain in a subject in need thereof, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt or derivative thereof; optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

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

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

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

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

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

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

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

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

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

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

[0373] Aspect 6.12: The method of any one of aspects 6.1 to 6.11, wherein the composition is administered once or twice per day.

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

[0375] Aspect 6.14: The method of aspects 6.1 to 6.13, wherein the administering of the composition to the subject reduces pain after a predetermined amount of time as determined in accordance with the IBS Symptom Severity Scale, the Brief Pain Inventory, the Visceral Sensitivity Index, the Pain Numeric Rating Scale (P-NRS), the Sickness Impact Profile, the Pain Disability Index, the Pain Catastrophizing Scale, the McGill Pain Questionnaire, or combinations thereof.

[0376] Aspect 6.15: The method of aspect 6.14, wherein the administering of the composition to the subject reduces gut or abdominal pain after a predetermined amount of time as determined in accordance with the Pain Numeric Rating Scale (P-NRS).

[0377] Aspect 6.16: A method of treating or preventing gut or abdominal pain in a subject by inhibiting or modulating a therapeutic target, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone; wherein the therapeutic target is at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB; andoptionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring 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).

[0378] Aspect 6.17: A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt or a derivative thereof, for use in a method of treating or preventing gut 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[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 gut or abdominal pain in a subj ect by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

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

[0381] Aspect 6.20: Nootkatone in a method of treatment of gut or abdominal pain, the method comprising: topically administering to a skin of a subject in need thereof a therapeutically effective amount of the nootkatone, wherein the therapeutically effective amount is an amount sufficient to modulate an 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

[0383] Aspect 6.22: The method of aspect 6.21, wherein the topical administration comprises topically administering an amount sufficient to reduce the extent of gut or abdominalpain, and relieves gut or abdominal pain by causing the regression of one or more symptoms pertaining to gut or abdominal pain.EXAMPLES

[0384] The presently disclosed subject matter will be better understood by reference to the following examples, which are provided as exemplary of the disclosure, and not by way of limitation. The following examples are included to demonstrate various embodiments as contemplated herein. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor(s) to function well in the practice of the invention, and thus can be considered to constitute desirable modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. All percentages are in wt.% and all measurements are conducted at 23°C unless indicated otherwise.Example 1Exemplary Aqueous Gel-based Compositions Comprising Nootkatone

[0385] Exemplary (Exemplary Comp. I) and comparative (Comparative Comp. I) formulations of the aqueous gel-based composition were formed according to the methods described herein. Provided in Table 1 below are the exemplary and comparative formulations of the aqueous gel-based composition.Table 1. Components and AmountsGelling agent may be a carbomer commercially available under the trade name Carbopol Ultrez 10.Solvent II may be diethylene glycol monoethyl ether commercially available under the trade name Transcutol P.Example 2Exemplary Cream-based Compositions Comprising Nootkatone

[0386] Exemplary (Exemplary Comp. II) and comparative (Comparative Comp. II) formulations of the cream-based composition were formed according to the methods described herein. Provided in Table 2 below are the exemplary and comparative formulations of the cream-based composition.Table 2. Components and AmountsEmulsifier may be a mixture of cetyl (Cl 6) and stearyl (Cl 8) fatty alcohols commercially available under the trade name Kolliphor CS A.Solvent II may be diethylene glycol monoethyl ether commercially available under the trade name Transcutol P.Example 3A 14-week Study to Assess Use of Compounds on Humans Affected by Atopic Dermatitis

[0387] A 14-week, placebo-controlled, double-blind, study is undertaken to evaluate the safety and tolerability of a topical cream (Exemplary Comp. II) for reducing atopic dermatitis.

[0388] Participants have self-reported mild to moderate atopic dermatitis, confirmed by an investigator at screening by photography. Participants currently experiencing or have a history of other concomitant skin conditions (e.g., psoriasis) that would interfere with evaluations of the effect of Exemplary Comp. II at the discretion of the investigator are excluded from the trial.

[0389] During the trial, patients topically apply a formulation containing nootkatone (the “test product”) according to the Study Procedure and Study Questionnaires and Assessments provided below.Study Procedure

[0390] Upon initial qualification, the participant will receive an email with study onboarding information including instructions to complete study assessments, as required. These study assessments can be accessed via the Chloe mobile app available on Apple iOS and Android devices. The participant’s activities are as follows:

[0391] Screening Period (3 weeks; Up to Dav -21):Complete the Informed ConsentComplete demographics, medical history, and concomitant medications intake Confirmation of mild to moderate severity of AD by the Investigator o Photo capture of the skin by Participants using Chloe o Investigator reviews images for confirmation of severityEligibility Confirmation and Enrollment

[0392] Randomization & Shipping Period (Dav 0 + up to 2 weeks):Randomization to one of two groups: o Exemplary Comp. II o Comparative Comp. IIProvide preferred shipment address for topical study product / placebo cream and study supplies.Shipment and receipt of topical study product / placebo cream and study supplies to participant’s home.Once the participant receives the shipment, they will move on to the Baseline Period.

[0393] Baseline Period (Dav 1 to 7):On Day 1 :Complete Patient Oriented Eczema Measure (POEM)Capture photo of target lesion / Target Lesion Severity Score (TLSS) o A target lesion will be identified by the Study Investigator from the photos captured at screening for AD confirmation o Participant will capture a photo of the target lesion using Chloe o Investigator will use the photo to complete the Target Lesion Severity Score (TLSS)Begin use of wrist-worn electronic device that tracks nighttime scratching during sleepDaily:Complete Itch-NRS (Average Itch and Worst Itch)Continue nightly use of wrist-wom electronic device that tracks nighttime scratching during sleep through Day 7.

[0394] Topical Study Product / Placebo Use Period (Dav 8 to 35):Daily:Start of Topical Study Product / Placebo application o Apply the topical study product / placebo cream twice a day to AD affected skin, especially to the target lesionCompletion of Study Product compliance questionAdverse Event Question: Complete Itch-NRS (Average Itch and Worst Itch)Adverse Event Inquiry: Continue nightly use of wearable device that tracks nighttime scratching through Day 35

[0395] At the End of Each Week (Days 14, 21, 28, 35):Adverse Event Visual: Capture photo of target lesion / Target Lesion Severity Score (TLSS) o Participant will capture a photo of the target lesion using Chloe o Investigator will use the photo to complete the Target Lesion Severity Score (TLSS)Skin Appearance Question: Patient Global Impression of Change (P-GIC)Complete a question about any additional adverse events / reactions related to study product / placebo use

[0396] At the End of Topical Study Product / Placebo Cream Use Period (Dav 35):Complete Patient Oriented Eczema Measure (POEM) Complete Experience Survey

[0397] Open Label Extension (Dav 36 to 63):Optional open label use of Exemplary Comp. IIParticipants who opt in to the extension will receive a shipment of the product Report any adverse reach ons / events related to product use at any time in Chloe Continue nightly use of wrist-wom electronic device that tracks nighttime scratching during sleep through Day 63

[0398] At the End of Open Label Extension (Dav 63)Completion of Study Product compliance questionComplete a Skin Appearance Question: Patient Global Impression of Change (P-GIC)Study Questionnaires and Assessments

[0399] Itch Numeric Rating Scale: The Itch Numeric Rating Scale (NRS) is a simple, selfadministered measure for itch severity. Average itch and Worst itch in the last 24 hours will be evaluated daily with a 10-point numeric rating scale (NRS). Additionally, objective actigraphydata will be collected from a wearable device worn nightly with an application that tracks nighttime scratching and syncs data to the participant’s smartphone.

[0400] Patient Oriented Eczema Measure (POEM): The POEM is a validated, patient- derived questionnaire for assessing symptoms of atopic dermatitis and monitoring severity. It is a 7-question assessment with a maximum score of 28 that translates to eczema severity. This will be administered at Baseline and at the end of the topical study product / placebo use period.

[0401] Patient Global Impression of Change (P-GIC): The Patient Global Impression of Change (P-GIC) is a 7-point likert scale that reflects the participant’s rating of overall improvement in skin appearance. This will be administered daily during the topical study product / placebo use period.

[0402] Target Lesion Severity Score (TLSS): The Target Lesion Severity Score (TLSS) is an Investigator-completed measure that assesses the severity of AD lesions based on erythema, induration, population, lichenification, oozing / crusting and scaling. Each of the 5 features is assessed on a 4-point scale, with a maximum TLSS score of 15 points. This will be completed by the Investigator using photos of the target lesion captured by participants at baseline and at the end of each week of application.

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

[0404] Experience Survey: The experience survey will consist of questions relating to product use, likelihood of continued use, product preferences, and experiences with the applications, the study tools and the study in general.

[0405] An alignment of the various assessments described above to the treatment of various conditions or diseases is provided in Table 3 below.Table 3. Alignment of Assessment to Treatment of Conditions or DiseasesExample 4Investigating the Safety, Dermal Tolerability, and Effectiveness in Improving Skin appearance of Exemplary Comp. II in Individuals, including Individuals with Diabetic Peripheral Neuropathy and Diabetic Dermopathy

[0406] A multi-center, double-blind, randomized, vehicle-controlled, single dose study of Exemplary Comp. II and vehicle cream (Comparative Comp. II) is performed to assess the safety, dermal tolerability and efficacy of nootkatone as compared to vehicle. Study duration includes Exemplary Comp. II or Comparative Comp. II twice daily for 8 weeks. Sixty (60) male and female patients over 18 years of age, afflicted with diabetic peripheral neuropathy (DPN) and met the inclusion / exclusion criteria are included in the study.

[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 improvements in skin appearance:Table 4: Study objectives and endpoints related to skin appearance

[0409] Testing the Cosmetic Test Product and Mode of Administration: Participants are randomized to receive one of the following study products, described as follows:Exemplary Comp. IIComparative Comp. II

[0410] Mode of administration: Exemplary Comp. II cream and Comparative Comp. II cream is administered topically twice daily for 8 weeks on the DPN affected areas. Participants are instructed to apply the test product on all DPN affected areas (skin imperfections), including the ones resolved, and any new skin imperfections (DPN lesions) that might appear during the 8-week application period. At baseline, a lesion that is representative of the participant's overall DPN condition, and is to be treated with cosmetic test product, is selected as the target lesion. This lesion is identified, measured, and documented in the participant's study record at each subsequent visit during the application period.

[0411] Study criteria evaluation:Safety Assessments:• Adverse Effects (AEs) and Serious Adverse Effects (SAEs)• Dermal tolerability (erythema, edema, buming / stinging, pain, pruritus) Investigator skin appearance assessments:• TLSS (Target Lesion Severity Score):Table 5: Participant assessmentsOther Measures: Photography of the target lesion.Statistical Methods: Appropriate statistical methods are used to validate the study results obtained herein.

[0412] An alignment of the various assessments described above to the treatment of various conditions or diseases is provided in Table 6 below.Table 6. Alignment of Assessment to Treatment of Conditions or DiseasesExample 5A 4-week Study to Assess Use of Compounds on Humans Affected by Pain

[0413] A 4-week, vehicle-controlled, double-blind, trial is undertaken to evaluate the safety and tolerability of a topical cream for reducing pain.

[0414] During the trial, patients topically apply a formulation containing nootkatone (the “test product”) to the treatment area(s) twice per day, once in the morning, and once in the evening, for a period of 4 weeks. Subjects are instructed to gently wash the areas of treatment shortly before the application of the test product; however, skin should be allowed to dry completely before application. Participants use the dosing guidelines shown in Table 7 below when applying the test product.Table 7. Test Product Dosing Guidelines1One fingertip unit is equivalent to 0.5 g of test product

[0415] The test product used in the trial has varying concentrations of nootkatone formulated in petroleum jelly: 0.375% w / w (Exemplary Comp. Ill), 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 petroleum jelly and is free of nootkatone (Comparative Comp. III).

[0416] The trial involves 4 weeks of test product use for each participant, and includes assessments at: baseline prior to starting use of the test product, as well as following 7, 14, 21, and 28 days of using the test product. Assessments are conducted virtually through selfreported questionnaires, and photos of atopic-dermatitis-affected body areas treated with test product at each assessment timepoint. Photos comply with standard photograph guidelines provided to participants, and are scored by one or more Board-certified dermatologists.

[0417] At each assessment participants are assessed according to the primary and secondary endpoints shown in Tables 8 and 9, below:Table 8: Primary EndpointsTable 9: Secondary Endpoints

[0418] An alignment of the various assessments described above to the treatment of various conditions or diseases is provided in Table 10 below.Table 10. Alignment of Assessment to Treatment of Conditions or DiseasesExample 6A 4-week Study to Assess Use of Compounds on Humans Affected by Atopic Dermatitis

[0419] A 4-week, vehicle-controlled, double-blind, trial is undertaken to evaluate the safety and tolerability of a topical cream for reducing atopic dermatitis.

[0420] Participants have a clinical diagnosis of mild to moderate atopic dermatitis according to the diagnostic criteria of Hanifin and Rajka that affects 5% to 20% (inclusive) of the total body surface area, excluding the face, scalp, axillae, and intertriginous areas. Patients with confounding skin conditions, including, for example psoriasis, rosacea, erythroderma, or ichthyosis (other than ichthyosis vulgaris) are excluded from the trial.

[0421] During the trial, patients topically apply a formulation containing nootkatone (the “test product”) to the treatment area(s) twice per day, once in the morning, and once in the evening, for a period of 4 weeks. Subjects are instructed to gently wash the areas of treatment shortly before the application of the test product; however, skin should be allowed to dry completely before application. Participants use the dosing guidelines shown in Table 11 below when applying the test product.Table 11. Test Product Dosing Guidelines1One fingertip unit is equivalent to 0.5 g of test product

[0422] The exemplary test product used in the trial has varying concentrations of nootkatone formulated in petroleum jelly: 0.375% w / w (Exemplary Comp. Ill), 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 petroleum jelly and is free of nootkatone (Comparative Comp. III).

[0423] The trial involves 4 weeks of test product use for each participant and includes assessments at: baseline prior to starting use of the test product, as well as following 7, 14, 21, and 28 days of using the test product. Assessments are conducted virtually through selfreported questionnaires, and photos of atopic-dermatitis-affected body areas treated with test product at each assessment timepoint. Photos comply with standard photograph guidelines provided to participants, and are scored by one or more Board-certified dermatologists.

[0424] At each assessment participants are assessed according to the primary and secondary endpoints shown in Tables 12 and 13, below:Table 12: Primary EndpointsTable 13: Secondary Endpoints

[0425] An alignment of the various assessments described above to the treatment of various conditions or diseases is provided in Table 14 below.Table 14. Alignment of Assessment to Treatment of Conditions or DiseasesExample 7Study to Assess Use of Compounds on Humans Affected by Psoriasis

[0426] A 4-week, vehicle-controlled, double-blind, trial is undertaken to evaluate the safety and tolerability of a topical cream for reducing psoriasis.

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

[0428] During the trial, participants topically apply a formulation containing nootkatone (the “test product”) to the treatment area(s) twice per day, once in the morning, and once in the evening, for a period of 4 weeks. Participants are instructed to gently wash the areas of treatment shortly before the application of the test product; however, skin should be allowed to dry completely before application. Participants use the dosing guidelines shown in Table 15 below when applying the test product.Table 15. Test Product Dosing Guidelines1One fingertip unit is equivalent to 0.5 g of test product

[0429] The exemplary test product used in the trial has varying concentrations of nootkatone formulated in petroleum jelly: 0.375% w / w (Exemplary Comp. Ill), 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 petroleum jelly and is free of nootkatone (Comparative Comp. III).

[0430] The trial involves 4 weeks of test product use for each participant, and includes 2 site visits for assessment of each participant: a baseline assessment immediately prior to starting use of the test product, and an assessment after 4 weeks of using the test product. During each visit, patients are 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 4-week assessment, participants are also asked to provide a Patient Global Impression of Change (PGIC).

[0431] The Psoriasis Area and Severity Index is derived by separately assessing the severity of erythema, induration, and desquamation on the head and neck, upper limbs, lower limbs, and trunk on a 0 to 4 point scale. A score is separately assigned to each symptom on each body area. Next, the sum of the scores for each body area is multiplied by a weightingfactor of 0.1 for the head, 0.2 for the upper limbs, 0.3 for the trunk, or 0.4 for the lower limbs. The resulting weighted scores are multiplied by a score of 0 to 6 based on the percent surface area of the body area that is affected by psoriasis (not affected = 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 values are then summed to derive the total score on the PASI scale.

[0432] The Physician Global Assessment (PGA) is an overall psoriasis severity rating on a 0 to 4 scale that is assessed during site visits. The criteria for each PGA grade are shown in Table 16, below:Table 16: Physician Global Assessment (PGA)

[0433] Investigators and participants separately assess and rate the severity of skin redness according to the criteria shown in Table 17 below.Table 17: Criteria for Assessment of Skin Redness

[0434] One target lesion measuring approximately 10 cm2or more at Baseline is selected for each subject. The target lesion must be representative of the subject's disease state and must not be located on the hands, feet, or genitalia. Photography of the target lesion is conducted via two views (close-up and regional body area). The target lesion is individually assessed for PGA, Redness (investigator and subject), Itch NRS, and Patient Global Impression of Change (PGIC). Additional assessments are made for the following individual measures: erythema, edema / papulation, oozing / crusts, excoriation, lichenification, and dryness.

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

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

[0437] The Patient Global Impression of Change (PGIC) is an overall rating on a 1 to 7 scale that is assessed during site visits. Subjects are asked, “Since beginning use of the Test Product, please describe your impression of improvement you have experienced regarding the look and feel of your skin”. The grades for the PGIC are shown in Table 18 below.Table 18. Patient Global Impression of Change (PGIC)

[0438] An alignment of the various assessments described above to the treatment of various conditions or diseases is provided in Table 14 below.Table 14. Alignment of Assessment to Treatment of Conditions or DiseasesExample 8

[0439] Methods employed in this study have been 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 conditions described below. Where presented, IC50 values were determined by a non-linear, least squares regression analysis using MathlQ™ (ID Business Solutions Ltd., UK), as shown in Table 19 below.Table 19: Analysis of Inhibition of Therapeutic Targets of CompoundsExample 9

[0440] Methods employed in this study have been 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 conditions described below. Where presented, IC50 values were determined by a non-linear, least squares regression analysis using MathlQ™ (ID Business Solutions Ltd., UK), as shown in Table 20 below.Table 20: Analysis of Inhibition of Therapeutic Targets of Compoundsc

[0441] Sodium Channel, Site 2 (Nav site 2) was assessed using the following parameters:Source: Wistar Rat brain (minus cerebellum)- Vehicle: 1.0% DMSOIncub. Time / Temp: 60 minutes @ 37°CIncub. Buffer: 50 mM HEPES, 50 mM Tris-HCl, pH 7.4, 130 mM Choline Chloride, 5.4 mM KC1, 0.8 mM MgCh, 5.5 mM Glucose, 40 pg / ml LqTX- Kd: 0.052 pMLigand: 5.0 nM [3H] Batrachotoxinin- Non-Specific Ligand: 100 pM VeratridineSpecific Binding: 77%Quantification Method: Radioligand BindingBmax: 0.7 pmole / mg Protein

[0442] Nitric Oxide Synthase, Neuronal (nNOS) was assessed using the following parameters:Source: Wistar Rat cerebellumSubstrate: 20.0 nM [3H]L-Arginine- Vehicle: 1.0% DMSOPre-Incub. Time / Temp: 15 minutes @ 25°C Incub. Time / Temp: 10 minutes @ 25°C- Incub. Buffer: 50 mM HEPES, pH 7.4, 1 mM EDTA, 1 mM NADPH, 1.25 mM CaC12.2H2O, 1 mM DTT, 10 pg / ml CalmodulinQuantification Method: Quantitation of [3H] Citrulline

[0443] Opiate K (OP2, KOP) was assessed using the following parameters:Source: Human recombinant HEK-293 cells- Vehicle: 1.0% DMSOPre-Incub. Time / Temp: 15 minutes @ 25°CIncub. Time / Temp: 60 minutes @ 25°CIncub. Buffer: 50 mM Tris-HCl, pH 7.4- Kd: 0.4 nMLigand: 0.6 nM [3H] Diprenorphine- Non-Specific Ligand: 10.0 pM NaloxoneSpecific Binding: 90%Quantification Method: Radioligand BindingBmax: 1.10 pmole / mg Protein

[0444] Sigma ol was assessed using the following parameters:Source: Human Jurkat cells- Vehicle: 1.0% DMSOIncub. Time / Temp: 2 hours @ 37°CIncub. Buffer: 50 mM Tris-HCl, pH 8.0- Kd: 16.0 nMLigand: 15.0 nM [3H] Pentazocine- Non-Specific Ligand: 10.0 pM HaloperidolSpecific Binding: 90%Quantification Method: Radioligand BindingBmax: 1.08 pmole / mg Protein

[0445] Adenosine A3 was assessed using the following parameters:Source: Human recombinant CHO-K1 cells- Vehicle: 1.0% DMSOIncub. Time / Temp: 60 minutes @ 25°C- Incub. Buffer: 25 mM HEPES, pH 7.4, 5 mM MgCh, 1 mM CaCl2, 0.1% BSA- Kd: 5.90 nM- Ligand: 0.5 nM [125I] AB-MECANon-Specific Ligand: 1.0 pM IB-MECASpecific Binding: 83%Quantification Method: Radioligand BindingBmax: 1.08 pmole / mg Protein

[0446] Prostanoid EP2 was assessed using the following parameters:Source: Human recombinant HEK-293 cells- Vehicle: 1.0% DMSOIncub. Time / Temp: 2 hours @ 25°C- Incub. Buffer: 10 mM MES, pH 6.0, 1 mM EDTA, 10 mM MgCb- Kd: 3.10 nMLigand: 4.0 nM [3H] Prostaglandin E2 (PGE2)- Non-Specific Ligand: 10.0 pM Prostaglandin E2 (PGE2)Specific Binding: 80%Quantification Method: Radioligand BindingBmax: 1.40 pmole / mg Protein

[0447] Transporter, Norepinephrine (NET) was assessed using the following parameters:Source: Human recombinant MDCK cells- Vehicle: 1.0% DMSOIncub. Time / Temp: 3 hours @ 4°CIncub. Buffer: 50 mM Tris-HCl, pH 7.4, 100 mM, NaCl, 1 pM Leupeptin, 10 pM PMSF- Kd: 0.024 pM- Ligand: 0.2 nM [125I] RTI-55- Non-Specific Ligand: 10.0 pM DesipramineSpecific Binding: 75%Quantification Method: Radioligand BindingBmax: 2.50 pmole / mg ProteinExample 10Nootkatone inhibited intrinsic dorsal root ganglion (DRG) firing in mice and humans

[0448] Dorsal root ganglia neurons sense danger in periphery and relay the message to central nervous system (CNS). Pruritogens released by skin and immune cells can directly activate specific neurons. Nootkatone was found to inhibit intrinsic dorsal root ganglia (DRG) firing in mice and humans. Specific markers were used to identify specific neuronal subtypes of mouse DRG namely calcitonin gene-related peptide (CGRP) for peptidergic neurons and Isolectin B4 (IB4) for non-peptidergic neurons. Nootkatone exhibited dose-dependent blocking of neuronal depolarization in non-peptidergic mouse DRGs.Mouse DRG Dissection and cell culture:

[0449] Mouse DRG dissection: All procedures in this investigation were performed in compliance with the rules and regulations in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. WT adult mice were euthanized with CO2 and sprayed thoroughly with 70% (vol / vol) ethanol just before the dissection of DRGs. All of the following procedures were performed under sterile conditions. The euthanized mouse was decapitated, and the dorsal skin was cut along its midline from neck to tail. The skin was removed from the entire dorsal surface of the body. The forelimbs were pinned down, and the spinal column was cut transversely at the last rib to ensure that only lumbar and no thoracic DRGs were collected. From the cut in the spinal column, two straight longitudinal incisions were made through the adjacent tissue on either side of the spinal column caudally to the tail. The spinal column was then horizontally hemisected to the tail, making sure to cut through the vertebrae on each side of the spinal column. The dorsal half of the spinal column was lifted, after which the DRGs were visible as white (partially translucent) bulbs along both sides of the spinal column if the cut was made correctly (not too high or too low along the dorsal-ventral midline). Fine forceps were used to grip the distal process of the DRGs, behind and beneath the bulbs, to remove each ganglion. Pinching of the DRG bulb directly was avoided to minimize damaging any neurons. All lumbar DRGs were removed. Distal and proximal processes emanating from DRGs were removed with Vannas-type iridectomy scissors, and the DRGs were then placed in a Petri dish containing cold Hanks' Balanced Salt Solution (HBSS).

[0450] Mouse DRG cell culture and calcium assay methodology: Lumbar mouse DRG neurons were removed, dissociated, and plated in 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 prior to collecting experimental data. Mouse DRG neurons were depolarized by applying 30 mM K+at 6-minute intervals to observe calcium influx resulting from membrane depolarization. The initial three applications of potassium (K+) served as controls. Nootkatone was tested at 10 pM, 30 pM. and 100 pM concentrations as follows: After the first three control applications of K+, nootkatone was sequentially applied as per the concentrations mentioned above. Every concentration of nootkatone was followed by a series of K+ applications to observe inhibition and reversibility. 100 uM allyl isothiocyanate (AITC) was applied 4 minutes after the last K+ and washed off after 60 seconds of incubation. 500 nM Capsaicin was applied 6-minutes after the allyl isothiocyanate (AITC) application and monitored for two minutes. Inmouse DRGs, 100 pM nootkatone showed blocking of neuronal depolarization in capsaicin / transient receptor potential vanilloid subfamily member 1 (TRPV1) negative neurons as shown in FIG.1A and FIG.1B

[0451] Human DRG cell culture and DRG calcium assay methodology: Human DRG neurons were extracted and dissociated for calcium imaging assay from 32 years old Hispanic male.A summary of the human DRG cell culture, DRG calcium assay and analysis has been provided below: i. Fluo-8 acetoxymethyl ester (Fluo-8 AM) Fluo-8 dye loading of human DRG neuronal culture. ii. Electrical field stimulation (EFS). iii. High voltage was set to activate 70-80% of neurons through action potential (AP) depolarization but not activate voltage-gated calcium channels by direct depolarization.1. Baseline (vehicle, 5 minutes).Application of high voltage electrical field stimuli (10 pulses).2. Addition of test article (nootkatone) at a pre-determined concentration (5 minutes).Application of high voltage electrical field stimuli (10 pulses).3. Addition of test article (nootkatone) at a pre-determined concentration (5 minutes).Application of high voltage electrical field stimuli (10 pulses).4. Continued application of test article (nootkatone).5. Addition of test article (nootkatone) + 30mM KC1.6. Addition of 200nM capsaicin.

[0452] Human DRG calcium assay Analysis: The steps followed for human DRG calcium assay experiments and subsequent data analysis is provided below:1. Measurement per EFS active neurons a. Number of calcium steps pre and post addition of nootkatone. b. Amplitude of first calcium step pre and post additions of nootkatone. c. Amplitude of the cumulative calcium transient pre and post addition of nootkatone.2. Measurement per KC1 responsive neurons. a. Amplitude of KC1 induced neurons.3. Numbers and percentages of responsive neurons per experimental condition i.e., nootkatone concentration.

[0453] Nootkatone was applied at lOOuM to observe its effect on KC1 induced neuronal depolarization / activity. Extracellular K+ and electric field stimulation were used to depolarize / activate neurons. The transient response to KC1 in human DRGs has been depicted in FIG.2. Nootkatone was applied at 30 (first application) and lOOuM (second application) to observe its effect on EFS induced neuronal depolarization / activity (as shown in FIG.3A and FIG.3B)

[0454] In human DRGs, 100 pM nootkatone exhibited blocking of neuronal depolarization in capsaicin / TRPVl positive neurons. The species difference in terms of capsaicin / TRPV 1 activity implied a better efficacy for nootkatone in both pruritus and pain as TRPV1 neurons have been implicated in both these indications in humans.Example 11Efficacy of Nootkatone in in-vivo Formalin induced pain mice model

[0455] The rodent formalin induced pain model is widely used as an acute and rapid in- vivo screening study to evaluate the potential analgesic effects of novel compounds. This model encompasses inflammatory, neurogenic, and central mechanisms of nociception. Injection of a 2.7% formalin solution into the surface of a mouse or rat’s hind paw allows modeling of both acute and tonic pain using a single chemical in a relatively limited time. This induces biphasic nociceptive behavioral responses where, the early-phase response is considered to arise from direct activation of the small primary afferents and the late-phase nociceptive response isconsidered to occur via sensitization of central nervous system neurons within the dorsal hom, (implicated in neuropathic pain).

[0456] Experimental Protocol for Rodent Formalin induced pain model: Effect of nootkatone in formalin-induced nociception in male C57BL / 6 mice was evaluated as follows. Male C57BL / 6 mice were treated with nootkatone (3mg / kg / 10mL; p.o, lOmg / kg / lOmL; p.o, 30mg / kg / 10mL; p.o, lOOmg / kg / lOmL; p.o, and 300mg / kg / 10mL; p.o) for 3 days and on day 3, 1 hour after treatment, the mice were injected with intraplantar formalin (2.7% in saline, 50 pl / mouse). On the day intraplantar formalin was to be injected, the positive control mice were treated with Gabapentin (100 mpk, i.p) and post 30 min of Gabapentin treatment, formalin was injected. From 0 min to 40 min post-formalin injection, nociceptive response (paw licking and biting duration in seconds) was recorded (as shown in FIG.4). Nociceptive response at 0 min to 5 min post formalin injection was considered as phase 1 (as shown in FIG.5), while response from 16 to 40 min was considered as phase 2 (as shown in FIG.6). Nootkatone showed positive results in phase 1 and phase 2 studies.Example 12Topical application of Nootkatone relieved acute pain in mice

[0457] This study was undertaken to assess efficacy of nootkatone in male C57BL / 6 mice using tail flick test effect. Mice were acclimatized one day prior and before starting the experiment in a mouse holder. At the time of experiment, mice were gently held in a mouse holder and the middle third of the tail was placed over a radiant heat source (Ugo Basile, Varese, Italy) with infrared intensity set at 25%. Latency to withdraw from the heat source (tail flick) was measured to the nearest 0.1 s. Withdrawal of the tail stopped the stimulus, latency to tail flick was recorded automatically, and the cut-of time was set at 10 s. The mean time of 3 measurements before the topical administration of compounds was performed as the baseline latency. Baseline tail flick latencies of mice were recorded, mice were topically applied with nootkatone (at concentrations ranges 1.5%, 3% and 6%) on tail and at 15 min, 30 min, Ihr, 1.5 hr and 2 hr post application tail flick latencies were recorded. Positive control mice were applied with 3% Lidocaine emulsion and at 15 min, 30 min, Ihr, 1.5 h rand 2 hr post application tail flick latencies were recorded.

[0458] The overall tail flick latency was an average of three measurements obtained at least Imin apart.

[0459] % Maximum Possible Effect (% MPE) was calculated using following formula:(Tail flick latency of test) - (Avg. Tail flick latency of Vehicle)% MPE = X 100(10) - (Avg. Tail flick latency of Vehicle)Where 10= cut-of time in seconds for tail flick test

[0460] Positive control 3% Lidocaine showed significant effect in all the tested time points. Animals in the negative control group did not show any effect in all the tested time points. As compared to negative control, topical administration of nootkatone showed dose dependent significant effect at all the tested time points (as shown in FIG.7).Example 13Effect of Nootkatone on chloroquine induced scratching / itch rodent model (Oral and Topical administration)

[0461] Oral nootkatone relieved chloroquine-induced scratching / itching in mice: Chloroquine, an antimalarial drug, induces biting and 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 Negative control (where no treatment or chloroquine was given), Group 2 is vehicle treated (lOmL / kg, PO) + Chloroquine (5mg / Kg, SC), Group 3 is Diphenhydramine (60 mg / Kg, PO) + Chloroquine (5mg / Kg, SC), Group 4 is nootkatone (lOmg / Kg, PO) + Chloroquine (5mg / Kg, SC), Group 5 is nootkatone (30mg / Kg, PO) + Chloroquine (5mg / Kg, SC) and Group 6 is nootkatone (lOOmg / Kg, PO) + Chloroquine (5 mg / Kg, SC). All animals except mice in Group 1 received vehicle for chloroquine subcutaneously injected (SC), chloroquine at 5 mg / kg injected subcutaneously in a volume of 10 mL / kg into the rostral of the back with a 27-gauge needle. Vehicle or test article (nootkatone) was given by oral gavage (PO) once at 60 min before chloroquine injection. Vehicle for Diphenhydramine: Water while vehicle for treatment arm 1 : Tween 80: 0.5% MC (0.5:99.5, v / v). The number of scratches was recorded for a period of 30 minutes by visual observation after pruritogen injection. Only scratches toward the injection site were counted (other sites, such as ears and face were excluded). Immediately afterthe scratch behavior test, all 8 animals in test article (nootkatone) groups (Groups 4-6; n=25), were subjected to blood collection via cardiac puncture. The collected blood was placed in tubes coated with lithium heparin, mixed gently, then kept on ice and centrifuged at 2,500 xg for 15 minutes at 4°C, within 1 hour of collection. The plasma was then harvested and kept frozen at <-70°C until shipping for further tests. As shown in FIG.8, 30mpk oral administration of nootkatone relieved chloroquine-induced scratching / itching in mice.

[0462] Topical nootkatone relieved chloroquine-induced scratching / itching in mice: Male ICR mice weighing 23 ± 3 g were used. The study was split into 2 runs separated by 2-3 days. All animals, except mice in Group 1 received vehicle for chloroquine subcutaneously injected (SC), chloroquine at 5 mg / kg injected subcutaneously in a volume of 10 mL / kg into the rostral of the back with a 27-gauge needle. Vehicle or test article (nootkatone) was given topically (TOP) around the chloroquine injection site once at 60 min prior to chloroquine injection. The positive control, Diphenhydramine, was dosed by oral gavage (PO) once at 60 min prior chloroquine injection. Vehicle for chloroquine: 0.9% NaCl, vehicle for Diphenhydramine: 5% DMSO / 2% Tween 80; vehicle for TAI: TBD. The number of scratches was recorded for a period of 30 minutes by visual observation after pruritogen injection (10 minutes per interval x 3 intervals). Only scratches toward the injection site were counted (other sites, such as ears and face were excluded). 10% topical nootkatone relieved chloroquine- induced scratching / itching in mice (as shown in FIG.9). Efficacy of 10% topical nootkatone was found to be better than clobestasol (steroid) and ruxolitinib (commercial JAK 1- 2 inhibitor)Example 14Effect of Nootkatone on bovine adrenal medulla (BAM) 8-22 induced itch rodent model

[0463] BALB / c mice were divided into six groups (n=8 / treatment group) as follows: Group 1 Negative control (where no treatment or chloroquine was given), Group 2 is vehicle treated (lOmL / kg, PO) + BAM 8-22 (150pg / animal, SC), Group 3 is cyproheptadine (3mg / Kg,PO) + BAM 8-22 (150pg / animal, SC), Group 4 is nootkatone (lOmg / Kg, PO) + BAM 8-22 (150pg / animal, SC), Group 5 is nootkatone (30mg / Kg, PO) + BAM 8-22 (150pg / animal, SC) and Group 6 is nootkatone (lOOmg / Kg, PO) + BAM 8-22 (150pg / animal, SC). All animals, except mice in Group 1 received vehicle for BAM 8-22 subcutaneously injected (SC), BAM8-22 at 150 ug / animal injected subcutaneously in a volume of 50 uL into the rostral of the back with a 27-gauge needle. Vehicle or test article was given by oral gavage (PO) once at 60 min before BAM 8-22 injection. Vehicle for BAM 8-22: 0.9% NaCl, vehicle for Cyproheptadine: 2% Tween 80; vehicle for treatment arm 1: Tween 80: 0.5% MC (400 cPs) in saline (0.5:99.5, v:v). The number of scratches was recorded for a period of 30 minutes by visual observation after pruritogen injection. Only scratches toward the injection site were counted (other sites, such as ears and face were excluded). lOOmg / Kg, PO nootkatone relieved BAM8-22-induced scratching / itching in mice (as shown in FIG.10).Example 15Topical Nootkatone Formulation in MC903 mouse model of Atopic Dermatitis

[0464] MC903, a low-calcemic analog of vitamin D3, induces skin and systemic atopic dermatitis / eczema-like inflammation. The application of MC903 topically on the ear induces skin inflammation and other AD-like phenotypes in C57BL / 6J wild type (WT) mice. This treatment increases the thickening of ear skin, which is a surrogate marker of ear skin inflammation.

[0465] During the first week of the MC903 treatment, only minor changes in ear appearance are visible such as redness, dryness, swelling, and hyper-vascularization. These changes are clearly observed from day 5 of the MC903 treatment and worsen over time, particularly during the last days of the experiment.

[0466] Experimental Protocol: Female C57BL / 6 mice of 8-9-week-old were used in the study. All mice were acclimatized prior to handling. The mice were housed in microisolator cages and maintained under specific pathogen-free conditions. All procedures were carried out under appropriate institutional guidelines for animal care. All animals, except those in Group 1 (sham), received MC903 (2 nmole / 20 pL, dissolved in 100% ethanol) topically (TOP) applied daily on the right ear from day 1 to day 14 for 14 consecutive days. From day 7 to day 14 the MC903 was applied one hour after test article (nootkatone at a concentration of 3% and 10%). Animals in Group 1 (sham) received 20 pL of ethanol (no antigen) applied daily on the right ear from day 1 to day 14 for 14 consecutive days. Petrolatum vehicle and test articles (nootkatone) were applied TOP twice daily (BID) at 6-hr intervals from day 7 to day 14 for 8 consecutive days (1 hour before MC903 challenge). The reference compound, clobetasol (0.01mg / ear), was administered topically (TOP) once daily from day 7 to day 14 for 8 consecutive days (1 hour before MC903 challenge).

[0467] Female C57BL / 6 mice were randomly divided into the following treatment groups:1. Sham: no MC903, no treatments (Negative Control)2. Vehicle: MC903 treatment and petrolatum vehicle3. 0.05% Clobetasol4. 1.5% Ruxolitinib (Groups 3 and 4 served as positive controls and comparators)5. 3% Nootkatone in petrolatum vehicle6. 10% Nootkatone in petrolatum vehicleMC903 treatments were performed from days 1 to 14. Clobetasol, ruxolitinib, and nootkatone treatments were performed from day 7 to day 14.Treatments were administered 1 hour before MC903 challenge. The scratching behavior was recorded for 60 minutes immediately after MC903 challenge. Clobestasol (steroid) and ruxolitinib (JAK 1- 2 inhibitor) were used as positive controls. 3% nootkatone was more efficacious than clobestasol (steroid) and ruxolitinib (JAK 1- 2 inhibitor) as shown in FIG.ll. 3% nootkatone showed robust efficacy on scratching behavior on day 7.Example 16Effect of Nootkatone in Imiquimod (IMQ)-induced Psoriasis Mouse Model

[0468] Experimental Protocol: Female Balb / c mice of 10-12-week-old were used in the study. All mice were acclimatized prior to handling. The mice were housed in microisolator cages and maintained under specific pathogen-free conditions. During this period, the mice were observed daily for clinical signs. Mice with any abnormalities or ill health or poor physical condition were excluded from the study. All procedures were carried out under appropriate institutional guidelines for animal care. On day 1, the mice were randomized based on fold back skin thickness and body weight. Mice back hair was removed by using a depilatory cream and clipper.

[0469] The study design is depicted below in Table 21 :Table 21:

[0470] Nootkatone in Vaseline gel at concentration ranges 2.5% and 10% were run topically in the IMQ psoriasis model with an additional itch readout. Imiquimod (5%) application: 47 mg on Back Skin and 15.5 mg on Right Ear, once daily for 5 days (Post 4 h of Treatment).

[0471] The key study parameters are given below: Parameters on day 1, 2, 3, 4, 5 & 6:■ Body weight■ Fold back skin thickness and Ear Thickness■ Psoriasis Area and Severity Index (PASI)■ Pruritus Testing on day 1, 4 & 6 for Ih Histopathology (Back Skin and right Ear) Bioanalysis (Optional): @ 4h post topical application of test compound on day 6 (Optional) Gene expression analysis for biomarker (Optional)

[0472] Nootkatone caused a slight but significant decrease in some psoriasis readouts (e.g., cumulative PASI shown in FIG.12 and FIG.13, back redness + thickness + scaling scores + ear redness + thickness + scaling scores, 0-24). In this study the effects were primarily observed at the later timepoint(s).Example 17Effect of Nootkatone on DSS-induced Locomotor Activity in Mice

[0473] Dextran sulfate sodium (DSS)-induced locomotor activity refers to the changes in movement patterns observed following the administration of DSS, a compound commonly used to induce colitis in experimental models. The assessment of locomotor activity following DSS administration is crucial for understanding the behavioral implications of DSS-induced colitis. During the assessment, the following activities were monitored: Ambulatory Time, Distance Traveled, Resting Time, Center Square Duration, Center Square Entries, and Rearing to the Wall. The open field test analysis was performed using the BehaviorCloud platform. Reduced locomotor activity is often indicative of discomfort or disease-related lethargy, while increased activity might suggest agitation or compensatory behavior. These locomotor responses to DSS are valuable for elucidating the peripheral and central impacts of colitis and the efficacy of therapeutic interventions. Mouse models were prepared as shown in FIG.14. The results of the assessment are shown in FIG.15A to FIG.15F.

[0474] Disease control mice showed significant reduction in locomotor activity (distance travelled, ambulatory time, resting time) when compared to vehicle control. Distance traveled and ambulatory time reduced significantly while resting time increased significantly in DSS group compared to vehicle. Nootkatone at 100 and 300 mg / kg showed an improved trend in locomotor activity as compared to the disease control mice. Zone activity analysis (center square duration & entries) showed that DSS mice were more anxious compared to vehicle control while nootkatone treated mice showed improved exploratory behavior. The DSS mice showed significantly reduced exploratory behavior as compared to the normal exploratory behavior of the control mice (rearing to the chamber wall) while the mice treated with nootkatone at 300 mg / kg showed an increase in exploratory behavior as compared to the DSS mice.Example 18Effect of Nootkatone on Visceral Pain in a Mouse Model of DSS-induced Colitis

[0475] The study aimed to explore the mechanisms of visceral pain in a mouse model of DSS (dextran sulfate sodium) induced colitis, a method commonly used to simulate inflammatory bowel disease (IBD) in laboratory settings. The primary focus of this research was to understand the pain pathways and their modulation in the context of IBD. To achieve this, the study employed a combination of Disease Activity Index (DAI) scoring and exposure analysis, both in plasma and colon tissues, to quantify inflammation and its systemic effects.DAI scoring, a comprehensive measure considering weight loss, stool consistency, and bleeding, provided a reliable gauge of colitis severity. Concurrently, exposure analysis in plasma and colon tissues assessed the presence and concentration of inflammatory markers, cytokines, and other biochemical indicators of inflammation. This dual approach ensured a thorough understanding of the inflammatory process at both local and systemic levels.

[0476] Behavioral parameters, specifically von Frey pain responses and capsaicin-induced pain responses, were critical components of the study to assess the sensory and pain aspects in the mouse model. The von Frey test, involving the application of calibrated filaments to measure mechanical pain sensitivity, helped in evaluating alterations in pain perception due to colitis. In contrast, the capsaicin-induced pain response test, which involved administering capsaicin (a component known to induce pain and mimic inflammatory pain in humans) and observing the pain response, provided insights into the nociceptive pathways and pain modulation in the context of colitis. These behavioral tests were crucial for correlating the extent of inflammation with the severity of pain, thereby contributing to a deeper understanding of visceral pain mechanisms in the context of IBD. Mouse models were prepared as shown in FIG.16. The results of the Von Frey analysis are shown in FIG.17A to FIG.17D. The results of the Capsaicin-induced visceral pain analysis are shown in FIG.17E to FIG.17I.

[0477] Von Frey analysis was performed by using two methods: Up and down method and Nociceptive scoring using 0.008g, 0.02g and 0.16g filaments. Nootkatone showed a dose dependent anti-hyperalgesic effect in both methods. Nootkatone at 300 mg / kg BID showed significant anti-hyperalgesic activity in up and down analysis.

[0478] DSS group showed highest nociceptive behavior after capsaicin instillation in colon. Nootkatone treatment exhibited clear dose dependent reduction in nociceptive behavior. Licking and squashing of abdomen after capsaicin instillation reduced in treated group; no abdominal retraction was observed. Stretching behavior was mixed up with rearing; hence not considered for compiling total responses. Total nociceptive responses were dose dependently reduced by nootkatone.Example 19Effect of Nootkatone on Visceral Pain in a Mouse Model of TNBS-induced Colitis

[0479] The study aimed to explore the mechanisms of visceral pain in a mouse model of TNBS (2,4,6-trinitrobenzenesulfonic acid) induced colitis, a method commonly used to simulate inflammatory bowel disease (IBD) in laboratory settings. The primary focus of this research was to understand the pain pathways and their modulation in the context of IBD. To achieve this, the study employed a combination of Disease Activity Index (DAI) scoring and exposure analysis, both in plasma and colon tissues, to quantify inflammation and its systemic effects. DAI scoring, a comprehensive measure considering weight loss, stool consistency, and bleeding, provided a reliable gauge of colitis severity. Concurrently, exposure analysis in plasma and colon tissues assessed the presence and concentration of inflammatory markers, cytokines, and other biochemical indicators of inflammation. This dual approach ensured a thorough understanding of the inflammatory process at both local and systemic levels.

[0480] Behavioral parameters, specifically von Frey pain responses and capsaicin-induced pain responses, were critical components of the study to assess the sensory and pain aspects in the mouse model. The von Frey test, involving the application of calibrated filaments to measure mechanical pain sensitivity, helped in evaluating alterations in pain perception due to colitis. In contrast, the capsaicin-induced pain response test, which involved administering capsaicin (a component known to induce pain and mimic inflammatory pain in humans) and observing the pain response, provided insights into the nociceptive pathways and pain modulation in the context of colitis. These behavioral tests were crucial for correlating the extent of inflammation with the severity of pain, thereby contributing to a deeper understanding of visceral pain mechanisms in the context of IBD. Mouse models were prepared as shown in FIG.18. The results of the Von Frey analysis are shown in FIG.19A to FIG.19D. The results of the Capsaicin-induced visceral pain analysis are shown in FIG.19E to FIG.19J.

[0481] Von Frey analysis was performed by using two methods: Up and down method and Nociceptive scoring using 0.008g, 0.02g and 0.16g filaments. Nootkatone showed a dose dependent anti-hyperalgesic effect in both methods. Nootkatone at 300 mg / kg BID showed significant anti-hyperalgesic activity in both methods.

[0482] TNBS-induced colitis model mice exhibited severe visceral pain as mice spent most of the time in freezing condition after capsaicin instillation in colon. As mice were in freezing condition, they exhibited minimal and varied spontaneous pain behavior. Nootkatone showed significant dose dependent reduction in freezing behavior.

Claims

CLAIMSWhat is claimed is:

1. A method of treating or preventing pruritus in a subject in need thereof, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone, or a pharmaceutically acceptable salt thereof; optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring in a nootkatone-containing source; or (b) the nootkatone, or a 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. The method of claim 1, wherein the subject is a cat, a dog or a horse.

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

5. The method of any one of claims 1 to 4, wherein the composition has less than about 1% w / w of other components that are naturally occurring in a nootkatone-containing source, and the nootkatone, or a 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. The method of claim 8, wherein the composition comprises at least 1.5% w / w of nootkatone.

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

11. The method of claim 8, wherein the composition comprises between about 1.5% and 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 per day.

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

14. The method of claims 1 to 13, wherein the administering of the composition to the subject reduces pruritus after a predetermined amount of time as determined in accordance with the Itch Numerical Rating Scale (I-NRS).

15. The method of any one of claims 1 to 13, wherein the administering of the composition to the subject reduces pruritus as evidence by a reduction of atopic dermatitis after a predetermined amount of time as determined in accordance with the Patient Oriented Eczema Measure (POEM).

16. 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 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB; and optionally wherein: (a) the composition has less than about 5% w / w of other components that are naturally occurring in a nootkatone-containing source; or (b) the nootkatone, or a pharmaceutically acceptable salt thereof, in the composition has a purity of at least about 95% w / w, or both (a) and (b).

17. A pharmaceutical composition comprising nootkatone, or a pharmaceutically acceptable salt 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS,adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin- 1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

18. 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 channels (NaV), kappa opiate receptor (KOR), sigma 1, nNOS, adenosine A3, prostanoid EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channels, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-KB.

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

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

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

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

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