Nokatones for 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

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 430,325, filed December 5, 2022, U.S. Provisional Patent Application No. 63 / 478,666, filed January 5, 2023, U.S. Provisional Patent Application No. 63 / 478,668, filed January 5, 2023, U.S. Provisional Patent Application No. 63 / 478,669, filed January 5, 2023, U.S. Provisional Patent Application No. 63 / 478,670, filed January 5, 2023, and U.S. Provisional Patent Application No. 63 / 478,671, filed January 5, 2023. The contents of each of these patents are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] The present disclosure relates generally to nootkatones, compositions, and methods for treating various diseases and conditions, and more particularly to treating pain, pruritus, atopic dermatitis, psoriasis, diabetic dermatosis, or diabetic peripheral neuropathy. Background Art

[0004] The skin is the first line of defense against environmental aggressors that could otherwise damage the sensitive underlying tissues and organs. For example, the skin maintains a relatively impermeable barrier between the organism and its environment, preventing dehydration. Furthermore, the skin plays a key role in a person's appearance. Generally speaking, most people desire younger, healthier skin. For some of these individuals, signs of skin aging, such as thinning skin, wrinkles, and age spots, are unpleasant reminders of lost youth. Consequently, in a youth-conscious society, treating the signs of skin aging has become a booming business. Treatments range from cosmetic creams and moisturizers to various forms of cosmetic surgery.

[0005] A wide variety of natural and synthetic agents are known for use in commercially available skin care compositions to treat various skin conditions, particularly skin conditions associated with one or more diseases and disorders, such as pain, pruritus, atopic dermatitis, psoriasis, diabetic dermatosis, or diabetic peripheral neuropathy.

[0006] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to injured tissue. However, in many cases, pain persists beyond its usefulness, or patients benefit from pain suppression. Various forms of pain include, but are not limited to, chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, and idiopathic pain.

[0007] Neuropathic pain is a form of chronic pain caused by sensory nerve damage (Dieleman, JP, 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 systemic metabolic damage to the nerves and pain caused by discrete nerve damage. Metabolic neuropathy includes postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve damage indications include post-amputation pain, postoperative nerve damage pain, and nerve entrapment injuries, such as neuropathic back pain.

[0008] Abdominal pain is a common and complex health problem worldwide, impacting individual well-being. This pain can range from mild to severe and is often caused by 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 changes in bowel habits, and pain can occur in different parts of the abdomen.

[0009] Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by recurrent abdominal pain associated with bowel movements and changes in the frequency or pattern of bowel movements. Symptoms often include abdominal pain, bloating, and abdominal distension, and in severe cases can significantly reduce quality of life.

[0010] Celiac disease is an inherited autoimmune disorder triggered by the consumption of gluten. It increases intestinal permeability, allowing gluten breakdown products to trigger an inflammatory response. The disease is characterized by chronic inflammation of the small intestine, which may lead to villous atrophy and cause symptoms such as abdominal pain, malabsorption, diarrhea, bloating, and nausea.

[0011] Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a group of chronic inflammatory bowel diseases that are common in developed countries. Ulcerative colitis affects the colon, from the terminal ileum to the anus. During flare-ups, it often causes pain, bloody diarrhea, fever, and weight loss. Treatment primarily focuses on controlling inflammation, typically using expensive monoclonal antibody therapies.

[0012] Endometriosis affects 10%-15% of women of reproductive age and is characterized by the growth of uterine tissue outside the uterus, typically within the ovaries. This tissue responds to hormones from the menstrual cycle, causing inflammation and pain. Symptoms include dysmenorrhea, dyspareunia, and chronic abdominal pain, but they don't always correlate with the severity of the condition. Some women with extensive endometriosis may experience no symptoms, while those with milder forms may experience severe pain.

[0013] Pruritus is a disease involving local or systemic itching and is a common and painful symptom in a variety of diseases. Although pruritus usually occurs on the skin, it can also occur in non-skin sites such as mucous membranes. Pruritus is a common manifestation of local skin diseases caused by hypersensitivity reactions, such as allergic reactions to insect bites or environmental allergens, urticaria, skin diseases caused by fungi and bacteria, external parasitic infections and hemorrhoids. Pruritus may also be a symptom caused by systemic diseases, such as hypothyroidism, thyrotoxicosis, diabetic mucosal candidiasis and Hodgkin's disease. (See, for example, Herndon, JH Jr., Int. J. Derm. 14, 465–484 (1975); Winkelmann, RK, Med. Clins. N. Am. 66, 1119–1133 (1982). Many systemic diseases and skin diseases are accompanied by persistent or recurrent pruritus. The clinical importance of pruritus is irrefutable, but currently available treatments limit its effective treatment.

[0014] Eczema is a chronic disease that causes inflammation, redness, and irritation of the skin. Atopic dermatitis is the most common form of eczema. The cause of eczema, including atopic dermatitis, remains unclear. Atopic dermatitis is a major global public health problem, affecting 1%-20% of the world's population. The incidence of atopic dermatitis is approximately 1%-3% in adults and approximately 10%-20% in children. Atopic dermatitis is the most common form of eczema in children. Since the 1960s, the prevalence of atopic dermatitis has increased more than threefold. The reasons for the increase in prevalence are currently unclear (Lee, JH, et al. A Comprehensive Review of the Treatment of Atopic Eczema, Allergy Asthma Immunol. Res., 2016 8(3), 181-190). Atopic dermatitis is a global public health problem and brings a heavy economic burden. In addition, atopic dermatitis affects the quality of life of the patient's family and the patient himself. Eczema, including atopic dermatitis, remains a challenging condition for both physicians and patients.

[0015] Psoriasis is a clinically heterogeneous, lifelong skin disease that manifests in a variety of forms, such as plaque, flexural, guttate, pustular, or erythrodermic. An estimated 60 million people worldwide suffer from psoriasis. In 2014, the World Health Organization recognized psoriasis as a serious noncommunicable disease and highlighted the suffering associated with misdiagnosis, inappropriate treatment, and stigma of the disease. The Global Burden of Disease Study estimated that in 2016, psoriasis accounted for 5.6 million disability-adjusted life years (DALYs) across all age groups, at least three times that of inflammatory bowel disease (Raharja, A., et al. Psoriasis: a brief overview. Clin Med (Lond). 2021 May; 21(3): 170-173.).

[0016] Diabetes causes a variety of skin-related complications, including diabetic dermopathy, diabetic blisters (diabetic bullae / diabetic bullae), diabetic peripheral neuropathy (DPN), xerosis cutis (dry skin), ichthyosis-like skin changes, susceptibility to fungal infections on the feet, acanthosis nigricans, diabetes-related itching, and nerve damage (diabetic neuropathy). Diabetic dermopathy, commonly known as shin plaques, is characterized by light brown or red, oval or round, slightly indented, scaly patches that most commonly appear on the lower legs. Diabetic bullae are blister-like lesions that spontaneously appear on the feet and hands of people with diabetes. These blisters may or may not show scarring or atrophy. Xerosis refers to abnormally dry skin that appears scaly, cracked, or has a rough texture, most commonly occurring on the feet. Ichthyosis-like skin changes (fish-scale skin) are typically characterized by large, bilateral areas of dryness and scaling, especially on the hands and feet. Acanthosis nigricans is a common skin pigmentation disorder characterized by the appearance of thick, soft, dark patches on the skin. The skin in the affected area may also be itchy or have an odor. Diabetic peripheral neuropathy (DPN) is nerve damage caused by chronic high blood sugar and diabetes. DPN can cause numbness, loss of sensation, and sometimes pain in the feet, legs, or hands. Diabetes-related pruritus is more likely to occur in patients with diabetes who also have dry skin or diabetic neuropathy and is often localized to the scalp, ankles, feet, trunk, or genitals. Because of its clinical significance, healthcare providers need to understand risk factors to develop appropriate management strategies for diabetic skin complications.

[0017] Thus, there is a continuing need in the art for compounds, compositions, and methods for treating pain, pruritus, atopic dermatitis, psoriasis, diabetic dermatosis, or diabetic peripheral neuropathy, as well as a variety of other diseases and conditions. Summary of the Invention

[0018] Provided herein are methods for treating pain in a subject in need thereof. The methods comprise administering to the subject a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present 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] Provided herein are methods for treating pruritus in a subject in need thereof. The methods comprise administering to the subject a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present 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] Provided herein are methods for treating atopic dermatitis or psoriasis in a subject in need thereof. The methods comprise administering to the subject a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present 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] Provided herein are methods for treating diabetic dermatosis or diabetic peripheral neuropathy in a subject in need thereof. The methods comprise administering to the subject a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present 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] Provided herein are methods for improving the appearance of skin in a subject in need thereof. The methods comprise administering to the subject a therapeutically effective amount of nootkatone, a dermatologically acceptable salt thereof, or a derivative thereof. In some embodiments, the composition has less than about 5% (w / w) of other components naturally present 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.

[0023] Nootkatone and pharmaceutically acceptable compositions thereof can be used to treat or lessen the severity of a variety of diseases, conditions or disorders, including but not limited to pain, pruritus, atopic dermatitis, psoriasis, diabetic dermatosis or diabetic peripheral neuropathy. In various embodiments, nootkatone and pharmaceutically acceptable compositions are inhibitors or modulators of one or more of the following therapeutic targets: voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB, and thus can be used to treat or lessen the severity of a variety of diseases, conditions or disorders described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1A and 1B The results show that nootkatone blocks neuronal depolarization in mouse dorsal root ganglion (DRG) neurons. Nootkatone at 100 μM blocks neuronal depolarization in mouse capsaicin / transient receptor potential vanilloid 1 (TRPV1)-negative neurons.

[0025] Figure 2 Shown are the transient responses of human DRG to 30 mM KCl (the effect of vehicle v / s nootkadone on 30 mM KCl).

[0026] Figure 3A and 3B Nootkatone-mediated neuronal depolarization in human DRG is shown. Nootkatone was applied at 30 uM (first application) and 100 uM (second application) to observe its effect on neuronal depolarization / activity induced by electric field stimulation (EFS).

[0027] Figure 4 is a graphical representation of the effect of nootkatone in an in vivo formalin-induced pain mouse model.

[0028] Figure 5 and Figure 6 showed that nootkatone alleviated acute pain at both stages (stage 1 and stage 2 in an in vivo formalin-induced mouse model).

[0029] Figure 7 The efficacy of topically applied nootkatone in a mouse acute pain model using the tail-flick test is demonstrated.

[0030] Figure 8 It was shown that oral administration of nootkatone at 30 mpk alleviated chloroquine-induced scratching / itching in mice.

[0031] Figure 9It was demonstrated that topical application of 10% nootkatone alleviated chloroquine-induced scratching / itching in mice.

[0032] Figure 10 It was demonstrated that 100 mg / Kg PO nootkatone alleviated BAM8-22-induced scratching / itching in mice.

[0033] Figure 11 A graphical representation of the topical application of nootkatone in the MC903-induced mouse atopic dermatitis model is shown.

[0034] Figure 12 The effects of topical nootkatone in an imiquimod (IMQ)-induced psoriasis mouse model are described. Nootkatone resulted in a slight but significant decrease in cumulative PASI readings from day 1 to day 6.

[0035] Figure 13 The effects of topical nootkatone in an imiquimod (IMQ)-induced psoriasis mouse model are described. Nootkatone resulted in a slight but significant decrease in the cumulative PASI reading on day 6.

[0036] Figure 14 Shown is the study design for the effect of nootkatone on DSS-induced locomotor activity.

[0037] Figure 15A 、 15B , 15C, 15D, 15E, and 15F are graphs showing the effects of nootkatone on DSS-induced locomotor activity.

[0038] Figure 16 Study design showing the effects of nootkatone on visceral pain in a mouse model of DSS-induced colitis.

[0039] Figure 17A 、 17B , 17C, 17D, 17E, 17F, 17G, 17H, and 17I are graphical representations illustrating the effects of nootkatone on visceral pain in a mouse model of DSS-induced colitis.

[0040] Figure 18 Study design showing the effects of nootkatone on visceral pain in a TNBS-induced colitis mouse model.

[0041] Figure 19A 、 19B , 19C, 19D, 19E, 19F, 19G, 19H, 19I, and 19J are graphical representations showing the effects of nootkatone on visceral pain in a TNBS-induced colitis mouse model. DETAILED DESCRIPTION

[0042] Provided herein are compounds, compositions, and methods for treating, alleviating, or ameliorating pain, pruritus, atopic dermatitis, psoriasis, diabetic dermatosis, or diabetic peripheral neuropathy in a subject in need thereof.

[0043] Nootkatone is a sesquiterpenoid compound with the following chemical structure:

[0044]

[0045] Nootkatone is a naturally occurring compound found in many plants, such as Nardostachys jatamansi, citrus fruits such as grapefruit (Citrus paradisi), and Alaskan yellow cedar (Chamaecyparis nootkatensis). Nootkatone was originally isolated from the heartwood of Alaskan yellow cedar (Erdtman, H., Hirose, Y., 1962. The chemistry of the natural order Cupressales. 46. The structure of nootkatone. Acta Chem. Scand. 16(6), 1311-1314.). Nootkatones can be obtained by extraction and purification from natural sources (Kelsey, RG, et al., 2015. Volatile terpenoids and tropolones in heartwood extracts of yellow-cedar, Monterey cypress, and their hybrid Leyland cypress. Ann. For. Sci. 72, 349–355.), as well as by total synthesis (Marshall, JA, Ruden, RA, 1971. Stereoselective total synthesis of racemic nootkatone. J. Org. Chem. 36(4), 594–596.) and biosynthesis (Sowden, RJ, et al., 2005. Biotransformation of these squitterpene (+)-valencene by cytochrome P450cam and P450BM-3. Org. Biomol. Chem. 3(1), 57–64.).

[0046] In various embodiments, nootkatone can be synthesized, isolated, and purified from a product mixture produced from a host modified to express enzymes of the nootkatone biosynthetic pathway or from a product mixture produced from a naturally occurring source (e.g., citrus plants). In some embodiments, nootkatone can also refer to a mixture of chemical compounds containing or enriched in nootkatone compounds and derived from a modified host such as a microorganism, or isolated or derived from a plant extract. In other embodiments, nootkatone can also refer to derivatives and analogs thereof. For example, the nootkatone compounds contemplated for use herein can be produced in vivo by expressing one or more enzymes involved in the nootkatone biosynthetic pathway in recombinant yeast, or produced 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.

[0047] In certain embodiments, nootkatone is derived from the oxidation of valencene produced by fermentation (e.g., by microorganisms carrying one or more valencene synthases and / or other molecules that catalyze the formation of valencene). It will be appreciated that nootkatone can be formed as part of a combination of compounds derived from the oxidation of a valencene-containing fermentation product produced by culturing a microorganism carrying one or more valencene synthases and / or other molecules that catalyze the formation of valencene. Such a combination can be purified to maximize the percentage of nootkatone relative to the other compounds.

[0048] As used herein, "extract" generally refers to a plant extract containing material from any species within an identified genus, unless a specific species has been identified. Unless otherwise indicated, any part of a plant can be used to obtain an extract for use in a composition, including but not limited to roots, stems, rhizomes, leaves, flowers, fruits, and / or extracts of these parts. Plant extracts can be commercially available from a variety of sources. In addition, suitable plant extracts can be obtained using any conventional extraction technique, including but not limited to one or more techniques described further below.

[0049] Plant extracts can be obtained by conventional extraction methods known in the art, for example, by water (e.g., steam) extraction or by solvent (e.g., alcohol) extraction. The compositions of the present disclosure are not limited to specific extraction methods and do not need to be extracted, as suitable extracts (e.g., standardized extracts) are readily available from many commercial suppliers. Exemplary extraction methods are described below.

[0050] To obtain an extract, a polar solvent such as an alcohol (e.g., methanol, ethanol, butanediol), an ether (e.g., diethyl ether), a ketone (e.g., acetone), an ester (e.g., ethyl acetate), water, or a mixture thereof can be used as a solvent. Certain extracts can also be 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 a mixture thereof. There are a variety of extraction methods that can be used to produce extracts suitable for the composition. These methods include, but are not limited to, the extraction methods disclosed in U.S. Patent No. 7,897,184, which is hereby incorporated by reference in its entirety.

[0051] Details of the treatment methods and compositions, including dosages, dosing regimens, and kits thereof, are described in further detail below.

[0052] Pharmaceutically / dermatologically acceptable salts and compositions

[0053] As described herein, nootkatone is provided as an inhibitor or modulator of one or more of the following therapeutic targets: at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB. In association with or independent of such inhibitory or modulatory activity, nootkatone can be used to treat diseases, conditions, and disorders including, but not limited to, pruritus, chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain. In addition, in association with or independent of such inhibitory or modulatory activity, nootkatone can be used to treat diseases, conditions, and disorders including, but not limited to, atopic dermatitis or psoriasis. In addition, related to or independent of this inhibitory or modulating activity, nootkatone can be used to treat diseases, conditions, and disorders including, but not limited to, diabetic dermatosis or diabetic peripheral neuropathy. Therefore, in another aspect of the present 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.

[0054] It should also be understood that the nootkatone of the present invention may be present in free form for therapeutic use or, where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, hydrates, stereoisomers, or any other adducts or derivatives that, upon administration to a subject in need thereof, are capable of providing, directly or indirectly, nootkatone or a metabolite or residue thereof as described herein.

[0055] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, or the like, and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. "Pharmaceutically acceptable salt" refers to any non-toxic salt or ester salt of the nootkatone disclosed herein that, upon administration to a recipient, is capable of providing, directly or indirectly, nootkatone or its inhibitory active metabolite or residue. As used herein, the term "inhibitory metabolite or residue thereof" refers to a metabolite or residue thereof that is also an inhibitor or modulator of one or more therapeutic targets.

[0056] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference in its entirety. Pharmaceutically acceptable salts of nootkatone disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts 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, camphor, camphorsulfonate, citrate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconoheptate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydrogen iodide, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, isobutyrate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 The present disclosure also contemplates the quaternization of any basic nitrogen-containing group of the nootkatone disclosed herein. Water-soluble, oil-soluble, or dispersible products can be obtained by such quaternization. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts also include (where appropriate) salts formed from non-toxic ammonium, quaternary ammonium, and amine cations, which can be formed with anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates as counterions.

[0057] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents or other liquid vehicles, dispersions or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. suitable for the desired particular dosage form. Remington's Pharmaceutical Sciences, 16th edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers and known preparation techniques for pharmaceutically acceptable compositions. Unless any conventional carrier medium is incompatible with the nootkatone of the present disclosure, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, its use is encompassed within the scope of the present disclosure. Some examples of materials that can be used 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, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate. Cellulose; 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; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffers, and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

[0058] In another aspect, the present disclosure describes a pharmaceutical composition comprising nootkatone and a pharmaceutically acceptable carrier.

[0059] In another aspect, the present disclosure describes 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.

[0060] Nootkatone or its pharmaceutically acceptable salt used for the composition can be obtained from any commercial source or any method or technology known in the art. For example, in some variations, nootkatone can be isolated from a natural source. In other variations, nootkatone can be synthesized according to any method known in the art.

[0061] 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 elements / components specifically recited in a particular embodiment. In addition, the phrase "consisting essentially of generally encompasses and allows for the presence of additional or optional elements / ingredients that do not significantly affect the basic and / or novel features of a 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.

[0062] In various embodiments, the composition comprises one or more pharmaceutically acceptable additives as inactive ingredients. The example of inactive ingredient includes but is not limited to excipients, such as diluents and adhesives, granulating agents, glidants (or flow aids), fillers, lubricants, preservatives, stabilizers, coating agents, disintegrants, spices, pigments, preservatives, solvents (such as alcohol) and combinations thereof. If used to form the composition, the inactive ingredient of various amounts can be used and combined with nootkatone or its pharmaceutically acceptable salt to form a composition suitable for topical application to human or animal skin. It should also be understood that, considering the presence of inactive ingredient (if used), the amount of active substance as herein described can be standardized relative to the composition of 100 weight portions.

[0063] Optionally, said composition can include one or more other components, such as additives.Suitable additives include those understood in the art, including but not limited to wetting agents, emollients, emulsifiers, surfactants, oils, extracts, skin protectants, disinfectants, preservatives, medicines and pharmaceutical substances, analgesic compounds, anti-neuralgia compounds, antioxidants, blood circulation promoters, antidepressant compounds, antianxiety compounds, antistress compounds, sunscreens, insect repellents, preservatives, exfoliants, spices, coloring agents, fillers, solvents, vehicles, carriers, additives of other types well known to persons skilled in the art and combinations thereof.These additives can be used alone or in combination.In general, optional additives can be any type used in medicines, nutrition products, personal care products and cosmetics.

[0064] Examples of such carrier components are oils, fats, waxes, surfactants, wetting agents, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, fragrances, dyes, lower alcohols, etc. If desired, other ingredients such as anti-inflammatory agents, antibacterial agents, antifungal agents, disinfectants, vitamins, sunscreens, antibiotics, skin bleaching agents, healing promoters / fibroblast proliferation compounds, neuromuscular blocking agents, sunscreens or other anti-acne agents may be added to the composition.

[0065] Examples of oils as carriers include fats and oils such as olive oil and hydrogenated oils; waxes such as beeswax and lanolin; hydrocarbons such as liquid paraffin, ozokerite and squalene; fatty acids such as stearic acid and oleic acid; alcohols such as cetyl alcohol, stearyl alcohol, lanolin alcohol and cetyl alcohol; and esters such as isopropyl myristate, isopropyl palmitate and butyl stearate. As examples of surfactants for the carrier, there may be mentioned anionic surfactants such as sodium stearate, sodium cetyl sulfate, polyoxyethylene lauryl ether phosphate, sodium N-acyl glutamate; cationic surfactants such as stearyl dimethyl benzyl ammonium chloride and stearyl trimethyl ammonium chloride; amphoteric surfactants such as alkylaminoethyl glycine hydrochloride solution and lecithin; and nonionic surfactants such as glyceryl monostearate, sorbitan monostearate, sucrose fatty acid esters, propylene glycol monostearate, polyoxyethylene oleyl ether, polyethylene glycol monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene coconut fatty acid monoethanolamide, polyoxypropylene glycol (e.g., the material sold under the trademark "Pluronic"), polyoxyethylene castor oil, and polyoxyethylene lanolin. Examples of humectants as carriers include glycerin, 1,3-butylene glycol, and propylene glycol; examples of lower alcohols include ethanol and isopropyl alcohol; examples of thickeners include xanthan gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and sodium carboxymethyl cellulose. Examples of antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, citric acid, ethoxyquin, α-lipoic acid, vitamin C, vitamin E, coenzyme Q-10, and idebenone; plant antioxidants include carotenoids such as lycopene; flavonoids such as silymarin (milk thistle), silybin, silymarin, and silymarin; soy (isoflavins), grape seed extract; polyphenols such as green tea extract, rosmarinic acid (rosemary), hypericin (St. John's wort), oleuropein (olive leaf), curcumin (turmeric root), tetrahydrocurcumin, and pycnogenol (maritime pine bark). Examples of anti-inflammatory agents include anti-inflammatory botanicals such as allantoin, aloe vera, ginkgo biloba, and green tea (also considered an antioxidant). Examples of skin bleaching agents are hydroquinone or kojic acid. Examples of healing promoters / fibroblast proliferation compounds include copper peptides or palmitoyl pentapeptide (pal-KTTKS). Examples of neuromuscular blocking agents are argircline or dimethylaminoethanol. Examples of chelating agents include disodium edetate and ethyl hydroxydiphosphate. Examples of buffers as carriers include citric acid, sodium citrate, boric acid, borax, and disodium hydrogen phosphate; examples of preservatives are methylparaben, ethylparaben, dehydroacetic acid, salicylic acid, and benzoic acid.

[0066] As used herein, "emollient" refers to a substance used to prevent or alleviate dryness and protect the skin. It is known that a variety of suitable emollients are known and can be used herein. For example, see Sagarin, Cosmetics, Science and Technology, 2nd edition, Volume 1, pp.32-43 (1972) and U.S. Patent No. 4,919,934, granted by Deckner et al. on April 24, 1990, both of which are incorporated herein by reference in their entirety. According to various aspects of the present disclosure, a representative composition comprising an emollient may include any component suitable for providing moisture retention, reducing transepidermal water loss (TEWL), smoothness, softness, enhanced substantiveness and / or similar effects. In addition, a representative emollient composition can be used to soften or smooth the skin by reducing roughness, cracking, irritation, etc.

[0067] It should be understood that certain components or additives can be classified according to different technical terms, and just because a component or additive is classified according to such terms does not mean that they are limited to that function. If used, one or more additives can be present in the composition in different amounts. Other ingredients optionally used in the composition are described in U.S. Patent No. 5,747,006 to Dornoff et al., U.S. Patent Nos. 5,980,904, 6,994,874, 7,060,304, 7,247,321 and 7,364,759 to Leverett et al., and U.S. Publication No. 2017 / 0252293 to Brumbaugh et al., the disclosures of which are incorporated herein by reference in their entirety.

[0068] The compositions can be prepared in a variety of ways. For example, the active substance and optionally one or more inactive substances of the composition can be mixed or blended and compressed or compounded using various techniques understood in the art. The compositions of the present disclosure are not limited to a particular sequence of manufacturing steps or manufacturing methods.

[0069] The composition can be in various forms. Examples of suitable forms include solids, gels, and liquids. For example, the composition can be formulated 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 the subject's skin. The composition can be formulated for spraying into an aerosol spray or a pump spray. In another example, the composition can be formulated for application using pre-moistened wipes. In another example, the composition can be formulated into a solid that is rubbed onto the subject's skin. In another embodiment, the composition is formulated for delivery via a patch that is applied to the subject's skin.

[0070] The composition can 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 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 nootkatone, or a pharmaceutically acceptable salt thereof.

[0071] In certain variations, the compositions comprise from about 0.1% to about 20% w / w, from about 0.1% to about 15% w / w, from about 0.1% to about 5% w / w, from about 0.1% to about 3% w / w, from about 0.1% to about 1.5% w / w, from about 0.1% to about 1% w / w, from about 0.1% to about 0.75% w / w, from about 0.1% to about 0.375% w / w, from about 0.375% to about 5% w / w, from about 0.375% to about 3% w / w, from about 0.375% to about 1.5% w / w, from about 0.375% to about 1% w / w, from about 0.375% to about 0.75% w / w,

[0014] In some embodiments, the present invention provides a pharmaceutically acceptable salt of nootkatone, or a pharmaceutically acceptable salt thereof, of about 0.75% to about 5% w / w, about 0.75% to about 3% w / w, about 0.75% to about 1.5% w / w, about 0.75% to about 1% w / w, about 1% to about 5% w / w, about 1% to about 3% w / w, about 1% to about 1.5% w / w, about 1.5% to about 5% w / w, about 1.5% to about 3% w / w, about 3% to about 5% w / w, about 1% to about 15% w / w, about 2% to about 10% w / w, about 4% to about 8% w / w, about 5% to about 15% w / w, or about 8% to about 12% w / w of nootkatone, or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the composition comprises less than about 50% w / w, less than about 40% w / w, less than about 30% w / w, less than about 25% w / w, less than about 20% w / w, less than about 15% w / w, less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2% w / w, less than about 1% w / w, less than about 0.5% w / w, less than about 0.25% w / w, less than about 0.1% w / w, less than about 0.05% w / w, less than about 0.01% w / w, or less than about 0.001% w / w of other components naturally occurring in a nootkadone-containing source. In one variation, the composition has no detectable amount of other components naturally occurring in a nootkadone-containing source. In one embodiment, the mass of components other than nootkatone naturally occurring in a nootkatone-containing source in the composition is less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% of the total mass of any nootkatone in the composition.

[0073] In other embodiments, the nootkatone or pharmaceutically acceptable salt thereof is present in the composition at 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 about 100% w / w.

[0074] In some variations, the composition comprises (i) nootkatone or a pharmaceutically acceptable salt thereof; and (ii) one or more additional sesquiterpenes. In some variations, the composition comprises a sesquiterpene mixture, wherein at least one sesquiterpene is nootkatone or a pharmaceutically acceptable salt thereof.

[0075] In various embodiments, composition is in the form of gel or emulsifiable paste. In these and other embodiments, composition comprises nootkatone and pharmaceutically / cosmetically acceptable excipient. " pharmaceutically / cosmetically acceptable excipient " is the component that adds in the composition except active ingredient nootkatone. Excipient can be added to promote manufacturing, enhance stability, enhance product characteristics, enhance skin permeability, enhance patient acceptance, enhance active substance release etc. Pharmaceutically / cosmetically acceptable excipient includes but is not limited to one or more emulsifiers, gelling agents, preservatives, chelating agents, viscosity modifiers, antioxidants, surfactants, emollients, opacifiers, skin conditioners, fragrances, coloring agents, fillers, wetting agents, pH adjusting agents, acidulants, solvents, vehicles, oily vehicles, suspending agents, dispersants and any other excipient known in the art for preparing pharmaceutically / cosmetically acceptable compositions. According to the disclosure, specific excipient can bring into play multiple effects in the composition, for example, it can serve as preservative and serve as pH adjusting agent.

[0076] In some embodiments, the composition comprises nootkatone or a pharmaceutically acceptable salt thereof formulated in petrolatum. In some variations, the composition consists essentially of nootkatone or a pharmaceutically acceptable salt thereof and petrolatum. In certain variations, the composition consists of nootkatone or a pharmaceutically acceptable salt thereof and petrolatum.

[0077] In certain embodiments, nootkatone or a pharmaceutically acceptable salt thereof; and (ii) one or more additional sesquiterpenoids and / or excipients can be formulated into an aqueous gel-based composition. In these and other embodiments, the composition comprises nootkatone or a pharmaceutically acceptable salt thereof formulated in an aqueous gel-based composition. In some variations, the composition consists essentially of nootkatone or a pharmaceutically acceptable salt thereof and one or more 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.

[0078] It is contemplated herein that gel-based compositions may include active components (e.g., nootkatone), gelling agents, pH adjusting agents, solvents, antioxidants, preservatives, or combinations thereof. Based on the gross weight of the composition, the active component may be present in an amount of about 0.1% by weight to about 50% by weight, about 1% by weight to about 40% by weight, about 1% by weight to about 30% by weight, about 1% by weight to about 20% by weight, or about 2% by weight to about 10% by weight. In some embodiments, based on the gross weight of the composition, the active component may be present in an amount greater than 0.1% by weight, greater than 0.5% by weight, greater than 1% by weight, greater than 3% by weight, or greater than 4% by weight.

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

[0080] The solvent may be present in the gel-based composition in an amount of from about 50% to about 99.9% by weight, from about 70% to about 99% by weight, from about 80% to about 99% by weight, or from about 90% to about 95% by weight, based on the 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% by weight, greater than 60% by weight, greater than 70% by weight, greater than 80% by weight, or greater than 90% by weight, based on the total weight of the composition.

[0081] Preservative can provide with any amount known in the art.In some embodiments, the amount of preservative in gel base composition is about 0.001 weight % to about 3 weight %, about 0.01 weight % to about 1 weight %, about 0.01 weight % to about 0.50 weight % or about 0.15 weight % to about 0.25 weight %.In some embodiments, based on the gross weight of gel base composition, the amount of preservative in gel base composition is greater than 0.01%, greater than 0.02%, greater than 0.03%, greater than 0.04%, greater than 0.05%, greater than 0.06%, greater than 0.07%, greater than 0.08%, greater than 0.09%, greater than 0.1%, greater than 0.11%, greater than 0.12%, greater than 0.13%, greater than 0.14%, greater than 0.16%, greater than 0.16%, greater than 0.17% or greater than 0.18%.

[0082] The pH adjusting agent may be present in the gel-based composition in an amount of about 0.1% to about 10% by weight, about 0.1% to about 5% by weight, about 0.5% to about 3% by weight, or about 0.5% to about 2% by weight, based on the 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%, greater than 0.2%, greater than 0.3%, greater than 0.4%, or greater than 0.5% by weight, based on the total weight of the composition.

[0083] Antioxidants can be provided in any suitable amount. In some embodiments, the amount of the antioxidant in the gel-based composition is from about 0.001 % by weight to about 3 % by weight, from about 0.01 % by weight to about 1 % by weight, from about 0.01 % by weight to about 0.50 % by weight, or from about 0.05 % by weight to about 0.15 % by weight. In some embodiments, the amount of the antioxidant in the gel-based composition is 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 the gross weight of the gel-based composition.

[0084] In other embodiments, nootkatone or a pharmaceutically acceptable salt thereof; and (ii) one or more additional sesquiterpenoids and / or excipients can be formulated as a cream-based composition. In these and other embodiments, the composition comprises nootkatone or a pharmaceutically acceptable salt thereof formulated in a cream-based composition. In some variations, the composition consists essentially of nootkatone or a pharmaceutically acceptable salt thereof and one or more excipients of a cream-based composition. In certain variations, the composition consists of nootkatone or a pharmaceutically acceptable salt thereof and one or more excipients of a cream-based composition.

[0085] It is contemplated herein that a cream-based composition may include an active ingredient (e.g., nootkatone), an emulsifier, an emollient, a solvent, an antioxidant, a preservative, or a combination thereof. Based on the gross weight of the composition, the active ingredient may be present in the composition in an amount of about 0.1% to about 50% by weight, about 1% to about 40% by weight, about 1% to about 30% by weight, about 1% to about 20% by weight, or about 2% to about 10% by weight. In some embodiments, the active ingredient may be present in the cream-based composition in an amount greater than 0.1% by weight, greater than 0.5% by weight, greater than 1% by weight, greater than 3% by weight, or greater than 4% by weight, based on the gross weight of the composition.

[0086] The emulsifier may be present in the cream-based composition in an amount of about 0.1% to about 50% by weight, about 1% to about 25% by weight, about 2% to about 20% by weight, or about 8% to about 12% by weight, based on the 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%, greater than 1%, greater than 5%, greater than 6%, or greater than 8% by weight, based on the total weight of the composition.

[0087] The emollient may be present in the cream-based composition in an amount of from about 0.1% to about 50%, from about 1% to about 25%, from about 2% to about 20%, or from about 8% to about 12% by weight, based on the 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%, greater than 1%, greater than 5%, greater than 6%, or greater than 8% by weight, based on the total weight of the composition.

[0088] The solvent may be present in the cream-based composition in an amount of from about 40% to about 99.9% by weight, from about 50% to about 90% by weight, from about 60% to about 85% by weight, or from about 70% to about 80% by weight, based on the 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%, greater than 50%, greater than 60%, greater than 65%, or greater than 70% by weight, based on the total weight of the composition.

[0089] The preservative can 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 about 0.001% to about 3% by weight, about 0.01% to about 1% by weight, about 0.01% to about 0.50% by weight, or about 0.20% to about 0.30% by weight. 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%, 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 the total weight of the cream-based composition.

[0090] Antioxidants can be provided in any suitable amount. In some embodiments, the amount of the antioxidant in the gel-based composition is from about 0.001 % by weight to about 3 % by weight, from about 0.01 % by weight to about 1 % by weight, from about 0.01 % by weight to about 0.50 % by weight, or from about 0.05 % by weight to about 0.15 % by weight. In some embodiments, the amount of the antioxidant in the gel-based composition is 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 the gross weight of the gel-based composition.

[0091] As noted above, gel-based or cream-based compositions contemplated herein may include an active ingredient (eg, nootkatone), a gelling agent, an emulsifier, an emollient, a pH adjuster, a solvent, an antioxidant, a preservative, or a combination thereof.

[0092] Gelling agents that can be used in the composition include polysaccharides (carrageenan, alginate), proteins (gelatin), cellulose derivatives (hydroxypropyl cellulose, hydroxyethyl cellulose), acrylic acid polymers (carbomer, carbomer), clays (bentonite, hectorite), polyacrylamide (Sepigel 305), hydrocarbon gels (polybutene, hydrogenated polydecene), silica (hydrophobic fumed silica, silicified silica), 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 can be made from a carboxyvinyl polymer (e.g., carbomer). Non-limiting examples of carbomers include Carbomer 981, Carbomer ETD 2020, Carbomer 980, Carbomer Ultrez 10, Pemulen TR1, Hydroxyethyl Acrylate / Sodium Acryloyldimethyl Taurate Copolymer (e.g., Sepineo TM Derm), Acrylamide / Sodium Acryloyldimethyl Taurate Copolymer / Isohexadecane, Polysorbate 80 (e.g. Sepineo TM P 600 or Simulgel TM 600), or a combination thereof. Other gelling agents can be made from cellulose derivatives (e.g., hydroxypropyl methylcellulose or hydroxyethyl cellulose), xanthan gum, aluminum / magnesium silicate (e.g., Veegum K or Veegum Ultra), guar gum, polyacrylamide (e.g., a mixture of polyacrylamide / C13-14 isoparaffin / laureth-7), acrylamide, AMPS copolymer dispersion 40% / isohexadecane, modified starch (e.g., structured Solanace), or a combination thereof. In an exemplary embodiment, the gelling agent includes a carbomer, such as Carbopol Ultrez 10.

[0093] The pH adjusting agent can include an organic acid, an inorganic base (neutralizing base), a buffer system or a combination thereof. The limiting examples of suitable organic acid include citric acid, lactic acid, acetic acid or a combination thereof. The limiting examples of inorganic base include sodium hydroxide (NaOH), potassium hydroxide (KOH), ammonium hydroxide or a combination thereof. The limiting examples of suitable buffer system include citric acid / monosodium citrate (citrate buffer), acetic acid / sodium acetate (acetate buffer), phosphate buffer or a combination thereof. In an exemplary embodiment, the pH adjusting agent includes an inorganic base, such as NaOH.

[0094] A variety of solvents can be used in the composition, each with different properties and functions (e.g., penetration enhancement, preservation, emulsification, etc.). The broad chemical composition of solvents suitable for cosmetic gels includes water, alcohols (e.g., ethanol or isopropyl alcohol), ethers (e.g., diethylene glycol monoethyl ether, ethyl ether, or ethoxydiglycol), esters (e.g., ethyl acetate, isopropyl myristate), hydrocarbons (e.g., mineral oil, isododecane), glycols (e.g., diethylene glycol, propylene glycol, or butylene glycol), and silicones (e.g., polydimethylsiloxane or cyclopentasiloxane). These solvents have a variety of properties, including volatility, polarity, permeability, diffusivity, solubility, evaporation rate, and texture, and formulators can select the most suitable solvent based on the desired properties of the gel-based or cream-based composition. In exemplary embodiments, the solvents include water, alcohols (e.g., ethanol), ethers (e.g., diethylene glycol monoethyl ether), glycols (e.g., propylene glycol), and esters (e.g., isopropyl myristate). In various embodiments, glycols can also serve as emulsifiers or preservatives. In many embodiments, ethers can also serve as hydrophobic oils. In various embodiments, esters may also serve as penetration enhancers.

[0095] The embodiments are not limited by the number or type of preservatives used in the compositions described herein. For example, the preservatives used in the embodiments may include, but are not limited to, pentanediol, ethylenediaminetetraacetic acid (EDTA) and its salts, chlorhexidine and its diacetate, dihydrochloride, digluconate derivatives, 1,1,1-trichloro-2-methyl-2-propanol, para-chloro-meta-xylenol, polyhexamethylene biguanide hydrochloride, dehydroacetic acid, diazolidinyl urea, 2,4-dichlorobenzyl alcohol, 4,4-dimethyl-1,3-oxazolidine, formaldehyde, glutaraldehyde, dimethylhydantoin, imidazolidinyl urea, 5-chloro-2-methyl-4-isothiazolin-3-one, o-phenylphenol, benzyl alcohol, benzoic acid and its salts, 4-hydroxybenzoic acid and its methyl, ethyl, propyl, isopropyl Ester, butyl ester, isobutyl ester (parabens), methylparaben, propylparaben, isopropylparaben, isobutylparaben, butylparaben, ethylparaben, triclosan, 2-phenoxyethanol, phenylmercuric acetate, quaternium-15, methyl salicylate, salicylic acid and its salts, sorbic acid and its salts, iodopropynyl butylcarbamate, calcium sorbate, zinc pyrithione, 5-bromo-S-nitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol, sulfites, bisulfites and benzalkonium chloride, phenoxyethanol, 2-phenoxyethanol, chloroxylenol, diazolidinyl urea, and combinations thereof. In an exemplary embodiment, the composition includes methylparaben, propylparaben, or a combination thereof.

[0096] A variety of antioxidants can be used in the composition. Examples of suitable antioxidants include, but are not limited to, amino acids (such as glycine, histidine, tyrosine, tryptophan and its derivatives), imidazoles (such as urocanic acid and its derivatives), peptides (such as D, L-carnosine, D-carnosine, L-carnosine) and their derivatives (such as anserine), carotenoids, carotenes (such as α-carotene, β-carotene, lycopene) and their derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (such as dihydrolipoic acid), gold Thioglucose, propylthiouracil and other thiols (such as thioredoxin, glutathione, cysteine, cystine, cystamine), sugar esters and salts thereof, N-acetyl esters and salts thereof, methyl esters and salts thereof, ethyl esters and salts thereof, propyl esters and salts thereof, amyl esters and salts thereof, butyl esters and salts thereof, lauryl esters and salts thereof, palmitoyl esters and salts thereof, oleyl esters and salts thereof, α-linoleyl esters and salts thereof, cholesterol esters and salts thereof and glycerol esters and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (such as esters, ethers, peptides, lipids, nucleotides, nucleosides and salts thereof), sulfoximine compounds (such as buthionine sulfoximine, homocysteine ​​sulfoximine, buthionine sulfone, penthionine sulfoximine, hexathionine sulfoximine, heptathionine sulfoximine), unsaturated fatty acids and their derivatives (such as α-linolenic acid, linoleic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol and their derivatives, vitamin C and its derivatives (such as ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and its derivatives (such as vitamin E Acetate), vitamin A and derivatives (such as vitamin A palmitate), vitamin B and derivatives thereof, coniferyl benzoate of benzoin, retinoic acid and derivatives thereof, α-glucosylrutin, ferulic acid, furfural, carnosine, butylated hydroxytoluene, trihydroxypropyl phenyl ketone, uric acid and derivatives thereof, mannose and derivatives thereof, superoxide dismutase, zinc and derivatives thereof (such as ZnO, ZnSO4), selenium and derivatives thereof (such as methionine selenium), stilbene and derivatives thereof (such as stilbene oxide, trans-stilbene oxide), etc. In certain embodiments, the one or more antioxidants may include vitamin B, nordihydroguaiaretic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, isoascorbic acid, sodium isoascorbate, ascorbyl palmitate and ascorbyl stearate. In an exemplary embodiment, the antioxidant includes BHT.

[0097] In some embodiments, the composition may include an emulsifier or emulsifiers. Emulsifiers can be provided to adjust the properties of the cream-based composition, such as density, viscosity, melting point and / or droplet size; and in some embodiments, emulsifiers can increase the stability of the cream-based composition. Various emulsions suitable for the 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 the various embodiments may include any emulsifier or combination of emulsifiers. For example, in some embodiments, the cream-based composition can be a common oil-in-water or water-in-oil emulsion, including nootkatone and water or one or more common oils, such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, soybean oil, mineral oil, and sesame oil. In other embodiments, the cream-based composition may include one or more emulsifiers, such as mixtures of cetyl (C16) and stearyl (C18) fatty alcohols with anionic emulsifiers, sesquioleates (e.g., sorbitan sesquioleate or polyglyceryl-2-sesquioleate), ethoxylated esters of natural oil derivatives (e.g., polyethoxylated esters of hydrogenated castor oil), silicone emulsifiers (e.g., silicone polyols), anionic emulsifiers, fatty acid soaps (e.g., potassium stearate) and fatty acid sulfates (e.g., sodium cetearyl sulfate), ethoxylated fatty alcohols, sorbitan esters, ethoxylated sorbitan esters, ethoxylated fatty acid esters (e.g., ethoxylated stearate), ethoxylated mono-, di-, and triglycerides, nonionic self-emulsifying waxes, ethoxylated fatty acids, methyl glucose esters such as polyglyceryl-3 methylglucose distearate, and mixtures thereof. In an exemplary embodiment, the emulsifier may be a mixture of cetyl (C16) and stearyl (C18) fatty alcohols and an anionic emulsifier commercially available under the trade name Kolliphor CSA from BASF.

[0098] The cream-based compositions of various embodiments may include a chelating agent or a combination of chelating agents. Examples of chelating agents useful in various embodiments include, but are not limited to, alanine, sodium polyphosphate, sodium metaphosphate, citric acid, phosphoric acid, tartaric acid, ethylenediaminetetraacetic acid (EDTA) and derivatives and their salts, dihydroxyethylglycine, and mixtures thereof. In particular embodiments, the chelating agent may be EDTA or disodium EDTA dihydrate.

[0099] In some embodiments, the cream-based composition may include one or more viscosity modifiers. The viscosity modifiers of such embodiments may generally include high molecular weight compounds, such as carboxyvinyl polymers, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxyethyl cellulose, methyl cellulose, natural gums (such as gelatin and tragacanth) and various alcohols (such as polyvinyl alcohol). In other embodiments, the viscosity modifier may include ethanol or isopropanol. In some embodiments, the viscosity modifier may be a high molecular weight saturated and unsaturated fatty alcohol, such as, but not limited to, carbitol, lauryl alcohol, myristyl alcohol, cetyl alcohol, isocetyl alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearic acid, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, erucyl alcohol, 2-octyldodecanol, cetearyl alcohol, lanolin alcohol, etc., and in certain embodiments, the viscosity modifier may be oleyl alcohol.

[0100] In some embodiments, the cream-based compositions described herein may include one or more surfactants. Such embodiments are not limited to the type of surfactant used. For example, in some embodiments, one or more surfactants may be anionic surfactants, such as alkyl sulfates, alkyl ether sulfates, alkyl sulfonates, alkyl aryl sulfonates, alkyl succinates, alkyl sulfosuccinates, N-alkoxy sarcosinates, acyl taurates, acyl isethionates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, α-olefin sulfonates, and alkali metal salts and alkaline earth metal salts and their ammonium salts and triethanolamine salts. Such alkyl ether sulfates, alkyl ether phosphates, and alkyl ether carboxylates may have 1 to 10 ethylene oxide or propylene oxide units per molecule, and in some embodiments, have 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 laurylbenzenesulfonate, triethanolamine laurylbenzenesulfonate. In other embodiments, one or more surfactants may be amphoteric surfactants, such as, for example, alkyl betaines, alkylaminopropyl betaines, alkyl sulfobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphoacetates or α-propionates, alkyl amphodiacetates or α-dipropionates, and more specifically cocodimethyl sulfopropyl betaine, lauryl betaine, cocamidopropyl betaine, or sodium cocoamphopropionate.

[0101] In certain embodiments, one or more surfactants may be nonionic surfactants such as, for example, the reaction products of aliphatic alcohols or alkylphenols having from 6 to 20 carbon atoms in the linear or branched alkyl group with ethylene oxide and / or propylene oxide, wherein the alkylene oxide may be present in an amount of from about 6 moles to about 60 moles per mole of alcohol. In certain embodiments, the nonionic surfactants may include alkylamines, monoalkylalkanolamides and dialkylalkanolamides, fatty acid esters of polyethylene glycol, ethoxylated fatty acid amides, saturated fatty acid alcohols reacted with ethylene oxide, alkyl polyglycosides, and sorbitan ether esters, and in some embodiments, the nonionic surfactants 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-19, ceteareth-20, ceteareth-21, ceteareth-22, ceteareth-23, ceteareth-24, ceteareth-25, ceteareth-26, ceteareth-27, ceteareth-28, ceteareth-29, ceteareth-30, ceteareth-31, ceteareth-32, ceteareth-33, ceteareth-34, ceteareth-35, ceteareth-36, ceteareth-37, ceteareth-38, ceteareth-39, ceteareth-40, ceteareth-41, ceteareth-42, ceteareth-43, ceteareth-44, ceteareth-45, ceteareth-46, ceteareth-47, ceteareth-48, ceteareth-49, ceteareth-50, ceteareth-51, ceteareth-52, ceteareth-53, ceteareth-54 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, etc. or a combination thereof, or one or more Ceteareths in combination with fatty acid alcohols (such as stearyl alcohol, oleyl alcohol, linolenic alcohol, arachidyl alcohol, cetyl alcohol), etc. In certain embodiments, the one or more surfactants may be commercially available Ceteareth-50 containing surfactants, such as CREMOPHOR CREMOPHOR CREMPHOR or a combination thereof.

[0102] In some embodiments, the cream-based composition may include one or more emollients. Typically, the emollient acts to activate the cream-based composition and to maintain the active agent on the skin surface or in the stratum corneum by spreading it. Emollients are well known in the art and are listed, for example, in the International Cosmetic Ingredient Dictionary, 8th Edition, 2000, which is hereby incorporated by reference in its entirety. In certain embodiments, the one or more emollients 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 triglyceride, cetyl lactate, cetyl palmitate, hydrogenated castor oil, glycerides, hydroxycetanol isostearate, hydroxycetanol phosphate, isopropyl isostearate, isostearyl isostearate, diisopropyl sebacate, polyoxypropylene (5) polyoxyethylene (20) cetyl ether (PPG-5-ceteth-20), 2-ethylhexyl isononanoate, 2-ethylhexyl stearate, C12 to C16 fatty alcohols, C12 to C16 fatty alcohol lactates, propyl 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 can be a mixture of the following: cetyl and stearyl alcohols (fatty alcohols), isopropyl myristate, 1-cetyl alcohol, acetylated lanolin, behenocyl dimethicone, C12-15 alkyl benzoate, cetearyl octanoate, cocoglycerides, dicaprylate / dicaprate dimethicone copolyol, In some embodiments, the emollients include but are not limited to: disodium EDTA, ...

[0103] In certain embodiments, the cream-based composition may include one or more opacifiers. The opacifier provides color or white to the composition, which can additionally eliminate undesirable colors that would otherwise be present. In some embodiments, components such as emollients, surfactants, and / or emulsifiers can provide sufficient opacity. In other embodiments, one or more additional opacifiers may be provided to the cream-based composition. Opacifiers are known in the art and include, but are not limited to, higher fatty alcohols (such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol, arachidyl alcohol, and behenyl alcohol), solid esters (such as cetyl palmitate, glyceryl laurate, stearamide MEA-stearate), high molecular weight fatty amides and alkanolamides, and various fatty acid derivatives such as propylene glycol esters and polyethylene glycol esters. In other embodiments, the opacifier may include inorganic substances, such as, for example, magnesium aluminum silicate, zinc oxide, titanium dioxide, or other sunscreens.

[0104] In some embodiments, the cream-based composition may include one or more skin conditioners. Skin conditioners are components that can generally improve skin moisture retention, slow skin moisture evaporation, and cause skin plasticization / softening. Common skin conditioners include, for example, mineral oil, petrolatum, aliphatic alcohols, lanolin and derivatives thereof, fatty acids, glycol fatty acids, sugars, glycerol, propylene glycol, sorbitol and polyethylene glycol, vitamins, and herb derivatives. Additional skin conditioners can be found in the CTFA Cosmetic Ingredient Handbook, 1st edition, 1988, which is hereby incorporated by reference in its entirety. In some embodiments, the one or more skin conditioning agents 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 protein, hydrolyzed keratin, amino acids, amine oxides, water-soluble derivatives of vitamins A, E and D, amino-functional (poly)silicone, ethoxylated glycerin, alpha-hydroxy acids and their salts, water-soluble fatty oil derivatives (such as PEG-24 hydrogenated lanolin, almond oil, grapeseed oil and castor oil); various other water-soluble skin conditioning agents listed, and mixtures thereof. In certain embodiments, skin conditioning agents may include lanolin or lanolin derivatives, caprylic / capric triglyceride, diisopropyl adipate, and combinations thereof.

[0105] In certain embodiments, cream-based composition comprises oil phase, aqueous phase and nootkatone.The amount of oil phase can be about 5 % by weight to about 50 % by weight, or about 10 % by weight to about 45 % by weight, or about 15 % by weight to about 40 % by weight, or about 20 % by weight to about 30 % by weight.The amount of aqueous phase can be about 10 % by weight to about 70 % by weight, or about 20 % by weight to about 60 % by weight, or about 25 % by weight to about 55 % by weight, or about 30 % by weight to about 45 % by weight.The amount of nootkatone (or its isomer) can be about 0.1 % by weight to about 30 % by weight, or about 1 % by weight to about 20 % by weight, or about 1 % by weight to about 10 % by weight.

[0106] In these and other embodiments, the oil phase comprises one or more emulsifiers and / or emollients, such as a mixture of cetyl (C16) and stearyl (C18) fatty alcohols and anionic emulsifiers, isopropyl myristate, white petrolatum, or a combination thereof. The aqueous phase comprises water. The cream-based composition may also include additional emulsifiers, such as diethylene glycol monoethyl ether. The cream-based formulation may also include an antioxidant, such as BHT. The cream-based composition may also include a preservative, such as methylparaben, propylparaben, or a combination thereof.

[0107] Uses of compounds, pharmaceutically acceptable salts, and compositions

[0108] Nootkatone and pharmaceutically acceptable compositions thereof can be used to treat or lessen the severity of a variety of diseases, conditions or disorders, including but not limited to pain, pruritus, atopic dermatitis, psoriasis, diabetic dermatosis or diabetic peripheral neuropathy. In various embodiments, nootkatone and pharmaceutically acceptable compositions are inhibitors or modulators of one or more of the following therapeutic targets: voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB, and thus can be used to treat or lessen the severity of a variety of diseases, conditions or disorders described herein.

[0109] In various embodiments, the terms "inhibit" and "modulate" are used interchangeably to refer to agents that reduce or inhibit biological activity, such as inhibiting the activity of ion channels (e.g., NaV1.7). NaV1.7 inhibitors include inhibitors having any combination of structural and / or functional properties disclosed herein.

[0110] In certain embodiments, nootkatone or a pharmaceutically acceptable salt thereof inhibits or modulates one or more therapeutic targets, and its IC 50Less than 50 micromolar (μM), optionally less than 40 μM, optionally less than 30 μM, optionally less than 20 μM, optionally less than 10 μM or optionally less than 1 μM. Alternatively, nootkatone or a pharmaceutically acceptable salt thereof inhibits or modulates one or more therapeutic targets with an IC 50 From about 0.01 μM to about 100 μM, optionally from about 0.1 μM to about 75 μM, optionally from about 1 μM to about 50 μM, optionally from about 1 μM to about 25 μM, or optionally from about 1 μM to about 10 μM.

[0111] In some embodiments, "treating" refers to curative or disease-modifying treatment, including treatment of patients at risk for or suspected of contracting a disease, as well as patients who are ill or have been diagnosed with a disease or medical condition, and includes inhibiting clinical relapse. In these and other embodiments, "treating" or "treating" refers to obtaining a beneficial or desired result, such as a clinical result, in a subject, including: (1) alleviating one or more symptoms caused by or associated with a disease, disorder, or condition; (2) reducing the extent of the disease, disorder, or condition; (3) slowing or halting the development or progression of one or more symptoms caused by or associated with a disease, disorder, or condition (e.g., stabilizing the disease, disorder, or condition); and (4) alleviating the disease, for example, by causing regression of one or more clinical symptoms (e.g., improving the disease state, enhancing the effect of another drug, delaying or halting the progression of the disease, and / or improving the quality of life).

[0112] In some embodiments, the method comprises administering nootkatone or a pharmaceutically acceptable salt thereof in an excipient to a subject 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 nootkatone or a pharmaceutically acceptable salt thereof in a single dosage unit. Therefore, a preferred oral single dosage unit (or recommended daily intake) 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.

[0113] 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 healthcare professional (e.g., physician, nurse, etc.), and indirect administration includes the step of providing or making available the pharmaceutical composition or drug to the healthcare professional for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.).

[0114] In some variations, the method comprises administering to a subject a nootkatone or a pharmaceutically acceptable salt thereof in an excipient formulation (e.g., petrolatum, a gel-based formulation, or a cream-based formulation) to form a composition comprising at least about 0.375% w / w, at least about 0.75% w / w, at least about 1% w / w, at least about 1.5% w / w, at least about 3% w / w, at least 4% w / w, at least 5% w / w, at least 6% w / w, at least 7% w / w, at least 8% w / w, at least 9% w / w, at least 10% w / w, at least 11% w / w, at least 12% w / w, at least 13% w / w, at least 14% w / w, at least 15% w / w, at least 16% w / w, at least 17% w / w, at least 18% w / w, at least 19% w / w, at least 20% w / w, or even more 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 nootkatone, or a pharmaceutically acceptable salt thereof.

[0115] In various embodiments, the amount of composition administered to a subject is based on a square centimeter (cm 2 ) skin area. The composition can be administered to a subject in an amount of at least 0.01 mg / cm 2 (mg nootkatone / cm 2 Skin), at least 0.02 mg / cm 2 , at least 0.03mg / cm 2 , at least 0.04mg / cm 2 , at least 0.05mg / cm 2 , at least 0.06mg / cm 2 , at least 0.07mg / cm 2 , at least 0.08mg / cm 2 , at least 0.09 mg / cm 2 , at least 0.1mg / cm 2 , at least 0.12mg / cm 2 , at least 0.14mg / cm 2 , at least 0.16mg / cm 2 , at least 0.18mg / cm 2, at least 0.2mg / cm 2 , at least 0.22mg / cm 2 , at least 0.24mg / cm 2 , at least 0.26mg / cm 2 , at least 0.28mg / cm 2 , at least 0.3mg / cm 2 , at least 0.32mg / cm 2 , at least 0.34mg / cm 2 , at least 0.36mg / cm 2 , at least 0.3 8mg / cm 2 , at least 0.4 mg / cm 2 Or even higher. The composition can be administered to a subject in an amount of about 0.01 mg / cm 2 to about 0.4 mg / cm 2 , about 0.05mg / cm 2 to about 0.3 mg / cm 2 , about 0.1mg / cm 2 to about 3 mg / cm 2 or about 0.15 mg / cm 2 to about 0.25 mg / cm 2 .

[0116] The composition can be applied daily, several times a day, or in any suitable manner to achieve the desired result. In the methods of the present disclosure, the frequency of application (e.g., topical application) can depend on several factors, including the severity of the disease condition (e.g., pain, itching, or the same symptoms) or the desired relief level of the symptom. Typically, the regimen includes applying the composition once or twice a day, including applying in the morning and / or applying in the evening. The amount and / or frequency of application of the composition depend on several factors, including the level and specific composition of the desired result. In some embodiments, the composition is applied once a day. In other embodiments, the composition is applied twice a day. In other embodiments, the composition is applied three times a day. In other embodiments, the composition is applied four times a day. However, it should be understood that the composition can be applied more than four times a day.

[0117] In some variations, the composition is used 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 some variations, the composition is used 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 used for about 1 week to about 1 year, about 4 weeks to about 8 weeks, about 4 weeks to about 12 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 32 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 48 weeks, or about 4 weeks to about 1 year.

[0118] Nootkatone or its pharmaceutically acceptable salt or its pharmaceutical composition can be administered as described herein. In some embodiments, the composition is administered topically to the subject. In other embodiments, the composition is administered orally.

[0119] In another aspect, the present disclosure describes a method of inhibiting a therapeutic target in a subject, such as at least one of a voltage-gated sodium channel (NaV), a kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, a norepinephrine transporter, a neurokinin-1 receptor (NK1R), an ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB, comprising administering to the subject a nootkatone or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In various embodiments, the nootkatone does not inhibit NaV1.5. In some embodiments, the phrase "does not inhibit" with respect to NaV1.5 refers to the nootkatone or a pharmaceutically acceptable salt thereof inhibiting NaV1.5 with an IC greater than 100 micromolar (μM). 50 Inhibits NaV1.5.

[0120] pain

[0121] In yet another aspect, the present disclosure describes a method for treating or lessening the severity of chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain in a subject, the method comprising administering an effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone or a pharmaceutically acceptable salt thereof.

[0122] In yet another aspect, the present disclosure features a method of treating or lessening the severity of intestinal or abdominal pain in a subject, wherein the intestinal or abdominal pain comprises irritable bowel syndrome (IBS) pain, celiac disease pain, inflammatory bowel disease (IBD) pain such as Crohn's disease pain or ulcerative colitis pain, endometriosis pain, or interstitial cystitis pain, 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 can cause intestinal or abdominal pain include acute cholecystitis, lactose intolerance, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), small intestinal bacterial overgrowth (SIBO), hiatal hernia, intestinal parasites such as giardiasis, food poisoning, constipation, irritable bowel syndrome (IBS), gastroenteritis (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 aneurysms, adhesions (bands of scar tissue in the abdomen), Meckel's diverticulum, Zollinger-Ellison syndrome, intussusception (common in children), Hirschsprung's disease (in children), porphyria, appendicitis (neutropenic enterocolitis), gastroesophageal reflux disease (GERD), gastritis, peptic ulcer, celiac disease, food intolerance or allergy, gallstones, pancreatitis, liver disease (such as hepatitis), kidney stones, urinary tract infection (UTI), diverticulitis, appendicitis, endometriosis, ovarian cysts, ectopic pregnancy, hernia, intestinal obstruction, and mesenteric ischemia. Each of these conditions can present with different symptoms, making accurate diagnosis crucial for effective treatment.

[0123] In yet another aspect, the present disclosure features a method for treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises postherpetic neuralgia, diabetic neuropathy, HIV-associated painful sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain following spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalus, wherein the method comprises administering an effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0124] In yet another aspect, the present disclosure features a method of treating or lessening the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burning pain, or toothache, wherein the method comprises administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0125] In yet another aspect, the present disclosure features a method for treating or lessening the severity of inflammatory pain, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia, wherein the method comprises administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0126] In yet another aspect, the present disclosure features a method of treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia, wherein the method comprises administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0127] In yet another aspect, the present disclosure describes a method wherein a subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or after treatment with a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0128] In another aspect, the present disclosure describes a method of inhibiting a therapeutic target in a subject, such as at least one of a voltage-gated sodium channel (NaV), a kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, a norepinephrine transporter, a neurokinin-1 receptor (NK1R), an ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB, comprising administering to the subject a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone. In various embodiments, the nootkatone does not inhibit NaV1.5.

[0129] In another aspect, the present disclosure describes a method of inhibiting a therapeutic target in a biological sample, such as at least one of a voltage-gated sodium channel (NaV), a kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, a norepinephrine transporter, a neurokinin-1 receptor (NK1R), an ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB, the method 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, the nootkatone does not inhibit NaV1.5.

[0130] In another aspect, the present disclosure features a method for treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, an epileptic disorder, a neurodegenerative disorder, a psychiatric disorder, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorder, neuroendocrine disease, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal dysmotility in a subject, comprising administering an effective amount of a nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a nootkatone.

[0131] In another aspect, the present disclosure describes a method of treating or lessening the severity of the following conditions in a subject: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; irritable bowel syndrome (IBS) pain; chronic and acute headaches; migraines; tension headaches; cluster headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV Related neuropathies; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injuries; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom limb pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; arthralgia; mechanical low back pain; neck pain; tendonitis; Injury / sports pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic, acute obstetric pain, labor pain; cesarean section pain; acute inflammation, burns, and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; maxillofacial pain; sinusitis pain; toothache; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behcet's disease pain; obesity dolorosa; static Pain caused by inflammatory bowel disease; pain in Guillain-Barré syndrome; leg pain and toe movement; Haglund's syndrome; erythromelalgia; pain in Fabry disease; bladder and genitourinary disorders; urinary incontinence; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), types I and II; widespread pain, paroxysmal excruciating pain, pruritus, tinnitus, or angina-induced pain, comprising administering an effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of nootkatone.

[0132] In another aspect, the present disclosure describes a method for treating or reducing the severity of neuropathic pain in a subject comprising administering a therapeutically effective amount of nootkatone, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuropathy, HIV-associated painful sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain following spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalus.

[0133] In some embodiments, a "therapeutically effective amount" refers to an amount that is effective in treating a disease when administered to a subject, for example, a therapeutically effective amount can be an amount sufficient to treat pain. A therapeutically effective amount can be determined experimentally.

[0134] In some embodiments, the composition is administered orally, vaginally, rectally, or by inhalation to a subject suffering from pain or one or more symptoms of pain. In another embodiment, the composition is administered orally, vaginally, rectally, or by inhalation to a subject who may anticipate experiencing pain or anticipate experiencing one or more symptoms of pain but is not yet experiencing pain or one or more symptoms of pain.

[0135] In some embodiments, the composition is applied to at least a portion of the body of a subject who may be suffering from pain or one or more pain symptoms. In some embodiments, the composition is applied to at least a portion of the hands, arms, legs, face and neck, or torso of a subject where the subject may be suffering from pain or one or more pain symptoms. In another embodiment, the composition is applied to at least a portion of the body of a subject where the subject may be suffering from pain or one or more pain symptoms. In another embodiment, the composition is applied to at least a portion of the body where the subject may be expected to suffer from pain, or to anticipate one or more pain symptoms, but has not yet suffered from pain or one or more pain symptoms.

[0136] In one aspect, a method of alleviating pain in a subject is provided, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In some embodiments, pain is assessed on a Likert scale of 0 to 10, where 0 corresponds to no pain and 10 corresponds to the worst pain imaginable. In some embodiments, pain is assessed based on the subject's experience within the past 24 hours. In some embodiments, pain is assessed 7 days, 14 days, 21 days, or 28 days after 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 relative to the subject's baseline assessment of pain before administering the composition. In some embodiments, the method comprises reducing the pain by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% relative to the subject's baseline assessment of pain before administering the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce the pain assessed relative to the subject's baseline assessment of pain before administering the composition 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. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce the pain relative to the subject's baseline assessment of pain before administering the composition by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. In various embodiments, pain is assessed based on the IBS Symptom Severity Scale, the Brief Pain Inventory, the Visceral Sensitivity Index, the Pain Numerical Rating Scale (P-NRS), the Disease Impact Scale, the Pain Disability Index, the Pain Catastrophizing Scale, the McGill Pain Questionnaire, or a combination thereof. In certain embodiments, pain is assessed based on the Pain Numerical Rating Scale (P-NRS) described herein.

[0137] In some variations of the above, the subject is formally diagnosed or clinically diagnosed with pain.

[0138] itching

[0139] In some aspects, methods are provided 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.

[0140] In the context of this disclosure, the term "pruritus" is intended to be interchangeable with the term "itch" and defines a well-known sensory state associated with the desire to scratch. Although itch and pain can be produced by a variety of chemical, mechanical, thermal, or electrical stimuli, the sensory state associated with itch is different from pain. Pruritus and pain differ in that: (1) itch, unlike pain, is caused only by the surface layers of the skin, mucous membranes, and conjunctivae; and (2) itch and pain do not usually occur simultaneously in the same skin area. For example, histamine applied to the skin causes itch but not pain. Furthermore, itch and pain are treated by different pharmacological principles, as itch appears to be insensitive to treatment with opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), both of which are effective for pain. Finally, itch occurs only on the skin; pain also arises from deeper structures. Pruritus can be localized to various well-defined skin areas, such as the skin of the ankles, wrists, lips, hands, chest, etc., or it can be a generalized itch that is not limited to a specific part of the skin.

[0141] Pruritus may be associated with a variety of skin diseases, regardless of their nature and regardless of the extent to which inflammation or hypersensitivity is part of the pathology. Non-limiting examples of such skin diseases are: acne vulgaris, alopecia, dry eczema, atopic dermatitis, melanoma, drug-induced skin reactions, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, lichen simplex chronicus, lichen planus, pemphigus, pemphigoid, photodermatoses, pityriasis rosea, pyoderma gangrenosum, dyshidrosis, psoriasis, prurigo nodularis, rosacea, scabies, seborrheic dermatitis, seborrhea, scleroderma, Sjögren's syndrome, stasis dermatitis, subacute cutaneous lupus erythematosus, sunburn, cutaneous manifestations of systemic lupus erythematosus, vitiligo, and urticaria.

[0142] The causes of itchy skin are often related to cutaneous hypersensitivity or allergic reactions, such as type I or IV allergic reactions. Thus, itching can be associated with atopic dermatitis and its various forms (atopic dermatitis, hand eczema, infantile eczema, childhood eczema, adult eczema, keratosis pilaris, ichthyosis vulgaris, hand and foot dermatitis, keratoconus, dyshidrosis, discoid eczema, nummular eczema) and allergic contact reactions, such as contact dermatitis and its various forms (allergic contact dermatitis, irritant contact dermatitis, and overtreatment dermatitis).

[0143] In some aspects, the present disclosure provides a method for treating pruritus in a subject in need thereof, comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone; optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in a nootkatone-containing source; or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b). The subject is a human, cat, dog, or horse. The composition is administered topically. The composition has less than about 1% w / w of other components naturally present 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 petrolatum. The composition comprises about 1.5% to about 10% w / w of nootkatone and is administered once or twice daily. The composition is administered for at least 12 weeks. In addition, administration of the composition to the subject reduces pruritus after a predetermined period of time as determined by the Pruritus Numerical Rating Scale (I-NRS).

[0144] In one aspect, the present disclosure provides a method for 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 a voltage-gated sodium channel (NaV), a kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, a norepinephrine transporter, a neurokinin-1 receptor (NK1R), an ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB; and optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in a nootkatone-containing source; or (b) the nootkatone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0145] In one aspect, the present invention provides a pharmaceutical composition comprising nootkatone or a pharmaceutically acceptable salt or derivative thereof for use in a method of treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0146] In one aspect, the present disclosure provides a use of nootkatone or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0147] In some embodiments, the composition used is a personal care product. In one variation, the composition used is a cosmetic, a medicine, or both. In some variations, the composition used meets the regulations of the U.S. Food and Drug Administration, including definition cosmetics, medicine, or both requirements.

[0148] In some variations, the methods provided herein alleviate or slow down or prevent the development or progression of one or more symptoms caused by or associated with pruritus. In other variations, the methods provided herein reduce the degree of pruritus or relieve pruritus by causing the regression of one or more symptoms. In various embodiments, nootkatone, its pharmaceutically acceptable salt or a pharmaceutical composition of nootkatone can effectively treat a variety of conditions associated with various types of pruritus classified by Twycross et al. (Quart. J. Med. 2003; 96: 7-26), which are incorporated by reference in their entirety, i.e., pruritus sensitivity (skin, such as scabies), neurogenic (due to damage to the afferent pathways of the nervous system, such as peripheral neuritis, brain tumors), neurogenic (due to central acting mediators that do not damage the central nervous system, such as cholestatic opioid peptides) and psychogenic.

[0149] In some embodiments, "therapeutically effective amount" also refers to an amount effective for treating a disease when administered to a subject, for example, a therapeutically effective amount may be an amount sufficient to treat pruritus. A therapeutically effective amount can be determined experimentally.

[0150] In some embodiments, the composition is applied to at least a portion of the body, wherein the subject may suffer from pruritus or one or more pruritus-like symptoms. In some embodiments, the composition is applied to at least a portion of the hands, arms, legs, face and neck, or trunk of the subject, wherein the subject may suffer from pruritus or one or more pruritus-like symptoms. In another embodiment, the composition is applied to at least a portion of the whole body, wherein the subject may suffer from pruritus or one or more pruritus-like symptoms. In another embodiment, the composition is applied to at least a portion of the whole body, wherein the subject may be expected to suffer from pruritus, or to have one or more pruritus-like symptoms, but has not yet suffered from pruritus or one or more pruritus-like symptoms. In some embodiments, pruritus is assessed based on the Itch Numerical Rating Scale (I-NRS) described herein.

[0151] In some variations of the above, the subject is formally diagnosed or clinically diagnosed with pruritus.

[0152] Atopic dermatitis

[0153] In some aspects, methods are provided 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.

[0154] In some variations, eczema is atopic dermatitis. Atopic dermatitis is a condition that causes redness, swelling, and itching on the affected subject's skin. Atopic dermatitis can be chronic and flare up periodically. Symptoms of atopic dermatitis may include: dry skin; itching; red to brownish-gray patches; small, raised bumps that may ooze fluid and / or form crusts when scratched; scaly skin; and skin sensitivity from scratching. Subjects with atopic dermatitis may also experience other conditions, such as asthma or hay fever. Atopic dermatitis can affect children, teenagers, and adults.

[0155] In some variations, the compositions herein are used to treat eczema in humans and other animals suffering from naturally occurring eczema, including, for example, atopic dermatitis.

[0156] In some embodiments, the composition used is a personal care product. In one variation, the composition used is a cosmetic, a medicine, or both. In some variations, the composition used meets the regulations of the U.S. Food and Drug Administration, including definition cosmetics, medicine, or both requirements.

[0157] In some variations, the methods provided herein reduce or slow or prevent 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 herein reduce the extent of eczema or relieve eczema by causing the regression of one or more symptoms.

[0158] In some embodiments, a "therapeutically effective amount" refers to an amount that is effective in treating a disease when administered to a subject, for example, a therapeutically effective amount can be an amount sufficient to treat eczema (including, for example, atopic dermatitis). A therapeutically effective amount can be determined experimentally.

[0159] In some embodiments, the composition is applied to at least a portion of the body where the subject is likely to have eczema or one or more symptoms of eczema. In some embodiments, the composition is applied to at least a portion of the hands, arms, legs, face and neck, or torso of a subject where the subject is likely to have eczema or one or more symptoms of eczema. In another embodiment, the composition is applied to at least a portion of the body where the subject is likely to have eczema or one or more symptoms of eczema. In another embodiment, the composition is applied to at least a portion of the body where the subject is likely to have eczema or one or more symptoms of eczema, but does not yet have eczema or one or more symptoms of eczema.

[0160] In some variations, the composition is administered to a subject with mild to severe eczema, including, for example, atopic dermatitis. In some variations, the composition is administered to a subject with mild to moderate eczema, including, for example, atopic dermatitis. In certain variations, about 5% to about 20% of the subject's total body surface area (excluding the face, scalp, axillae, and intertriginous areas) is affected by eczema, including, for example, atopic dermatitis.

[0161] In some embodiments, administering the composition to a subject reduces redness, average lesion size, itching, or pain caused by eczema (including, for example, atopic dermatitis), or improves overall skin tone in areas affected by eczema, or any combination of the foregoing.

[0162] In one aspect, a method of reducing redness in a subject suffering from eczema is provided, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In a variation of the foregoing aspect, the method reduces redness in a subject suffering from atopic dermatitis. In some embodiments, redness is assessed on a scale of 0 to 10, where 0 corresponds to no redness and 10 corresponds to the worst imaginable redness. 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 relative to the baseline redness of the subject assessed before administering 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% relative to the baseline redness of the subject assessed before administering 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 relative to the subject's baseline redness as 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% relative to the subject's baseline redness as assessed prior to administration of the composition.

[0163] In one aspect, there is provided a method for alleviating the severity of eczema in a subject suffering from eczema, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In a variation of the aforementioned aspects, 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 scale, where 0 corresponds to clearing and 4 corresponds to severe. In some embodiments, the severity is assessed based on one or more criteria of a group consisting of erythema, induration or papules and exudation or crusting. In some embodiments, the severity is assessed according to the Investigator's Global Assessment (IGA) scale of 0 to 4 points described in Table 5 herein. In some embodiments, the severity is assessed according to the Participant's Global Assessment (PGA) scale of 0 to 4 points described in Table 5 herein. In some of the above-mentioned embodiments, the severity of eczema is assessed according to the Eczema Area and Severity Index score (EASI) of 0 to 72 points described in Table 5 herein. In some embodiments, the method comprises reducing the severity on the IGA scale by about 4 points, about 3 points, about 2 points, or about 1 point relative to the baseline severity of the subject assessed before administration of the composition. In some embodiments, the method comprises reducing the severity on the PGA scale by about 4 points, about 3 points, about 2 points, or about 1 point relative to the baseline severity of the subject assessed before administration of the composition. In some embodiments, the method comprises reducing the severity on the EASI 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 relative to the baseline severity of the subject assessed before administration of the composition. In some embodiments, the method comprises reducing the severity by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% relative to the baseline severity of the subject assessed before administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce the severity on the IGA scale by about 4 points, about 3 points, about 2 points, or about 1 point relative to the baseline severity of 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 severity on the PGA scale by about 4 points, about 3 points, about 2 points, or about 1 point relative to the baseline severity of 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 severity on the EASI 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 relative to the baseline severity of 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% relative to the subject's baseline severity assessed prior to administration of the composition.

[0164] In one aspect, there is provided a method for improving the skin appearance of a subject suffering from eczema, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In a variation of the foregoing aspect, the method improves the skin appearance of a subject suffering from atopic dermatitis. In some embodiments, the improvement in skin appearance is assessed by a subject suffering from atopic dermatitis. In some embodiments, the improvement in skin appearance is measured by a Global Impression of Change (GIC) scale of 1 to 7 points as described in Table 8 herein. In some embodiments, the method results in a very significantly improved, significantly improved, slightly improved, or no change in appearance compared to the skin appearance before applying the composition. In some embodiments, the method comprises administering the composition for a period of time, the period of time being sufficient to cause a very significantly improved, significantly improved, slightly improved, or no change in appearance compared to the skin appearance before applying the composition.

[0165] In one aspect, a method of reducing the severity of a target lesion in a subject suffering from eczema is provided, comprising administering to the subject any composition comprising a nootkatone or pharmaceutical composition as described herein. In a variation of the foregoing aspect, the method reduces the severity of a target lesion in a subject suffering from atopic dermatitis. In some embodiments, the severity of the target lesion is assessed based on one or more criteria selected from the group consisting of erythema, edema or papules, exudation or crusting, excoriation, lichenification, and dryness. In some embodiments, the target lesion is at least 10 cm in area. 2 .

[0166] In one aspect, a method of reducing the average lesion size in a subject suffering from eczema is provided, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In a variation of the foregoing aspect, the method reduces the average lesion size in a subject suffering from atopic dermatitis. In some embodiments, the method comprises reducing the average lesion size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% relative to the baseline average lesion size of the subject measured before administering the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce the average lesion size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% relative to the baseline average lesion size of the subject measured before administering the composition.

[0167] In one aspect, a method of alleviating itching in a subject suffering from eczema is provided, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In a variation of the foregoing aspect, the method reduces itching in a subject suffering from atopic dermatitis. In some embodiments, itching is assessed on a Likert scale of 0 to 10, where 0 corresponds to no itching and 10 corresponds to the worst itching imaginable. In some embodiments, itching is assessed based on the subject's experience within the past 24 hours. In some embodiments, itching is assessed 7 days, 14 days, 21 days, or 28 days after the start of application 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 relative to the subject's baseline assessment of itching before applying the composition. In some embodiments, the method comprises reducing itch by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% relative to the subject's baseline assessment of itch 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 itch by about 10 points, about 9 points, about 8 points, about 7 points, about 6 points, about 5 points, about 4 points, about 3 points, about 2 points, or about 1 point relative to the subject's baseline assessment of itch prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce itch by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% relative to the subject's baseline assessment of itch prior to administration of the composition.

[0168] In one aspect, there is provided a method for alleviating the pain of a subject suffering from eczema, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In a modification of the aforementioned aspects, the method alleviates the pain of a subject suffering from atopic dermatitis. In some embodiments, pain is assessed on a Likert scale of 0 to 10, wherein 0 corresponds to no pain, and 10 corresponds to the most severe pain imaginable. In some embodiments, pain is assessed based on the experience of the subject in the past 24 hours. In some embodiments, pain is assessed 7 days, 14 days, 21 days, or 28 days after starting to administer the composition. In some embodiments, the method comprises reducing the pain assessed 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 relative to the pain baseline assessment of the subject before administering 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% relative to the subject's baseline assessment of pain before 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 relative to the subject's baseline assessment of pain before 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% relative to the subject's baseline assessment of pain before administration of the composition.

[0169] In some variations of the above, the subject has been formally diagnosed or clinically diagnosed with eczema, including, for example, atopic dermatitis.

[0170] psoriasis

[0171] In some embodiments, the composition is applied to at least a portion of the body of a subject who may be suffering from psoriasis or one or more symptoms of psoriasis. In some embodiments, the composition is applied to at least a portion of the hands, arms, legs, face and neck, or torso of a subject who may be suffering from psoriasis or one or more symptoms of psoriasis. In another embodiment, the composition is applied to at least a portion of the body of a subject who may be suffering from psoriasis or one or more symptoms of psoriasis. In another embodiment, the composition is applied to at least a portion of the body of a subject who may be expected to suffer from psoriasis, or to suffer from one or more symptoms of psoriasis, but does not yet have psoriasis or one or more symptoms of psoriasis.

[0172] In some embodiments, the subject has mild to moderate psoriasis. In some embodiments, about 3% to about 15% of the subject's total body surface area (excluding the face, scalp, hands, or soles of the 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.

[0173] In some embodiments, administering the composition to a subject reduces itching, redness, scaling, burning, stinging, cracking, flaking, or pain, or a combination thereof, caused by psoriasis.

[0174] In one aspect, a method of reducing redness in a subject suffering from psoriasis is provided, comprising administering to the subject any of the compositions described herein. In some embodiments, redness is assessed on a scale of 0 to 5, where 0 corresponds to no redness and 5 corresponds to extreme 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 relative to the baseline redness of the subject assessed before administering 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% relative to the baseline redness of the subject assessed before administering 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 relative to the baseline redness of the subject assessed before administering 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% relative to the subject's baseline redness assessed prior to administration of the composition.

[0175] In one aspect, there is provided a method for reducing the severity of a target lesion caused by psoriasis in a subject, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In some embodiments, the severity of the target lesion is assessed based on one or more criteria selected from the group consisting of erythema, edema / pimples, exudation / crustation, excoriation, lichenification, and dryness. In some embodiments, the target lesion is assessed based on one or more criteria selected from the group consisting of Physician Global Assessment (PGA), redness, itching numerical rating scale (I-NRS), and patient global impression of change (PGIC) as described in Table 11 herein. In some embodiments, the area of ​​the target lesion is at least 10 cm 2 .

[0176] In one aspect, a method of reducing the average lesion size caused by psoriasis in a subject is provided, comprising administering to the subject any composition comprising a nootkatone or pharmaceutical composition as described herein. In some embodiments, the method comprises reducing the average lesion size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10%, relative to the baseline average lesion size of the subject measured before administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce the average lesion size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10%, relative to the baseline average lesion size of the subject measured before administration of the composition.

[0177] In one aspect, there is provided a method for alleviating the severity of psoriasis in a subject suffering from psoriasis, comprising administering any of the compositions described herein to the subject. In some embodiments, the severity of psoriasis in the subject is assessed on a scale of 0 to 4, wherein 0 corresponds to clearing and 4 corresponds to severe. In some embodiments, the severity of psoriasis is assessed based on one or more criteria selected from the group consisting of erythema, edema or papules, exudation / scabs, excoriations, lichenification and dryness. In some embodiments, the severity of psoriasis is assessed on a 0 to 4-point physician global assessment (PGA) scale as described in Table 9 herein. In some embodiments, the method comprises reducing the severity of psoriasis of the subject relative to the baseline severity assessed before administering the composition by about 4 points, about 3 points, about 2 points or about 1 point. In some embodiments, the method comprises reducing the severity by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% relative to the baseline severity of 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 severity of psoriasis by about 4 points, about 3 points, about 2 points, or about 1 point relative to the baseline severity of 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 severity by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% relative to the baseline severity of the subject assessed prior to administration of the composition.

[0178] In one aspect, a method of reducing the severity of psoriasis in a subject suffering from psoriasis is provided, comprising administering to the subject any of the compositions described herein. In some embodiments, the severity of psoriasis is assessed using the Psoriasis Area and Severity Index (PASI) scale, which ranges from 0 to 72 points, wherein the severity of erythema, induration, and scaling is assessed on a scale of 0 to 4 for the head and neck, upper limbs, lower limbs, and trunk, respectively; the sum of the scores for each body region is multiplied by a weighting factor, 0.1 for the head, 0.2 for the upper limbs, 0.3 for the trunk, or 0.4 for the lower limbs; each weighted score is multiplied by a score from 0 to 6 based on the percentage of the surface area of ​​the body region affected by psoriasis (unaffected = score 0, 1-9% = score 1, 10-29% = score 2, 30-49% = score 3, 50-69% = score 4, 70-89% = score 5, 90-100% = score 6); and the resulting scores are then summed to yield a total PASI score. In some embodiments, the method comprises reducing the severity of psoriasis 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 relative to the subject's baseline severity as assessed prior to administration of the composition. In some embodiments, the method comprises reducing the severity as assessed by the PASI scale by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% relative to the subject's baseline severity as 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 severity of psoriasis 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 relative to the subject's baseline severity as 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 according to 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% relative to the subject's baseline severity assessed prior to administration of the composition.

[0179] In one aspect, a method of reducing the total body surface area (BSA) affected by psoriasis is provided, comprising administering to a 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 the baseline total BSA affected by psoriasis in the subject assessed before the 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 the baseline total BSA affected by psoriasis in the subject assessed before the administration of the composition.

[0180] In one aspect, a method of reducing the average plaque size of a subject with psoriasis is provided, comprising administering to the subject any of the compositions described herein. In some embodiments, the method comprises reducing the average plaque size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% relative to the subject's baseline average plaque size measured prior to administration of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to reduce the average plaque size by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% relative to the subject's baseline average plaque size measured prior to administration of the composition.

[0181] In one aspect, a method of alleviating itching (or pruritus) in a subject suffering from psoriasis is provided, comprising administering to the subject any of the compositions described herein. In some embodiments, itching is assessed on a Likert scale of 0 to 10, where 0 corresponds to no itching and 10 corresponds to the worst itching imaginable. In some embodiments, itching is assessed based on the subject's experience within the past 24 hours. In some embodiments, itching is assessed 7 days, 14 days, 21 days, or 28 days after 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 relative to the subject's baseline assessment of itching before 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% relative to the subject's baseline assessment of itching before administration of the composition. In some embodiments, the methods comprise administering the composition for a period of time sufficient to reduce the assessed itch relative to the subject's baseline assessment of itch prior to administration of the composition 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. In some embodiments, the methods comprise administering the composition for a period of time sufficient to reduce itch relative to the subject's baseline assessment of itch prior to administration of the composition by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.

[0182] In one aspect, a method of alleviating pain in a subject suffering from psoriasis is provided, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In some embodiments, pain is assessed on a Likert scale of 0 to 10, where 0 corresponds to no pain and 10 corresponds to the worst pain imaginable. In some embodiments, pain is assessed based on the subject's experience within the past 24 hours. In some embodiments, pain is assessed 7 days, 14 days, 21 days, or 28 days after 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 relative to the subject's baseline assessment of pain before administering the composition. In some embodiments, the method comprises reducing the pain by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% relative to the subject's baseline assessment of pain before administering the composition. In some embodiments, the methods comprise administering the composition for a period of time sufficient to reduce the assessed pain relative to the subject's baseline assessment of pain prior to administration of the composition 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. In some embodiments, the methods comprise administering the composition for a period of time sufficient to reduce pain relative to the subject's baseline assessment of pain prior to administration of the composition by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.

[0183] In one aspect, a method for improving the appearance of the skin of a subject suffering from psoriasis is provided, comprising administering to the subject any composition comprising nootkatone or a pharmaceutical composition as described herein. In some embodiments, the improvement in skin appearance is assessed by a subject suffering from psoriasis. In some embodiments, the improvement in skin appearance is measured by the Patient Global Impression of Change (PGIC) scale of 1 to 7 points as described in Table 11 herein. In some embodiments, the method results in a very significantly improved, significantly improved, slightly improved, or no change in appearance of the skin compared to the appearance of the skin before the application of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to cause a very significantly improved, significantly improved, slightly improved, or no change in appearance of the skin compared to the appearance of the skin before the application of the composition.

[0184] In some variations of the above, the subject has been formally diagnosed or clinically diagnosed with psoriasis.

[0185] In some aspects, the present disclosure describes a method for treating psoriasis in a subject in need thereof, comprising: administering to the subject a composition comprising a therapeutically effective amount of nootkatone; optionally wherein: (a) the composition has less than about 5% w / w of other components naturally occurring in 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, cat, dog, or horse. The composition is administered topically. The composition has less than about 1% w / w of other components 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 petrolatum. The composition comprises about 1.5% and / or about 10% w / w nootkatone. The composition is administered once or twice daily for at least 12 weeks.

[0186] Improve skin appearance

[0187] Nootkatone and dermatologically acceptable compositions can be used to improve the appearance of skin, such as skin exhibiting one or more diseases, conditions, or illnesses, including but not limited to pain, itching, atopic dermatitis, psoriasis, diabetic dermatosis, or diabetic peripheral neuropathy. The phrase "improving the appearance of skin" includes but is not limited to: cleaning the skin or reducing slight residual discoloration, as well as reducing erythema, induration, papules, edema, excoriation, lichenification, exudation / scabs, redness, or a combination thereof. In various embodiments, nootkatone and dermatologically acceptable compositions are functional cosmetic compositions that improve skin elasticity, skin tension, prevent dry skin, exhibit skin-improving effects, such as reducing wrinkles, brightening the skin, reducing skin inflammation, skin lesions, and combinations thereof. In various embodiments, the prevention, improvement, or treatment of skin conditions provides skin moisturizing, skin flaking, reducing skin redness, reducing skin inflammation, reducing skin flushing, reducing skin dryness, enhancing skin radiance, enhancing skin tone, enhancing skin clarity, enhancing skin firmness, enhancing skin firmness, enhancing skin elasticity, and / or improving overall skin appearance. In various embodiments, nootkatone and dermatologically acceptable compositions are inhibitors or modulators of one or more of the following therapeutic targets: voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB, and are therefore useful in treating or lessening the severity of various diseases, disorders, or conditions described herein.

[0188] In various embodiments, the terms "inhibit" and "modulate" are used interchangeably to refer to agents that reduce or inhibit biological activity, such as inhibiting the activity of ion channels (e.g., NaV1.7). NaV1.7 inhibitors include inhibitors having any combination of structural and / or functional properties disclosed herein.

[0189] In certain embodiments, nootkatone or a dermatologically acceptable salt thereof inhibits or modulates one or more therapeutic targets, and its IC 50 Less than 50 micromolar (μM), optionally less than 40 μM, optionally less than 30 μM, optionally less than 20 μM, optionally less than 10 μM or optionally less than 1 μM. Alternatively, nootkatone or a dermatologically acceptable salt thereof inhibits or modulates one or more therapeutic targets, and its IC 50 From about 0.01 μM to about 100 μM, optionally from about 0.1 μM to about 75 μM, optionally from about 1 μM to about 50 μM, optionally from about 1 μM to about 25 μM, or optionally from about 1 μM to about 10 μM.

[0190] In some embodiments, the method includes administering nootkatone or a dermatologically acceptable salt thereof in an excipient to a subject to form a composition. The composition can contain 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 nootkatone or a dermatologically acceptable salt thereof in a single dosage unit. Therefore, a preferred oral single dosage unit (or recommended daily intake) 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.

[0191] 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 healthcare professional (e.g., a physician, nurse, etc.), and indirect administration includes the step of providing or making available the cosmetic composition or drug to the healthcare professional for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.).

[0192] In some aspects, methods are provided 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, itching, atopic dermatitis, psoriasis, diabetic dermatosis, or diabetic peripheral neuropathy.

[0193] In various embodiments, the methods of use may also be referred to as cosmetic methods for improving the appearance of the skin of a subject having skin imperfections. Specifically, the composition can be used to improve the appearance of the skin of a subject having skin imperfections. The subject is typically a human and can be of varying ages. The composition is not limited to a particular subject or location on the subject's skin. For example, a person can apply the composition to their face, neck, arms, hands, chest, torso, legs, feet, etc., or any combination thereof.

[0194] In some embodiments, the composition is applied to at least a portion of the body where the subject may be suffering from pain, itch, atopic dermatitis, psoriasis, diabetic skin disease or diabetic peripheral neuropathy, or one or more symptoms of pain, itch, atopic dermatitis, psoriasis, diabetic skin disease or diabetic peripheral neuropathy. In some embodiments, the composition is applied to at least a portion of the subject's hands, arms, legs, face and neck, trunk where the subject may be suffering from pain, itch, atopic dermatitis, psoriasis, diabetic skin disease or diabetic peripheral neuropathy, or one or more symptoms of pain, itch, atopic dermatitis, psoriasis, diabetic skin disease or diabetic peripheral neuropathy. In another embodiment, the composition is applied to at least a portion of the whole body where the subject may be suffering from pain, itch, atopic dermatitis, psoriasis, diabetic skin disease or diabetic peripheral neuropathy, or one or more symptoms of pain, itch, atopic dermatitis, psoriasis, diabetic skin disease or diabetic peripheral neuropathy. In another embodiment, the composition is administered to at least a portion of the body where the subject may be expected to have pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disease, or diabetic peripheral neuropathy, or is expected to have one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disease, or diabetic peripheral neuropathy, but does not already have psoriasis or one or more symptoms of pain, pruritus, atopic dermatitis, psoriasis, diabetic skin disease, or diabetic peripheral neuropathy.

[0195] In one aspect, there is provided a method for improving the appearance of the skin of a subject suffering from pain, itching, atopic dermatitis, psoriasis, diabetic skin disease, or diabetic peripheral neuropathy, comprising administering to the subject any composition comprising nootkatone or a cosmetic composition as described herein. In some embodiments, the improvement in skin appearance is assessed by a subject suffering from pain, itching, atopic dermatitis, psoriasis, diabetic skin disease, or diabetic peripheral neuropathy. In some embodiments, the improvement in skin appearance is measured by the Patient Global Impression of Change (PGIC) scale of 1 to 7 points as described in Table 8 herein. In some embodiments, the method results in a very significantly improved, significantly improved, slightly improved, or no change in appearance compared to the appearance of the skin before the application of the composition. In some embodiments, the method comprises administering the composition for a period of time sufficient to cause a very significantly improved, significantly improved, slightly improved, or no change in appearance compared to the appearance of the skin before the application of the composition.

[0196] In some variations of the above, the subject has been formally diagnosed or clinically diagnosed with pain, pruritus, atopic dermatitis, psoriasis, diabetic dermopathy, or diabetic peripheral neuropathy.

[0197] Manufacturing of pharmaceuticals / cosmetics

[0198] In one aspect, the present disclosure provides the use of a nootkatone or pharmaceutical composition as described herein in the manufacture of a medicament for inhibiting a therapeutic target, such as at least one of a voltage-gated sodium channel (NaV), a kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin-like EP2, a norepinephrine transporter, a neurokinin-1 receptor (NK1R), an ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB. In various embodiments, the nootkatone does not inhibit NaV1.5.

[0199] In yet another aspect, the present disclosure provides use of a nootkatone or pharmaceutical composition described herein in the manufacture of a medicament for treating or lessening the severity of chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain in a subject.

[0200] In yet another aspect, the present disclosure provides use of a nootkatone or pharmaceutical composition described herein in the manufacture of a medicament for treating or lessening the severity of intestinal pain or abdominal pain in a subject, wherein the intestinal pain or abdominal pain includes irritable bowel syndrome (IBS) pain, celiac disease pain, inflammatory bowel disease (IBD) pain, such as Crohn's disease pain or ulcerative colitis pain, endometriosis pain, or interstitial cystitis pain.

[0201] In yet another aspect, the present invention provides use of a nootkatone or pharmaceutical composition as described herein in the manufacture of a medicament for treating or reducing the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises postherpetic neuralgia, diabetic neuropathy, HIV-associated painful sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain following spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic neuropathy.

[0202] In yet another aspect, the present disclosure provides use of a nootkatone or pharmaceutical composition described herein in the manufacture of a medicament for treating or lessening the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burning pain, or toothache.

[0203] In yet another aspect, the present invention provides use of a nootkatone or pharmaceutical composition as described herein in the manufacture of a medicament for treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0204] In yet another aspect, the present disclosure provides use of a nootkatone or pharmaceutical composition described herein in the manufacture of a medicament for treating or lessening the severity of idiopathic pain in a subject, wherein idiopathic pain includes fibromyalgia.

[0205] In yet another aspect, the present invention provides the use of a nootkatone or pharmaceutical composition as described herein in the manufacture of a medicament in combination with one or more additional therapeutic agents to be administered concurrently with, prior to, or after treatment with the nootkatone or pharmaceutical composition.

[0206] In another aspect, the present disclosure provides use of a nootkatone or pharmaceutical composition described herein in the manufacture of a medicament for treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, generalized neuralgia, epilepsy, an epileptic disorder, a neurodegenerative disorder, a psychiatric disorder, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorder, neuroendocrine disease, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal dysmotility.

[0207] In another aspect, the present disclosure provides the use of a nootkatone or pharmaceutical composition described herein in the manufacture of a medicament for treating or lessening the severity of the following diseases: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; irritable bowel syndrome (IBS) pain; chronic and acute headaches; migraines; tension headaches; cluster headaches; chronic and acute neuropathic pain. , postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation-induced neuropathic pain; postmastectomy pain; central pain; spinal cord injury pain; poststroke pain; thalamic pain; complex regional pain syndrome; phantom limb pain; intractable pain; acute pain, acute postoperative pain; acute Musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury / sports pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn, and traumatic pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; maxillofacial pain; sinusitis pain; toothache; multiple sclerosis (MS) pain pain in depression; pain in leprosy; pain in Behçet's disease; adiposity dolorosa; pain in phlebitis; pain in Guillain-Barré syndrome; pain in the legs and toes; Haglund's syndrome; erythromelalgia; pain in Fabry disease; bladder and genitourinary disorders; urinary incontinence; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), types I and II; widespread pain, paroxysmal excruciating pain, pruritus, tinnitus, or angina-induced pain.

[0208] In another aspect, the present disclosure provides a use of a nootkatone or pharmaceutical composition as described herein in the manufacture of a medicament for treating or reducing the severity of neuropathic pain. In another aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuropathy, HIV-associated painful sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalus.

[0209] In yet another aspect, the present disclosure provides use of a nootkatone or pharmaceutical composition described herein in the manufacture of a medicament for treating or reducing the severity of pruritus in a subject.

[0210] In yet another aspect, the present disclosure provides use of a nootkatone or pharmaceutical composition described herein in the manufacture of a medicament for treating or lessening the severity of atopic dermatitis or psoriasis in a subject.

[0211] In yet another aspect, the present disclosure provides use of a nootkatone or pharmaceutical composition described herein in the manufacture of a medicament for treating or lessening the severity of diabetic dermopathy or diabetic peripheral neuropathy in a subject.

[0212] In yet another aspect, the present disclosure provides use of a nootkatone or cosmetic composition described herein in the manufacture of a cosmetic for improving the appearance of skin.

[0213] Embodiments of the present disclosure also include methods for preparing the above-mentioned compositions by, for example, conventional mixing. For example, in some embodiments, nootkatone can be combined with any combination of the above-mentioned components in purified water using conventional mixing, and after forming a stable emulsion, the pH and viscosity can be adjusted using known methods to obtain a cream with an appropriate pH. In other embodiments, various combinations of components can be combined in purified water using conventional mixing, and then nootkatone can be added to the mixture. The pH, viscosity, opacity, and / or density can be adjusted to obtain a cosmetically acceptable cream.

[0214] Administration of pharmaceutically acceptable salts and compositions

[0215] In certain embodiments of the present disclosure, an "effective amount" of nootkatone, a pharmaceutically acceptable salt, or a pharmaceutically acceptable composition thereof is an amount effective to treat or lessen the severity of one or more of pruritus, chronic pain, intestinal or abdominal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, or idiopathic pain.

[0216] According to the methods of the present disclosure, nootkatone and compositions can be administered using any amount and any route of administration effective to treat or lessen the severity of one or more of the pain or non-pain conditions described 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 specific agent, its mode of administration, and the like. For ease of administration and uniformity of dosage, nootkatone can be formulated in dosage unit form. As used herein, the expression "dosage unit form" refers to physically discrete dosage units suitable for the subject to be treated. However, it should be understood that the total daily usage of the nootkatone and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound used; the specific ingredients used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field. As used herein, the term "subject" or "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0217] The pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powders, ointments, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. As used herein, the phrase "parenteral administration" or "administered parenterally" means modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. In certain embodiments, the nootkatones of the present disclosure may be administered orally or parenterally daily at a dosage level of about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, and optionally about 1 mg / kg to about 25 mg / kg of the subject's body weight, one or more times daily to achieve the desired therapeutic effect.

[0218] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to nootkatone, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0219] Suspensions, in addition to nootkatone, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0220] Sterols such as cholesterol are known to form complexes with cyclodextrins. Thus, in certain embodiments, when the inhibitor is a steroidal alkaloid, it can be formulated with cyclodextrins such as α-, β-, and γ-cyclodextrins, dimethyl-β-cyclodextrin, and 2-hydroxypropyl-β-cyclodextrin.

[0221] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectable preparations.

[0222] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, by autoclaving, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In various embodiments, the first part of the formulation can be sterilized by filtration (e.g., nootkatone) and the second part of the formulation can be sterilized by autoclaving (e.g., excipients).

[0223] In order to prolong the effect of nootkatone, it is generally necessary to slow the absorption of nootkatone injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The absorption rate of nootkatone depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending nootkatone in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of nootkatone in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the properties of the specific polymer used, 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 embedding nootkatone in liposomes or microemulsions compatible with body tissues.

[0224] 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 the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarder such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) adsorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0225] In the soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycol, similar types of solid compositions can also be used as fillers. Solid dosage forms such as tablets, dragees, capsules, pills and granules with coatings and shells such as those well-known in the field of enteric coatings and pharmaceutical formulations can be prepared. They can optionally contain an emulsifier and can also have a composition that allows them to optionally only or preferentially release the active ingredient in a certain part of the intestinal tract in a delayed manner. The example of operable embedded composition includes polymeric substances and waxes. In the soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycol, similar types of solid compositions can also be used as fillers.

[0226] Tablets can be optionally prepared by compression or molding with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersant. Molded tablets can be made by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine.

[0227] 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 or coated with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide a slow or controlled release of the active ingredient, for example, using hydroxypropylmethylcellulose in varying proportions to provide a desired release profile, as well as other polymer matrices, liposomes, and / or microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by the addition of a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injection medium immediately before use. These compositions may also optionally contain an emulsifier and may be compositions that release the active ingredient only or preferably in a specific portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, where appropriate, containing one or more of the above-mentioned excipients.

[0228] Formulations of the pharmaceutical compositions of the present disclosure for rectal, vaginal, or urethral administration may be presented as suppositories, which may be prepared by mixing one or more compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, which are solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the nootkatone.

[0229] Alternatively or additionally, the composition can be formulated for delivery via a catheter, stent, guidewire or other intraluminal device. Delivery via such a device may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0230] Formulations 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.

[0231] Nootkatone can also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical formulation field. In such solid dosage forms, the active compound nootkatone can be mixed with at least one inert diluent such as sucrose, lactose, or starch. As a general practice, such dosage forms may also contain additional substances in addition to the inert diluent, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. They may optionally contain an emulsifier and may also be a composition that releases the active ingredient 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.

[0232] Dosage forms for topical or transdermal administration of nootkatone include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Nootkatone can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0233] In addition to nootkatone, the ointments, pastes, creams and gels may contain 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.

[0234] In addition to nootkatone, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

[0235] Transdermal patches have the additional advantage of providing controlled delivery of nootkatone to the body. This dosage form can be prepared by dissolving or dispersing nootkatone in a suitable medium. Absorption enhancers can also be used to increase the flux of nootkatone through the skin. The rate of this flux can be controlled by providing a rate-controlling membrane or dispersing nootkatone in a polymer matrix or gel.

[0236] Ophthalmic formulations, eye ointments, eye drops, and ear drops are also considered to be within the scope of this disclosure. Pharmaceutical compositions suitable for parenteral administration include one or more compounds in combination with one or more of the following: pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, sterile powders to be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0237] Examples of suitable aqueous and non-aqueous carriers that can be used in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Suitable fluidity can be maintained, for example, by the use of coating materials (such as lecithin), by maintaining the desired particle size (in the case of dispersions), and by the use of surfactants.

[0238] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the compositions. In addition, prolonged absorption of injectable pharmaceutical forms may be achieved by including agents that delay absorption such as aluminum monostearate and gelatin.

[0239] In some cases, in order to prolong the effect of a drug, it is necessary to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of the drug depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0240] When nootkatone is administered to humans and animals as a drug, it can be administered in the form of a pharmaceutical composition, or in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient and a pharmaceutically acceptable carrier.

[0241] Addition of nootkadone to the animal feed is preferably accomplished by preparing a suitable feed premix containing an effective amount of nootkadone and adding the premix to the complete feed.

[0242] Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be mixed into the feed. The preparation and administration of such feed premixes and complete feeds are described in reference books (e.g., "Applied Animal Nutrition", WF Freshman and CO., San Francisco, USA, 1969 or "Livestock Feeds and Feeding", O and B books, Corvallis, Ore., USA, 1977).

[0243] The method of introduction can also be provided by rechargeable or biodegradable devices. In recent years, various sustained-release polymer devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers, including hydrogels, including biodegradable and non-degradable polymers, can be used to form implants to continuously release nootkatone at a specific target site.

[0244] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied 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.

[0245] The selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, or its ester, salt or amide, the route of administration, the time of administration, the rate of excretion of the particular compound 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.

[0246] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, the physician or veterinarian can start the dosage of nootkatone used in the pharmaceutical composition at a level below the desired level to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0247] In general, a suitable daily dose of nootkatone is the amount of nootkatone that effectively produces the lowest dose of nootkatone that is effective for the treatment of the disease. This effective dose generally depends on the factors mentioned above. Typically, a patient's intravenous, intracerebroventricular, and subcutaneous nootkatone dosage is from about 0.0001 to about 100 mg per kilogram of body weight per day.

[0248] 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 form.

[0249] The patient receiving such treatment is any animal in need thereof, including primates, particularly humans, and other mammals such as horses, cattle, pigs, and sheep; and poultry and pets in general.

[0250] Nootkatone can be administered directly or mixed with a pharmaceutically acceptable and / or sterile carrier, and can also be administered in combination with other antimicrobial agents such as penicillins, cephalosporins, aminoglycosides, and glycopeptides. Thus, combination therapy includes sequential, simultaneous, and separate administration of nootkatone, so that the therapeutic effect of the first administration of nootkatone can still be detected when subsequent treatments are performed.

[0251] The present disclosure contemplates formulations of the subject compounds in any of the aforementioned pharmaceutical compositions and formulations. In addition, the present disclosure contemplates administration via any of the aforementioned routes of administration. One skilled in the art can select an appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated.

[0252] The activity of nootkatones as inhibitors of therapeutic targets used in this disclosure can be determined according to the methods generally described in the Examples herein or according to methods available to those skilled in the art.

[0253] Additional therapeutic agents

[0254] It will also be understood that the nootkatones and pharmaceutically acceptable compositions of the present disclosure can be used in combination therapies, that is, the nootkatones and pharmaceutically acceptable compositions can be administered concurrently with, before, or after one or more other desired therapies or medical procedures. The specific combination of treatments (therapeutic agents or procedures) for use in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It will also be understood that the therapies used can achieve the desired effect for the same condition (e.g., a compound of the invention can be administered concurrently with another agent used to treat the same disease), or they can achieve different effects (e.g., to control any adverse effects). As used herein, additional therapeutic agents that are typically administered to treat or prevent a particular disease or condition are referred to as "suitable for the disease or condition being treated." For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles, such as etodolac, indomethacin, sulindac, tolmetin; naphthylalkanones, such as nabumetone; oxicams, such as piroxicam; para-aminophenol derivatives, such as acetaminophen; propionic acids, such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin; 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). In addition, non-drug analgesic methods can be used in combination with the administration of one or more compounds of the present disclosure. For example, anesthesiology (intraspinal infusion, nerve block), neurosurgery (CNS pathway neurolysis), nerve stimulation (transcutaneous electrical nerve stimulation, spinal stimulation), physical therapy (physical therapy, orthopedic device, diathermy) or psychotherapy (cognitive method-hypnosis, biofeedback or behavioral approach) methods can also be utilized. Other suitable therapeutic agents or methods are generally described in The Merck Manual, 19th edition, Robert S.Porter and Justin L.Kaplan, ed., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the U.S. Food and Drug Administration website www.fda.gov, the entire contents of which are incorporated herein by reference.

[0255] In another embodiment, the additional appropriate therapeutic agent is selected from the group consisting of: (1) opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphanol, methadone, pethidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, or pentazocine; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, fluphenazine, fenfluramine ... (3) barbiturate sedatives, such as amobarbital, aprebarbital, butabarbital, butalbital, mephenal, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiopental, or thiopental; (4) benzodiazepines with sedative effects. Class, such as chlordiazepoxide Clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam; (5) sedative histamine (H1) antagonists, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine; (6) tranquilizers, such as glutethimide, meprobamate, methaqualone, or dichlorpheniramine; (7) skeletal muscle relaxants, such as baclofen, carisoprodol, chlorpheniramine, (8) NMDA receptor antagonists, such as 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 a combination of morphine and dextromethorphan, topiramate, neramexane, or a perzinfotel including an NR2B antagonist, such as ifenprodil, trexedil, or (–)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone; (9) an α-adrenergic agent, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline; (10) a tricyclic antidepressant, such as desipramine, imipramine, amitriptyline, or nortriptyline; (11) an anticonvulsant, such as carbamazepine Lamotrigine, topiramate, lacosamide or valproic acid; (12) tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazacycloocta[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanapitin, dapiride, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S, 3S); (13) muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropium chloride, darifenacin, solifenacin, temiverine, and ipratropium bromide; (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) coal tar analgesics, especially acetaminophen; (16) neuroleptics, such as droperidol Do, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonaprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifepronol, asenapine, lurasidone, amisulpride, balaperidone, parindor, elivanserin, osanetan, rimonabant, meclizine, or sarizotan; (17) vanilloid receptor agonists (e.g., resinferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300); (18) β-adrenergic drugs, such as propranolol; (19) local anesthetics, such as mexiletine; (20) corticosteroids, such as dexamethasone; (21) 5-HT receptor agonists or antagonists, particularly 5-HT1B / 1D agonists, such as eletriptan, sumatriptan, naratrol, (22) 5-HT2A receptor antagonists, such as R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenethyl)]-4-piperidinol (MDL-100907); (23) cholinergic (nicotinic) analgesics, such as isoprenicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine; (24) Tramadol ER Tapentadol ER (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b] Indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide; (26) α-2-δ ligands, such as gabapentin Gabapentin GR Gabapentin, enacarbil Pregabalin 3-Methylgabapentin, (1α,3α,5α)(3-aminomethylbicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6-(amino acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-aminomethyl-5-methyl-nonanoic acid, (3S,5R)- 3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid; (27) cannabinoids, such as KHK-6188; (28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonists; (29) serotonin reuptake inhibitors, such as sertraline, the sertraline metabolite norsertraline, fluoxetine, norfluoxetine (fluoxetine demethyl metabolite), fluvoxamine , paroxetine, citalopram, the citalopram metabolite norcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanothiazide, ritoxetine, dapoxetine, nefazodone, cilamin, and trazodone; (30) norepinephrine (noradrenaline) reuptake inhibitors, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezomine, atomoxetine, mianserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazine In particular, selective norepinephrine reuptake inhibitors, such as reboxetine, in particular (S,S)-reboxetine; (31) dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine Milnacipran and imipramine; (32) inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[ (1R,3S)-3-Amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolbutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboximidamide, NXN-462, or guanidinoethyl disulfide; (33) Acetylcholinesterase inhibitors, such as donepezil; (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid; (35) Leukotriene B4 antagonists, such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3 -[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-pentanoic acid (ONO-4057) or DPC-11870; (36) 5-lipoxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1-methyl-2-quinolone (ZD-2138) or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504); (37) sodium channel blockers, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate; (38) NaV1.7 blockers, such as XEN-402 and those disclosed in WO2011 / 140425, WO2012 / 106499, WO2012 / 112743, WO2012 / 125613 or PCT / US2013 / 21535, the entire contents of each application are incorporated herein by reference; (39) NaV1.8 blockers, such as those disclosed in WO2008 / 135826 and WO2006 / 011050, the entire contents of each application are incorporated herein by reference; (40) NaV1.7 and NaV1.8 blocker combinations, such as DSP-2230 or BL-1021; (41) 5-HT3 antagonists, such as ondansetron; (42) TPRV1 receptor agonists, such as capsaicin. and pharmaceutically acceptable salts and solvates thereof; (43) nicotinic receptor antagonists, such as varenicline; (44) N-type calcium channel antagonists, such as Z-160; (45) nerve growth factor antagonists, such as tanezumab; (46) endopeptidase stimulators, such as senrebotase; and (47) angiotensin II antagonists, such as EMA-401.

[0256] In one embodiment, the additional suitable therapeutic agent is selected from V-116517, pregabalin, controlled release pregabalin, ezogabine Ketamine / amitriptyline topical cream AVP-923, perampanel (E-2007), ralfinamide, transdermal bupivacaine CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0257] The amount of additional therapeutic agent present in the compositions of the present disclosure will not exceed the amount normally administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions of the present disclosure will be about 10% to 100% of the amount normally present in a composition comprising that therapeutic agent as the only therapeutically active agent.

[0258] Nootkatone or its pharmaceutically acceptable composition can also be incorporated into a composition for coating an implantable medical device, such as a prosthesis, an artificial valve, a vascular graft, a stent, and a catheter. Therefore, in another aspect, the present disclosure includes a composition for coating an implantable device, the composition comprising nootkatone as described above and in the categories and subcategories herein, and a carrier suitable for coating the implantable device. In yet another aspect, the present disclosure includes an implantable device coated with a composition comprising nootkatone as described above and in the categories and subcategories herein, and a carrier suitable for coating the implantable device. U.S. Patent Nos. 6,099,562, 5,886,026, and 5,304,121 describe the general preparation of suitable coatings and coated implantable devices. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered with a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or a combination thereof to impart controlled release properties to the composition.

[0259] Another aspect of the present disclosure relates to inhibiting the activity of a therapeutic target in a biological sample or subject, the method comprising administering to the subject a nootkatone or a composition comprising a nootkatone, or contacting the biological sample with a nootkatone or a composition comprising a nootkatone. As used herein, the term "biological sample" includes, but is not limited to, cell culture or extracts thereof, biopsy material obtained from a mammal or extracts thereof, and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0260] Inhibiting the activity of a therapeutic target in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, studying therapeutic targets in biological and pathological phenomena; and comparative evaluation of new therapeutic target inhibitors.

[0261] In some embodiments, the present disclosure relates to a kit comprising a composition and instructions explaining how to use the composition to treat or prevent pain or pruritus in a subject in need thereof.

[0262] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to the value or parameter itself. For example, a description referring to "about X" includes a description of "X." In some embodiments, the term "about" when used in connection with a measurement or to modify a value, unit, constant, or range of values ​​refers to a variation of + / - 10%, 5%, 2%, or 1%.

[0263] Reference herein to two values ​​or parameters includes (and describes) embodiments that include these two values ​​or parameters themselves. For example, a description referring to "between x and y" includes a description of "x" and "y" themselves.

[0264] Aspects of various embodiments of the present disclosure

[0265] Aspect 1

[0266] Aspect 1.1: A method of treating or preventing pruritus in a subject in need thereof, the method comprising:

[0267] administering to the subject a composition comprising a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt or derivative thereof;

[0268] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0269] Aspect 1.2: The method of Aspect 1.1, wherein the subject is a human.

[0270] Aspect 1.3: The method of Aspect 1.1, wherein the subject is a cat, dog or horse.

[0271] Aspect 1.4: The method of any of Aspects 1.1 to 1.3, wherein the composition is administered topically.

[0272] Aspect 1.5: The method of any of Aspects 1.1 to 1.4, wherein the composition has less than about 1% w / w of other components naturally present in a nootkatone-containing source, and the nootkatone in the composition has a purity of at least about 99% w / w.

[0273] Aspect 1.6: The method of any of Aspects 1.1 to 1.5, wherein the composition further comprises an emulsifier.

[0274] Aspect 1.7: The method of any of Aspects 1.1 to 1.5, wherein the composition further comprises a gelling agent.

[0275] Aspect 1.8: The method of any of Aspects 1.1 to 1.7, wherein the composition comprises nootkatone.

[0276] Aspect 1.9: The method of any of Aspects 1.1 to 1.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0277] Aspect 1.10: The method of any of Aspects 1.1 to 1.9, wherein the composition comprises at least 5% w / w nootkatone.

[0278] Aspect 1.11: The method of any of Aspects 1.1 to 1.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0279] Aspect 1.12: The method of any of Aspects 1.1 to 1.11, wherein the composition is administered once or twice daily.

[0280] Aspect 1.13: The method of any of Aspects 1.1 to 1.12, wherein the composition is administered for at least 12 weeks.

[0281] Aspect 1.14: The method of Aspects 1.1 to 1.13, wherein administering the composition to the subject reduces itching after a predetermined amount of time as determined by the Itch Numerical Rating Scale (I-NRS).

[0282] Aspect 1.15: The method of any of Aspects 1.1 to 1.13, wherein administration of the composition to the subject reduces pruritus as evidenced by a reduction in atopic dermatitis after a predetermined amount of time as determined by a Patient-Oriented Eczema Measurement (POEM).

[0283] Aspect 1.16: A method of treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, the method comprising:

[0284] administering to the subject a composition comprising a therapeutically effective amount of nootkatone;

[0285] wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB; and

[0286] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0287] Aspect 1.17: A pharmaceutical composition comprising nootkatone or a pharmaceutically acceptable salt or derivative thereof, for use in a method of treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0288] Aspect 1.18: Use of nootkatone or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0289] Aspect 1.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in treating pruritus, wherein the nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously or orally.

[0290] Aspect 1.20: Nootkatone in a method of treating pruritus, the method comprising:

[0291] A therapeutically effective amount of nootkatone is topically administered to the skin of a subject in need thereof, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0292] Aspect 1.21: The method of Aspect 1.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0293] Aspect 1.22: The method of Aspect 1.21, wherein the topical administration comprises topically administering an amount sufficient to reduce the severity of itching and to relieve itching by causing resolution of one or more symptoms associated with itching.

[0294] Aspect 2

[0295] Aspect 2.1: A method of treating or preventing psoriasis in a subject in need thereof, comprising:

[0296] administering to the subject a composition comprising a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt or derivative thereof;

[0297] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0298] Aspect 2.2: The method of Aspect 2.1, wherein the subject is a human.

[0299] Aspect 2.3: The method of Aspect 2.1, wherein the subject is a cat, dog or horse.

[0300] Aspect 2.4: The method of any of Aspects 2.1 to 2.3, wherein the composition is administered topically.

[0301] Aspect 2.5: The method of any of Aspects 2.1 to 2.4, wherein the composition has less than about 1% w / w of other components naturally present in a nootkatone-containing source, and the nootkatone in the composition has a purity of at least about 99% w / w.

[0302] Aspect 2.6: The method of any of Aspects 2.1 to 2.5, wherein the composition further comprises an emulsifier.

[0303] Aspect 2.7: The method of any of Aspects 2.1 to 2.5, wherein the composition further comprises a gelling agent.

[0304] Aspect 2.8: The method of any of Aspects 2.1 to 2.7, wherein the composition comprises nootkatone.

[0305] Aspect 2.9: The method of any of Aspects 2.1 to 2.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0306] Aspect 2.10: The method of any of Aspects 2.1 to 2.9, wherein the composition comprises at least 5% w / w nootkatone.

[0307] Aspect 2.11: The method of any of Aspects 2.1 to 2.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0308] Aspect 2.12: The method of any of Aspects 2.1 to 2.11, wherein the composition is administered once or twice daily.

[0309] Aspect 2.13: The method of any of Aspects 2.1 to 2.12, wherein the composition is administered for at least 12 weeks.

[0310] Aspect 2.14: The method of Aspects 2.1 to 2.13, wherein administration of the composition to the subject reduces psoriasis after a predetermined amount of time as determined by the Psoriasis Area and Severity Index (PASI), Target Lesion Severity Score (TLSS), or a combination thereof.

[0311] Aspect 2.15: The method of any of Aspects 2.1 to 2.13, wherein administration of the composition to the subject reduces psoriasis as evidenced by a decrease in itching after a predetermined amount of time as determined by the Itch Numerical Rating Scale (I-NRS).

[0312] Aspect 2.16: A method of treating or preventing psoriasis in a subject by inhibiting or modulating a therapeutic target, the method comprising:

[0313] administering to the subject a composition comprising a therapeutically effective amount of nootkatone;

[0314] wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB; and

[0315] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0316] Aspect 2.17: A pharmaceutical composition comprising nootkatone or a pharmaceutically acceptable salt or derivative thereof, for use in a method of treating or preventing psoriasis in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0317] Aspect 2.18: Use of nootkatone or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for treating or preventing psoriasis in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0318] Aspect 2.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in treating psoriasis, wherein the nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0319] Aspect 2.20: Nootkatone in a method of treating psoriasis, the method comprising:

[0320] A therapeutically effective amount of nootkatone is topically administered to the skin of a subject in need thereof, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0321] Aspect 2.21: The method of Aspect 2.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0322] 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 alleviate psoriasis by causing resolution of one or more psoriasis-associated symptoms.

[0323] Aspect 3

[0324] Aspect 3.1: A method of treating or preventing atopic dermatitis in a subject in need thereof, comprising:

[0325] administering to the subject a composition comprising a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt or derivative thereof;

[0326] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0327] Aspect 3.2: The method of Aspect 3.1, wherein the subject is a human.

[0328] Aspect 3.3: The method of Aspect 3.1, wherein the subject is a cat, dog or horse.

[0329] Aspect 3.4: The method of any of Aspects 3.1 to 3.3, wherein the composition is administered topically.

[0330] Aspect 3.5: The method of any of Aspects 3.1 to 3.4, wherein the composition has less than about 1% w / w of other components naturally present in a nootkatone-containing source, and the nootkatone in the composition has a purity of at least about 99% w / w.

[0331] Aspect 3.6: The method of any of Aspects 3.1 to 3.5, wherein the composition further comprises an emulsifier.

[0332] Aspect 3.7: The method of any of Aspects 3.1 to 3.5, wherein the composition further comprises a gelling agent.

[0333] Aspect 3.8: The method of any of Aspects 3.1 to 3.7, wherein the composition comprises nootkatone.

[0334] Aspect 3.9: The method of any of Aspects 3.1 to 3.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0335] Aspect 3.10: The method of any of Aspects 3.1 to 3.9, wherein the composition comprises at least 5% w / w nootkatone.

[0336] Aspect 3.11: The method of any of Aspects 3.1 to 3.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0337] Aspect 3.12: The method of any of Aspects 3.1 to 3.11, wherein the composition is administered once or twice daily.

[0338] Aspect 3.13: The method of any of Aspects 3.1 to 3.12, wherein the composition is administered for at least 12 weeks.

[0339] Aspect 3.14: The method of Aspects 3.1 to 3.13, wherein administration of the composition to the subject reduces atopic dermatitis after a predetermined amount of time determined according to Patient-Oriented Eczema Measurement (POEM), Target Lesion Severity Score (TLSS), or a combination thereof.

[0340] Aspect 3.15: The method of any of Aspects 3.1 to 3.13, wherein administration of the composition to the subject reduces atopic dermatitis as evidenced by a reduction in itch after a predetermined amount of time as determined by the Itch Numerical Rating Scale (I-NRS).

[0341] Aspect 3.16: A method of treating or preventing atopic dermatitis in a subject by inhibiting or modulating a therapeutic target, the method comprising:

[0342] administering to the subject a composition comprising a therapeutically effective amount of nootkatone;

[0343] wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB; and

[0344] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0345] Aspect 3.17: A pharmaceutical composition comprising nootkatone or a pharmaceutically acceptable salt or derivative thereof, for use in a method of treating or preventing atopic dermatitis in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0346] Aspect 3.18: Use of nootkatone or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for treating or preventing atopic dermatitis in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0347] Aspect 3.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in treating atopic dermatitis, wherein the nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0348] Aspect 3.20: Nootkatone in a method of treating atopic dermatitis, the method comprising:

[0349] A therapeutically effective amount of nootkatone is topically administered to the skin of a subject in need thereof, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0350] Aspect 3.21: The method of Aspect 3.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0351] 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 alleviate the atopic dermatitis by causing resolution of one or more symptoms associated with atopic dermatitis.

[0352] Aspect 4

[0353] Aspect 4.1: A method of treating or preventing diabetic dermopathy or diabetic peripheral neuropathy in a subject in need thereof, the method comprising:

[0354] administering to the subject a composition comprising a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt or derivative thereof;

[0355] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0356] Aspect 4.2: The method of Aspect 4.1, wherein the subject is a human.

[0357] Aspect 4.3: The method of Aspect 4.1, wherein the subject is a cat, dog or horse.

[0358] Aspect 4.4: The method of any of Aspects 4.1 to 4.3, wherein the composition is administered topically.

[0359] Aspect 4.5: The method of any of Aspects 4.1 to 4.4, wherein the composition has less than about 1% w / w of other components naturally present in a nootkatone-containing source, and the nootkatone in the composition has a purity of at least about 99% w / w.

[0360] Aspect 4.6: The method of any of Aspects 4.1 to 4.5, wherein the composition further comprises an emulsifier.

[0361] Aspect 4.7: The method of any of Aspects 4.1 to 4.5, wherein the composition further comprises a gelling agent.

[0362] Aspect 4.8: The method of any of Aspects 4.1 to 4.7, wherein the composition comprises nootkatone.

[0363] Aspect 4.9: The method of any of Aspects 4.1 to 4.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0364] Aspect 4.10: The method of any of Aspects 4.1 to 4.9, wherein the composition comprises at least 5% w / w nootkatone.

[0365] Aspect 4.11: The method of any of Aspects 4.1 to 4.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0366] Aspect 4.12: The method of any of Aspects 4.1 to 4.11, wherein the composition is administered once or twice daily.

[0367] Aspect 4.13: The method of any of Aspects 4.1 to 4.12, wherein the composition is administered for at least 12 weeks.

[0368] Aspect 4.14: The method of Aspects 4.1 to 4.13, wherein administration of the composition to the subject reduces diabetic dermopathy or diabetic peripheral neuropathy after a predetermined amount of time as determined by the Target Lesion Severity Score (TLSS).

[0369] Aspect 4.15: The method of any of Aspects 4.1 to 4.13, wherein administration of the composition to the subject reduces diabetic dermopathy or diabetic peripheral neuropathy as evidenced by a decrease in itch after a predetermined amount of time as determined by the Itch Numerical Rating Scale (I-NRS).

[0370] 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:

[0371] administering to the subject a composition comprising a therapeutically effective amount of nootkatone;

[0372] wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB; and

[0373] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0374] Aspect 4.17: A pharmaceutical composition comprising nootkatone or a pharmaceutically acceptable salt or derivative thereof, for use in a method for 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 channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0375] Aspect 4.18: Use of nootkatone or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for 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 channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0376] Aspect 4.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in treating diabetic dermopathy or diabetic peripheral neuropathy, wherein the nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0377] Aspect 4.20: Nootkatone in a method of treating diabetic dermopathy or diabetic peripheral neuropathy, the method comprising:

[0378] A therapeutically effective amount of nootkatone is topically administered to the skin of a subject in need thereof, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0379] Aspect 4.21: The method of Aspect 4.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0380] Aspect 4.22: The method of Aspect 4.21, wherein the topical administration comprises topically administering an amount sufficient to reduce the extent of the diabetic skin disorder or diabetic peripheral neuropathy and to alleviate the diabetic skin disorder or diabetic peripheral neuropathy by causing resolution of one or more symptoms associated with the diabetic skin disorder or diabetic peripheral neuropathy.

[0381] Aspect 5

[0382] Aspect 5.1: A method for improving the appearance of skin in a subject in need thereof, comprising:

[0383] administering to the subject a composition comprising a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt or derivative thereof;

[0384] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0385] Aspect 5.2: The method of Aspect 5.1, wherein the subject is a human.

[0386] Aspect 5.3: The method of Aspect 5.1, wherein the subject is a cat, dog or horse.

[0387] Aspect 5.4: The method of any of Aspects 5.1 to 5.3, wherein the composition is administered topically.

[0388] Aspect 5.5: The method of any of Aspects 5.1 to 5.4, wherein the composition has less than about 1% w / w of other components naturally present in a nootkadone-containing source, and the nootkadone in the composition has a purity of at least about 99% w / w.

[0389] Aspect 5.6: The method of any of Aspects 5.1 to 5.5, wherein the composition further comprises an emulsifier.

[0390] Aspect 5.7: The method of any of Aspects 5.1 to 5.5, wherein the composition further comprises a gelling agent.

[0391] Aspect 5.8: The method of any of Aspects 5.1 to 5.7, wherein the composition comprises nootkatone.

[0392] Aspect 5.9: The method of any of Aspects 5.1 to 5.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0393] Aspect 5.10: The method of any of Aspects 5.1 to 5.9, wherein the composition comprises at least 5% w / w nootkatone.

[0394] Aspect 5.11: The method of any of Aspects 5.1 to 5.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0395] Aspect 5.12: The method of any of Aspects 5.1 to 5.11, wherein the composition is administered once or twice daily.

[0396] Aspect 5.13: The method of any of Aspects 5.1 to 5.12, wherein the composition is administered for at least 12 weeks.

[0397] Aspect 5.14: The method of Aspects 5.1 to 5.13, wherein administering the composition to the subject improves the appearance of the skin after a predetermined amount of time as determined by the Redness Numeric Rating Scale (R-NRS), the Patient's Global Impression of Change (P-GIC), the EuroQol 5 Dimensions (EQ-5D), or a combination thereof.

[0398] Aspect 5.15: The method of any of Aspects 5.1 to 5.13, wherein administering the composition to the subject improves skin appearance as evidenced by:

[0399] reduction in atopic dermatitis after a predetermined amount of time as determined by the Patient-Oriented Eczema Measure (POEM), the Target Lesion Severity Score (TLSS), or a combination thereof;

[0400] a reduction in diabetic dermopathy or diabetic peripheral neuropathy after a predetermined amount of time as determined by the Target Lesion Severity Score (TLSS); or

[0401] reduction in atopic dermatitis and reduction in diabetic dermatosis or diabetic peripheral neuropathy.

[0402] Aspect 5.16: A method of improving the appearance of a subject's skin by inhibiting or modulating a therapeutic target, the method comprising:

[0403] administering to the subject a composition comprising a therapeutically effective amount of nootkatone;

[0404] wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB; and

[0405] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0406] Aspect 5.17: A pharmaceutical composition comprising nootkatone or a pharmaceutically acceptable salt or derivative thereof, for use in a method of improving the appearance of a subject's skin by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0407] Aspect 5.18: Use of nootkatone or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for improving the appearance of a subject's skin by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0408] 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.

[0409] Aspect 5.20: Nootkatone in a method of improving the appearance of skin, the method comprising:

[0410] A therapeutically effective amount of nootkatone is topically administered to the skin of a subject in need thereof, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0411] Aspect 5.21: The method of Aspect 5.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0412] Aspect 5.22: The method of Aspect 5.21, wherein the topical administration comprises topically administering an amount sufficient to improve the appearance of the skin by causing resolution of one or more symptoms associated with skin imperfections.

[0413] Aspect 6

[0414] Aspect 6.1: A method of treating or preventing intestinal or abdominal pain in a subject in need thereof, the method comprising:

[0415] administering to the subject a composition comprising a therapeutically effective amount of nootkatone or a pharmaceutically acceptable salt or derivative thereof;

[0416] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0417] Aspect 6.2: The method of Aspect 6.1, wherein the subject is a human.

[0418] Aspect 6.3: The method of Aspect 6.1, wherein the subject is a cat, dog or horse.

[0419] Aspect 6.4: The method of any of Aspects 6.1 to 6.3, wherein the composition is administered orally.

[0420] Aspect 6.5: The method of any of Aspects 6.1 to 6.4, wherein the composition has less than about 1% w / w of other components naturally present in a nootkatone-containing source, and the nootkatone in the composition has a purity of at least about 99% w / w.

[0421] Aspect 6.6: The method of any of Aspects 6.1 to 6.5, wherein the composition is in the form of a tablet or a pill.

[0422] Aspect 6.7: The method of any of Aspects 6.1 to 6.5, wherein the intestinal or abdominal pain is a symptom of inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), or a combination thereof.

[0423] Aspect 6.8: The method of any of Aspects 6.1 to 6.7, wherein the composition comprises nootkatone.

[0424] Aspect 6.9: The method of any of Aspects 6.1 to 6.8, wherein the composition comprises at least 1.5% w / w nootkatone.

[0425] Aspect 6.10: The method of any of Aspects 6.1 to 6.9, wherein the composition comprises at least 5% w / w nootkatone.

[0426] Aspect 6.11: The method of any of Aspects 6.1 to 6.8, wherein the composition comprises about 1.5% to about 10% w / w nootkatone.

[0427] Aspect 6.12: The method of any of Aspects 6.1 to 6.11, wherein the composition is administered once or twice daily.

[0428] Aspect 6.13: The method of any of Aspects 6.1 to 6.12, wherein the composition is administered for at least 12 weeks.

[0429] Aspect 6.14: The method of Aspects 6.1 to 6.13, wherein administration of the composition to the subject reduces pain after a predetermined amount of time as determined according to the IBS Symptom Severity Scale, Brief Pain Inventory, Visceral Sensitivity Index, Pain Numerical Rating Scale (P-NRS), Sickness Impact Scale, Pain Disability Index, Pain Catastrophizing Scale, McGill Pain Questionnaire, or a combination thereof.

[0430] Aspect 6.15: The method of Aspect 6.14, wherein administration of the composition to the subject reduces intestinal or abdominal pain after a predetermined amount of time as determined according to a Pain Numerical Rating Scale (P-NRS).

[0431] Aspect 6.16: A method of treating or preventing intestinal or abdominal pain in a subject by inhibiting or modulating a therapeutic target, the method comprising:

[0432] administering to the subject a composition comprising a therapeutically effective amount of nootkatone;

[0433] wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB; and

[0434] Optionally wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone in the composition has a purity of at least about 95% w / w, or both (a) and (b).

[0435] Aspect 6.17: A pharmaceutical composition comprising nootkatone or a pharmaceutically acceptable salt or derivative thereof, for use in a method for treating or preventing intestinal or abdominal pain in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0436] Aspect 6.18: Use of nootkatone or a pharmaceutically acceptable salt or derivative thereof in the preparation of a medicament for treating or preventing intestinal pain or abdominal pain in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0437] Aspect 6.19: Nootkatone, or a pharmaceutically acceptable salt or derivative thereof, for use in treating intestinal or abdominal pain, wherein the nootkatone, or a pharmaceutically acceptable salt or derivative thereof, is administered topically, subcutaneously, or orally.

[0438] Aspect 6.20: Nootkatone in a method of treating intestinal or abdominal pain, the method comprising:

[0439] A therapeutically effective amount of nootkatone is topically administered to the skin of a subject in need thereof, wherein the therapeutically effective amount is an amount sufficient to modulate the amount or activity of a therapeutic target.

[0440] Aspect 6.21: The method of Aspect 6.20, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

[0441] Aspect 6.22: The method of Aspect 6.21, wherein the topical administration comprises topically administering an amount sufficient to reduce the severity of the intestinal or abdominal pain and to relieve the intestinal or abdominal pain by causing resolution of one or more symptoms associated with the intestinal or abdominal pain.

[0442] Example

[0443] The presently disclosed subject matter will be better understood with reference to the following examples, which are provided as illustrations of the present disclosure and not as limitations. The following examples are included to illustrate the various embodiments contemplated herein. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that the inventors have found to function well in the practice of the present invention and, therefore, can be considered to constitute ideal modes for its practice. However, in light of this disclosure, it should be understood by those skilled in the art that many changes can be made in the specific embodiments that have been disclosed and still obtain similar or similar results without departing from the spirit and scope of the present invention. Unless otherwise indicated, all percentages are percentages by weight and all measurements are made at 23°C.

[0444] Example 1

[0445] Exemplary Aqueous Gel-Based Compositions Comprising Nootkatone

[0446] Exemplary (Exemplary Component I) and comparative (Comparative Component I) formulations of aqueous gel-based compositions were formed according to the methods described herein. Table 1 below provides exemplary and comparative formulations of aqueous gel-based compositions.

[0447] Table 1. Components and quantities

[0448]

[0449]

[0450] The gelling agent may be a carbomer commercially available under the trade name Carbopol Ultrez 10.

[0451] Solvent II may be diethylene glycol monoethyl ether commercially available under the trade name Transcutol P.

[0452] Example 2

[0453] Exemplary cream-based compositions comprising nootkatone

[0454] Exemplary (Exemplary Component II) and comparative (Comparative Component II) formulations of cream-based compositions were formed according to the methods described herein. Table 2 below provides exemplary and comparative formulations of cream-based compositions.

[0455] Table 2. Components and quantities

[0456]

[0457] The emulsifier may be a mixture of cetyl (C16) and stearyl (C18) fatty alcohols commercially available under the trade name Kolliphor CS A.

[0458] Solvent II may be diethylene glycol monoethyl ether commercially available under the trade name Transcutol P.

[0459] Example 3

[0460] A 14-week study evaluating the effects of a compound on people with atopic dermatitis

[0461] A 14-week placebo-controlled, double-blind study was conducted to evaluate the safety and tolerability of a topical cream (Exemplary Component II) for the reduction of atopic dermatitis.

[0462] Participants self-reported mild to moderate atopic dermatitis, confirmed by the investigator at screening by photographic confirmation. Participants who were currently experiencing or had a history of other concomitant skin conditions (such as psoriasis) that, at the investigator's discretion, interfered with the assessment of the effect of Exemplary Component II were excluded from the trial.

[0463] During the trial, patients applied topically a nootkatone-containing formulation ("test product") according to the study procedures and study questionnaires and assessments provided below.

[0464] Study Procedure

[0465] After the initial eligibility review, participants will receive an email with study enrollment information, including instructions for completing the required study assessments. These study assessments can be accessed through the Chloe mobile app on Apple iOS and Android devices. Participant activities are as follows:

[0466] Screening Period (3 weeks; up to Day -21):

[0467] - Completed informed consent form

[0468] - Complete demographics, medical history, and concomitant medication intake

[0469] - Investigator-determined AD severity is mild to moderate

[0470] ○ Participants took skin photos using Chloe

[0471] ○ Investigator review of images to confirm severity

[0472] - Eligibility confirmation and enrollment

[0473] Randomization and shipping period (Day 0 + up to 2 weeks):

[0474] - Randomly assigned to one of the following two groups:

[0475] ○Exemplary Component II

[0476] ○Comparative component II

[0477] - Provide the preferred shipping address for topical investigational product / placebo cream and study supplies.

[0478] - Delivery of topical study product / placebo cream and study supplies to and receipt of the participant's home.

[0479] -Once participants receive their shipments, they will enter a baseline period.

[0480] Baseline period (Days 1 to 7):

[0481] Day 1:

[0482] -Complete the Patient-Oriented Eczema Measure (POEM)

[0483] - Target lesion photographs / Target Lesion Severity Score (TLSS)

[0484] ○ Study investigators will identify target lesions from photographs taken at screening to confirm AD

[0485] ○ Participants will use Chloe to take pictures of the target lesion

[0486] ○ Investigators will use photographs to complete the Target Lesion Severity Score (TLSS)

[0487] -Start using a wrist-worn electronic device to track nighttime scratching during sleep

[0488] daily:

[0489] - Completed Itch-NRS (average itching and worst itching)

[0490] - Continue to track nighttime scratching during sleep using the wrist-worn electronic device until Day 7.

[0491] Topical Study Product / Placebo Period (Day 8 to Day 35):

[0492] daily:

[0493] - Start topical study product / placebo application

[0494] ○ Apply topical study product / placebo cream twice daily to AD-affected skin, especially target lesions

[0495] -Complete research product compliance issues

[0496] - Adverse event question: Complete Itch-NRS (average itching and worst itching)

[0497] - Adverse event investigation: Continue to use the wearable device to track nighttime scratching until day 35

[0498] At the end of each week (Days 14, 21, 28, and 35):

[0499] - Adverse event observation: taking target lesion photos / target lesion severity score (TLSS)

[0500] ○ Participants will use Chloe to take pictures of the target lesion

[0501] ○ Investigators will use photographs to complete the Target Lesion Severity Score (TLSS)

[0502] - Skin appearance issues: Patient global impression of change (P-GIC)

[0503] - Complete questions regarding any other adverse events / reactions related to study product / placebo use

[0504] At the end of the topical study product / placebo cream application period (Day 35):

[0505] -Complete the Patient-Oriented Eczema Measure (POEM)

[0506] -Complete the experience survey

[0507] Open-label extension period (Day 36 to Day 63):

[0508] -Optional Open Label Use Example Component II

[0509] - Participants who choose to postpone will receive the product shipment

[0510] - Report any adverse reactions / events related to product use at any time

[0511] - Continue to use the wrist-worn electronic device to track nighttime scratching during sleep until day 63

[0512] End of open-label extension period (Day 63)

[0513] -Complete research product compliance issues

[0514] -Complete the Skin Appearance Question: Patient Global Impression of Change (P-GIC)

[0515] Research Questionnaires and Assessments

[0516] Itch Numeric Rating Scale The Itch Numeric Rating Scale (NRS) is a simple, self-administered measure of itch severity. Daily, participants will rate their average and worst itching over the past 24 hours using a 10-point NRS. Additionally, objective activity data will be collected from a wearable device worn nightly with an app that tracks nighttime scratching and syncs the data to their smartphone.

[0517] Patient-Oriented Eczema Measure (POEM) : POEM is a validated, patient-derived questionnaire used to assess symptoms and monitor severity of atopic dermatitis. It is a 7-question assessment with a maximum score of 28, which translates to eczema severity. This will be administered at baseline and at the end of the topical study product / placebo period.

[0518] Patient Global Impression of Change (P-GIC) : Patient Global Impression of Change (P-GIC) is a 7-point Likert scale that reflects the participant's rating of the overall improvement in skin appearance. This will be applied daily during the topical study product / placebo use period.

[0519] Target Lesion Severity Score (TLSS) : The Target Lesion Severity Score (TLSS) is a measurement completed by the investigator that assesses the severity of AD lesions based on erythema, induration, hyperplasia, lichenification, exudation / crusting, and desquamation. Each of the 5 characteristics is assessed on a 4-point scale, with a maximum TLSS score of 15. This will be completed by the investigator using target lesion photographs captured by the participant at baseline and at the end of each applied week.

[0520] Adverse event investigation : At the end of each week during the topical study product / placebo use period, participants will be asked about any additional negative experiences in an objective manner, such as "Have you experienced any unusual symptoms or problems since the last week?"

[0521] Experience Survey : The experience survey will include questions related to product usage, likelihood of continued use, product preferences, and experience with the app, research tools, and research in general.

[0522] A comparison of the various assessments described above with the treatment of various conditions or diseases is provided in Table 3 below.

[0523] Table 3. Comparison of assessment and treatment of illness or disease

[0524]

[0525] Example 4

[0526] To investigate the safety, skin tolerability, and effectiveness of Exemplary Composition II in improving skin appearance in subjects, including subjects with diabetic peripheral neuropathy and diabetic dermopathy

[0527] A multicenter, double-blind, randomized, vehicle-controlled, single-dose study of exemplary component II and a vehicle cream (comparative component II) was conducted to evaluate the safety, skin tolerance, and efficacy of nootkatone compared to vehicle. The study duration included exemplary comparative regimen II or comparative comparative regimen II, twice daily for 8 weeks. 60 male and female patients over 18 years of age with diabetic peripheral neuropathy (DPN) and meeting inclusion / exclusion criteria were included in the study.

[0528] Study and treatment duration : Approximately 13 weeks (4 weeks screening; 8 weeks application and 1 week follow-up).

[0529] Study objectives and endpoints related to safety, tolerability, and improvement in skin appearance :

[0530] Table 4: Study objectives and endpoints related to skin appearance

[0531]

[0532] Testing cosmetics Testing products and application methods : Participants were randomized to receive one of the following investigational products, as described below:

[0533] - Exemplary Component II

[0534] -Comparative Component II

[0535] Administration :Exemplary component II cream and comparative component II cream are applied topically twice daily to the affected areas of DPN for 8 weeks. Participants are instructed to apply the test product to all DPN affected areas (skin blemishes), including areas that have resolved, as well as any new skin blemishes (DPN lesions) that may appear during the 8-week application period. At baseline, lesions that represent the participant's overall DPN condition and will be treated with the cosmetic test product are selected as target lesions. At each subsequent visit during the application period, this lesion is identified, measured, and recorded in the participant's study record.

[0536] Research Standards Evaluation :

[0537] Safety Assessment:

[0538] Adverse events (AEs) and serious adverse events (SAEs)

[0539] Skin tolerance (erythema, edema, burning / stinging, pain, itching)

[0540] Investigator's assessment of skin appearance:

[0541] TLSS (Target Lesion Severity Score):

[0542] Table 5: Participant Evaluations

[0543]

[0544] Other measures : Photography of target lesions.

[0545] Statistical methods : Appropriate statistical methods were used to validate the research results obtained in this paper.

[0546] A comparison of the various assessments described above with treatments for various conditions or diseases is provided in Table 6 below.

[0547] Table 6. Comparison of assessment and treatment of illness or disease

[0548]

[0549]

[0550] Example 5

[0551] A 4-week study evaluating the effects of the compound on pain patients

[0552] A 4-week vehicle-controlled, double-blind trial was conducted to evaluate the safety and tolerability of a topical cream for pain relief.

[0553] During the trial, patients applied a formulation containing nootkatone ("test product") topically to the treatment area twice daily, once in the morning and once in the evening, for 4 weeks. Subjects were instructed to gently cleanse the treatment area before applying the test product; however, the skin should be completely dry before application. Participants used the dosing guidelines shown in Table 7 below when applying the test product.

[0554] Table 7. Test Product Dosage Guidelines

[0555] body parts <![CDATA[Coverage per unit (in fingertip units) 1 > whole body 40 hand 1 arm 3 leg 6 face and neck 2.5 Torso (front and back) 14

[0556] 1 One fingertip unit is equivalent to 0.5g of test product

[0557] The test products used in the trial had different concentrations of nootkatone formulated in petrolatum: 0.375% w / w (Exemplary Component III), 0.75% w / w (Exemplary Component IV), 1.5% w / w (Exemplary Component V), 3% w / w (Exemplary Component VI). The vehicle test product contained petrolatum and did not contain nootkatone (Comparative Component III).

[0558] The trial involved four weeks of test product use for each participant and included assessments at baseline, before starting the test product, and on days 7, 14, 21, and 28 after use. Assessments were conducted virtually using a self-report questionnaire and photographs of the atopic dermatitis-affected body area treated with the test product at each assessment time point. The photographs adhered to standard photographic guidelines provided to participants and were scored by one or more board-certified dermatologists.

[0559] At each assessment, participants were evaluated according to the primary and secondary endpoints shown in Tables 8 and 9 below:

[0560] Table 8: Primary End Points

[0561]

[0562] Table 9: Secondary End Points

[0563]

[0564]

[0565] A comparison of the various assessments described above with treatments for various conditions or diseases is provided in Table 10 below.

[0566] Table 10. Comparison of assessment and treatment of disease or illness

[0567]

[0568] Example 6

[0569] A 4-week study evaluating the effects of a compound in patients with atopic dermatitis

[0570] A 4-week vehicle-controlled, double-blind trial was conducted to evaluate the safety and tolerability of a topical cream for the relief of atopic dermatitis.

[0571] Participants had a clinical diagnosis of mild to moderate atopic dermatitis according to the diagnostic criteria of Hanifin and Rajka, affecting 5% to 20% of the total body surface area (inclusive), excluding the face, scalp, axillae, and wrinkle areas. Patients with mixed skin diseases (including, for example, psoriasis, rosacea, erythroderma, or ichthyosis (except ichthyosis vulgaris)) were excluded from the trial.

[0572] During the trial, patients applied a formulation containing nootkatone ("test product") topically to the treatment area twice daily, once in the morning and once in the evening, for 4 weeks. Subjects were instructed to gently cleanse the treatment area before applying the test product; however, the skin should be completely dry before application. Participants used the dosing guidelines shown in Table 11 below when applying the test product.

[0573] Table 11. Test Product Dosage Guidelines

[0574] body parts <![CDATA[Unit coverage (in fingertip units) 1 > whole body 40 hand 1 arm 3 leg 6 face and neck 2.5 Torso (front and back) 14

[0575] 1 One fingertip unit is equivalent to 0.5g of test product

[0576] The exemplary test products used in the trial had different concentrations of nootkatone formulated in petrolatum: 0.375% w / w (exemplary component III), 0.75% w / w (exemplary component IV), 1.5% w / w (exemplary component V), 3% w / w (exemplary component VI). The vehicle test product contained petrolatum and did not contain nootkatone (comparative component III).

[0577] The trial involved four weeks of test product use for each participant and included assessments at baseline, before starting the test product, and on days 7, 14, 21, and 28 after use. Assessments were conducted virtually using a self-report questionnaire and photographs of the atopic dermatitis-affected body area treated with the test product at each assessment time point. The photographs adhered to standard photographic guidelines provided to participants and were scored by one or more board-certified dermatologists.

[0578] At each assessment, participants were evaluated according to the primary and secondary endpoints shown in Tables 12 and 13 below:

[0579] Table 12: Primary End Points

[0580]

[0581] Table 13: Secondary End Points

[0582]

[0583] A comparison of the various assessments described above with the treatment of various conditions or diseases is provided in Table 14 below.

[0584] Table 14. Comparison of assessment and treatment of disease or illness

[0585]

[0586]

[0587] Example 7

[0588] A study evaluating the effects of a compound on patients with psoriasis

[0589] A 4-week vehicle-controlled, double-blind trial was conducted to evaluate the safety and tolerability of a topical cream for the relief of psoriasis.

[0590] Participants had a clinical diagnosis of mild to moderate plaque psoriasis affecting 3% to 15% (inclusive) of their total body surface area, excluding the face, scalp, hands, or soles of the feet. Participants with mixed skin diseases (including, for example, atopic dermatitis, rosacea, erythroderma, or ichthyosis (except ichthyosis vulgaris)) were excluded from the trial.

[0591] During the trial, participants applied a formulation containing nootkatone ("test product") topically to the treatment area twice daily, once in the morning and once in the evening, for 4 weeks. Participants were instructed to gently cleanse the treatment area before applying the test product; however, the skin should be completely dry before application. Participants used the dosing guidelines shown in Table 15 below when applying the test product.

[0592] Table 15. Test Product Dosage Guidelines

[0593] body parts <![CDATA[Unit coverage (in fingertip units) 1 > whole body 40 hand 1 arm 3 leg 6 face and neck 2.5 Torso (front and back) 14

[0594] 1 One fingertip unit is equivalent to 0.5g of test product

[0595] The exemplary test products used in the trial had different concentrations of nootkatone formulated in petrolatum: 0.375% w / w (exemplary component III), 0.75% w / w (exemplary component IV), 1.5% w / w (exemplary component V), 3% w / w (exemplary component VI). The vehicle test product contained petrolatum and did not contain nootkatone (comparative component III).

[0596] The trial involved four weeks of test product use for each participant and included two on-site assessments for each participant: a baseline assessment immediately before starting the test product and an assessment after four weeks of use. At each visit, patients were assessed for the 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. Participants were also asked to provide a Patient Global Impression of Change (PGIC) during the four-week assessment period.

[0597] The Psoriasis Area and Severity Index is calculated by assessing the severity of erythema, induration, and scaling on a 0-4 scale for each of the head and neck, upper extremities, lower extremities, and trunk. Each symptom is assigned a score for each body region. Next, the sum of the scores for each body region is multiplied by a weighting factor, with the head assigned 0.1, the upper extremities assigned 0.2, the trunk assigned 0.3, and the lower extremities assigned 0.4. The resulting weighted score is then multiplied by a scale from 0 to 6 based on the percentage of the body area affected by psoriasis (unaffected = 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 added together to give the total PASI score.

[0598] The Physician Global Assessment (PGA) is an overall psoriasis severity rating on a scale of 0 to 4 assessed during the on-site visit. The criteria for each PGA level are shown in Table 16 below:

[0599] Table 16: Physician Global Assessment (PGA)

[0600] level Severity describe 0 Clear No evidence of psoriasis, but post-inflammatory discoloration may be present 1 Almost cleared Only mild plaque elevation, scaling, and erythema 2 Mild Mild plaque elevation, scaling, and erythema 3 Moderate Moderate plaque elevation, scaling, and erythema 4 severe Very obvious plaque elevation, scaling, and erythema

[0601] The investigators and participants each assessed and rated the severity of skin redness according to the criteria shown in Table 17 below.

[0602] Table 17: Skin redness assessment criteria

[0603] level describe 0 No 1 slight 2 Mild 3 Moderate 4 severe 5 Extremely severe

[0604] For each subject, a lateral sac measuring approximately 10 cm at baseline was selected. 2 Target lesions were 100 mm or larger. Target lesions had to be representative of the subject's disease state and must not be located on the hands, feet, or genitals. Target lesions were photographed from two viewing angles (close-up and regional body area). Target lesions were individually assessed for PGA, redness (investigator and subject), itching NRS, and Patient Global Impression of Change (PGIC). The following individual measurements were additionally assessed: erythema, edema / papule, exudation / crustation, excoriation, lichenification, and dryness.

[0605] The Pruritus Numerical Rating Scale (I-NRS) is a measure of the intensity of the worst itching reported daily by patients (24-hour recall). Participants rate the severity of their itchy skin by selecting a number from 0 (no itching) to 10 (worst itching imaginable) that best describes the worst itching they experienced in the past 24 hours.

[0606] The Pain Numeric Rating Scale (P-NRS) is a measure of the intensity of the worst itching reported daily by patients (24-hour recall). Participants rated the severity of their skin pain by selecting a number from 0 (no pain) to 10 (worst pain imaginable) that best described the worst pain they had experienced in the past 24 hours.

[0607] The Patient Global Impression of Change (PGIC) is an overall rating scale of 1 to 7 assessed during the on-site visit. Subjects were asked, "Since starting to use the test product, please describe your impression of the improvement in the look and feel of your skin." The PGIC scale is shown in Table 18 below.

[0608] Table 18. Patient Global Impression of Change (PGIC)

[0609] level describe 1 Very significant improvement 2 Significant improvement 3 Slightly improved 4 No change 5 Slightly worsened 6 Significant deterioration 7 Very significant deterioration

[0610] A comparison of the various assessments described above with treatments for various conditions or diseases is provided in Table 14 below.

[0611] Table 14. Comparison of assessment and treatment of disease or illness

[0612]

[0613] Example 8

[0614] The methods used in this study were adapted from the scientific literature to maximize reliability and reproducibility. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. The assays were performed under the conditions described below. As presented, IC 50 The value is obtained using MathIQ TM (ID Business Solutions Ltd., UK) determined by nonlinear least squares regression analysis, as shown in Table 19 below.

[0615] Table 19: Analysis of compound inhibition of therapeutic targets

[0616]

[0617] Example 9

[0618] The methods used in this study were adapted from the scientific literature to maximize reliability and reproducibility. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. The assays were performed under the conditions described below. As presented, IC 50 The value is obtained using MathIQ TM (ID Business Solutions Ltd., UK) determined by nonlinear least squares regression analysis, as shown in Table 20 below.

[0619] Table 20: Analysis of compound inhibition of therapeutic targets

[0620]

[0621]

[0622] Sodium channel, site 2 (Nav site 2) was evaluated using the following parameters:

[0623] -Source: Wistar rat brain (excluding cerebellum)

[0624] - Vehicle: 1.0% DMSO

[0625] - Incubation time / temperature: 60 minutes at 37°C

[0626] - Incubation buffer: 50 mM HEPES, 50 mM Tris-HCl, pH 7.4, 130 mM choline chloride, 5.4 mM KCl, 0.8 mM MgCl2, 5.5 mM glucose, 40 μg / ml LqTX

[0627] -Kd:0.052μM

[0628] -Ligand: 5.0 nM [ 3H]daraline

[0629] - Non-specific ligand: 100 μM veratridine

[0630] -Specific binding: 77%

[0631] - Quantitative method: radioligand binding

[0632] -Bmax: 0.7pmole / mg protein

[0633] Neuronal nitric oxide synthase (nNOS) was assessed using the following parameters:

[0634] -Source: Wistar rat cerebellum

[0635] -Substrate: 20.0 nM [3H]L-arginine

[0636] - Vehicle: 1.0% DMSO

[0637] - Pre-incubation time / temperature: 15 minutes at 25°C

[0638] - Incubation time / temperature: 10 minutes at 25°C

[0639] - Incubation buffer: 50 mM HEPES, pH 7.4, 1 mM EDTA, 1 mM NADPH, 1.25 mM CaCl2.2H2O, 1 mM DTT, 10 μg / ml calmodulin

[0640] -Quantitative method: [3H] citrulline quantification

[0641] Opioid kappa (OP2, KOP) was assessed using the following parameters:

[0642] -Source: Human recombinant HEK-293 cells

[0643] - Vehicle: 1.0% DMSO

[0644] - Pre-incubation time / temperature: 15 minutes at 25°C

[0645] - Incubation time / temperature: 60 minutes at 25°C

[0646] - Incubation buffer: 50 mM Tris-HCl, pH 7.4

[0647] -Kd:0.4nM

[0648] -Ligand: 0.6 nM [3H]diprenorphine

[0649] - Nonspecific ligand: 10.0 μM naloxone

[0650] -Specific binding: 90%

[0651] - Quantitative method: radioligand binding

[0652] -Bmax: 1.10 pmole / mg protein

[0653] Sigmaσ1 was evaluated using the following parameters:

[0654] -Source: Human Jurkat cells

[0655] - Vehicle: 1.0% DMSO

[0656] - Incubation time / temperature: 2 hours at 37°C

[0657] - Incubation buffer: 50 mM Tris-HCl, pH 8.0

[0658] -Kd:16.0nM

[0659] -Ligand: 15.0 nM [3H]pentazocine

[0660] - Nonspecific ligand: 10.0 μM haloperidol

[0661] -Specific binding: 90%

[0662] - Quantitative method: radioligand binding

[0663] -Bmax: 1.08pmole / mg protein

[0664] Adenosine A3 was assessed using the following parameters:

[0665] -Source: Human recombinant CHO-K1 cells

[0666] - Vehicle: 1.0% DMSO

[0667] - Incubation time / temperature: 60 minutes at 25°C

[0668] - Incubation buffer: 25 mM HEPES, pH 7.4, 5 mM MgCl2, 1 mM CaCl2, 0.1% BSA - Kd: 5.90 nM

[0669] -Ligand: 0.5 nM [ 125 I]AB-MECA

[0670] - Nonspecific ligand: 1.0 μM IB-MECA

[0671] -Specific binding: 83%

[0672] - Quantitative method: radioligand binding

[0673] -Bmax: 1.08pmole / mg protein

[0674] Prostaglandin EP2 was assessed using the following parameters:

[0675] -Source: Human recombinant HEK-293 cells

[0676] - Vehicle: 1.0% DMSO

[0677] - Incubation time / temperature: 2 hours at 25°C

[0678] - Incubation buffer: 10 mM MES, pH 6.0, 1 mM EDTA, 10 mM MgCl2

[0679] -Kd:3.10nM

[0680] -Ligand: 4.0 nM [ 3 H]Prostaglandin E2 (PGE2)

[0681] -Nonspecific ligand: 10.0 μM prostaglandin E2 (PGE2)

[0682] -Specific binding: 80%

[0683] - Quantitative method: radioligand binding

[0684] -Bmax: 1.40pmole / mg protein

[0685] The transporter norepinephrine (NET) was assessed using the following parameters:

[0686] -Source: Human recombinant MDCK cells

[0687] - Vehicle: 1.0% DMSO

[0688] - Incubation time / temperature: 3 hours at 4°C

[0689] - Incubation buffer: 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1 μM leupeptin, 10 μM PMSF

[0690] -Kd: 0.024 μM

[0691] -Ligand: 0.2 nM [ 125 I]RTI-55

[0692] - Nonspecific ligand: 10.0 μM desipramine

[0693] -Specific binding: 75%

[0694] - Quantitative method: radioligand binding

[0695] -Bmax: 2.50pmole / mg protein

[0696] Example 10

[0697] Nootkatone inhibits intrinsic dorsal root ganglion (DRG) firing in mice and humans

[0698] Dorsal root ganglion neurons sense surrounding danger and transmit this information to the central nervous system (CNS). Pruritogens released by skin and immune cells can directly activate specific neurons. Nootkatone was found to inhibit firing in the intrinsic dorsal root ganglia (DRG) of 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. In non-peptidergic mouse DRG, nootkatone exhibited a dose-dependent blockade of neuronal depolarization.

[0699] Mouse DRG dissection and cell culture:

[0700] Mouse DRG Dissection: All procedures in this study were performed in accordance with the rules and regulations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. WT adult mice were euthanized with CO2 and thoroughly sprayed with 70% (vol / vol) ethanol before DRG dissection. All following procedures were performed under sterile conditions. The euthanized mice were decapitated and the dorsal skin was incised along the midline from the neck to the tail. The skin was removed from the entire dorsal surface of the body. With the forelimbs immobilized, the spinal column was incised transversely at the last rib to ensure that only lumbar DRGs were collected, not thoracic DRGs. Starting from the incision in the spinal column, two straight longitudinal incisions were made through the adjacent tissue on both sides of the spine toward the tail. The spinal column was then cut in half horizontally toward the tail, ensuring that the vertebrae on both sides of the spine were severed. The posterior half of the spinal column was lifted, and if the incision was made correctly (not too high or too low along the dorsoventral midline), the DRGs were visible as white (partially translucent) spheres on both sides of the spinal column. Remove each ganglion by grasping the distal processes of the DRG (located posterior and inferior to the bulbous structure) using fine forceps. Avoid direct compression of the DRG bulb to minimize damage to any neurons. Remove all lumbar DRGs. Use Vannas-type iridectomy scissors to remove the distal and proximal processes from the DRG, then place the DRG in a culture dish containing cold Hanks' balanced salt solution (HBSS).

[0701] Mouse DRG cell culture and calcium measurement method: Mouse lumbar DRG neurons were removed, isolated, and plated on poly-D-lysine-coated plates for 24 hours. Before collecting experimental data, mouse DRG neurons were incubated with Fura-2-acetoxymethyl ester (Fura-2-AM) dye for at least 1 hour. 30mM K was applied every 6 minutes. + Mouse DRG neurons were depolarized to observe calcium influx caused by membrane depolarization. The first three administrations of potassium (K + ) was used as a control. Nootkatone was tested at concentrations of 10 μM, 30 μM, and 100 μM as follows: After the first three K+ control applications, nootkatone was applied sequentially at the above concentrations. Each 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 out after 60 seconds of incubation. 500 nM capsaicin was applied 6 minutes after the application of allyl isothiocyanate (AITC) and monitored for two minutes. In mouse DRG, 100 μM nootkatone was shown to block neuronal depolarization in capsaicin / transient receptor potential vanilloid subfamily member 1 (TRPV1) negative neurons, as shown in Figure 3. Figure 1A and Figure 1B shown.

[0702] Human DRG cell culture and DRG calcium assay methods: Human DRG neurons were isolated from a 32-year-old Hispanic male and used for calcium imaging assays.

[0703] A summary of human DRG cell culture, DRG calcium determination, and analysis is as follows:

[0704] i. Fluo-8 acetoxymethyl ester (Fluo-8 AM) Fluo-8 dye loading of human DRG neuron cultures.

[0705] ii. Electric field stimulation (EFS).

[0706] iii. Setting a high voltage activates 70-80% of neurons through action potential (AP) depolarization, but does not activate voltage-gated calcium channels by direct depolarization.

[0707] 1. Baseline (vehicle, 5 minutes).

[0708] High voltage electric field stimulation (10 pulses) was applied.

[0709] 2. Add the test substance (nootkatone) at a predetermined concentration (5 minutes).

[0710] High voltage electric field stimulation (10 pulses) was applied.

[0711] 3. Add the test substance (nootkatone) at a predetermined concentration (5 minutes).

[0712] High voltage electric field stimulation (10 pulses) was applied.

[0713] 4. Continue applying the test substance (Nootkatone).

[0714] 5. Add test substance (nootkatone) + 30 mM KCl.

[0715] 6. Add 200 nM capsaicin.

[0716] Human DRG calcium measurement analysis: The steps followed for the human DRG calcium measurement experiment and subsequent data analysis are provided below:

[0717] 1. Measuring the activation of each EFS neuron

[0718] a. Number of calcium steps before and after addition of nootkatone.

[0719] b. Amplitude of the first calcium step before and after addition of nootkatone.

[0720] c. Amplitude of cumulative calcium transients before and after addition of nootkatone.

[0721] 2. Measure the KCl response of each neuron.

[0722] a. Amplitude of KCl-induced neuronal oscillations.

[0723] 3. The number and percentage of responsive neurons under each experimental condition (i.e., nootkatone concentration).

[0724] Nootkatone was applied at 100 μM to observe its effect on KCl-induced neuronal depolarization / activity. Extracellular K+ and electric field stimulation were used to depolarize / activate neurons. The transient response of human DRG to KCl was shown in Figure 2. Figure 2 Nootkatone was applied at 30 uM (first application) and 100 uM (second application) to observe its effect on EFS-induced neuronal depolarization / activity (as shown in Figure 3A and Figure 3B shown).

[0725] In human DRG, 100 μM nootkatone blocked neuronal depolarization in capsaicin / TRPV1-positive neurons. Species differences in capsaicin / TRPV1 activity suggest that nootkatone may have greater efficacy in treating itch and pain, as TRPV1 neurons are implicated in both of these indications in humans.

[0726] Example 11

[0727] Efficacy of Nootkatone on Formalin-induced Pain Model in Mice

[0728] 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 the inflammatory, neurogenic, and central mechanisms of nociception. Injection of a 2.7% formalin solution into the surface of the hind paw of mice or rats allows for the simulation of acute and tonic pain using a single chemical in a relatively limited timeframe. This induces a biphasic nociceptive behavioral response, where the early response is thought to result from direct activation of small primary afferents, while the late nociceptive response is thought to occur through sensitization of central nervous system neurons within the dorsal horn (associated with neuropathic pain).

[0729] Experimental protocol for the formalin-induced pain model in rodents: The effect of nootkatone on formalin-induced nociception in male C57BL / 6 mice was evaluated as follows. Male C57BL / 6 mice were treated with nootkatone (3 mg / kg / 10 mL; po, 10 mg / kg / 10 mL; po, 30 mg / kg / 10 mL; po, 100 mg / kg / 10 mL; po and 300 mg / kg / 10 mL; po) for 3 days, and formalin (2.7% saline, 50 μl / mouse) was injected intraplantarly one hour after treatment on the third day. On the day of the intraplantar injection of formalin, positive control mice were treated with gabapentin (100 mpk, ip) and formalin was injected 30 minutes after gabapentin treatment. Nociceptive responses (paw licking and paw biting duration in seconds) were recorded from 0 to 40 minutes after the formalin injection (as Figure 4 The nociceptive response from 0 to 5 minutes after formalin injection was considered as stage 1 (as shown in Figure 5 ), while the reaction between 16 and 40 minutes was considered as stage 2 (as shown in Figure 6 Nootkatone has shown positive results in both Phase 1 and Phase 2 studies.

[0730] Example 12

[0731] Topical application of nootkatone alleviates acute pain in mice

[0732] This study was conducted to evaluate the efficacy of nootkadone in male C57BL / 6 mice using the tail-flick test. One day before the experiment began, mice were placed in a mouse holder to acclimate to the environment. During the experiment, mice were gently placed in a mouse holder with the middle third of their tails placed on a radiant heat source (Ugo Basile, Varese, Italy) with an infrared intensity setting of 25%. The latency to leaving the heat source (tail-flick) was measured to the nearest 0.1 second. Tail-flicking stopped stimulation and the tail-flick latency was automatically recorded with a cut-off time of 10 seconds. The average time of 3 measurements before topical application of the compound was used as the baseline latency. The baseline tail-flick latency of mice was recorded. Nootkadone (concentration range of 1.5%, 3% and 6%) was applied topically to the tails of mice, and the tail-flick latency was recorded 15 minutes, 30 minutes, 1.5 hours and 2 hours after application. 3% lidocaine emulsion was applied to positive control mice, and the tail-flick latency was recorded 15 minutes, 30 minutes, 1 hour, 1.5 hours, and 2 hours after the application.

[0733] The overall tail-flick latency was the average of three measurements obtained at least 1 min apart.

[0734] The Maximum Probable Effect % (MPE %) was calculated using the following formula:

[0735]

[0736] Where 10 = cut-off time for the tail-flick test (in seconds)

[0737] The positive control, 3% lidocaine, showed significant effects at all time points tested. The animals in the negative control group showed no effects at all time points tested. Topical application of nootkatone showed significant effects at all time points tested in a dose-dependent manner compared to the negative control (e.g. Figure 7 shown).

[0738] Example 13

[0739] Effects of nootkatone on a chloroquine-induced scratching / itch rodent model (oral and topical administration)

[0740] Oral administration of nootkatone alleviates chloroquine-induced scratching / itching in mice: Chloroquine (an antimalarial drug) induces an itchy sensation of biting and pricking in mice. Male ICR mice weighing 23±3 g were divided into six groups (n=8 / treatment group) as follows: Group 1 negative control (no treatment or chloroquine), Group 2 vehicle treatment (10 mL / kg, PO) + chloroquine (5 mg / Kg, SC), Group 3 diphenhydramine (60 mg / Kg, PO) + chloroquine (5 mg / Kg, SC), Group 4 nootkatone (10 mg / Kg, PO) + chloroquine (5 mg / Kg, SC), Group 5 nootkatone (30 mg / Kg, PO) + chloroquine (5 mg / Kg, SC), Group 6 nootkatone (100 mg / Kg, PO) + chloroquine (5 mg / Kg, SC). All animals (except mice in Group 1) received the vehicle for chloroquine subcutaneous injection (SC), with 5 mg / kg of chloroquine injected subcutaneously into the anterior end of the back using a 27-gauge needle in a volume of 10 mL / kg. Vehicle or test substance (nokadone) was given once by oral gavage (PO) 60 minutes before the injection of chloroquine. The vehicle for diphenhydramine was water, while the vehicle for treatment group 1 was Tween 80:0.5% MC (0.5:99.5, v / v). After the injection of the pruritogen, the number of scratches within 30 minutes was recorded by visual observation. Only scratches at the injection site were counted (other sites such as ears and face were excluded). Immediately after the scratching behavior test, all 8 animals in the test substance (nokadone) group (Groups 4-6; n=25) were bled by cardiac puncture. The collected blood was placed in a tube coated with lithium heparin, mixed gently, and then placed on ice and centrifuged at 2,500 × g for 15 minutes at 4°C within 1 hour of collection. The plasma was then collected and stored frozen at ≤-70°C until transported for further testing. Figure 8 As shown, oral administration of 30 mpk of nootkatone alleviated chloroquine-induced scratching / itching in mice.

[0741] Topical nootkatone alleviates chloroquine-induced scratching / itching in mice: Male ICR mice weighing 23±3 g were used. The study was divided into two runs, 2-3 days apart. All animals (except mice in group 1) received the vehicle for chloroquine subcutaneous injection (SC), with 5 mg / kg of chloroquine injected subcutaneously into the anterior end of the back using a 27-gauge needle in a volume of 10 mL / kg. Vehicle or test article (nootkatone) was administered topically (TOP) around the chloroquine injection site 60 minutes before chloroquine injection. The positive control, diphenhydramine, was administered once by oral gavage (PO) 60 minutes before chloroquine injection. The vehicle for chloroquine: 0.9% NaCl, the vehicle for diphenhydramine: 5% DMSO / 2% Tween 80; the vehicle for TA1: TBD. After injection of the pruritogen, the number of scratches was recorded by visual observation within 30 minutes (10 minutes per interval × 3 intervals). Only scratching at the injection site was counted (other sites such as ears and face were excluded). 10% topical nootkatone alleviated chloroquine-induced scratching / itching in mice (e.g. Figure 9 10% topical nootkatone was found to be more effective than clobetasol (a steroid) and ruxolitinib (a commercial JAK 1-2 inhibitor)

[0742] Example 14

[0743] Effects of nootkatone on a rodent model of itch induced by bovine adrenal medullary (BAM) 8-22

[0744] BALB / c mice were divided into six groups (n=8 / treatment group) as follows: Group 1 negative control (no treatment or chloroquine), Group 2 vehicle treatment (10 mL / kg, PO) + BAM 8-22 (150 μg / animal, SC), Group 3 cyproheptadine (3 mg / Kg, PO) + BAM 8-22 (150 μg / animal, SC), Group 4 nootkatone (10 mg / Kg, PO) + BAM 8-22 (150 μg / animal, SC), Group 5 nootkatone (30 mg / Kg, PO) + BAM 8-22 (150 μg / animal, SC), and Group 6 nootkatone (100 mg / Kg, PO) + BAM 8-22 (150 μg / animal, SC). All animals (except mice in Group 1) received a vehicle for subcutaneous (SC) injection of BAM 8-22, with 150ug / animal of BAM 8-22 injected subcutaneously into the anterior end of the back using a 27-gauge needle in a volume of 50uL. Vehicle or test article was administered by oral gavage (PO) 60 minutes before injection of BAM 8-22. Vehicle for BAM 8-22: 0.9% NaCl, vehicle for cyproheptadine: 2% Tween 80; vehicle for treatment group 1: Tween 80: 0.5% MC (400cPs) in saline (0.5:99.5, v:v). After injection of the pruritogen, the number of scratches was recorded by visual observation within 30 minutes. Only scratches at the injection site were counted (other sites such as ears and face were excluded). 100mg / Kg PO nootkatone alleviated BAM8-22-induced scratching / itching in mice (e.g. Figure 10 shown).

[0745] Example 15

[0746] Topical Nootkadone Formulations in the MC903 Mouse Model of Atopic Dermatitis

[0747] MC903, a hypocalcemic analog of vitamin D3, induces cutaneous and systemic atopic dermatitis / eczema-like inflammation. Topical application of MC903 to the ears of C57BL / 6J wild-type (WT) mice induced cutaneous inflammation and other AD-like phenotypes. This treatment increased ear skin thickness, a surrogate marker of ear skin inflammation.

[0748] During the first week of MC903 treatment, only minor changes in ear appearance, such as redness, dryness, swelling, and hypervascularization, were observed. These changes were clearly observed from the fifth day of MC903 treatment and worsened over time, especially in the last few days of the experiment.

[0749] Experimental Protocol: This study used 8-9 week old female C57BL / 6 mice. All mice were acclimated prior to treatment. Mice were housed in microisolator cages and maintained under specific pathogen-free conditions. All procedures were performed in accordance with appropriate institutional animal care guidelines. All animals, except for Group 1 (sham-operated) animals, had MC903 (2 nmole / 20 μL dissolved in 100% ethanol) applied topically (TOP) to the right ear daily for 14 consecutive days from day 1 to day 14. From day 7 to day 14, MC903 was applied one hour after the test article (3% and 10% nootkatone). Animals in Group 1 (sham-operated) had 20 μL of ethanol (no antigen) applied to the right ear daily for 14 consecutive days from day 1 to day 14. Vaseline vehicle and test article (nootkatone) were applied TOP twice a day (BID) at 6 hour intervals for 8 consecutive days from day 7 to day 14 (1 hour before MC903 challenge). The reference compound clobetasol (0.01 mg / ear) was topically applied once daily (1 hour before MC903 challenge) for 8 consecutive days from day 7 to day 14.

[0750] Female C57BL / 6 mice were randomly divided into the following treatment groups:

[0751] 1. Sham operation: no MC903, no treatment (negative control)

[0752] 2. Vehicle: MC903 treatment and petrolatum vehicle

[0753] 3. 0.05% clobetasol

[0754] 4.1.5% Ruxolitinib (Groups 3 and 4 served as positive control and comparison groups)

[0755] 5. 3% Nootkatone in petrolatum vehicle

[0756] 6. 10% Nootkatone in petrolatum vehicle

[0757] MC903 treatment was administered from day 1 to day 14. Clobetasol, ruxolitinib, and nootkadone treatment were administered from day 7 to day 14.

[0758] Treatment was administered 1 hour before MC903 challenge. Scratching behavior was recorded for 60 minutes immediately after MC903 challenge. Clobetasol (steroid) and ruxolitinib (JAK 1-2 inhibitor) were used as positive controls. Figure 11 As shown, 3% nootkatone was more effective than clobetasol (steroid) and ruxolitinib (JAK 1-2 inhibitor). 3% nootkatone showed a strong effect on scratching behavior on day 7.

[0759] Example 16

[0760] Effects of nootkatone on imiquimod (IMQ)-induced psoriasis mouse model

[0761] Experimental Protocol: Female Balb / c mice, 10-12 weeks old, were used in the study. All mice were acclimated prior to handling. Mice were housed in microisolator cages and maintained under specific pathogen-free conditions. During this period, mice were observed daily for clinical signs. Mice exhibiting any abnormalities or showing poor health or body condition were excluded from the study. All procedures were performed in accordance with appropriate institutional animal care guidelines. On day 1, mice were randomized into groups based on dorsal skinfold thickness and body weight. Hair on the backs of the mice was removed using depilatory cream and a hair shaving razor.

[0762] The research design is shown in Table 21 below:

[0763] Table 21:

[0764] Serial number Treatment group, n = 10 (each group), randomized according to back thickness and body weight on day 1 1 G1, sham control + vehicle (topical; QD x 6) 2 G2, clobetasol propionate (0.05%, topical; QD x 6) + IMQ (5%, topical; QD x 5) 3 G3, vehicle (topical; QD x 6) + IMQ (5%, topical; QD x 5) 7 G7, TA-4 (nokadone, 2.5%, topical; QD x 6) + IMQ (5%, topical; QD x 5) 8 G8, TA-5 (nokadone, 10%, topical; QD x 6) + IMQ (5%, topical; QD x 5)

[0765] Nootkatone in petrolatum gel was applied topically in the IMQ psoriasis model at concentrations ranging from 2.5% to 10%, and additional itch readings were taken. Imiquimod (5%) was applied: 47 mg to the back skin and 15.5 mg to the right ear once daily for 5 days (4 hours after treatment).

[0766] Key study parameters are as follows:

[0767] Parameters for Days 1, 2, 3, 4, 5 and 6:

[0768] ■Weight

[0769] ■Thickness of back skin folds and ear thickness

[0770] Psoriasis Area and Severity Index (PASI)

[0771] ■One-hour itch test on days 1, 4, and 6

[0772] Histopathology (dorsal skin and right ear)

[0773] Bioassay (optional): 4 hours after topical application of test compound on day 6 (optional)

[0774] Gene expression analysis of biomarkers (optional)

[0775] Nootkatone caused a small but significant decrease in some psoriasis readings (e.g., Figure 12 and Figure 13Cumulative PASI, back redness + thickness + desquamation score + ear redness + thickness + desquamation score, 0-24, is shown in ). In this study, effects were mainly observed at the later time points.

[0776] Example 17

[0777] Effects of nootkatone on DSS-induced locomotor activity in mice

[0778] Dextran sodium sulfate (DSS)-induced locomotor activity refers to changes in locomotor patterns observed after the administration of DSS, a compound commonly used to induce colitis in experimental models. Assessment of locomotor activity after DSS administration is crucial for understanding the behavioral effects of DSS-induced colitis. During the assessment, the following activities were monitored: walking time, distance traveled, rest time, time spent in the center area, number of center area entries, and wall standing. Open field test analysis was performed using the BehaviorCloud platform. Decreased locomotor activity often indicates discomfort or illness-related lethargy, while increased activity may indicate anxiety or compensatory behavior. These locomotor responses to DSS are valuable for elucidating the peripheral and central effects of colitis and the efficacy of therapeutic interventions. As Figure 14 The mouse model was prepared as shown in the following table. Figures 15A to 15F shown.

[0779] Compared with the vehicle control, the motor activity (distance traveled, walking time, rest time) of the disease control mice was significantly reduced. Compared with the vehicle group, the distance traveled and walking time of the DSS group were significantly reduced, while the rest time was significantly increased. Compared with the disease control mice, 100 and 300mg / kg doses of nootkatone showed a trend of improved motor activity. Regional activity analysis (central area residence time and number of entries) showed that DSS mice were more anxious compared with the vehicle control, while mice treated with nootkatone showed improved exploratory behavior. Compared with the normal exploratory behavior of the control mice (standing against the box wall), the DSS mice showed significantly reduced exploratory behavior, while the mice treated with 300mg / kg nootkatone showed an increase in exploratory behavior compared with the DSS mice.

[0780] Example 18

[0781] Effects of nootkatone on visceral pain in a DSS-induced colitis mouse model

[0782] The study aimed to explore the mechanisms of visceral pain in a mouse model of DSS (dextran sulfate sodium)-induced colitis, a common method for simulating inflammatory bowel disease (IBD) in a laboratory setting. The main focus of this study was to understand the pain pathways and their regulation in the context of IBD. To achieve this goal, the study used a combination of the Disease Activity Index (DAI) score and plasma and colon tissue exposure analysis to quantify inflammation and its systemic effects. The DAI score is a comprehensive measurement that takes into account weight loss, stool consistency, and bleeding, providing a reliable assessment of the severity of colitis. Simultaneously, exposure analysis in plasma and colon tissue assessed the presence and concentration of inflammatory markers, cytokines, and other biochemical indicators of inflammation. This dual approach ensures a thorough understanding of the inflammatory process at both the local and systemic levels.

[0783] Behavioral parameters, specifically the von Frey pain response and capsaicin-induced pain response, are essential components of studies assessing sensory and pain aspects in mouse models. The von Frey test involves the application of a calibrated filament to measure mechanical pain sensitivity, which helps assess alterations in pain perception caused by colitis. In contrast, the capsaicin-induced pain response test involves the administration of capsaicin (a component known to induce pain and mimic human inflammatory pain) and observing the pain response, providing insight into nociceptive pathways and pain regulation in the context of colitis. These behavioral tests are crucial in correlating the degree of inflammation with pain severity, thereby providing a deeper understanding of the mechanisms of visceral pain in the context of IBD. Figure 16 The mouse model was prepared as shown in Figure 2. The results of Von Frey analysis were shown in Figure 2. 17A to 17D The results of capsaicin-induced visceral pain analysis are shown in Figures 17E to 17I shown.

[0784] Von Frey analysis was performed using two methods: the up-down method and nociceptive scoring using 0.008g, 0.02g, and 0.16g filaments. Nootkatone demonstrated dose-dependent antihyperalgesic effects in both methods. Nootkatone at a dose of 300mg / kg BID exhibited significant antihyperalgesic activity in the up-down method.

[0785] The DSS group exhibited the highest nociceptive behaviors after colonic instillation of capsaicin. Nootkatone treatment demonstrated a significant dose-dependent reduction in nociceptive behaviors. Licking and squeezing of the abdomen were reduced in the treated group after capsaicin instillation; no abdominal retraction was observed. Stretching behaviors were confounded with rearing behaviors and therefore not included in the statistical analysis of total responses. Nootkatone dose-dependently reduced overall nociceptive responses.

[0786] Example 19

[0787] Effects of nootkatone on visceral pain in a TNBS-induced colitis mouse model

[0788] The study aimed to explore the mechanisms of visceral pain in a mouse model of TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced colitis, a common method for mimicking inflammatory bowel disease (IBD) in laboratory settings. The main focus of this study was to understand pain pathways and their regulation in the context of IBD. To achieve this goal, the study used a combination of the Disease Activity Index (DAI) score and plasma and colonic tissue exposure analysis to quantify inflammation and its systemic effects. The DAI score is a comprehensive measurement that takes into account weight loss, stool consistency, and bleeding, providing a reliable assessment of colitis severity. Simultaneously, exposure analysis in plasma and colonic tissue assessed the presence and concentrations of inflammatory markers, cytokines, and other biochemical indicators of inflammation. This dual approach ensured a thorough understanding of the inflammatory process at both the local and systemic levels.

[0789] Behavioral parameters, specifically the von Frey pain response and capsaicin-induced pain response, are essential components of studies assessing sensory and pain aspects in mouse models. The von Frey test involves the application of a calibrated filament to measure mechanical pain sensitivity, which helps assess alterations in pain perception caused by colitis. In contrast, the capsaicin-induced pain response test involves the administration of capsaicin (a component known to induce pain and mimic human inflammatory pain) and observing the pain response, providing insight into nociceptive pathways and pain regulation in the context of colitis. These behavioral tests are crucial in correlating the degree of inflammation with pain severity, thereby providing a deeper understanding of the mechanisms of visceral pain in the context of IBD. Figure 18 The mouse model was prepared as shown in Figure 2. The results of Von Frey analysis were shown in Figure 2. 19A to 19D The results of capsaicin-induced visceral pain analysis are shown in Figures 19E to 19J shown.

[0790] Two Von Frey assays were performed: the up-down method and nociceptive scoring using 0.008g, 0.02g, and 0.16g filaments. Nootkatone demonstrated dose-dependent anti-hyperalgesic effects in both assays. Nootkatone at 300mg / kg BID demonstrated significant anti-hyperalgesic activity in both assays.

[0791] Mice in the TNBS-induced colitis model exhibit severe visceral pain, as they spend most of their time in a state of torpor following capsaicin infusion into the colon. While in torpor, mice exhibit minimal and varied spontaneous pain behaviors. Nootkatone demonstrates a significant, dose-dependent reduction in torpor.

Claims

1. A method for 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 naturally present in the nootkadone-containing source; or (b) the nootkadone 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 administered topically.

5. The method of any one of claims 1 to 4, wherein the composition has less than about 1% w / w of other components naturally present 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 nootkatone.

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

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

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

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

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

15. The method of any one of claims 1 to 13, wherein administering the composition to the subject reduces itching as evidenced by a reduction in atopic dermatitis after a predetermined amount of time as determined by 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 channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB; and Optionally, wherein: (a) the composition has less than about 5% w / w of other components naturally present in the nootkadone-containing source; or (b) the nootkadone 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 channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2), and NF-κB.

18. Use of nootkatone or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing pruritus in a subject by inhibiting or modulating a therapeutic target, wherein the therapeutic target is at least one of voltage-gated sodium channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

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

20. Nootkatone in a method for treating pruritus, the method comprising: A therapeutically effective amount of the nootkatone or a pharmaceutically acceptable salt thereof is topically administered to the skin of a subject in need thereof, wherein the therapeutically effective amount is sufficient to modulate the 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 channel (NaV), kappa opioid receptor (KOR), σ1, nNOS, adenosine A3, prostaglandin EP2, norepinephrine transporter, neurokinin-1 receptor (NK1R), ASIC(3) channel, MRGPRX1, nuclear factor erythroid 2 (NFE2) and NF-κB.

22. The method of claim 21, wherein the topical administration comprises topically administering an amount sufficient to reduce the severity of itching and to relieve itching by causing resolution of one or more symptoms associated with itching.

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