WO2018129315A1

WO2018129315A1 - Methods and compositions for the treatment of disease

Info

Publication number: WO2018129315A1
Application number: PCT/US2018/012581
Authority: WO
Inventors: Christoph Westphal; Thomas Wessel
Original assignee: Flex Pharma Inc
Current assignee: Salarius Pharmaceuticals Inc
Priority date: 2017-01-06
Filing date: 2018-01-05
Publication date: 2018-07-12
Anticipated expiration: 2019-07-06

Abstract

The invention relates to methods and compositions comprising a TRP channel or ASIC channel activator for preventing or treating a disease, disorder, or condition described herein.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF DISEASE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62/443,485 filed January 6, 2017, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND

Transient receptor potential (TRP) channels are nonselective cation channels that function as cellular sensors that respond to and integrate diverse signals, including temperature, mechanical stress, exogenous chemicals, and endogenous chemicals, such as intracellular and extracellular messengers. These channels are involved in multiple functions, including pain, temperature, and mechanical sensation, calcium and magnesium homeostasis, lysosomal function, cardiovascular regulation, and control of cell growth and proliferation.

Acid-sensing ion channels (ASIC) are neuronal voltage-insensitive cationic channels that are activated by extracellular protons. ASIC channels are primarily expressed in the nervous system, and conduct mostly Na⁺. Because of their involvement in multiple cellular processes, TRP and ASIC channels play a major contributing role in a wide variety of neurological disorders, including neuropathic pain, cell injury during cerebral ischemia, and mucolipidosis type IV.

There exists a need in the art for improved methods and compositions for treating conditions such as Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof. As shown herein, compositions that include activators of ion channels (e.g., TRP or ASIC channels) may be useful to treat the above-mentioned conditions. SUMMARY OF THE INVENTION

In one aspect, the present disclosure features a method for preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof in a subject. In some embodiments, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single shogaol analog and less than about 25% of the total shogaol concentration in the composition (e.g., by mole or by weight) of a related analog thereof (e.g., less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1 %, less than about 0.1%, or is substantially free of a related analog thereof). In an embodiment, the composition comprises a single shogaol analog and is substantially free of a related analog thereof.

In some embodiments, the single shogaol analog is, e.g., 6-shogaol. In some

embodiments, the amount of the single shogaol analog (e.g., 6-shogaol) in the composition is from about 0.01 mg to about 1000 mg (e.g., about 0.1 mg to about 500 mg, about 0.5 mg to about 250 mg, about 10 mg to about 100 mg, about 25 mg to about 75 mg). In some

embodiments, the amount of the single shogaol analog (e.g., 6-shogaol) in the composition is from about 5 mg to about 1000 mg (e.g., about 10 mg to about 250 mg, about 15 mg to about 200 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single shogaol analog (e.g. 6-shogaol) in the composition is from about 0.0001 % (w/v) or (w/w) to about 10% (w/v) or (w/w). In some embodiments, the amount of the single shogaol analog (e.g. 6-shogaol) in the composition is from about 0.001% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w).

In some embodiments, the composition further comprises a single gingerol analog, e.g., 6-gingerol. In some embodiments, the amount of the single gingerol analog (e.g., 6-gingerol) in the composition is from about 0.01 mg to about 1000 mg (e.g., about 0.1 mg to about 500 mg, about 0.5 mg to about 250 mg, about 10 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single gingerol analog (e.g., 6-gingerol) in the composition is from about 5 mg to about 1000 mg (e.g., about 10 mg to about 250 mg, about 15 mg to about 200 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single gingerol analog (e.g. 6-gingerol) in the composition is from about 0.0001% (w/v) or (w/w) to about 10% (w/v) or (w/w). In some embodiments, the amount of the single gingerol analog (e.g. 6-gingerol) in the composition is from about 0.001% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w). In one aspect, the present disclosure features a method for preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich' s ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof in a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single gingerol analog and less than about 25% of the total gingerol concentration in the composition (e.g., by mole or by weight) of a related analog thereof (e.g., less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, less than about 0.1%, or is substantially free of a related analog thereof). In an embodiment, the composition comprises a single gingerol analog and is substantially free of a related analog thereof.

In some embodiments, the single gingerol analog is, e.g., 6-gingerol. In some embodiments, the amount of the single gingerol analog (e.g., 6-gingerol) in the composition is from about 0.01 mg to about 1000 mg (e.g., about 0.1 mg to about 500 mg, about 0.5 mg to about 250 mg, about 10 mg to about 100 mg, about 25 mg to about 75 mg). In some

embodiments, the amount of the single gingerol analog (e.g., 6-gingerol) in the composition is from about 5 mg to about 1000 mg (e.g., about 10 mg to about 250 mg, about 15 mg to about 200 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single gingerol analog (e.g. 6-gingerol) in the composition is from about 0.0001 % (w/v) or (w/w) to about 10% (w/v) or (w/w). In some embodiments, the amount of the single gingerol analog (e.g. 6-gingerol) in the composition is from about 0.001% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w).

In some embodiments, the composition further comprises a single shogaol analog, e.g., 6- shogaol. In some embodiments, the amount of the single shogaol analog (e.g., 6-shogaol) in the composition is from about 0.01 mg to about 1000 mg (e.g., about 0.1 mg to about 500 mg, about 0.5 mg to about 250 mg, about 10 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single shogaol analog (e.g., 6-shogaol) in the composition is from about 5 mg to about 1000 mg (e.g., about 10 mg to about 250 mg, about 15 mg to about 200 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single shogaol analog (e.g. 6-shogaol) in the composition is from about 0.0001 % (w/v) or (w/w) to about 10% (w/v) or (w/w). In some embodiments, the amount of the single shogaol analog (e.g. 6-shogaol) in the composition is from about 0.001% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w).

In any and all aspects, in some embodiments, the molar ratio of the single gingerol analog (e.g., 6-gingerol) and the single shogaol analog (e.g., 6-shogaol) is from about 1000: 1 to about 1 : 1 (e.g., about 750: 1, about 500: 1, about 250: 1 , about 200: 1, about 100: 1, about 50: 1, about 25 : 1, about 10: 1, about 5 : 1, about 2.5 : 1).

In some embodiments, the composition further comprises a single capsaicinoid analog, e.g., capsaicin. In some embodiments, the amount of the single capsaicinoid analog (e.g., capsaicin) in the composition is from 0.001 mg to about 20 mg (e.g., about 0.01 mg to about 10 mg, about 0.05 mg to about 5 mg, about 0.075 mg to about 2.5 mg, about 0.1 mg to about 1 mg). In some embodiments, the amount of the single capsaicinoid analog (e.g. capsaicin) in the composition is from about 0.0001% (w/v) or (w/w) to about 10% (w/v) or (w/w). In some embodiments, the amount of the single capsaicinoid analog (e.g. capsaicin) in the composition is from about 0.001 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w). In some embodiments, the molar ratio of the single gingerol analog (e.g., 6- gingerol) and the single capsaicinoid analog (e.g., capsaicin) is from about 1000: 1 to about 5: 1 (e.g., about 750: 1, about 500: 1, about 250: 1, about 200: 1, about 100: 1, about 50: 1, about 25 : 1, about 10: 1). In some embodiments, the molar ratio of the single shogaol analog (e.g., 6-shogaol) and the single capsaicinoid analog (e.g., capsaicin) is from about 1000: 1 to about 5 : 1 (e.g., about 750: 1, about 500: 1, about 250: 1, about 200: 1, about 100: 1, about 50: 1, about 25: 1, about 10: 1).

In some embodiments, the composition further comprises trans -cinnamaldehyde. In some embodiments, the amount of the trans -cinnamaldehyde in the composition is from 5 mg to about 1000 mg (e.g., about 10 mg to about 250 mg, about 15 mg to about 200 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of trans- cinnamaldehyde in the composition is from about 0.0001% (w/v) or (w/w) to about 20% (w/v) or (w/w). In some embodiments, the amount of trans-cinnamaldehyde in the composition is from about 0.001% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w). In some embodiments, the molar ratio of the single gingerol analog (e.g., 6-gingerol) and trans-cinnamaldehyde is from about 1000: 1 to about 1: 1 (e.g., about 750: 1, about 500: 1, about 250: 1, about 200: 1, about 100: 1, about 50: 1, about 25: 1, about 10: 1, about 5: 1, about 2.5: 1). In some embodiments, the molar ratio of the single shogaol analog (e.g., 6-shogaol) and trans-cinnamaldehyde is from about 1000: 1 to about 1: 1 (e.g., about 750: 1, about 500: 1, about 250: 1, about 200: 1, about 100: 1, about 50: 1, about 25: 1, about 10: 1, about 5: 1, about 2.5: 1).

In some embodiments, the composition has a residence time of greater than about 5 seconds in the mouth of a subject, e.g., greater than about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, about 10 seconds, about 11 seconds, about 12 seconds, about 13 seconds, about 14 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 45 seconds, about 60 seconds, about 90 seconds, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, or more. In some embodiments, the composition has a residence time of greater than about 60 seconds in the mouth of a subject, e.g., greater than about 90 seconds, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, or more.

In some embodiments, the composition is formulated to have minimal systemic exposure in the subject, e.g., wherein the systemic exposure is measured through the concentration of the active ingredient (e.g., a gingerol, e.g., 6-gingerol) in the blood, urine, or tissue (e.g., adipose tissue) of the subject. In some embodiments, the composition is formulated to have less than about 50% total systemic exposure in a subject, e.g., less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, less than about 0.1%, less than about 0.05%, less than about 0.01%, or less systemic exposure in a subject. In another aspect, the present disclosure features a method for preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereofin a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single capsaicinoid analog and less than about 25% of the total capsaicinoid concentration in the composition (e.g., by mole or by weight) of a related analog thereof (e.g., less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, less than about 0.1%, or is substantially free of a related analog thereof). In an embodiment, the composition comprises a single capsaicinoid analog and is substantially free of a related analog thereof.

In some embodiments, the single capsaicinoid analog is, e.g., capsaicin. In some embodiments, the amount of the single capsaicinoid analog (e.g., capsaicin) in the composition is from 0.001 mg to about 20 mg (e.g., about 0.01 mg to about 10 mg, about 0.05 mg to about 5 mg, about 0.075 mg to about 2.5 mg, about 0.1 mg to about 1 mg). In some embodiments, the amount of the single capsaicinoid analog (e.g. capsaicin) in the composition is from about 0.0001 % (w/v) or (w/w) to about 10% (w/v) or (w/w). In some embodiments, the amount of the single capsaicinoid analog (e.g. capsaicin) in the composition is from about 0.001 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w).

In some embodiments, the composition further comprises a single gingerol analog, e.g., 6-gingerol. In some embodiments, the amount of the single gingerol analog (e.g., 6-gingerol) in the composition is from about 0.01 mg to about 1000 mg (e.g., about 0.1 mg to about 500 mg, about 0.5 mg to about 250 mg, about 10 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single gingerol analog (e.g., 6-gingerol) in the

composition is from about 5 mg to about 1000 mg (e.g., about 10 mg to about 250 mg, about 15 mg to about 200 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single gingerol analog (e.g. 6-gingerol) in the composition is from about 0.0001% (w/v) or (w/w) to about 10% (w/v) or (w/w). In some embodiments, the amount of the single gingerol analog (e.g. 6-gingerol) in the composition is from about 0.001% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w).

In some embodiments, the molar ratio of the single capsaicinoid analog (e.g., capsaicin) and the single gingerol analog (e.g., 6-gingerol) is from about 1000: 1 to about 1 : 1 (e.g., about 750: 1, about 500: 1, about 250: 1, about 200: 1, about 100: 1, about 50: 1, about 25 : 1, about 10: 1, about 5: 1, about 2.5 : 1).

In some embodiments, the composition further comprises a single shogaol analog, e.g., 6- shogaol. In some embodiments, the amount of the single shogaol analog (e.g., 6-shogaol) in the composition is from about 0.01 mg to about 1000 mg (e.g., about 0.1 mg to about 500 mg, about 0.5 mg to about 250 mg, about 10 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single shogaol analog (e.g., 6-shogaol) in the composition is from about 5 mg to about 1000 mg (e.g., about 10 mg to about 250 mg, about 15 mg to about 200 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of the single shogaol analog (e.g. 6-shogaol) in the composition is from about 0.0001 % (w/v) or (w/w) to about 10% (w/v) or (w/w). In some embodiments, the amount of the single shogaol analog (e.g. 6-shogaol) in the composition is from about 0.001% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w). In some embodiments, the molar ratio of the single capsaicinoid analog (e.g., capsaicin) and the single shogaol analog (e.g., 6-shogaol) is from about 1000: 1 to about 1 : 1 (e.g., about 750: 1, about 500: 1 , about 250: 1, about 200: 1, about 100: 1, about 50: 1, about 25: 1, about 10: 1 , about 5: 1, about 2.5 : 1).

In some embodiments, the composition further comprises trans -cinnamaldehyde. In some embodiments, the amount of the trans -cinnamaldehyde in the composition is from 5 mg to about 1000 mg (e.g., about 10 mg to about 250 mg, about 15 mg to about 200 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg). In some embodiments, the amount of trans- cinnamaldehyde in the composition is from about 0.0001% (w/v) or (w/w) to about 20% (w/v) or (w/w). In some embodiments, the amount of trans-cinnamaldehyde in the composition is from about 0.001% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1 % (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w). In some embodiments, the molar ratio of the single capsaicinoid analog (e.g., capsaicin) and trans-cinnamaldehyde is from about 1000: 1 to about 1 : 1 (e.g., about 750: 1, about 500: 1, about 250: 1, about 200: 1, about 100: 1, about 50: 1, about 25 : 1, about 10: 1, about 5: 1, about 2.5: 1).

In some embodiments, the composition has a residence time of greater than about 5 seconds in the mouth of a subject, e.g., greater than about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, about 10 seconds, about 11 seconds, about 12 seconds, about 13 seconds, about 14 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 45 seconds, about 60 seconds, about 90 seconds, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, or more. In some embodiments, the composition has a residence time of greater than about 60 seconds in the mouth of a subject, e.g., greater than about 90 seconds, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, or more. In some embodiments, the composition is formulated to have minimal systemic exposure in the subject, e.g., wherein the systemic exposure is measured through the concentration of the active ingredient (e.g., a capsaicinoid, e.g., capsaicin) in the blood, urine, or tissue (e.g., adipose tissue) of the subject. In some embodiments, the composition is formulated to have less than about 50% total systemic exposure in a subject, e.g., less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, less than about 0.1 %, less than about 0.05%, less than about 0.01%, or less systemic exposure in a subject. In another aspect, the present disclosure features a method for preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich' s ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereofin a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single capsaicinoid analog (e.g., capsaicin) and one of a single gingerol analog (e.g., 6-gingerol) or a single shogaol analog (e.g., 6-shogaol), and wherein said composition is substantially free of a related analog thereof. In some embodiments, the composition comprises a single capsaicinoid analog (e.g., capsaicin) and one of a single gingerol analog (e.g., 6-gingerol) or a single shogaol analog (e.g., 6-shogaol), and less than about 25% of the total capsaicinoid, gingerol, or shogaol concentration in the composition (e.g., by mole or by weight) of related analogs thereof (e.g., less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1 %, less than about 0.1%, or is substantially free of a related analog thereof).

In another aspect, the present disclosure features a method for the prevention or treatment of a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox-Gastaut syndrome, limb-girdle muscular dystrophy,

Morvan' s syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof, wherein the method comprises orally administering a composition comprising a dosage of a single gingerol analog (e.g., 6-gingerol), a single shogaol analog (e.g., 6-shogaol), or a single capsaicinoid analog (e.g., capsaicin), wherein if present, the dosage of the single gingerol analog (e.g., 6-gingerol) or single shogaol analog (e.g., 6-shogaol) in the composition is between about 0.01 mg and about 1000 mg; and if present, the dosage of the single capsaicinoid analog (e.g., capsaicin) in the composition is between about 0.001 mg and about 100 mg. In an embodiment, the composition comprises a single gingerol analog (e.g., 6-gingerol), a single shogaol analog (e.g., 6-shogaol), or a single capsaicinoid analog (e.g., capsaicin), and is substantially free of related analogs thereof.

Morvan' s syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof, wherein the method comprises orally administering a composition comprising a dosage of a single gingerol analog (e.g., 6-gingerol), a single shogaol analog (e.g., 6-shogaol), or a single capsaicinoid analog (e.g., capsaicin), wherein if present, the dosage of the single gingerol analog (e.g., 6-gingerol) or single shogaol analog (e.g., 6-shogaol) in the composition is between about 0.05 mM and about 500 mM; and if present, the dosage of the single capsaicinoid analog (e.g., capsaicin) in the composition is between about 0.05 μΜ and about 100 μΜ. In an embodiment, the composition comprises a single gingerol analog (e.g., 6-gingerol), a single shogaol analog (e.g., 6-shogaol), or a single capsaicinoid analog (e.g., capsaicin), and is substantially free of related analogs thereof.

Morvan' s syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof, wherein the method comprises orally administering a composition comprising a single gingerol analog (e.g., 6-gingerol), a single shogaol analog (e.g., 6-shogaol), or a single capsaicinoid analog (e.g., capsaicin), wherein if present, the dosage of the single gingerol analog (e.g., 6-gingerol) or single shogaol analog (e.g., 6-shogaol) in the composition is between about 0.001% (w/v) or (w/w) and about 10% (w/v) or (w/w) or between about 0.01 % (w/v) or (w/w) and about 50% (w/v) or (w/w); and if present, the dosage the single capsaicinoid analog (e.g., capsaicin) in the composition is between about 0.0001 % (w/v) or (w/w) and about 5% (w/v) or (w/w) or between about 0.01% (w/v) or (w/w) and about 10% (w/v) or (w/w). In an

embodiment, the composition comprises a single gingerol analog (e.g., 6-gingerol), a single shogaol analog (e.g., 6-shogaol), or a single capsaicinoid analog (e.g., capsaicin), and is substantially free of related analogs thereof. In another aspect, the present disclosure features a method for the prevention or treatment of a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox-Gastaut syndrome, limb-girdle muscular dystrophy,

Morvan' s syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof, wherein the method comprises orally administering a composition comprising a single capsaicinoid analog (e.g., capsaicin) and one of a single gingerol analog (e.g., 6-gingerol) or a single shogaol analog (e.g., 6-shogaol), wherein the dosage of the single gingerol analog (e.g., 6- gingerol) or the single shogaol analog (e.g., 6-shogaol) in the composition is between about 0.01 mg and about 1000 mg; and the dosage of the single capsaicinoid analog (e.g., capsaicin) in the composition is between about 0.001 mg and about 100 mg. In an embodiment, the composition comprises a single gingerol analog (e.g., 6-gingerol) or a single shogaol analog (e.g., 6-shogaol) and a single capsaicinoid analog (e.g., capsaicin), and is substantially free of related analogs thereof.

In another aspect, the present disclosure features a method for preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich' s ataxia, Lennox-Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereofin a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single gingerol analog and is administered in a dosage sufficient to prevent, diminish the severity of, or reduce the frequency of a symptom of said disease, disorder, or condition in the subject. In an embodiment, the composition comprises a single gingerol analog (e.g., 6-gingerol) and is substantially free of related analogs thereof.

In another aspect, the present disclosure features a method for preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich' s ataxia, Lennox-Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereofin a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single shogaol analog and is administered in a dosage sufficient to prevent, diminish the severity of, or reduce the frequency of a symptom of said disease, disorder, or condition in the subject. In an embodiment, the composition comprises a single shogaol analog (e.g., 6-shogaol) and is substantially free of related analogs thereof.

In another aspect, the present disclosure features a method for preventing or treating adisease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox-Gastaut syndrome, limb-girdle muscular dystrophy,

Morvan' s syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereofin a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single capsaicinoid analog and is administered in a dosage sufficient to prevent, diminish the severity of, or reduce the frequency of a symptom of said disease, disorder, or condition in the subject. In an

embodiment, the composition comprises a single capsaicinoid analog (e.g., capsaicin) and is substantially free of related analogs thereof.

In another aspect, the present disclosure features a method for preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich' s ataxia, Lennox-Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereofin a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single capsaicinoid analog and one of a single gingerol analog or a single shogaol analog, and is administered in a dosage sufficient to prevent, diminish the severity of, or reduce the frequency of a symptom of said disease, disorder, or condition in the subject. In an embodiment, the composition comprises a single gingerol analog (e.g., 6-gingerol) or a single shogaol analog (e.g., 6-shogaol) and a single capsaicinoid analog (e.g., capsaicin), and is substantially free of related analogs thereof.

In another aspect, the present disclosure features a method for preventing or treating Charcot Marie Tooth disease in a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single gingerol analog, e.g., in an amount sufficient to prevent, diminish the severity of, or reduce the frequency of a symptom of Charcot Marie Tooth disease in the subject. In an embodiment, the composition comprises a single gingerol analog (e.g., 6-gingerol) and is substantially free of related analogs thereof. In another aspect, the present disclosure features a method for preventing or treating Charcot Marie Tooth disease in a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single shogaol analog, e.g., in an amount sufficient to prevent, diminish the severity of, or reduce the frequency of a symptom of Charcot Marie Tooth disease in the subject. In an embodiment, the composition comprises a single shogaol analog (e.g., 6-shogaol) and is substantially free of related analogs thereof.

In another aspect, the present disclosure features a method for preventing or treating Charcot Marie Tooth disease in a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single capsaicinoid analog (e.g., capsaicin), e.g., in an amount sufficient to prevent, diminish the severity of, or reduce the frequency of a symptom of Charcot Marie Tooth disease in the subject. In an embodiment, the composition comprises a single capsaicinoid analog (e.g., capsaicin) and is substantially free of related analogs thereof.

In another aspect, the present disclosure features a method for preventing or treating an

Charcot Marie Tooth disease in a subject, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single capsaicinoid analog and one of a single gingerol analog or a single shogaol analog, e.g., in an amount sufficient to prevent, diminish the severity of, or reduce the frequency of a symptom of Charcot Marie Tooth disease in the subject. In an embodiment, the composition comprises a single gingerol analog (e.g., 6-gingerol) or a single shogaol analog (e.g., 6-shogaol) and a single capsaicinoid analog (e.g., capsaicin), and is substantially free of related analogs thereof.

In another aspect, the present disclosure features a method of evaluating a subject for a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof in a subject comprising: a) acquiring, e.g. , indirectly or directly, knowledge of a result of a test for the efficacy of the administration of a test aliquot of a composition comprising a single gingerol analog, a single shogaol analog, or a single capsaicinoid analog to the subject that is substantially free of related analogs thereof; and b) administering, e.g. , in response to said result, an amount of said composition sufficient to alleviate a symptom of said disease, disorder, or condition to said subject. In an embodiment, the composition comprises a single gingerol analog (e.g., 6- gingerol), a single shogaol analog (e.g., 6-shogaol), or a single capsaicinoid analog (e.g., capsaicin), and is substantially free of related analogs thereof.

In any of the above-mentioned aspects, in some embodiments, the methods and compositions may comprise any of the features described below. In some embodiments, a symptom of a disease, disorder, or condition described herein further comprises an unwanted or abnormal muscle contraction. In some embodiments, the unwanted muscle contraction comprises a muscle cramp (e.g., a night cramp). In some embodiments, the muscle contraction comprises a muscle spasm. In some embodiments, the muscle contraction comprises muscle pain. In some embodiments, the muscle contraction comprises muscle spasticity. In some embodiments, the muscle contraction comprises an overall increase in muscle tone, or spasticity. In some embodiments, the muscle contraction comprises a dystonia (e.g., a cervical dystonia). In some embodiments, the muscle contraction comprises a fasciculation. In some embodiments, the muscle contraction occurs in a skeletal muscle. In some embodiments, the muscle contraction occurs in a smooth muscle. In some embodiments, the subject has a central nervous system disorder or injury, e.g. , a brain injury, stroke, or traumatic spinal cord injury.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are methods, products, and compositions to prevent and treat a subject having a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox-Gastaut syndrome, limb-girdle muscular dystrophy, Morvan' s syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof. In some embodiments, the methods, products, and compositions of the present invention comprise an agonist or activator of a TRP channel (e.g., TRPV1 or TRPA1) or an ASIC channel, or a use thereof. In some embodiments, the methods, products, and compositions of the present invention comprise a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), a capsaicinoid (e.g., capsaicin) or a use thereof, and are substantially free of a related analog thereof.

Definitions

The use of the words "a" or "an" when used in conjunction with the term "comprising' herein may mean "one," but are also consistent with the meaning of "one or more," "at least one," and "one or more than one." The term "acidulant" as used herein refers to an acidic compound (e.g. , an acid) used to lower the pH of a composition. In some embodiments, the pH can be lowered in the range of about 2.5 to about 6.5 (e.g. , pH of 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or 6.5). In some

embodiments, the pH can be lowered in the range of about 1.5 to about 5.0 (e.g. , pH of 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0), for example, in the range of about 1.5 to about 4.4 (e.g., pH of 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.4).

"Acquire" or "acquiring" as the terms are used herein, refer to obtaining possession of a value, e.g., a numerical value, or image, or a physical entity (e.g., a sample), by "directly acquiring" or "indirectly acquiring" the value or physical entity. "Directly acquiring" means performing a process (e.g., applying or measuring a current to or from a subject, or capturing a signal from a subject or sample or performing a synthetic or analytical method) to obtain the value or physical entity. "Indirectly acquiring" refers to receiving the value or physical entity from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Directly acquiring a value or physical entity includes performing a process that includes a physical change in a physical substance or the use of a machine or device. Exemplary changes include applying a current to, or measuring a current from, the muscle of a subject. Directly acquiring a value includes performing a process that uses a machine or device, e.g. , a device to induce a cramp or a device to measure a parameter related to a cramp.

The term "agonist," as used herein, refers to a molecule that stimulates a biological response. In some embodiments, an agonist is an activator. In some embodiments, the agonists and activators referred to herein may activate a TRP ion channel (e.g. , TRPV1 or TRPA1) or an ASIC ion channel.

The term "administering" and "administration" refers to a mode of delivery. A daily dosage can be divided into one, two, three or more doses in a suitable form to be administered one, two, three or more times throughout a time period. In preferred embodiments of the present invention, compositions and solutions are administered orally.

The terms "analog" or "related analogs" as used herein in regard to a compound or compounds refer to a substance that has a similar chemical structure to another compound, but differs from it with respect to a certain component or components.

The term "derivative" as used herein refers to a substance produced from another substance either directly or by modification or partial substitution.

"Dystonia" as used herein refers to sustained muscle contractions that cause repetitive movements or twisting and other abnormal postures. In some embodiments, a dystonia can occur in a limb, e.g., a hand or foot. "Fasciculation" as used herein refers to a series of small, rapid involuntary muscle contractions and relaxations. In some embodiments, fasciculations are commonly known as "muscle twitches".

"Muscle cramp" as used herein is a muscle cramp which is treated with the composition described herein. In some embodiments, it is not induced but rather arises spontaneously either from activity or underlying disease etiology, e.g. , athletic activity or a night cramp. In some embodiments, a muscle cramp is induced for test purposes. In some embodiments, the muscle cramp comprises a cramp in a muscle other than the muscle of the test muscle cramp. In some embodiments, the muscle cramp can be a contraction of a skeletal muscle or the smooth muscle. In some embodiments, the muscle cramp is a contraction of a skeletal muscle, e.g. , the flexor hallucis brevis muscle.

"Muscle spasm" as used herein refers to an involuntary contraction or a muscle, or even a few fibers of a muscle. In some embodiments, the magnitude or duration of a spasm is less than that of a cramp.

As used herein, the terms "prevent" or "preventing" as used in the context of a disorder or disease, refer to administration of an agent to a subject such that the onset of at least one symptom of the disorder or disease is delayed as compared to what would be seen in the absence of administration of said agent. As compared with an equivalent untreated control, such prevention is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%, as measured by any standard technique.

The term "spasticity" as referred to herein is the uncontrolled tightening or contracting of the muscles that is common in individuals with spinal cord injuries and a variety of nervous system diseases. In some embodiments, spasticity refers to a velocity-dependent increase in the tonic stretch reflex (muscle tone) with exaggerated tendon jerks, clonus, and spasms, resulting from the hyper excitability of the stretch reflex.

The term "subject" as used herein refers to a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline mammal. In some embodiments, the term subject refers to a human (e.g., a human male or female).

As used herein, the term "substantially pure" refers to a composition that is free of organic and/or inorganic species that do not activate the TRPV1, TRPA1, or/or ASIC channels, and where 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 99.5% (w/w) of the composition is comprised of a single chemical species. Substantially pure compositions can be prepared and analyzed using standard methods known in the art (e.g. , chromatographic separation, extractions, and the like). In some embodiments, substantially pure compositions do not include isomeric impurities (e.g. , geometric isomers) and/or salts or solvates of a particular chemical species.

"Treat" or "treating" as used herein refers to administering a composition for therapeutic purposes or administering treatment to a subject already suffering from a disorder to improve the subject's condition. By "treating a condition or disorder" or "alleviating a condition or disorder" is meant that the condition or disorder (e.g., described herein) and the symptoms associated with the condition or disorder are, e.g. , prevented, alleviated, reduced, cured, or placed in a state of remission. As compared with an equivalent untreated control, such alleviation or degree of treatment is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%, as measured by any standard technique.

The term "viscosity" as used herein refers to a measurement of a fluid's internal resistance to flow (e.g. , "thickness"). Viscosity is generally expressed in centipoise (cP) or pascal-seconds.

Other features and advantages of the invention will be apparent from the Detailed Description and Claims.

Products and Compositions

The products and compositions described herein are comestible formulations suitable for administration to a subject (e.g., a human) and include one or more agents capable of preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan' s syndrome, myoclonic seizures, myotonic dystrophy, Raynaud' s disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof. In some embodiments, the products and compositions described herein comprise a compound capable of activating an ion channel (e.g., a TRP or ASIC ion channel). In some embodiments, the products and compositions described herein comprise a gingerol (e.g., 6- gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin). In some embodiments, the products and compositions further comprise an excipient as described herein. In some embodiments, the compositions described herein are pharmaceutical compositions. Exemplary, non- limiting compositions include those that are solid dosage forms for oral administration (e.g., tablets, capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid filled lozenges), troches, gums, candies, chews, foodstuffs, films, and the like), liquid dosage forms for oral

administration (e.g., emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), linctuses, drops, sprays, elixirs, mouthwashes, and the like), ready-to-drink beverages, dry compositions that can be reconstituted with a liquid (e.g., powders, granules, or tablets that may be reconstituted with water), gels, semi-solids (e.g., ice cream, pudding, or yogurt), frozen liquids (e.g., ice pops), hard candies, dissolving strips (e.g., an edible strip containing pullulan and compositions of the invention), and chewing gums.

TRP Channels and ASIC Channels

In some embodiments, the products and compositions described herein comprise a compound capable of activating an ion channel (e.g., a TRP or ASIC ion channel, e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), a capsaicinoid (e.g., capsaicin)). Transient Receptor Protein (TRP) channels are a family of nonselective ion channels that function as cellular sensors and respond to and integrate diverse signals, including temperature, mechanical stress, exogenous chemicals, and endogenous chemicals, such as intracellular and extracellular messengers. These channels are involved in multiple functions, including pain, temperature, and mechanical sensation, calcium and magnesium homeostasis, lysosomal function, cardiovascular regulation, and control of cell growth and proliferation. Misregulation or aberrant function of TRP channels have also been implicated in numerous muscle conditions (Brinkmeier, H. Adv Exp Med Biol (2011) 704:749-758; Yang X.R. et al. Adv Exp Med Biol (2010) 661 : 109-122; Szallasi, A. (Ed.) TRP Channels as Therapeutic Targets (2015) Waltham, MA: Elsevier).

Members of the TRP channel family share some structural similarity and are organized in sub- families, comprising TRPA, TRPC, TRPV, TRPM, TRPML, TRMPN, and TRPP. Each of these sub-families comprise subunit genes, which include, for example, TRPV1, TRPV2, TRPV4, TRPV3, TRPV5, TRPV6, TRPA1, TRPP3, TRPP2, TRPP5, TRPC4, TRPC5, TRPC1, TRPC3, TRPC7, TRPC6, TRPM1, TRPM3, TRPM6, TRPM7, TRPM4, TRPM5, TRPM2, TRPM8, TRPML1, TRPML3, and TRPML2. The compositions described herein may comprise at least one activator or agonist of any of the TRP channels, and may be used to prevent or treat a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof .

Acid-sensing ion channels (ASIC) are neuronal voltage-insensitive cationic channels that are activated by extracellular protons. ASIC channels are primarily expressed in the nervous system, and conduct mostly Na⁺. Recent evidence has linked certain muscle conditions and disorders to aberrant ASIC channel function (see, e.g., Gautam, M. and Benson, C.J. (2013) FASEB J 27:793-802). There are four ASIC channel genes, ASIC1, ASIC2, ASIC3 and ASIC4, which encode at least six ASIC channels, ASIC3, ASCI4 and splice variants of ASIC1, and ASIC2, ASICla, ASIClb, ASIC2a, ASIC2b. The compositions described herein may comprise at least one activator or agonist of any of the ASIC channels and may be used in prevention or treatment of a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof. TRP and ASIC Channel Activators

In some embodiments, the products and compositions described in the present invention feature a compound capable of activating an ion channel (e.g., a TRP or ASIC ion channel). Exemplary compounds include, but are not limited to, gingerols (e.g., 6-gingerol, 8-gingerol, 10- gingerol, 12-gingerol, 14-gingerol, and other synthetic and naturally occurring variants thereof, e.g., methoxy-10-gingerol), shogaols (e.g., 6-shogaol, 8-shogaol, 10-shogaol, 12-shogaol, 14- shogaol, and other synthetic and naturally occurring variants thereof), paradols (e.g., 6-paradol), gingerdiones (e.g., 10-gingerdione), gingerenone A, capsaicinoids (e.g., capsaicin and

dihydrocapsaicin), and cinnamaldehyde (e.g., trans-cinnamaldehyde). In some embodiments, the products and compositions described herein comprise gingerols (e.g., 6-gingerol, 8-gingerol, 10-gingerol, 12-gingerol, 14-gingerol, and other synthetic and naturally occurring variants thereof, e.g., methoxy- 10-gingerol), shogaols (e.g., 6-shogaol, 8-shogaol, 10-shogaol, 12- shogaol, 14-shogaol, and other synthetic and naturally occurring variants thereof), capsaicinoids (e.g., capsaicin and dihydrocapsaicin), paradols (e.g., 6-paradol), and cinnamaldehyde (e.g., trans-cinnamaldehyde). In some embodiments, the products and compositions described herein comprise a single gingerol analog (e.g., 6-gingerol), a single shogaol analog (e.g., 6-shogaol), a single capsaicinoid analog (e.g., capsaicin), a single paradol (e.g., 6-paradol), or cinnamaldehyde (e.g., trans-cinnamaldehyde), and is substantially free of an analog thereof. In some embodiments, the products and compositions described herein comprise 6-gingerol, 6-shogaol, capsaicin, 6-paradol, or cinnamaldehyde. In some embodiments, the products and compositions described herein comprise 6-gingerol, 6-shogaol, capsaicin, 6-paradol, or cinnamaldehyde, and are substantially free of a related analog thereof. In some embodiments, the products and compositions described herein comprise an isotopically labeled analog of a compound described herein, e.g., a deuterated analog of a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), a capsaicinoid (e.g., capsaicin), a paradol (e.g., 6-paradol) or cinnamaldehyde (e.g., trans- cinnamaldehyde) .

A gingerol (e.g., 6-gingerol), shogaol (e.g., 6-shogaol), capsaicinoid (e.g., capsaicin), paradol (e.g., 6-paradol) or cinnamaldehyde (e.g., trans-cinnamaldehyde) may be present in a composition of the invention at a concentration range of about 0.001% to about 10% by weight by weight (w/w) based on the total weight of the composition (e.g., about 0.001, about 0.005, about 0.01, about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10%) or at a concentration range of about 0.001% to about 10% by weight by volume (w/v) based on the total volume of the composition (e.g., about 0.001, about 0.005, about 0.01, about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10%), though one or more of these compounds may be present in lower or higher concentrations (e.g., less than about 0.01%, e.g., about 0.008%, about 0.005%, about 0.004%, about 0.001% (w/w) or (w/v), or more than about 10%, e.g., about 12%, about 15%, about 20%, about 30%, about 35%, about 40%, about 50% (w/w) or (w/v)). In some embodiments, a gingerol (e.g., 6-gingerol), shogaol (e.g., 6-shogaol), capsaicinoid (e.g., capsaicin), paradol (e.g., 6-paradol) or cinnamaldehyde (e.g., trans-cinnamaldehyde) may be present in a composition of the invention at a concentration range of about 0.001% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.01% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 0.1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 1% (w/v) or (w/w) to about 50% (w/v) or (w/w), or about 5% (w/v) or (w/w) to about 50% (w/v) or (w/w). A gingerol (e.g., 6-gingerol), shogaol (e.g., 6-shogaol), capsaicinoid (e.g., capsaicin), a paradol (e.g., 6-paradol), or cinnamaldehyde (e.g., trans-cinnamaldehyde) may be present at a concentration range of about 0.001 mg to about 1000 mg per unit dosage (e.g., about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg).

Each of these components is described in more detail below.

Gingerols, Shogaols, and Paradols

Ginger, derived from the rhizomes Zingiber officinale Roscoe, is a well-known spice and has been a central component of foods for thousands of years. It is most frequently prescribed as a traditional medicine for treatment of gastrointestinal and respiratory diseases, and has been shown to be effective in promoting blood circulation and for the removal of blood stasis (Koo, K.L. et aL Thromb Res (2001) 103:387-397; Shih, H.C. et al. Int J Mol Sci (2014) 15:3926- 3951). Ginger rhizomes produce hundreds of compounds that have been classified into several groups, e.g., zingerone, gingerols, gingerdiols, gingerdiones, paradols, and shogaols, in addition to other closely related analogs. The largest class of compounds present in ginger extract is the gingerols, of which 6-gingerol is the most abundant. However, the closely related species 8- gingerol, 10-gingerol, and 12-gingerol are also present, in some embodiments, the products and compositions described herein comprise a single gingerol analog (e.g., 6-gingerol) and are substantially free of an analog thereof.

In some embodiments, the products and compositions described herein comprise a single gingerol analog (e.g., 6-gingerol) with a purity of greater than about 90%, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single gingerol analog (e.g., 6-gingerol) is greater than about 90%, e.g., about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.9%, or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single gingerol analog (e.g., 6-gingerol) is greater than about 95%, e.g., about 96%, about 97%, about 98%, about 99%, about 99.9% or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single gingerol analog (e.g., 6-gingerol) is greater than about 98%, e.g., about 98.5%, about 99%, about 99.5%, about 99.9%, about 99.99%, or more, e.g., relative to other synthetically generated impurities.

in some embodiments, the products and compositions described herein comprise a mixture of two stereoisomers of 6-gingerol, e.g., (R)-6-gingerol and (S)-6-gingerol. In some embodiments, the mixture comprises a ratio of (R)-6-gingerol and (S)-6-gingerol of about 1 : 1 (e.g., a racemic mixture). In some embodiments, the mixture comprises a ratio of (R)-6-gingerol to (S) -6 -gingerol of about 51 :49, about 52: 48, about 53:47, about 54:46, about 55:45, about

60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 85: 15, about 90: 10, about 95:5, about 99: 1, or higher. In some embodiments, the mixture comprises a ratio of (R)-6-gingerol to (S)-6-gingerol of about 70:30, about 75:25, about 80:20, about 85: 15, about 90: 10, about 95:5, about 99: 1, or higher. In some embodiments, the mixture comprises a ratio of (R)-6-gingerol to (S)-6-gingerol of about 80:20, about 85: 15, about 90: 10, about 95:5, about 99: 1, or higher.

In some embodiments, the products and compositions described herein comprise (R)-6- gingerol and less than about 50% of (S) -6-gingerol, e.g., less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, less than about 0.5%, less than about 0.1%, or less than about 0.05% of (S)-6-gingerol. In some embodiments, the products and compositions described herein comprise (R)-6-gingerol and are substantially free of (S)-6-gingerol.

Shogaols are another class of compounds produced by ginger rhizomes, with the species 6-shogaol being the most abundant. However, the most common method for production of shogaols is through the dehydration of gingerols during drying and heating of ginger extract. Paradols are also naturally found in ginger extract, although these molecules (e.g., 6-paradol) are produced in larger amounts by other plants, including the Guinea pepper (Aframomum melegueta). Both shogaols and paradols, like gingerols, have been shown to be potent activators of various ion channels, e.g., the TRPV1 channel and the TRPA1 channel (see, e.g., Riera, C. E. et al. Br J Pharmacol (2009) 157: 1398-1409), as well as exhibiting antimicrobial and antitumor activity (see, e.g., Chung, W.Y. et al. Mutat Res (2001) 496: 199-206; ad, S.D. et al.

Phytochemistry (2005) 66: 1614-1635).

In some embodiments, the products and compositions described herein comprise a single shogaol analog (e.g., 6-shogaol) with a purity of greater than about 90%, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single shogaol analog (e.g., 6-shogaol) is greater than about 90%, e.g., about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.9%, or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single shogaol analog (e.g., 6-shogaol) is greater than about 95%, e.g., about 96%, about 97%, about 98%, about 99%, about 99.9% or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single shogaol analog (e.g., 6-shogaol) is greater than about 98%, e.g., about 98.5%, about 99%, about 99.5%, about 99.9%, about 99.99%, or more, e.g., relative to other synthetically generated impurities.

In some embodiments, the products and compositions described herein comprise a single paradol analog (e.g., 6-paradol) with a purity of greater than about 90%, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single paradol analog (e.g., 6-paradol) is greater than about 90%, e.g., about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.9%, or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single paradol analog (e.g., 6-paradol) is greater than about 95%, e.g., about 96%, about 97%, about 98%, about 99%, about 99.9% or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single paradol analog (e.g., 6- paradol) is greater than about 98%, e.g., about 98.5%, about 99%, about 99.5%, about 99.9%, about 99.99%, or more, e.g., relative to other synthetically generated impurities.

Capsaicin

Capsaicin and several related compounds belong to a class of compounds called capsaicinoids and are produced as secondary metabolites by chili peppers. Capsaicin and other capsaicinoids are odorless, fat soluble compounds with a highly pungent taste, and are responsible for providing the spicy flavor of chili peppers through direct activation of TRP ion channels. Capsaicin has been shown to exert multiple pharmacological and physiological effects including analgesia and anticancer, anti-inflammation, antioxidant, and anti-obesity activities (Hayman, M. and Kam, P.C.A. Curr Anaesth Crit Care (2008) 19:338-343).

In some embodiments, the products and compositions described herein comprise a single capsaicinoid analog (e.g., capsaicin) with a purity of greater than about 90%, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single capsaicinoid analog (e.g., capsaicin) is greater than about 90%, e.g., about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.9%, or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single capsaicinoid analog (e.g., capsaicin) is greater than about 95%, e.g., about 96%, about 97%, about 98%, about 99%, about 99.9% or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the single capsaicinoid analog (e.g., capsaicin) is greater than about 98%, e.g., about 98.5%, about 99%, about 99.5%, about 99.9%, about 99.99%, or more, e.g., relative to other synthetically generated impurities.

Trans-cinnamaldehyde

Trans-cinnamaldehyde is one of the major components of cinnamon, a spice obtained from the inner bark of trees in the Cinnamomu family, and is responsible for its characteristic flavor and odor. Trans-cinnamaldehyde is widely used as a commercial food additive and scent. In addition, trans-cinnamaldehyde has been shown to have potent anti-inflammatory and antioxidant activity, e.g, through its ability to inhibit production of nitric oxide and suppress of the transcription factor NF-κΒ (Cassia da Silveira e Sa et al. Molecules (2014) 19: 1459-1480).

In some embodiments, the products and compositions described herein comprise trans- cinnamaldehyde with a purity of greater than about 90%, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the trans-cinnamaldehyde is greater than about 90%, e.g., about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.9%, or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the trans-cinnamaldehyde is greater than about 95%, e.g., about 96%, about 97%, about 98%, about 99%, about 99.9% or more, e.g., relative to other synthetically generated impurities. In some embodiments, the purity of the trans-cinnamaldehyde is greater than about 98%, e.g., about 98.5%, about 99%, about 99.5%, about 99.9%, about 99.99%, or more, e.g., relative to other synthetically generated impurities.

Capsaicin Trans-cinnamaldehyde

Additional Components of the Composition

The composition of the present invention may additionally include, for example, electrolytes (e.g. , potassium salt or other salts), buffering agents, sweeteners, flavoring and coloring agents, vitamins, minerals, preservatives, viscosity modifiers, thickening agents, dissolving agents, solvents, and antioxidants as described below. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 7^th Edition, Rowe et al., Eds.,

Pharmaceutical Press (2009).

Viscosity Modifiers and Thickening Agents

Viscosity is the ratio of shear stress to shear rate, expressed as dynes-second/cm², or poise. A centipoise (cP) is one one -hundredth of a poise.

The composition of the present invention may have a viscosity greater than water (i.e., about 1.0 cP at 20°C), e.g. , about 100, 200, 300, 400, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 8000, 9000 cP or more. If a consistency of corn syrup is desired, viscosities in the range of about 2500 cP are suitable. If a consistency of a soft gel or honey is desired, viscosities in the range of about 10000 cP to about 15000 cP are suitable. For puddinglike products, viscosities in the range of about 30000 cP to about 38000 cP are desirable. Viscosity of the compositions of the present invention may be measured with, e.g. , a rheometer or viscometer, though additional methods of measuring viscosity are known in the art.

Viscosity modifiers and thickening agents may be added to compositions of the present invention. Such viscosity modifiers and thickening agents include, for example, collagen, gellan gum, carbohydrate gel-forming polymers, carob bean gum, locust bean gum, carrageenan, alginates (e.g. , alginic acid, sodium alginate, potassium alginate, ammonium alginate, and calcium alginate), agar, guar gum, xanthan gum, microcrystalline cellulose, carboxymethyl cellulose, ethyl cellulose, clear starch, pectin, gelatin, arrowroot, cornstarch, katakuri starch, potato starch, sago, tapioca, furcellaran, karo syrup (e.g., light karo syrup and dark karo syrup), glycerin, and sodium pyrophosphate. A viscosity modifier or thickening agent may be present in the composition in an amount of from about 0.01% to about 10% by weight based on the total weight or volume of the composition (e.g. , about 0.01, about 0.1, about 0.5, about 1, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%), though the viscosity modifier or thickening agent may be present in lower or higher

concentrations (e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%). In some embodiments, the viscosity modifier or thickening agent is present in the composition from about 40% to about 60% (e.g, about 50%).

Electrolytes and Buffering agents

Exemplary electrolytes and buffering agents include potassium salts, chloride salts, bromide salts, sodium salts, magnesium salts, calcium salts, citrate salts, acetate salts, phosphate salts, salicylates, bicarbonate salts (e.g., sodium bicarbonate), lactate salts, sulphate salts, tartrate salts, benzoate salts, selenite salts, molybdate salts, iodide salts, oxides, and combinations thereof. An electrolyte or buffering agent may be present in a composition of the invention at a concentration range of about 0.01% to about 10% by weight based on the total weight or volume of the composition (e.g. , about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%), though an electrolyte or buffering agent may be present in lower or higher concentrations.

In certain embodiments, the compositions of the present invention include high concentrations of potassium (e.g. , potassium chloride). The concentration of potassium in the composition may be, e.g. , about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, or about 7% or more by weight based on the total weight or volume of the composition. In certain embodiments, the compositions of the present invention include high concentrations of magnesium (e.g. , magnesium chloride). The concentration of magnesium in the composition may be, e.g. , about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, or about 7% or more by weight based on the total weight or volume of the composition.

In some embodiments, an electrolyte or buffering agent may be added to the

compositions of the present invention to affect the pH level. In some embodiments, the pH of the composition, e.g., with the addition of an electrolyte or buffering agent, is e.g., about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, or about 8.5.

Sweeteners

Sweeteners may be included in the compositions of the invention. Exemplary sweeteners include corn syrup (e.g., high fructose corn syrup or karo syrup), mannose, maltose, glucose polymers, sucrose (e.g. , cane sugar or beet sugar), glucose, dextrose, lactose, galactose, fructose, polysaccharides (e.g. , malodextrins), rice syrup, honey, and natural fruit juices (e.g. , orange juice, papaya juice, pineapple juice, apple juice, grape juice, apricot juice, pear juice, tomato juice, agave nectar, or cranberry juice). Additionally, non- or low-caloric sweeteners can be used in the compositions of the invention. Examples of such non-caloric or low-caloric sweeteners include, but are not limited to, saccharin, sodium saccharin, cyclamates, acetosulfam, sorbitol, mannitol, sucralose, xylitol, erythritol, Stevia extract, L-aspartyl-L-phenyl-alanine ester (e.g. , aspartame), L-aspartyl-D-alanine alkyl amides, L-aspartyl-L-1- hydroxymethylalkaneamide, and L-aspartyl-1 -hydroxy ethylalkaneamide. In some embodiments, sweeteners may be present in a composition of the invention at a concentration range of about 2% to about 20% by weight based on the total weight or volume of the composition (e.g. , about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%), though sweeteners may be present in lower or higher concentrations. Flavoring and Coloring Agents

Exemplary flavors and flavoring agents include almond oil, amaretto oil, anethole, anise oil, apple, benzaldehyde, blackberry, black walnut oil, blueberry, caraway, caraway oil, cardamom oil, cardamom seed, cherry juice, cherry syrup, chocolate, cinnamon, cinnamon oil, cinnamon water, citric acid, citric acid syrup, clove oil, cocoa, coriander oil, dextrose, eriodictyon, ethyl acetate, ethyl vanillin, fennel oil, ginger, glucose, glycerin, glycyrrhiza, grape, honey, lavender oil, lemon oil, lime, mannitol, methyl salicylate, mint (e.g., peppermint, spearmint), myristica oil, orange oil, orange peel, orange syrup, peppermint, peppermint oil, peppermint water, phenylethyl alcohol, pineapple, raspberry juice, raspberry syrup, rosemary oil, rose oil, rose water, sarsaparilla syrup, sorbitol, spearmint oil, strawberry, sucrose, thyme oil, tolu balsam, vanilla, vanillin, watermelon, and wild cherry syrup. Additional flavoring agents may be found in Food Chemicals Codex and Fenaroli' s Handbook of Flavor Ingredients.

Flavoring agents may be present in a composition of the invention at a concentration range of about 0.01% to about 20% by weight based on the total weight or volume of the composition (e.g. , about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 17.5%, or about 20%), though flavoring agents may be present in lower or higher concentrations.

Small amounts of a coloring agent may be utilized in the compositions of the present invention. Coloring agents include, e.g. , beta-carotene, riboflavin dyes, FD&C dyes (e.g. , Yellow No. 5, Blue No. 1, Blue No. 2, and Red No. 40), FD&C lakes, chlorophylls and chlorophyllins, caramel coloring, annatto, cochineal, turmeric, saffron, paprika, and fruit, vegetable, and/or plant extracts (e.g. , grape, black currant, aronia, carrot, beetroot, red cabbage, elderberry, and hibiscus extracts). The amount of coloring agent used will vary depending on the agents used in the composition and the color intensity desired in the finished product.

Coloring agents may be present in a composition of the invention at a concentration range of about 0.01% to about 20% by weight based on the total weight or volume of the composition (e.g. , about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 17.5%, or about 20%), though coloring agents may be present in lower or higher concentrations.

Vitamins and Minerals

Non-limiting examples of vitamins and minerals that may be included in the

compositions of the present invention include, e.g. , choline bitartate, niacinamide, thiamin, folic acid, d-calcium pantothenate, biotin, vitamin A, vitamin C, vitamin B i hydrochloride, vitamin B2, vitamin B₃, vitamin B₆ hydrochloride, vitamin B12, vitamin D, vitamin E acetate, vitamin K, and salts of calcium, potassium, magnesium, zinc, iodine, iron, and copper. In some

embodiments, vitamins and minerals may be present in a composition of the invention at a concentration range of about 0.01% to about 50% by weight based on the total weight or volume of the composition (e.g. , about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%), though vitamins and minerals may be present in lower or higher concentrations. In some embodiments, when included in a composition of the invention, the composition may contain at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of the U.S. recommended daily intake (RDI) for such vitamins and minerals.

Preservatives

A preservative may additionally be utilized in the compositions described herein.

Exemplary preservatives include, for example, sorbate, polysorbate (e.g., polysorbate 20, polysorbate 40, polysorbate 80), a paraben (e.g., methylparaben sodium, propylparaben sodium), benzoate, and polyphosphate preservatives (e.g. , sorbic acid, benzoic acid, calcium sorbate, sodium sorbate, potassium sorbate, calcium benzoate, sodium benzoate, potassium benzoate, and mixtures thereof). In some embodiments, the preservative may be present in a composition of the invention at a concentration range of about 0.0005% to about 0.5% (e.g. , about 0.0005%, about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, or about 0.5%) by weight based on the total weight or volume of the composition, though preservatives may be present in lower or higher concentrations.

In some embodiments, a preservative may be added to the compositions of the present invention to affect the pH. In some embodiments, the pH of the composition, e.g., with the addition of a preservative, is e.g., about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, or about 8.5. In some embodiments, the pH of the composition, e.g., with the addition of a preservative, is within the range of about 1.5 to about 7.5, about 1.75 to about 7.0, about 2.0 to about 6.5, about 2.1 to about 6.0, about 2.2 to about 5.5, about 2.3 to about 5.0, about 2.4 to about 4.5, about 2.5 to about 4.0, about 2.6 to about 3.5. In some embodiments, the pH of the composition, e.g., with the addition of a preservative, is within the range of about 1.5 to about 4.0.

Antioxidants

An antioxidant agent may also be included in the compositions to, for example, reduce exercise-induced oxidative stress. Exemplary antioxidants include vitamin C and vitamin E; beta-carotene, lutein, or other carotenoids; cyanidin, delphinidin, malvidin, or other

anthocyanidins; apigenin, luteolin, or other flavones; hesperitin, naringenin, or other flavonones; isorhamnetin, quercetin, kaempferol or other flavonols; butylated hydroxyanisole and butylated hydroxy toluene; and epigallocatechin-3-gallate, epicatechin, thearubigins, or other flavan-3-ols. In some embodiments, an antioxidant may be present in a composition of the invention at a concentration range of about 0.0005% to about 0.5% (e.g. , about 0.0005%, about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, or about 0.5%) by weight based on the total weight or volume of the composition, though antioxidants may be present in lower or higher concentrations.

Dissolving Agent or Solvent

A dissolving agent or solvent may also be included in the compositions to, for example, improve the suspension or emulsification of particular components. In addition, certain dissolving agents or solvents may have a preservative function. Exemplary dissolving agents or solvents include acetic acid, acetone, butanol, dimethyl sulfoxide, ethanol, ethyl acetate, isopropanol, methanol, petroleum ether and the like. In some embodiments, a dissolving agent or solvent may be present in a composition of the invention at a concentration range of about 0.0005% to about 0.5% (e.g. , about 0.0005%, about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, or about 0.5%) by weight based on the total weight or volume of the composition, though dissolving agents or solvents may be present in lower or higher concentrations.

Additional components of the compositions described herein may include amino acids (e.g. , leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine), stimulants (e.g. , caffeine), emulsifying agents, carbon dioxide (e.g. , to carbonate a liquid composition), stabilizers, humectants, anticaking agents, or herbal extracts. These components may be included at levels from about 0.0005% to about 25% (e.g. , about 0.0005%, about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 5%, about 10%, about 15%, about 20%, or about 25%) by weight based on the total volume of the composition, though an additional component may be present in lower or higher

concentrations.

Formulations and Methods of Preparing Compositions

The compositions and solutions of the present invention may be formulated as ready-to- drink beverages, concentrates (e.g. , syrups), dry compositions (e.g. , powders, granules, or tablets that may be reconstituted with a liquid (e.g. , with water), gels, solids, semi-solids (e.g. , ice cream, pudding, or yogurt), frozen liquids (e.g. , ice pops), lozenges or hard candies, mouthwashes, dissolving strips (e.g. , an edible strip containing pullulan and compositions of the invention), and chewing gum. Formulation of these compositions may require the use of a formulation base, which is a substance or material mixed with or added to the ion channel activator and pharmaceutically acceptable excipient in order to achieve the desired form.

In solid dosage forms for oral administration (e.g., tablets (e.g., orally disintegrating tablets, sublingual tablets, or buccal tablets), capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid filled lozenges), troches, gums, candies, chews, foodstuffs, dissolving strips, films, semi-solid formulations, dragees, and the like), the compositions of the invention are mixed with a pharmaceutically-acceptable carrier, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, crospovidine, croscarmellose (e.g., croscarmellose sodium), hypromellose, sodium starch glycolate, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol, sodium lauryl sulfate, and glycerol monostearate; (8) absorbents, such as kaolin, colloidal silicon dioxide, and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, sodium stearyl fumurate, stearic acid, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

In some embodiments, compositions of the present invention are formulated to increase residence time in the upper gastrointestinal tract (e.g., mouth or esophagus). In some embodiments, the composition is formulated to have an extended residence time in the upper gastrointestinal tract of a subject (e.g., a residence time of greater than about 5 seconds in the mouth of a subject, e.g., a residence time of greater than about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, about 10 seconds, about 11 seconds, about 12 seconds, about 13 seconds, about 14 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 45 seconds, about 60 seconds, about 90 seconds, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, or more in the mouth of a subject). In some embodiments, the composition is formulated to have an extended residence time in the upper gastrointestinal tract of a subject (e.g., a residence time of greater than about 60 seconds in the mouth of a subject, e.g., greater than about 90 seconds, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, or more in the mouth of a subject). In some embodiments, the composition is formulated as a mouthwash and has an extended residence time in the upper gastrointestinal tract of a subject (e.g., a residence time of greater than about 30 seconds in the mouth of a subject or more).

In some embodiments, the composition is formulated to have reduced systemic exposure in the subject, e.g., wherein the active ingredient (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) has only minimal systemic exposure relative to the dosage amount. In some embodiments, the systemic exposure in a subject is measured through the concentration of the active ingredient (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) in the blood, urine, or tissue (e.g., adipose tissue) of a subject. In some embodiments, the composition is formulated to have less than about 50% total systemic exposure relative to the dosage amount in a subject, e.g., wherein the systemic exposure is measured through the concentration of the active ingredient (e.g., a gingerol, a shogaol, or a capsaicinoid) in the blood, urine, or tissue (e.g., adipose tissue) of a subject. In some embodiments, the systemic exposure of the composition (e.g., the active ingredient of the composition (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, less than about 0.1%, less than about 0.05%, less than about 0.01%, or lower relative to the dosage amount in a subject. In some embodiments, the composition of the present invention is formulated as to provide little to no systemic exposure in a subject.

In some embodiments, the compositions may be in the form of a dry powder, granule, tablet, or capsule that may be reconstituted in a specified amount of a liquid. The dried components may be mixed together and milled (e.g. , to create a homogenous powder) or mixed in aqueous solution and dried by using methods known to one of skill in the art. Dried powders or granules may be "loose" or fashioned into tablets.

In other embodiments, the compositions of the present invention may be in the form of a gel or paste further comprising a humectant (e.g., glycerin, propylene glycol, lithium chloride, alpha hydroxy acids, diols, urea, quillaia, polyols, sugar alcohols (e.g., sorbitol, glycerol, xylitol, mannitol), glyceryl triacetate, or neoagarobiose), a gum (e.g., xanthan gum, guar gum), an abrasive (e.g., silica, (e.g., Zeodent^®)), a plasticizer, an additive (e.g., a sweetener, preservative, buffering agent, penetration agent, surfactant, coloring agent, flavoring agent, cleaning agent, and the like) or a thickener (e.g., silica (e.g., Zeodent )). These additional components may be present in the composition of the invention from about 0.5% to about 99% (e.g. , about 0.5%, about 0.1%, about 0.5%, about 1%, about 5%, about 10%, about 20%, about 30% about 40%, about 50%, about 75%, about 90%, about 95%, or about 99%) by weight based on the total volume of the composition, though these components may be present in lower or higher concentrations.

The gel or paste may be further packaged on or within a delivery device such as a bioadhesive strip, patch, film, or may be provided for application directly to the oral cavity (e.g., mucosal surfaces (e.g., in the mouth, nose, or throat), teeth, gums, or lips). For example, a paste or gel can be packaged in a unit that contains between about 0.1 ounces to about 16 ounces of the paste or gel. For example, the packaging can contain about 0.1 ounces, about 0.25 ounces, about 0.5 ounces, about 1 ounce, about 2 ounces, about 3 ounces, about 4 ounces, about 5 ounces, about 6 ounces, about 7 ounces, about 8 ounces, about 9 ounces, about 10 ounces, about 11 ounces, about 12 ounces, about 13 ounces, about 14 ounces, about 15 ounces, or about 16 ounces.

To make pills containing the composition of the invention, the powdered ingredients are mixed together with a binding agent, such as acacia or tragacanth, and are then made into a plastic mass by incorporation of any liquid drugs and addition of an inert liquid. The resulting mass, known as a pill mass, is then rolled into spheres and coated with talc, gelatin, or sugar.

To make tablets, components of the products and compositions described herein (e.g. , 6- gingerol, 6-shogaol, capsaicin, or trans-cinnamaldehyde) are mixed with suitable diluents, such as dextrin, lactose, salt, starch, or synthetic substances, designed to ensure disintegration of the tablet in the body. To prevent sticking in the machine, a lubricant such as liquid paraffin, stearic acid, talc, or a synthetic substance is usually added. Furthermore, it is essential that the tablet machines are fed with the drug mixture in a free-flowing form to ensure complete filling of the molds. To achieve this, the composition mixture is customarily granulated by mechanically forcing pellets of the mixture through a sheet of perforated-metal. The granulated mixture is fed into the tablet machine, which feeds the correct dose into a cavity, the mixture then being compressed by means of a punch that fits into the cavity. To be successful, the tablet maker must choose correct diluents and lubricants, prepare suitable granules, and obtain the right degree of compression in the tablet machine. Excessive compression may mean that the tablet will not disintegrate in the body; insufficient compression results in fragile tablets that may break, causing inaccurate dosage. Coatings of various types may be applied to the tablet to protect the ingredients from deterioration, to hide the taste of certain components, to control the release of the active components from the tablet, or to produce a more attractive tablet. For sugar coatings, a concentrated sucrose syrup containing suspended starch, calcium or magnesium carbonate, or other suitable substance is applied, each successive layer being dried before the application of the next. After the final layer is dried, it is highly polished to give an elegant finish. Sugar coatings provide both protection and a sweet taste. Film coatings can also be used, in which a very thin transparent film, usually a cellulose derivative, is applied. Enteric coating is designed to resist solution in the stomach and to dissolve in the more alkaline intestinal fluid. Many substances have been used for enteric coatings, one of which is cellulose acetate phthalate (cellacephate). In the manufacture of layered tablets, incorporating two or more drugs, a compressed tablet is fed to a second machine where another layer is compressed around it. In this way, drugs normally incompatible may be formulated in the same tablet.

Other solid dosages such as lozenges, troches, candies, dragees, or pastilles disintegrate or dissolve in the mouth, slowly releasing the active ingredient (e.g. , 6-gingerol, 6-shogaol, capsaicin, or trans-cinnamaldehyde). The base usually consists of a mixture of sugar and gum or gelatin. Lozenges and troches are generally manufactured by compression techniques, while pastilles are fabricated by fusion and the use of molds. Dry extracts are prepared by the methods for fluid extracts, followed by evaporation, usually under reduced pressure, either to a pilular consistency or to dryness. Dry extracts are usually granulated by being passed through a sieve and may be used for the preparation of tablets.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), linctuses, drops, mouthwash, and elixirs. In addition to the components of the products and compositions described herein, e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin), the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Suspensions, in addition to the active agent may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

The compositions and solutions described herein may be bottled or packaged in, for example, glass bottles, plastic bottles and containers (e.g. , polyethylene terephthalate or foil- lined ethylene vinyl alcohol), metal cans (e.g. , coated aluminum or steel), lined cardboard containers, pouches, packs, wrappers, or any other packaging known to one of skill in the art. For example, a ready-to-drink beverage can be bottled or packaged in a unit that contains between about 10-1000 mL of the beverage. For example, the packaging can contain about 10 mL, 20 mL, 50 mL, 100 mL, 200 mL, 300 mL, 400 mL, 500 mL, 600 mL, 700 mL, 800 mL, 900 mL, or 1000 mL of the beverage. Alternatively, the packaging can contain 200 mL, 250 mL, 330 mL, 350 mL, 355 mL, 375 mL, 440 mL, or 500 mL of the beverage. A ready-to-drink beverage can also be bottled or packaged in a unit that contains between about 1-32 fluid ounces of beverage (e.g. , the unit may contain about 1, 2, 5, 6.75, 8, 8.3, 8.4, 8.45, 9.6, 10, 12, 15, 15.5, 16, 18.6, 20, 23, 24, or 32 fluid ounces). Where a shelf-stable composition or solution is desired, the packaging is appropriately sterilized before being filled by the pasteurized, ultra-pasteurized, or sterilized composition or solution. Where required for mutual stability of two or more components (for example if a component is unstable at low pH), the packaging may feature multiple containers that can be mixed shortly before ingestion or that can be consumed serially.

Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) are mixed with an inert solid diluent (e.g. , potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g. , a mixer, a fluid bed apparatus or a spray drying equipment. Oil-based Formulations

The compositions of the invention can be formulated as an oil-based formulation for oral administration.

In one embodiment, the oil-based formulation includes a formulation base composition including an oil and a lipophilic additi ve, which can be solid or pasty at room temperature. The lipophilic additive can include waxes, fatty acid mono-, di- or triglycerides, fatty acids and polyethylene glycols and the polyethylene glycol fatty acid esters, as well as their mixtures and can be present in ranges from about 5 to 20% by weight or the composition (e.g. , about 5%, about 6%, about 10%, about 15%, about 17%, about 18%, about 19%, or about 20%). The waxes can be beeswax, candelilla wax, carnauba wax, polyethylene oxide wax or petroleum wax (or microcrystalline wax). The fatty acid mono-, di-, or triglycerides can have different degrees of esterification. The fatty acids can be selected from among palmitic acid, stearic acid, or behenic acid and their calcium, sodium, potassium or magnesium salts. The polyethylene glycols and fatty acid polyethylene glycol esters can have a molecular weight of between about 600 to 6000. The oil can include vegetable oils such as soya oil, sunflower oil, com oil, olive oil or nut oil, and among the mineral oils such as liquid paraffin, as well as their mixtures. The oil- based formulations can be present in the form of a soft or hard capsule and can be prepared by- traditional techniques known in the art. In one such technique, the lipophilic additive is incorporated into the oil which is heated at a temperature sufficiently high to melt the lipophilic additive completely and obtain a homogeneous mixture. After cooling to approximately 50° C, components of the products and compositions described herein (e.g., a gingerol (e.g., 6- gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) are incorporated into this mixture with stirring. The mixture thus obtained is cooled to a temperature between 25 and 40° C, and optionally, soft or hard capsules are filled with this mixture. For a detailed discussion of lipids and lipid-based formulations see, for example, Porter et a!., Nat Rev Drug Discov 2007, 6(3):231-248.

In another embodiment, components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) can be formulated as an oil for topical administration. Generally, the activators described herein at concentration ranges of about > 20% to about 95% (w/w) are solubilized in a solvent capable of solubilizing the ion channel activator. Solvents that may be used include volatile solvents (e.g. , methanol, ethanol, acetone, isopropanol, n-propanol, cyclohexane and alkanes with molecular weight less than dodecane (CI 2)), semi-volatile solvents (e.g., volatile essential oils such as clove oil, tea tree oil, sesame oil, and cineole), and non-volatile solvents (e.g. , polyethylene glycol 400, Lutrol® (polyethylene poiyoxypropyiene block copolymer available from BASF), glyceryl monooleate, glycerin, lanolin, low melting waxes, sesquiterpenes and alkanes, alkenes, alkanoic and alkenoic acids > C28). The oils may further include a crystallization inhibitor, for example, polyvinylpyrrolidone, Luvitol® BD 10 P (BASF), povidone and its derivatives (e.g., crospovidone); dextrin derivatives, polyethylene glycol, polypropylene glycol, mannitol and glycerin, and mono and diglycerides of essential oils, polyglycerin fatty acid esters, sucrose palmitic acid ester, pentaerythritol ester of wood rosin (Pentalyn A®), and Eudagrits®. Crystallization inhibitors may range from about 0.1 to about 10% w/w. The oils of the ion channel activators described herein may be administered orally as an oil. Controlled Release Formulations

It is also within the scope of the invention to provide compositions that are formulated for modified release (e.g., delayed release, prolonged and/or slow release, extended release, or rapid release) of the components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)), e.g., to reduce gastrointestinal side-effects. Such compositions are well-known in the art and include e.g. , diffusion-controlled drug delivery systems, osmotic pressure controlled drug delivery systems, or erodible drug delivery systems. Exemplary delivery systems are the SQZgel™ (MacroMed, Inc.), comprising a pH-sensitive polymer mixture combined with an outer coating in which the acidic environment of the stomach causes the polymer to imbibe with water and swell, entrapping the ion channel activator, e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6- shogaol), or a capsaicinoid (e.g., capsaicin). Upon entering the higher pH of the intestines, the polymer slowly shrinks, or "squeezes" at a "dialed-in" rate releasing the active composition in a sustained manner); the Egalet® extrusion based technology (Egalet A/S), comprising a biodegradable coat and a matrix, including the ion channel activator (e.g., a gingerol (e.g., 6- gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)), which is surface erodible, hydrophobic, and composed of PEG-stearate); Diffucaps/Surecaps (small beads approximately 1 mm or less in diameter that can be incorporated into hard gelatin capsules, where the ion channel activator (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) release profiles are created by layering drug onto a neutral core such as sugar spheres, crystals, or granules followed by a rate-controlling, functional membrane); and MeltDose®, which involves formulating solubilized, individual moelcules into tablets).

The components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) can be formulated for pH controlled release. Examples of suitable formulation principles are, for example, compositions provided with an enteric coating or hydrogels of a type described in US Patent Nos. 6,537,584 and 5,484,610, which are hereby incorporated by reference.

Another suitable formulation includes the formulation of components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) together with vitamin E concentrate in soft or hard gelatin capsules. Another specific example of a suitable formulation includes formulation of products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) together with ethanol, tocopherolethylene glycol 1000 succinate (TPGS), corn oil, and wax in soft or hard gelatin capsules. Variations of this formulation can include ethanol, TPGS, corn oil, and polyglycolized glycerides (e.g. , Gelucire) in soft or hard gelatin capsules. The resulting product can be a semi-solid or solid dosage form. The release rate of this formulation is dependent on degradation due Lo lipases in the intestine.

A further example of a suitable formulation is an oral pulsed dose drug delivery system.

This dosage form can be perceived as a modified form of the Schering Repetab tablets. A portion of the composition of the present invention is put in the core of a tablet. The core can for example, be made by conventional wet granulation or continuous granulation such as extrusion followed by compaction of the granulate into tablets. The core is then coated using an appropriate technology, for example, by air-suspension using an enteric coating polymer such as Eudragits. The first releasing dose is compression coated on the core or air-suspension coated either with the enteric coat or on top of the enteric coat. In an embodiment of the invention, the first releasing dose is air-suspension coated with the enteric coat, in a further embodiment of the invention, the first releasing dose is compression coated on the core, in order to avoid release of the composition according to the invention prior to the degradation of the enteric coat, such degradation typically occurring at pH values higher than those found in the gastric ventricle (i.e., the degradation of the enteric coat typically occurs after passage of the gastric ventricle).

Another example of a suitable formulation is an oral sustained drug delivery system. In this delivery system, the core can for example, be made by conventional wet granulation or continuous granulation such as extrusion followed by compaction of the granulate into tablets. The core is then coated using appropriate technology, for example, by air-suspension using ethylcellulose and a hydrophilic excipient such as hydroxy! propyl cellulose (HPC).

In some embodiments, components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) are in the form of micro-crystals with hydrophilic surfaces. The micro-crystals can be film coated directly in order to achieve a sustained release formulation. The compositions of the invention can also be complexed with genuine cyclodextrins and cyclodextrm-derivatives (e.g. , a!kyl- and hydroxyalky!-derivatives or sulfobutyl-derivatives). The complexation is achieved by methods known in the art. Complexation can lead to a higher solubility and a higher dissolution rate and higher bioavailability.

In other embodiments, the composition can include a pharmaceutically acceptable excipient that is an agent for delayed or controlled release of the components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)). In some aspects, the agent is a water-soluble polymer, including but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, ethyl cellulose, or carboxymethyl cellulose.

The components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) can be targeted to the mucus/mucosal lining of the mouth, tongue, nose, or gastrointestinal tract (GIT) through the use of bioadhesives. A bioadhesive is defined as a synthetic or biological material which is capable of adhering to a biological substrate or tissue. When the biological substrate is mucus, the term "mucoadhesive" has been employed. When the biological tissue involved is the mouth or the stomach, the terms "buccoadhesive" or "gastroadhesive" have been employed. Bioadhesives can remain attached to the biological substrate for an extended period of time. The period of time a bioadhesive is required to remain attached to a biological substrate will vary according to the target site and the condition being treated. Other delivery systems that can target the TRP or ASIC channel activators, (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) described herein to the colon include, but are not limited to:

(a) covalent linkage of the components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) with the carrier to form a prodrug that is stable in the stomach and small intestine and releases the ion channel activator in the large intestine upon enzymatic transformation by the intestinal microflora; examples of these prodrugs include azo-conjugates, cyclodextrin-conjugates, glycoside- conjugates, glucuronate conjugates, dextran-conjugates, polypeptide and polymeric conjugates;

(b) approaches to deliver intact molecule to the colon, such as coating with pH- sensitive polymers to release components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) at neutral to alkaline pH, or coating with biodegradable polymers which release the ion channel activator upon degradation by the bacteria in the colon;

(c) embedding the components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) in biodegradable matrices and hydrogels which release the ion channel activator (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) in response to the pH or biodegradation; (d) time released systems where once the multicoated formulation passes the stomach, the components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) are released after a lag time of 3-5 hrs which is equivalent to the transit time of the small intestine;

(e) using redox-sensitive polymers where a combination of azo and disulfide

polymers provide release of the components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) in response to the redox potential of the colon;

(f) osmotic controlled delivery where the components of the products and

compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) are released through semi-permeable membrane due to osmotic pressure.

Micro and Nanoparticle Formulations

In one embodiment, components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) are prepared as loaded nano- and micro-particles for sustained release and are formulated by the nano-precipitation or the oil-in-water single emulsion solvent evaporation/extraction method. First, the specific component (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) are prepared as loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles by the nano-precipitation method. The volume of oil- water ratio can be adjusted (e.g. , from about 1:2 to 1:5, e.g. , about 1:2, 1:3, 1 :4, or 1:5), and size of the nanoparticles can be selected (e.g. , from about 162 +/- 3 nm to 153 +/- 3 nm, e.g. , about 154, 155, 156, 157, 158, 159, 160, 161, or 162) to increase drug loading efficiency and drug release period. To get a more sustained release, a modified single emulsion method can be applied with biocompatible polymers such as polylactic acid (PLLA), polyhydroxy butyrate (PHB), polyglycolic acid (PGA), PLGA, and poly-e-caprolactone (PCL).

In another embodiment, stomach specific mucoadhesive nanoparticles (SSMN) can be used to improve controlled delivery of components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) by continuous release of the activator for a prolonged period to its absorption site to ensure optimal bioavailability. The components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) with a narrow absorption window are mostly associated with improved absorption at the jejunum and ileum due to enhanced absorption properties of these sites (e.g. , large surface area), or because of enhanced solubility in the stomach as opposed to the more distal parts of the gastrointestinal tract. Ion channel activators (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) that may benefit from using stomach specific mucoadhesive nanoparticles includes those that act locally in the stomach, those with low solubility at high pH values, those that are primarily absorbed in the stomach, those with a narrow window of absorption, e.g. , ion channel activators (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) that are absorbed mainly from the proximal part of the small intestine, those that absorb rapidly from the gastro intestinal tract, those that degrade in the colon, and those that are unstable in intestinal fluids. Longer residence time in the stomach could be advantageous for local action especially in the upper part of the small intestine. Routes of Administration

The compositions described herein may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art and as relating to the particular disease or condition to be treated. The compositions used in the methods described herein may be administered, for example, by topical, enteral, or parenteral applications. Topical applications include but are not limited to epicutaneous, inhalation, enema, eye drops, ear drops, and applications through mucous membranes in the body. Enteral applications include oral administration, rectal administration, vaginal administration, and gastric feeding tubes. Parenteral administration includes intravenous, intraarterial, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intrastemal, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

In some embodiments of the current invention, components of the products and compositions described herein (e.g., a gingerol (e.g., 6-gingerol), a shogaol (e.g., 6-shogaol), or a capsaicinoid (e.g., capsaicin)) are administered through the oral cavity to achieve mucosal and transmucosal effects. Exemplary applications include buccal, nasal, intradermal, inhalational, topical, subcutaneous, sublingual, sublabial, and insufflation administrations. Compositions of the current invention may include a penetration enhancer to increase the bioavailability of the ion channel activator within the oral cavity. Exemplary penetration enhances include surfactants (e.g., anionic surfactants (e.g, sodium lauryl sulfate), cationic surfactants (e.g., cetyl pyridinium chloride), and nonionic surfactants (e.g., poloxamer, Brij, Span, Myrj, Tween)), bile salts (e.g., sodium glycocholate, sodium taurodeoxycholate, sodium taurocholate), fatty acids (e.g., oleic acid, caprylic acid, lauric acid, lysophosphatidylcholine, phosphatidylcholine), cyclodextrins (e.g, α-, β-, or γ-cyclodextrans, methylated cyclodextrins), chelators (e.g., EDTA, citric acid, sodium salicylate, methyl salicylates), polymers (e.g., positively charged polymers (e.g., chitosan, trimethyl chitosan)), and cationic compounds (e.g., poly L-arginine, L-lysine).

For intravenous or intrathecal delivery or direct injection, the composition must be sterile and fluid to the extent that the composition is deliverable by syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride in the composition. Long-term absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

The choice of the route of administration will depend on whether a local or systemic effect is to be achieved. For example, for local effects, the composition can be formulated for topical administration and applied directly where its action is desired. For systemic, long term effects, the composition can be formulated for enteral administration and given via the digestive tract. For systemic, immediate and/or short term effects, the composition can be formulated for parenteral administration and given by routes other than through the digestive tract.

Within the scope of the present invention are also parenteral depot systems from biodegradable polymers. These systems are injected or implanted into the muscle or subcutaneous tissue and release the incorporated drug over extended periods of time, ranging from several days to several months. Both the characteristics of the polymer and the structure of the device can control the release kinetics which can be either continuous or pulsatile. Polymer- based parenteral depot systems can be classified as implants or microparticles. The former are cylindrical devices injected into the subcutaneous tissue whereas the latter are defined as spherical particles in the range of 10 - 100 μιη. Extrusion, compression or injection moldings are used to manufacture implants whereas for microparticles, the phase separation method, the spray-drying technique and the water-in-oil-in- water emulsion techniques are frequently employed. The most commonly used biodegradable polymers to form microparticles are polyesters from lactic and/or glycolic acid, e.g. poly(glycolic acid) and poly(L-lactic acid) (PLG/PLA microspheres). Of particular interest are in situ forming depot systems, such as thermoplastic pastes and gelling systems formed by solidification, by cooling, or due to the sol- gel transition, cross-linking systems and organogels formed by amphiphilic lipids. Examples of thermosensitive polymers used in the aforementioned systems include, N-isopropylacrylamide, poloxamers (ethylene oxide and propylene oxide block copolymers, such as poloxamer 188 and 407), poly(N-vinyl caprolactam), poly(siloethylene glycol), polyphosphazenes derivatives and PLGA-PEG-PLGA. Dosage

The compositions of the present invention are formulated into acceptable dosage forms by conventional methods known to those of skill in the art. Actual dosage levels of the active ingredients in the compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of absorption of the particular agent being employed, the duration of the treatment, other drugs, substances, and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the composition required. For example, the physician or veterinarian can start doses of the substances of the invention employed in the composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a composition of the invention will be that amount of the substance which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the effective daily dose of a therapeutic composition may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

The frequency of treatment may also vary. The subject can be treated one or more times per day (e.g. , once, twice, three, four or more times) or every so-many hours (e.g. , about every 2, 4, 6, 8, 12, or 24 hours). The composition can be administered 1, 2, or 3 times per 24 hours. The time course of treatment may be of varying duration, e.g. , for two, three, four, five, six, seven, eight, nine, ten, or more days, two weeks, 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, or more than one year. For example, the treatment can be twice a day for three days, twice a day for seven days, twice a day for ten days. Treatment cycles can be repeated at intervals, for example weekly, bimonthly or monthly, which are separated by periods in which no treatment is given. The treatment can be a single treatment or can last as long as the life span of the subject (e.g. , many years).

Foodstuff and Food Supplements

The present invention also relates to the use of the composition as foodstuff, food supplement or dietetic product (a foodstuff intended for a particular diet). In particular, the composition ca be incorporated into foodstuffs which are industrially produced or craftsmen- prepared, such as oils, butter, margarine, bread spreads, or baked goods. It can also be presented in the form of a powder for dilution in water or food bars.

The composition of the invention can further be administered in combination with a dietary supplement to promote and/or maintain general health. Examples of dietary supplements include, but are not limited to, a vitamin (e.g. , Vitamin A, Vitamin B i, B2, B3, B5, B₆, B₇, B9, B 12, Vitamin C, Vitamin D, Vitamin E, and Vitamin K), a mineral (e.g. , potassium, chlorine, sodium, calcium, magnesium, phosphorus, zinc, iron, manganese, copper, iodine, selenium, and molybdenum), an herb or botanical (e.g. , St. John's-wort, kava, Shilajit, and Chinese herbal medicines), an amino acid (e.g. , glycine, serine, methionine, cysteine, aspartic acid, glutamic acid, glutamine, tryptophan, and phenylalanine), and a concentrate, constituent, extract, and/or a combination of any of the above. Methods of Treatment

The compositions of the invention may be useful for preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof. In some embodiments, the compounds, compositions, and methods described herein comprise preventing or treating a symptom or side effect of a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof.

Angelmann syndrome is a neurological disorder that entails seizures, intellectual and developmental disabilities, sleep disturbance, and halting movements, and is often accompanied by a happy demeanor in the subject. Additional symptoms include movement or balance disorders (e.g., ataxia of gait), speech impairment, microcephaly, strabismus, and

hypopigmented skin/eyes. Angelmann syndrome is caused by the deletion or inactivation of a region on chromosome 15. Although there is currently no cure for Angelmann syndrome, medications may be used to treat related symptoms, such as an antoconvulsant or a laxative.

Charcot Marie Tooth (CMT) disease is one of the most commonly inherited neurological disorders, affecting both the motor and sensory nerves in nearly 1 in every 2,500 people. CMT is characterized by the progressive loss of muscle tissue and touch sensation. Symptoms often begin in childhood or early adulthood, and include foot drop, hammer toe, tooth grinding, scoliosis, tremor, pain, and gastrointestinal problems. CMT is caused by mutations in various genes expressing neuronal proteins, such as those affecting the myelin sheath or the axons.

CMT may be divided into several subtypes, such as CMT1, CMT2, CMT3, CMT4, and CMTX, based on the proteins and regions of neurons affected. Management of CMT may entail physical therapy, occupational therapy, use of orthopedic devices, and medications to treat pain and muscle tightness. CMT is also referred to as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy.

Friedrich' s ataxia is an inherited neurological disease characterized by progressive damage to the nervous system. The main cause of the disease involves mutations to the FXN gene that leads to reduced expression of the mitochondrial protein frataxin. Symptoms of Friedrich' s ataxia include gait disturbances, vision and hearing impairment, slurred speech, scoliosis, heart disorders, diabetes, and muscle weakness; however, cognitive function is often not affected. Treatments include surgical interventions (e.g., relating to the spine or heart), physical or occupational therapy, and medication (e.g., an ACE inhibitor).

Lennox- Gastaut syndrome (LGS) is a type of childhood onset epilepsy characterized by multiple seizure types and intellectual impairment. LGS typically appears in children between the ages of 2 and 8 years old, and entails both tonic and atonic seizures. Although the cause of LGS is unknown, contributing factors may include lack of oxygen during birth, severe brain injuries linked to pregnancy, or an infection (e.g., a viral infection).

Limb-girdle muscular dystrophy (LGMD) is a type of muscular dystrophy characterized by progressive muscle wasting, such as in the hip and shoulder muscles. Signs and symptoms of LGMD include gait abnormalities, muscle hypertrophy, respiratory problems, palpitations, and muscle weakness. The cause of LGMD often includes mutations in the α, β, γ, and δ sarcoglycans (i.e., the sarcoglycanopathies). LGMD may be divided into several subclasses, including LGMD1 and LGMD1 subfamilies that differ based on the dominant or recessive nature of the affected gene(s).

Morvan' s syndrome is an autoimmune disease that entails neuromyotonia, muscle cramping, muscle weakness, pruritus, weight loss, hyperhidrosis, insomnia, and delirium.

Evidence suggests that increased levels of antibodies against voltage-gated potassium channels may play role in the pathophysiology of the disease. Treatment options include plasmapheresis, thymectomy, immunosuppression, and medication (e.g., steroids). Morvan' s syndrome may also be referred to as Morvan' s "fibrillary chorea".

Myoclonic seizures are characterized by brief, involuntary twitching or cramping of a muscle caused by sudden contraction. They may occur on their own (e.g., due to injury), or be one of several symptoms of a variety of neurological disorders including multiple sclerosis, Parkinson's disease, Alzheimer's disease, lyme disease, Creutzfeldt-Jakob disease, or epilepsy.

Myotonic dystrophy is an autosomal-dominant disorder resulting in muscle weakness or muscle loss. Symptoms may appear at any time from childhood to adulthood, and begin with muscle weakness in the hands, feet, neck, or face. There two major classes of myotonic dystrophy, including Type 1 (i.e., Steinert disease) or Type 2 (i.e., proximal myotonic myopathy), although other forms of the disease have been described. Current treatments primarily focus on management of disease symptoms, such as use of a pacemaker, ventilation, and medication (e.g., imipramine, clomipramine, or taurine).

Raynaud' s disease is a condition in which spasms in the vasculature result in reduced blood flow in certain appendages, such as fingers and toes, and less commonly the nose, ears, or lips. Hyperactivation of the sympathetic nervous system may lead to vasoconstriction of peripheral blood vessels, which in turn results in tissue hypoxia. Episodes of Raynaud's disease can be triggered by cold weather, stress, another condition (e.g., a connective tissue disorder (e.g., scleroderma, lupus, arthritis, polymyositis, Ehlers-Danlos syndrome), an obstructive disease (atherosclerosis, Buerger's disease, Takayasu' s arteritis, subclavian aneurysms, thoracic outlet syndrome), a hand injury, anorexia nervosa), smoking, or as a side effect of certain medications (e.g., a beta-blocker, ergotamine, or a stimulant). Symptoms of Raynaud's disease include pain, numbness, sensations of cold, and pale coloring in the affected areas.

Multiple system atrophy (MSA) is a neurodegenerative disorder that affects the involuntary functions of the body, such as blood pressure, heart rate, bladder function, and digestion. MSA typically develops in adulthood, and can impair multiple physiological systems at once. Also known as Shy-Drager syndrome, there are two major classes of MSA:

parkinsonian MSA and cerebellar MSA. Exemplary symptoms of parkinsonian MSA include muscle rigidity, tremors, slow movement, and impaired posture and balance. Cerebellar MSA presents with impairement of movement and coordination, slurred or slow speech, visual disturbances, and difficulty swallowing or chewing. Both classes of MSA can further affect posture, blood pressure, urinary and bowel function, and body temperature regulation.

Treatments for MSA include management of symptoms, primarily through medications to raise blood pressure (e.g., corticosteroids, pyridostigmine, midorine, and droxidopa) and reduce Parkinson's -like symptoms (e.g., levodopa, carbidopa),

Status epilepticus (SE) refers to a condition involving epileptic seizures that are greater than five minutes long, or wherein a subject experiences multiple seizures within a given five minute period. SE may be divided into convulsive SE or nonconvulsive SE, and seizures may include tonic-clonic type seizures, absence seizures, or complex partial seizures. Possible causes of SE include stroke, hemorrhage, intoxicants, alcoholism or alcohol withdrawal, gastroenteritis, a metabolic disturbance, sleep deprivation. SE treatments include administration of medications (e.g., a benzodiazepine, phenytoin, fosphenytoin, carbamazepine, valproate, or a barbiturate,

Tardive dyskinesia (TD) is a disorder characterized by involuntary, repetitive body movements with a slow or belated onset. TD is often caused by the long-term or high dosage of an antipsychotic drug or a drug used to treat a gastrointestinal disorder. Symptoms of TD include grimacing, lip smacking, lip puckering, tongue movements, excessive eye blinking, or respiratory irregularity. While there are no approved drugs to treat TD available, efficacy has been shown by several agents including tetrabenazine, reserpine, ondansetron, and others.

Cancer refers to a malignant neoplasm that may present in a variety of tissues within the body and may have rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Exemplary cancers include adenocarcinoma; adrenal gland cancer; anal cancer; appendix cancer; biliary cancer; bladder cancer; breast cancer; brain cancer; cervical cancer; colorectal cancer; connective tissue cancer; epithelial carcinoma;

endometrial cancer; esophageal cancer; Ewing's sarcoma; eye cancer; gastric cancer;

gastrointestinal stromal tumor (GIST); head and neck cancer; oral cancer; throat cancer;

hematopoietic cancers (e.g., leukemia or lymphoma such as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) and multiple myeloma (MM)); kidney cancer; liver cancer; lung cancer; muscle cancer; osteosarcoma; ovarian cancer; pancreatic cancer; penile cancer; rectal cancer; salivary gland cancer; skin cancer; testicular cancer; thyroid cancer; urethral cancer; vaginal cancer.

A cancer (e.g., a cancer described herein) may be treated by a standard of care anticancer agent, therapy, or treatment. Exemplary anticancer agents include an alkylating agent (e.g., cyclophosphoramide, bendamustine, carmustine, chlorambucil, lomustine, melphalan, procarbazine, streptozocin, ifosfamide, temozolomide); an anti-metabolite (e.g., capecitabine, 5'- fluorouracil, methotrexate, gemcitabine, pemetrexed, fludarabine, raltitrexed); an anti-tumor antibiotic (e.g., mitomycin, bleomycin, epirubicin, doxorubicin, mitoxantrone, actinomycin), a plant alkaloid (e.g., etoposide, paclitaxel, irinotecan, docetaxel, vincristine, eribulin, topptecan, vinblastine); a DNA-linking agent (e.g., carboplatin, cisplatin, oxaliplatin); a bisphosphonate

(e.g., zoledronate); an antibody (e.g., bevacizumab, catuximab, gefitinib, imatinib, trastuzumab, denosumab, rituximab, sunitinib, afatinib, aflibercept, BCG, dabrafenib); a checkpoint inhibitor (e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor).

In some embodiments, a compound, composition, or method described herein may be used to prevent or treat a side effect of a cancer treatment. Said side effects may include anemia; appetite loss; attention, thinking, or memory problems; gait abnormalities; bleeding;

gastrointestinal tract blockage; blood clotting; dehydration; constipation; diarrhea; dysphagia; dry mouth; edema; alopecia; fatigue; headaches; heart problems; infection; hypercalcemia; lymphedema; nausea; vomiting; neutropenia; osteoporosis; pain (e.g., muscle pain); muscle cramping; muscle spasms; muscle spasticity; neuropathy; mouth or throat sores; dyspnea;

insomnia; skin conditions; weight gain; weight loss; incontinence; infertility; thrombocytopenia; or a nervous system effect (e.g., tingling, burning, weakness, numbness, loss of balance, trembling, stiff neck, headache).

In some embodiments, the compounds, compositions, and methods described herein include prevention or treatment of a subject having been diagnosed with or identified as having Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof. In some embodiments, the subject is further experiencing an unwanted muscle cramp or muscle dystonia.

The symptoms of any of the above-identified diseases or disorders may be prevented or improved by administration of a compound of the present invention (e.g. , a gingerol (e.g., 6- gingerol), a shogaol (e.g., 6-shogaol), a capsaicinoid (e.g., capsaicin), e.g., wherein the composition is substantially free of a related analog thereof. In some embodiments, the prevention or improvement of symptoms relating to any of the above-identified diseases or disorders may be measured by a particular endpoint test known to one of skill in the art, e.g., the ALS Assessment Questionnaire, the Numerical Rating Scale, the Modified Ashworth Scale, the Patient Global Impression of Change Scale, the Clinical Global Impression Scale, the Toronto Western Spasmodic Torticollis Rating Scale, the Tsui score, the Oropharyngeal Swallow Efficiency Test, the visual analogue scale, the Insomnia Severity Index Sleep Survey, the Epworth Sleepiness Scale, or another similar test, scale, survey, or standard. In some embodiments, symptoms relating to any of the above-identified diseases or disorders are improved by about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more upon treatment with a composition of the present invention, e.g., as measured by any of the above-identified endpoint tests, scales, surveys, or standards. Combination Therapies

In certain embodiments, additional therapeutic agent(s) may be administered with compositions of the present invention for, e.g. , Angelman syndrome, Charcot Marie Tooth disease, Friedrich's ataxia, Lennox-Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof. . In one embodiment, the candidate therapeutic agents are agents already known in the art for use for other conditions or disorders, e.g. , neuromuscular therapeutic agents, epilepsy, or cancer treatment. When combination therapy is employed, the additional therapeutic agent(s) can be administered as a separate formulation or may be combined with any of the compositions described herein.

. In some embodiments, the compositions can be used in combination with a sleep aid. Sleep aids that can be used in combination with the compositions and methods described herein include: antihistamines (e.g. , diphenhydramine and doxylamine); benzodiazepines (e.g. , estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), temazepam (Restoril), and triazolam (Halcion)); non-benzodiazepine sedative hypnotics (e.g. , eszopiclone (Lunesta), zalepon (Sonata), and Zolpidem (Ambien)); and melatonin receptor agonist hypnotics (e.g. , ramelteon (Rozerem). Still other sleep aids that can be used in combination with the compositions and methods described herein include: chamomile, valerian root, kava kava, lemon balm, passionflower, lavender, St. John's Wort, melatonin, tryptophan (e.g. , L- tryptophan), 5 -hydroxy tryptophan (5-HTP), catnip, hops, rhodiola, oatstraw, lavender, GAB A, L-theanine, linden, ginseng (e.g. , Siberian ginseng), honey, nutmeg, mugwort, butterbur, rauwolfia, taumelloolch, American hellebore, quassia, tulip tree, brewer's yeast, inositol, skullcap, phosphatidylserine, calcium, magnesium, vitamin B6, vitamin B 12, and pantothenic acid (B5).

In another embodiment, any of the compositions described herein can be used for the treatment of painful muscle contractions of the head or neck as in tension, cluster or migraine headache. In some embodiments, the compositions can be used with analgesics, including aspirin, ibruprofen, acetaminophen, or naproxen; with triptans including sumatriptan, rizatriptan, naratriptan; with mild sedatives including butalbital; with anti-depressants including

amitriptyline; with dihydroergotamine mesylate; or with ketorolac.

Any of the compositions described herein can be also be used for the treatment of focal dystonia. In some embodiments, the compositions can be used with botulinum toxin; with anticholinergic agents including trihexyphenidyl and benztropine; with GABAergic agents including benzodiazepines; and with dopaminergic agents including tetrabenazine and levodopa.

In further embodiments, the compositions described herein can be also be used for the treatment of muscle claudication pain due to inactivity or restriction as seen in "economy class syndrome", paralysis, peripheral artery disease or immobilization. In some embodiments, the compositions can be used with cilostazol or with pentoxifylline. The compositions described herein can be also be used for the treatment of sarcoidosis. In some embodiments, the compositions can be used with non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen and aspirin; with corticosteroids, including prednisone and prednisolone; and with steroid-sparing agents, including azathioprine, methotrexate, mycophenolic acid, and leflunomide.

In other embodiments, any of the compositions described herein can also be used in combination with a treatment for pain or a disorder relating to the oral cavity, such as oral lesions, canker sores, cold sores, thrush, gingivitis, leukoplakia, halitosis, or dry mouth. In some embodiments, the composition can be used with or antibacterial or antiviral agents to treat or prevent tooth decay or carries.

In other embodiments, any of the compositions described herein can also be used in combination with a treatment for pain or a disorder relating to the stomach or gastrointestinal tract, such as indigestion, heartburn, colitis, irritable bowel syndrome, constipation, diarrhea, lactose intolerance, gastroesophageal reflux disease, ulcers, nausea, or stomach cramps. In some embodiments, the compositions can be used with antacids (e.g., simethicone, magaldrate, aluminum salts, calcium salts, sodium salts, magnesium salts, alginic acid) laxatives , ¾ antagonists (e.g., ranitidine, famotidine, nizatidine, cimetidine) or proton pump inhibitors (e.g., omeprazole, lansoprazole, esomeprazole, dexlansoprazole, rabeprazole, or pentoprazole), and antidiarrheals (e.g., bismuth subsalicylate).

In other embodiments, any of the compositions described herein can be also be used for the treatment of disease, disorder or injury to the peripheral nervous system such as cramp fasciculation syndrome, peripheral neuropathy, carpal tunnel syndrome or EBV. In some embodiments, the compositions can be used to treat cramp fasciculation syndrome with β- blockers; analgesics including ibuprofen and acetaminophen; magnesium; or carbamazepine. In some embodiments, the compositions can be used to treat peripheral neuropathy with tricyclic antidepressants, including amitriptyline; with antiepileptic therapies including gabapentin and sodium valproate; with synthetic cannabinoids including nabilone; with pregabalin; or with serotonin-norepinephrine reuptake inhibitors (SNRIs), including duloxetine. In some embodiments, the compositions can be used to treat carpal tunnel syndrome with corticosteroids.

EQUIVALENTS

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this disclosure has been described with reference to specific aspects, it is apparent that other aspects and variations may be devised by others skilled in the art without departing from the true spirit and scope of the disclosure. The appended claims are intended to be construed to include all such aspects and equivalent variations. Any patent, publication, or other disclosure material, in whole or in part, that is said to be incorporated by reference herein is incorporated herein only to the extent that the incorporated material does not conflict with existing definitions, statements, or other disclosure material set forth in this disclosure. As such, and to the extent necessary, the disclosure as explicitly set forth herein supersedes any conflicting material incorporated herein by reference.

While this disclosure has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the disclosure encompassed by the appended claims.

Claims

CLAIMS What is claimed is:

1. A method for preventing or treating a disease, disorder, or condition selected from Angelman syndrome, Charcot Marie Tooth disease, Friedrich' s ataxia, Lennox- Gastaut syndrome, limb-girdle muscular dystrophy, Morvan's syndrome, myoclonic seizures, myotonic dystrophy, Raynaud's disease, multiple system atrophy, status epilepticus, tardive dyskinesia, and cancer or a side effect of treatment thereof in a subject in need thereof, the method comprising orally administering an effective amount of a composition to the subject, wherein the composition comprises a single shogaol analog (e.g., 6-shogaol) and less than about 25% of the total shogaol concentration in the composition (e.g., by weight) of a related analog thereof.

2. The method of claim 1, wherein the disease, disorder, or condition is Charcot Marie Tooth disease, tardive dyskinesia, or a side effect of a cancer treatment.

3. The method of any one of the preceding claims, wherein the disease, disorder, or condition is Charcot Marie Tooth disease.

4. The method of any one of the preceding claims, wherein the disease, disorder, or condition is a side effect of cancer treatment (e.g., anemia; appetite loss; attention, thinking, or memory problems; gait abnormalities; bleeding; gastrointestinal tract blockage; blood clotting; dehydration; constipation; diarrhea; dysphagia; dry mouth; edema; alopecia; fatigue; headaches; heart problems; infection; hypercalcemia; lymphedema; nausea; vomiting; neutropenia;

osteoporosis; pain (e.g., muscle pain); muscle cramping; muscle spasms; muscle spasticity; neuropathy; mouth or throat sores; dyspnea; insomnia; skin conditions; weight gain; weight loss; incontinence; infertility; thrombocytopenia; or a nervous system effect (e.g., tingling, burning, weakness, numbness, loss of balance, trembling, stiff neck, headache)).

5. The method of any one of the preceding claims, wherein the composition is administered in a dosage sufficient to prevent, diminish the severity of, or reduce the frequency of a symptom of said disease, disorder, or condition in the subject (e.g., a muscle cramp, muscle pain, muscle spasm, or muscle spasticity).

6. The method of any one of the preceding claims, wherein the subject is administered between about 0.5 mg and about 100 mg of 6-shogaol per administration.

7. The method of any one of the preceding claims, wherein the composition is administered once, twice, or three times daily.

8. The method of any one of the preceding claims, wherein the composition is formulated as a liquid or a solid.

9. The method of any one of the preceding claims, wherein the composition is formulated as a solid (e.g., a tablet).

10. The method of claim 9, wherein the tablet is an orally disintegrating tablet.

11. The method of any one of the preceding claims, wherein the composition further comprises a single gingerol analog (e.g., 6-gingerol), a capsaicinoid, or trans-cinnamaldehyde.

12. The method of any one of the preceding claims, wherein the composition has a residence time of greater than about 10 seconds in the mouth of the subject.