HK1231783A1

HK1231783A1 - Ion channel activators and methods of use

Info

Publication number: HK1231783A1
Application number: HK17105681.4A
Authority: HK
Inventors: Christoph Westphal; Jennifer CERMAK; Roderic O. COLE; Glenn F. Short, Iii; Robert Perni; Sridevi PONDURU
Original assignee: 弗莱克斯制药股份有限公司
Priority date: 2014-04-14
Filing date: 2015-04-14
Publication date: 2017-12-29

Description

Ion channel activators and methods of use

Priority requirement

This application claims priority to U.S. provisional application No. 61/979,349, filed on 14/4/2014, U.S. provisional application No. 62/073,131, filed on 31/10/2014, and U.S. provisional application No. 62/073,258, filed on 31/10/2014, each of which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to compositions and methods of preparation of ion channel activators, formulations and medical uses of these compositions.

Background

Transient Receptor Potential (TRP) channels are non-selective cation channels that act as cellular sensors that respond to and integrate different signals, including temperature, mechanical stress, exogenous chemicals, and endogenous chemicals, such as intracellular and extracellular messengers. These pathways are involved in a number of functions, including pain, temperature and mechanical sensation, calcium and magnesium homeostasis, lysosomal function, cardiovascular regulation, and control of cell growth and proliferation.

Acid-sensitive ion channels (ASICs) are neuronal voltage insensitive cation channels activated by extracellular protons. ASIC channels are mainly expressed in the nervous system and mostly conduct 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, cellular damage during cerebral ischemia, and mucolipidosis type IV.

There is a need in the art for improved methods and compositions for treating peripheral nervous system conditions (e.g., peripheral neuropathy), central nervous system conditions, muscle conditions and disorders (e.g., fibromyalgia, muscle cramps and spasms (e.g., nocturnal spasms), painful muscle contractions (e.g., muscle contractions of the head or neck), neuromuscular disorders (e.g., motor neuron disease) or dystonia (e.g., cervical dystonia, blepharospasm, back spasms, or leg spasms due to spinal stenosis)), connective tissue diseases (e.g., degenerative joint disease), throat disorders (e.g., dysphagia or spasmodic dysphonia), tactile sensitivity, electrolyte imbalance and/or vitamin deficiency, respiratory conditions (e.g., asthma), cough, and sarcoidosis. As shown herein, compositions comprising activators of ion channels (e.g., TRP or ASIC channels) may be useful in treating the conditions mentioned above.

Disclosure of Invention

In one aspect, the invention features a composition formulated for oral administration that includes an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof). In some embodiments, the composition comprises a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof). In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some embodiments, the composition further comprises a plurality of pharmaceutically acceptable excipients.

In some embodiments, the composition is formulated for modulated release (e.g., delayed release, extended release, or rapid release) of the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or a combination thereof). In some embodiments, the pharmaceutically acceptable excipient comprises a modified release (e.g., delayed release, extended release, or rapid release) agent of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) such that the ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) is not substantially released in the stomach of a subject when orally administered to the subject. In some embodiments, the modified release (e.g., delayed release, extended release, or rapid release) agent is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and mixtures thereof.

In some embodiments, the pharmaceutically acceptable excipient comprises a coating. In some embodiments, the coating is selected from the group consisting of: enteric coatings, sugar coatings, and polymeric coatings. In some embodiments, the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or a combination thereof) is embedded in a biodegradable microparticle or nanoparticle for sustained release.

In some embodiments, the composition further comprises a formulation base. In some embodiments, the formulation base comprises an oil and a lipophilic additive. In some embodiments, the oil is selected from the group consisting of: vegetable oil, mineral oil, soybean oil, sunflower seed oil, corn oil, olive oil, nut oil and liquid paraffin. In some embodiments, the lipophilic additive is selected from the group consisting of: polyethylene glycol, fatty acid monoglycerides, diglycerides or triglycerides, palmitic acid, stearic acid, behenic acid, polyethylene glycol fatty acid esters, candelilla wax, carnauba wax, polyethylene oxide wax and petroleum wax. In some embodiments, the composition further comprises a coloring agent, a dissolving agent, a flavoring agent, a sweetener, a viscosity modifier, an electrolyte, a vitamin, a mineral, an antioxidant, or a preservative.

In any embodiment of the invention, the TRPV1 channel activator is a capsaicinoid (capsaicinoid), capsicum ester (capsinoid), oleoylethanolamide, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsaicinoid ester (capsiate), 1-monoacylglycerol having C18 and C20 unsaturation and C8-C12 saturated fatty acid, 2-monoacylglycerol having C18 and C20 unsaturated fatty acid, mioga-diole (mioga), mioga-trioxanal (miogatral), polygondialdehyde, terpenoid having α -unsaturated 1, 4-dialdehyde moiety, sanshonol (sanshool), evodiamine (evodine), acesulfame potassium (acesulfame-K), cyclamate (cyclamate), CuSO (cyclodextrin), CuSO (capsinoid)₄、ZnSO₄、FeSO₄Arvanil, arachidoteneAcid ethanolamide (anandamide), N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynonenal, 1- [2- (1-adamantyl) ethyl]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea or gingerol (gingerol).

In a particular embodiment, the capsaicinoid is capsaicin (capsaicin). In some aspects of this embodiment, the TRPV1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).

In some embodiments, the TRPV1 channel activator is naturally occurring or non-naturally occurring. In some embodiments, the naturally-occurring TRPV1 channel activator is selected from the group consisting of: capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, nonivamide (nonivamide), pseudocapsaicin, resiniferatoxin (resiniferatoxin), tinyatoxin (tinyatoxin), capsaicinoid, dihydrocapsaicinoid, nordihydrocapsaicinoid, norcapsaicin, coniferyl capsaicinoid (capsicinate), dihydroconiferyl capsaicinoid and other coniferyl esters, capsaicinoid analogs (capsicinoninids), and 3-hydroxyacetanilide.

In some embodiments, the non-naturally occurring TRPV1 channel activator is selected from the group consisting of: 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl formate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl acetate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl propionate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl butyrate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl 2, 2-dimethylpropionate, [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl, and mixtures thereof, Octadecanoic acid 4- [ ((6E) -8-methylnon-6-enamidoyl) methyl ] -2-methoxyphenyl ester, {4- [ ((6E) -8-methylnon-6-enamidoyl) methyl ] -2-methoxyphenoxy } carboxylic acid 4- [ ((6E) -8-methylnon-6-enamidoyl) methyl ] -2-methoxyphenyl ester, 8-methylnonanoic acid homovanillyl ester, 8-methylnonanoic acid 3- (3-methoxy-4-hydroxyphenyl) propyl ester, homovanillic acid 8-methylnonanyl ester, 8-methylnonanoic acid substituted benzyl ester derivatives, heptanoylisobutylamide, heptanoylguaiacinamide, 7-phenylhepta-6-yn-acid-4-hydroxy-3-methoxybenzene methyl Amides, polyhydrofannil, denatonium capsaicinoid, N- [4- (2-aminoethoxy) -3-methoxyphenylmethyl ] -N '- [2- (4-chlorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxyphenylmethyl ] -N' - [2- (4-fluorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxyphenylmethyl ] -N '- [2- (2, 4-dichlorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxyphenylmethyl ] -N' - [2- (4-benzyloxyphenyl) ethyl ] thiourea, salts of N, n- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (4- (N-octyloxy) phenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [ 4-N-octyloxybenzyl ] thiourea, N-phenylmethylalkynamide capsaicin derivatives, N- (4-O-glycerol-3-methoxybenzyl) nonanamide, N-nonanoylvanillyl oxamide-4-glyceryl ether, N- (4-O-sodium acetate) -3-methoxybenzyl-nonanamide (N-nonanoylvanillyl oxamide-4-O-sodium acetate), N- (4-O-diol-3-methoxybenzyl) -nonanamide (N-nonanoyl vanillylamide-4-diol ether), 20-homovanillyl-michigan toxin, 20-homovanillyl-12-deoxyphorbol-13-phenylacetate), cigasecine (civamide) (N- [ (4-hydroxy-3-methoxyphenyl) -methyl ] -8-methyl- (Z) -6-nonanamide), novanil (nuvanil), casamanil (capsavanil), ovani (olvanil), avanib and palvanil (palvanil) (N-palmitoyl-vanillylamide).

In some embodiments of the invention, the TRPV1 channel activator is allyl isothiocyanate, gingerol, cinnamaldehyde (cinnamyl), acrolein (acrolein), farnesyl thiosalicylic acid, Δ₉-tetrahydrocannabinol (Δ)₉-tetrahydrocanabinol), eugenol (eugenol), shogaol (shogaol), sanshool, allicin (allicin), diallyl sulfide, diallyl disulfide, diallyl trisulfide or farnesyl thioacetic acid. In some aspects of this embodiment, the TRPV1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).

In some embodiments, the ASIC channel activator comprises acetic acid, phosphoric acid, citric acid, malic acid, succinic acid, lactic acid, tartaric acid, fumaric acid, or ascorbic acid.

In some embodiments, the ASIC channel activator is present at about 0.001% to about 10% (w/w), or about 0.001% to about 10% (v/v).

In some embodiments, the composition is a liquid or a solid. In some embodiments, the composition is formulated as a liquid. In some embodiments, the liquid is selected from the group consisting of: emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), sweet syrups, drops, sprays, and elixirs. In some embodiments, the composition is formulated as a solid. In some embodiments, the solid is selected from the group consisting of: tablets, capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid-filled lozenges), gums, candies, chewable tablets, foods, dissolving strips, films, and semi-solid formulations. In some embodiments, the solid is a tablet or capsule. In some embodiments, the capsule is a hard or soft capsule.

In some embodiments, the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combinations thereof) comprises about 0.01% or more, e.g., about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.075%, about 0.1% or more of the liquid formulation. In some embodiments, the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combinations thereof) comprises about 0.1% or more, e.g., about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.75%, about 1% or more of the liquid formulation. In some embodiments, the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combinations thereof) comprises about 1% or more, e.g., about 2%, about 3%, about 4%, about 5%, about 7.5%, about 10% or more, of the liquid formulation. In some embodiments, the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combination thereof) comprises about 0.5% to 5% of the liquid formulation. In some embodiments, the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combination thereof) comprises about 0.5% to 2.5% of the liquid formulation. In some embodiments, the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combinations thereof) comprises about 10% or more, e.g., about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more, of the liquid formulation.

In some embodiments, the composition comprises a liquid formulation (e.g., an emulsion, a microemulsion, a solution, a suspension, a syrup (e.g., a syrup concentrate), a sweet syrup, drops, or an elixir) and the effective amount of the liquid formulation is at least about 1mL, about 2mL, about 4mL, about 6mL, about 8mL, about 10mL, about 12mL, about 14mL, about 16mL, about 18mL, about 20mL, about 22.5mL, about 25mL, or more. In some embodiments, the effective amount of the liquid formulation is between about 1mL and about 10 mL. In some embodiments, the effective amount of the liquid formulation is between about 5mL and about 10 mL. In some embodiments, the effective amount of the liquid formulation is between about 10mL and about 25 mL.

In some embodiments, the composition comprises a liquid formulation (e.g., an emulsion, a microemulsion, a solution, a suspension, a syrup (e.g., a syrup concentrate), a sweet syrup, drops, or an elixir) and the effective amount of the liquid formulation is at least about 25mL, about 30mL, about 35mL, about 40mL, about 45mL, about 50mL, about 60mL, about 75mL, about 100mL, about 150mL, about 200mL, about 300mL, about 400mL, about 500mL, about 600mL, about 750mL, about 1000mL, or more. In some embodiments, the effective amount of the liquid formulation is between about 25mL and about 100 mL. In some embodiments, the effective amount of the liquid formulation is between about 50mL and about 500 mL. In some embodiments, the effective amount of the liquid formulation is between about 100mL and about 1000 mL.

In some embodiments, the composition comprises a liquid formulation (e.g., an emulsion, a microemulsion, a solution, a suspension, a syrup (e.g., a syrup concentrate), a sweet syrup, drops, or an elixir) and the effective amount of the liquid formulation is at least about 1 fluid ounce, about 2 fluid ounces, about 3 fluid ounces, about 4 fluid ounces, about 5 fluid ounces, about 6 fluid ounces, about 7 fluid ounces, about 8 fluid ounces, about 9 fluid ounces, about 10 fluid ounces, about 11 fluid ounces, about 12 fluid ounces, or more. In some embodiments, the effective amount of the liquid formulation is at least about 12 fluid ounces, about 16 fluid ounces, about 20 fluid ounces, about 24 fluid ounces, about 32 fluid ounces, about 40 fluid ounces, about 48 fluid ounces, about 56 fluid ounces, about 64 fluid ounces, or more.

In some embodiments, the composition comprises a solid formulation (e.g., a tablet, capsule, powder, crystal, paste, gel, lozenge (e.g., a liquid-filled lozenge), gum, candy, food, dissolving strip, film, or semi-solid formulation) and the effective amount of the solid formulation is about 0.5mg, about 1mg, about 10mg, about 25mg, about 50mg, about 100mg, about 250mg, about 500mg, about 750mg, about 1g, about 2g, about 5g, about 10g, or more. In some embodiments, the effective amount of the solid formulation is between about 0.5mg and about 100 mg. In some embodiments, the effective amount of the solid formulation is between about 100mg and about 500 mg. In some embodiments, the effective amount of the solid formulation is between about 500mg and about 1000 mg.

In some embodiments, a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) is formulated for once-a-day use. In some embodiments, the composition is formulated for use at least about 1 time/day, about 2 times/day, about 3 times/day, about 4 times/day, about 5 times/day, or more. In some embodiments, the composition is formulated for use about 1-3 times per day. In some embodiments, the composition is formulated for use for a period of about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or longer.

In another aspect, the invention features a composition formulated for oral administration comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient, wherein the composition is a liquid or a solid, and wherein the composition is formulated for delayed release of the ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof). In some embodiments, the composition comprises a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutically acceptable excipient comprises a delayed release agent of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) such that, when orally administered to a subject, the ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) is not substantially released in the stomach of the subject. In some embodiments, the delayed release agent is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and mixtures thereof.

In some embodiments, the composition is formulated as a liquid. In some embodiments, the liquid is selected from the group consisting of: emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), sweet syrups, drops, sprays, and elixirs. In some embodiments, the composition is formulated as a solid. In some embodiments, the solid is selected from the group consisting of: tablets, capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid-filled lozenges), gums, candies, chewable tablets, foods, dissolving strips, films, and semi-solid formulations. In some embodiments, the solid is a tablet or capsule. In some embodiments, the capsule is a hard or soft capsule.

In any embodiment of the invention, the TRPV1 channel activator is a capsaicinoid, an oilAcylethanolamine, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsinoid ester, 1-monoacylglycerol having C18 and C20 unsaturation and C8-C12 saturated fatty acids, 2-monoacylglycerol having C18 and C20 unsaturated fatty acids, mioga dialdehyde, isorhodinol, polygodial, terpenoids having α -unsaturated 1, 4-dialdehyde moiety, sanshool, evodiamine, acesulfame potassium, cyclamate, CuSO₄、ZnSO₄、FeSO₄Avanib, arachidonic acid ethanolamide, N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynonenal, 1- [2- (1-adamantyl) ethyl]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea or gingerol.

In a particular embodiment, the capsaicinoid is capsaicin. In some aspects of this embodiment, the TRPV1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).

In some embodiments, the TRPV1 channel activator is naturally occurring or non-naturally occurring. In some embodiments, the naturally-occurring TRPV1 channel activator is selected from the group consisting of: capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, nonivamide, pseudocapsaicin, resiniferatoxin, tintoxin, capsaicinoids, dihydrocapsaicin esters, nordihydrocapsaicin esters, norcapsaicin, coniferyl capsaicinoids, dihydrocapsaicin coniferyl esters and other coniferyl esters, capsaicinoid analogs, and 3-hydroxyacetanilide.

In some embodiments, the non-naturally occurring TRPV1 channel activator is selected from the group consisting of: 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl formate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl acetate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl propionate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl butyrate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl 2, 2-dimethylpropionate, [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl, and mixtures thereof, Octadecanoic acid 4- [ ((6E) -8-methylnon-6-enamidoyl) methyl ] -2-methoxyphenyl ester, {4- [ ((6E) -8-methylnon-6-enamidoyl) methyl ] -2-methoxyphenoxy } carboxylic acid 4- [ ((6E) -8-methylnon-6-enamidoyl) methyl ] -2-methoxyphenyl ester, 8-methylnonanoic acid homovanillyl ester, 8-methylnonanoic acid 3- (3-methoxy-4-hydroxyphenyl) propyl ester, homovanillic acid 8-methylnonanyl ester, 8-methylnonanoic acid substituted benzyl ester derivatives, heptanoylisobutylamide, heptanoylguaiacinamide, 7-phenylhepta-6-yn-acid-4-hydroxy-3-methoxybenzene methyl Amides, polyvanil, denatonium capsaicinoid, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (4-chlorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [2- (4-fluorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (2, 4-dichlorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [2- (4-benzyloxyphenyl) ethyl ] thiourea, n- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (4- (N-octyloxy) phenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [ 4-N-octyloxybenzyl ] thiourea, N-phenylmethylalkynamide capsaicin derivatives, N- (4-O-glycerol-3-methoxybenzyl) nonanamide, N-nonanoylvanillyl oxamide-4-glyceryl ether, N- (4-O-sodium acetate) -3-methoxybenzyl-nonanamide (N-nonanoylvanillyl oxamide-4-O-sodium acetate), N- (4-O-diol-3-methoxybenzyl) -nonanamide (N-nonanoyl vanillyl oxamide-4-diol ether), 20-homovanillyl-michigan toxin, 20-homovanillyl-12-deoxyphorbol-13-phenylacetate), zuccasin (N- [ (4-hydroxy-3-methoxyphenyl) -methyl ] -8-methyl- (Z) -6-nonanamide), knufanib, cassavanib, ovani, avanib and pravanib (N-palmitoyl-vanillyl oxamide).

In other embodiments of the invention, the TRPA1 channel activator is allyl isothiocyanate, gingerol, cinnamaldehyde, acrolein, farnesyl thiosalicylic acid, Δ₉-tetrahydrocannabinol, eugenol, shogaol, sanshool, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide or farnesylthioacetic acid. In some aspects of this embodiment, the TRPA1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).

In some embodiments, the ASIC channel activator comprises acetic acid, phosphoric acid, citric acid, malic acid, succinic acid, lactic acid, tartaric acid, fumaric acid, or ascorbic acid. In some embodiments, the ASIC channel activator is present at about 0.001% to about 10% (w/w), or about 0.001% to about 10% (v/v).

In some embodiments, the composition is capable of reducing gastrointestinal side effects.

In another aspect, the invention features a composition that includes an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof), a formulation matrix, and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof), a formulation matrix, and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof), a formulation matrix, and a plurality of pharmaceutically acceptable excipients.

In some embodiments, the formulation base comprises an oil and a lipophilic additive. In some embodiments, the oil is selected from the group consisting of: vegetable oil, mineral oil, soybean oil, sunflower seed oil, corn oil, olive oil, nut oil and liquid paraffin. In some embodiments, the lipophilic additive is selected from the group consisting of: polyethylene glycol, fatty acid monoglycerides, diglycerides or triglycerides, palmitic acid, stearic acid, behenic acid, polyethylene glycol fatty acid esters, candelilla wax, carnauba wax, polyethylene oxide wax and petroleum wax. In some embodiments, the composition further comprises a coloring agent, a dissolving agent, a flavoring agent, a sweetener, a viscosity modifier, an electrolyte, a vitamin, a mineral, an antioxidant, or a preservative.

In some embodiments, the composition is formulated as a liquid or a solid. In some embodiments, the composition is formulated as a liquid. In some embodiments, the liquid is selected from the group consisting of: emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), sweet syrups, drops, sprays, and elixirs. In some embodiments, the composition is formulated as a solid. In some embodiments, the solid is selected from the group consisting of: tablets, capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid-filled lozenges), gums, candies, chewable tablets, foods, dissolving strips, films, and semi-solid formulations. In some embodiments, the solid is a tablet or capsule. In some embodiments, the capsule is a hard or soft capsule.

In any embodiment of the invention, the TRPV1 channel activator is a capsaicinoid, a capsicum ester, oleoylethanolamide, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsaicinoid ester, 1-monoacylglycerol having C18 and C20 unsaturation and C8-C12 saturated fatty acids, 2-monoacylglycerol having C18 and C20 unsaturated fatty acids, mioga dialdehyde, mioga-ginger trialdehyde, polygodial dialdehyde, terpenoid having α -unsaturated 1, 4-dialdehyde moiety, sanshool, evodiamine, acesulfame potassium, cyclamate, CuSO ₄、ZnSO₄、FeSO₄Alfanil, arachidonic acid ethanolamide, N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynoneneAldehyde, 1- [2- (1-adamantyl) ethyl]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea or gingerol.

In another aspect, the invention features a composition formulated for oral administration to a subject, the composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient, wherein upon administration, the residence time of the ion channel activator in the oral cavity of the subject is greater than about 5 seconds. In some embodiments, the composition comprises a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients.

In some embodiments, the residence time of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in the oral cavity of an individual is greater than about 5 seconds, 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 residence time of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in the oral cavity of an individual is between about 5 seconds and about 2 minutes. In some embodiments, the residence time of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in the oral cavity of an individual is between about 5 seconds and about 60 seconds. In some embodiments, the residence time of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in the oral cavity of an individual is between about 5 seconds and about 30 seconds.

In some embodiments, the residence time of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in the oral cavity of a subject is greater than about 60 seconds, 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 longer. In some embodiments, the residence time of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in the oral cavity of an individual is between about 60 seconds and about 5 minutes. In some embodiments, the residence time of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in the oral cavity of an individual is between about 60 seconds and about 3 minutes. In some embodiments, the residence time of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in the oral cavity of an individual is between about 60 seconds and about 2 minutes.

In any embodiment of the invention, the TRPV1 channel activator is a capsaicinoid, a capsicum ester, oleoylethanolamide, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsaicinoid ester, 1-monoacylglycerol having C18 and C20 unsaturation and C8-C12 saturated fatty acids, 2-monoacylglycerol having C18 and C20 unsaturated fatty acids, mioga dialdehyde, mioga-ginger trialdehyde, polygodial dialdehyde, terpenoid having α -unsaturated 1, 4-dialdehyde moiety, sanshool, evodiamine, acesulfame potassium, cyclamate, CuSO ₄、ZnSO₄、FeSO₄Avanib, arachidonic acid ethanolamide, N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynonenal, 1- [2- (1-adamantyl) ethyl]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea or gingerol.

In some embodiments, the non-naturally occurring TRPV1 channel activator is selected from the group consisting of: 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl formate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl acetate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl propionate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl butyrate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl 2, 2-dimethylpropionate, [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl, and mixtures thereof, Octadecanoic acid 4- [ ((6E) -8-methylnon-6-enamidoyl) methyl ] -2-methoxyphenyl ester, {4- [ ((6E) -8-methylnon-6-enamidoyl) methyl ] -2-methoxyphenoxy } carboxylic acid 4- [ ((6E) -8-methylnon-6-enamidoyl) methyl ] -2-methoxyphenyl ester, 8-methylnonanoic acid homovanillyl ester, 8-methylnonanoic acid 3- (3-methoxy-4-hydroxyphenyl) propyl ester, homovanillic acid 8-methylnonanyl ester, 8-methylnonanoic acid substituted benzyl ester derivatives, heptanoylisobutylamide, heptanoylguaiacinamide, 7-phenylhepta-6-yn-acid-4-hydroxy-3-methoxybenzene methyl Amides, polyvanil, denatonium capsaicinoid, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (4-chlorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [2- (4-fluorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (2, 4-dichlorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [2- (4-benzyloxyphenyl) ethyl ] thiourea, n- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (4- (N-octyloxy) phenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [ 4-N-octyloxybenzyl ] thiourea, N-phenylmethylalkynamide capsaicin derivatives, N- (4-O-glycerol-3-methoxybenzyl) nonanamide, N-nonanoylvanillyl oxamide-4-glyceryl ether, N- (4-O-sodium acetate) -3-methoxybenzyl-nonanamide, N-nonanoylvanillyl oxamide-4-O-sodium acetate), N- (4-O-diol-3-methoxybenzyl) -nonanamide, N-nonanoyl vanillyl oxamide-4-diol ether), 20-homovanillyl-michigan toxin, 20-homovanillyl-12-deoxyphorbol-13-phenylacetate), globin (N- [ (4-hydroxy-3-methoxyphenyl) -methyl ] -8-methyl- (Z) -6-nonanamide), Nonoulli, Kazavanil, Ovatinib, Arvinib and Parvinib (N-palmitoyl-vanillyl amide).

In some embodiments of the invention, the TRPA1 channel activator is allyl isothiocyanate, gingerol, cinnamonAldehyde, acrolein, farnesylthiosalicylic acid,. DELTA.₉-tetrahydrocannabinol, eugenol, shogaol, sanshool, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide or farnesylthioacetic acid. In some aspects of this embodiment, the TRPA1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).

In some embodiments, a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) comprises a liquid or solid formulation. In some embodiments, the liquid formulation is selected from the group consisting of: emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), sweet syrups, drops, sprays, and elixirs. In some embodiments, the solid formulation is selected from the group consisting of: tablets, capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid-filled lozenges), gums, candies, chewable tablets, foods, dissolving strips, films, and semi-solid formulations. In some embodiments, the solid formulation is a tablet or capsule. In some embodiments, the capsule is a hard or soft capsule.

In some embodiments, the composition comprises a liquid formulation (e.g., an emulsion, a microemulsion, a solution, a suspension, a syrup (e.g., a syrup concentrate), a sweet syrup, drops, or an elixir) and the effective amount of the liquid formulation is at least about 1mL, about 2mL, about 4mL, about 6mL, about 8mL, about 10mL, about 12mL, about 14mL, about 16mL, about 18mL, about 20mL, about 22.5mL, about 25mL, or more. In some embodiments, the effective amount of the liquid formulation is between about 1mL and 10 mL. In some embodiments, the effective amount of the liquid formulation is between about 5mL and 10 mL. In some embodiments, the effective amount of the liquid formulation is between about 10mL and 25 mL.

In some embodiments, the composition comprises a liquid formulation (e.g., an emulsion, a microemulsion, a solution, a suspension, a syrup (e.g., a syrup concentrate), a sweet syrup, drops, or an elixir) and the effective amount of the liquid formulation is at least about 25mL, about 30mL, about 35mL, about 40mL, about 45mL, about 50mL, about 60mL, about 75mL, about 100mL, about 150mL, about 200mL, about 300mL, about 400mL, about 500mL, about 600mL, about 750mL, about 1000mL, or more. In some embodiments, the effective amount of the liquid formulation is between about 25mL and 100 mL. In some embodiments, the effective amount of the liquid formulation is between about 50mL and 500 mL. In some embodiments, the effective amount of the liquid formulation is between about 100mL and 1000 mL.

In some embodiments, the composition comprises a solid formulation (e.g., a tablet, capsule, powder, crystal, paste, gel, troche, gum, candy, chewable tablet, food, dissolving strip, film, or semi-solid formulation) and the effective amount of the solid formulation is about 0.5mg, about 1mg, about 10mg, about 25mg, about 50mg, about 100mg, about 250mg, about 500mg, about 750mg, about 1g, about 2g, about 5g, about 10g, or more. In some embodiments, the effective amount of the solid formulation is between about 0.5mg and about 100 mg. In some embodiments, the effective amount of the solid formulation is between about 100mg and about 500 mg. In some embodiments, the effective amount of the solid formulation is between about 500mg and about 1000 mg.

In some embodiments, an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) is ingested by, e.g., swallowed by, an individual. In some embodiments, an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) is contained in the oral cavity by an individual, e.g., not swallowed by the individual. In some embodiments, inclusion in the oral cavity may additionally comprise, for example, effectively swirling the ion channel activator in the oral cavity of the subject or placing the ion channel activator against the skin or surface of the oral cavity or tongue (e.g., sublingual delivery). In some embodiments, an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) is dissolved in the oral cavity of an individual or chewed by an individual prior to swallowing.

In another aspect, the invention features a method of treating painful muscle contractions in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the painful muscle contraction is a muscle contraction of the head or neck. In some embodiments, the painful muscle contraction is associated with a tension headache, a cluster headache, or a migraine.

In another aspect, the invention features a method of treating tactile sensitivity in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the tactile sensitivity is associated with autism, dysmotility, neuropathic pain, anxiety, a noxious bite, or a noxious bite. In some embodiments, the anxiety disorder is selected from the group consisting of: panic disorder, Obsessive Compulsive Disorder (OCD), post-traumatic stress disorder (PTSD), social anxiety disorder, phobia, and Generalized Anxiety Disorder (GAD).

In another aspect, the invention features a method of treating dystonia in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the dystonia is selected from the group consisting of: focal dystonia, blepharospasm, cervical dystonia, cranial dystonia, laryngeal dystonia, back spasms, hand dystonia or leg spasms due to spinal stenosis.

In another aspect, the invention features a method of treating a Peripheral Nervous System (PNS) condition in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the PNS condition is selected from the group consisting of: spasmodic fasciculation Syndrome, Isaacs' Syndrome, or neuromuscular rigidity (NMT), peripheral neuropathy, carpal tunnel Syndrome, and Epstein-Barr virus (EBV) infection.

In another aspect, the invention features a method of treating a laryngeal disorder in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the laryngeal condition is associated with chemical injury, cancer, surgical injury, or infection by a pathogen. In some embodiments, the laryngeal disease is selected from the group consisting of: acid reflux, laryngeal spasm, dysphagia, and spasmodic dysphonia.

In another aspect, the invention features a method of treating a condition associated with electrolyte imbalance or vitamin deficiency in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the condition is selected from the group consisting of: hyponatremia, nephropathy, rickets, calcium, magnesium deficiency, thiamine deficiency, hypoparathyroidism, medullary cystic disease and adrenocortical carcinoma.

In another aspect, the invention features a method of treating a Central Nervous System (CNS) condition in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the CNS condition is associated with a tumor. In some embodiments, the CNS condition is selected from the group consisting of: multiple sclerosis, amyotrophic lateral sclerosis, cerebral palsy, stroke, motor neuron disease, spinal cord injury, and stenosis.

In another aspect, the invention features a method of treating a muscle condition or disorder in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the muscle condition is associated with muscle pain, muscle cramping, muscle spasm, fasciculation, or any combination thereof. In some embodiments, the muscle condition or disorder is a neuromuscular disorder (e.g., multiple sclerosis, spinal cord spasm, spinal muscular atrophy, myasthenia gravis, spinal cord injury, traumatic brain injury, cerebral palsy, hereditary spastic paraplegia, a motor neuron disease (e.g., amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal bulbar muscular atrophy (e.g., Kennedy's disease), or post-polio syndrome), neuralgia, fibromyalgia, Machado-Joseph disease (Machado-Joseph disease), fasciculation tremor syndrome, carpal tunnel syndrome, acrodynia, neurofibromatosis, neuromuscular rigidity (e.g., focal neuromuscular rigidity, assack syndrome), Peripheral neuropathy, piriformis syndrome, plexus disease (e.g., brachial plexus disease or lumbosacral plexus disease), radiculopathy (e.g., lower lumbar radiculopathy), and encephalitis).

In some embodiments, the muscle condition is muscle pain, muscle cramping, muscle spasm, spasticity, or fasciculation associated with a motor neuron disease (e.g., amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscle atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal bulbar muscular atrophy (e.g., kennedy's disease), or post-polio syndrome).

In some embodiments, the muscle condition is associated with dialysis, diuretics, β -blockers, statins, fibrates, β₂-an agonist, an ACE inhibitor, an ARB, an antipsychotic, or any combination thereof associated with treating the subject. In some embodiments, the muscle condition is associated with treatment of the subject with a statin and a fibrate. In some embodiments, the muscle condition occurs in one or more skeletal muscles. In some embodiments, the muscle condition is refractory to approved therapy. In some embodiments, the approved treatment is botulinum (botox), cyclobenzaprine (cyclopenaprine), oxyphenamine (orphenadrine), baclofen (baclofen), or any combination thereof. In some embodiments, the muscle condition is fibromyalgia. In some embodiments, the muscle condition relates to muscle claudication pain. In some embodiments, the muscle claudication pain is associated with inactivity, immobilization, economy class syndrome, paralysis, peripheral arterial disease, or immobilization.

In another aspect, the invention features a method of treating a respiratory condition in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the respiratory condition comprises asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pneumonia, cystic fibrosis, influenza, or the common cold.

In another aspect, the invention features a method of treating cough in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the cough is associated with a respiratory condition (e.g., asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pneumonia, cystic fibrosis, influenza, or cold), exposure to an allergen, or inflammation.

In another aspect, the invention features a method of treating sarcoidosis in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients.

In another aspect, the invention features a method of treating connective tissue disease in a subject in need thereof, the method comprising orally administering to the subject a composition comprising an effective amount of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) and a pharmaceutically acceptable excipient. In some embodiments, the method comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients. In some embodiments, the connective tissue disease is selected from the group consisting of: Ehlers-Danlos syndrome, epidermolysis bullosa, Marfang's syndrome, osteogenesis imperfecta, arthritis, scleroderma, Sjogren's syndrome ((R)) ) Lupus, vasculitis, mixed connective tissue disease, cellulitis, polymyositis, and dermatomyositis. In some embodiments, the arthritis is rheumatoid arthritis, osteoarthritis, gout, or psoriatic arthritis, or wherein the vasculitis is Wegener's granulomatosis or charger-schtelus Syndrome (Churg-Strauss Syndrome).

In any of the above aspects, in some embodiments, the method of treatment comprises orally administering to the subject a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, a TRPA receptor agonist, a peptide receptor agonist,ASIC channel activator, or combination thereof), wherein the TRPV1 channel activator is capsaicin, a capsaicinoid, or a capsicum ester, or is selected from the group consisting of oleoylethanolamide, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsaicinoid ester, 1-monoacylglycerol having C18 and C20 unsaturation and C8-C12 saturated fatty acids, 2-monoacylglycerol having C18 and C20 unsaturated fatty acids, mioga ginger trialdehyde, polygondialdehyde, terpenoids having α -unsaturated 1, 4-dialdehyde moieties, sanshool, evodiamine, acesulfame potassium, cyclamate, CuSO ₄、ZnSO₄、FeSO₄Alfanil, arachidonic acid ethanolamide, N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynonenal or 1- [2- (1-adamantyl) ethyl]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea, gingerol and magnesium salts.

In some embodiments of the invention, the TRPA1 channel activator is allyl isothiocyanate, gingerol, cinnamaldehyde, acrolein, farnesyl thiosalicylic acid, Δ₉-tetrahydrocannabinol, eugenol, shogaol, sanshool, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide or processA menthyl thioacetic acid. In some aspects of this embodiment, the TRPA1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).

In another aspect, the invention features a method of treating an undesired or abnormal muscle contraction (e.g., spasticity, cramping, dystonia, or fasciculation) or the absence of normal muscle contraction (e.g., gait abnormality, such as foot drop) in a subject, comprising: for example, directly or indirectly obtaining knowledge of test results regarding efficacy of administering a test aliquot of a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) to alleviate test muscle contraction in the individual; and administering, e.g., in response to the result, a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in an amount sufficient to alleviate the individual's absence or requirement of abnormal muscle contraction or the absence of normal muscle contraction. In some embodiments, testing includes directly acquiring the knowledge. In some embodiments, testing comprises further performing the testing.

In some embodiments, the muscle contraction comprises a muscle spasm. In some embodiments, the muscle contraction comprises a muscle cramp. In some embodiments, the muscle contraction comprises a dystonia. In some embodiments, the muscle contraction comprises fasciculation. In some embodiments, the muscle contraction occurs in skeletal muscle. In some embodiments, the muscle contraction occurs in smooth muscle. In some embodiments, the test muscle contraction is a test muscle spasm or a test muscle cramp.

In some embodiments, the composition comprises a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof). In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some embodiments, the composition comprises an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients.

In some embodiments, the TRPV1 channel activator is a capsaicinoid, a capsicum ester, oleoylethanolamide, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsaicinoid ester, 1-monoacylglycerol having C18 and C20 unsaturation and C8-C12 saturated fatty acids, 2-monoacylglycerol having C18 and C20 unsaturated fatty acids, mioga dialdehyde, polygondialdehyde, terpenoid having α -unsaturated 1, 4-dialdehyde moiety, sanshool, evodiamine, acesulfame potassium, cyclamate, CuSO₄、ZnSO₄、FeSO₄Avanib, arachidonic acid ethanolamide, N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynonenal, 1- [2- (1-adamantyl) ethyl ]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea or gingerol.

In some embodiments of the invention, the TRPA1 channel activator is allyl isothiocyanate, gingerol, cinnamaldehyde, acrolein, farnesyl thiosalicylic acid, Δ₉-tetrahydrocannabinol, eugenol, shogaol, sanshool, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide or farnesylthioacetic acid. In some aspects of this embodiment, the TRPA1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).

In some embodiments, the subject has a central nervous system disorder or injury, such as brain injury, stroke, or traumatic spinal cord injury. In some embodiments, the subject has been diagnosed with or identified as having multiple sclerosis. In some embodiments, the subject has been diagnosed with or identified as having a dystonia, such as cervical dystonia. In some embodiments, the subject is diagnosed with or identified as having spinal cord spasm. In some embodiments, the subject has been diagnosed with or identified as having a disorder associated with muscle spasticity, e.g., any of the disorders disclosed herein, e.g., nocturnal spasticity, multiple sclerosis, spinal cord spasticity, or dystonia.

In some embodiments, the muscle contraction selected, treated, or diagnosed comprises a contraction of a muscle other than the muscle contracted in the test muscle contraction. In some embodiments, the test muscle contraction comprises a foot muscle (e.g., flexor hallucis brevis) contraction, and the muscle spasm comprises a spasm of a muscle other than the foot (e.g., flexor hallucis brevis). In some embodiments, the muscle contraction is not induced by the applied electrical stimulation.

In some embodiments, the muscle contraction is a nocturnal cramp. In some embodiments, the muscle contraction is associated with multiple sclerosis. In some embodiments, the muscle contraction is associated with spinal cord spasm. In some embodiments, the muscle contraction is associated with dystonia.

In some embodiments, the test comprises inducing the test muscle spasm by applying an electrical stimulus (e.g., a transcutaneous or surface stimulus). In some embodiments, the test comprises determining muscle contraction that can be induced in the individual by application of electrical stimulation (e.g., transdermal stimulation or surface stimulation).

In some embodiments, the testing comprises: a) administering to the subject a test aliquot of the composition; b) inducing test muscle contraction, for example, by applying electrical stimulation (e.g., transdermal or surface stimulation); and c) evaluating the effect of the composition administered to the test aliquot on the test muscle contraction. In some embodiments, step a is performed before step b. In some embodiments, step a is performed after step b.

In some embodiments, the testing comprises: a) administering to the subject a test aliquot of the composition; b) inducing test muscle contraction, for example, by applying electrical stimulation (e.g., transdermal or surface stimulation); and c) assessing the effect of the administered composition on the test muscle contraction, e.g., by assessing the electrical activity of the test muscle (e.g., by EMG).

In some embodiments, the testing comprises: a) inducing contraction of the first test muscle, for example, by applying electrical stimulation (e.g., transcutaneous or surface stimulation); b) administering to the subject a test aliquot of the composition; c) inducing a second test muscle contraction, for example, by applying electrical stimulation (e.g., transcutaneous or surface stimulation); and d) assessing the effect of the administered composition on the contraction of the second test muscle. In some embodiments, step b is performed before step c. In some embodiments, step c is performed before step b. In some embodiments, the steps are performed in the order a, b, c, and d.

In some embodiments, the testing further comprises: e) providing a muscle contraction parameter value, e.g. a reference curve, e.g. a value of intensity or duration, of the first test muscle contraction, e.g. by evaluating the electrical activity of the test muscle (e.g. by EMG); and optionally f) providing a muscle contraction parameter value, e.g. a treatment profile, e.g. a value of intensity or duration, for the second test muscle contraction, e.g. by assessing the electrical activity of the test muscle (e.g. by EMG). In some embodiments, the testing comprises comparing the value of step e with the value of step f to assess the effectiveness of the test aliquot of the composition for testing muscle contraction. In some embodiments, the muscle contraction parameter is the area under the curve, peak amplitude, or duration of the test muscle contraction. In some embodiments, a decrease in the value of step f compared to the value of step e is indicative of efficacy in alleviating the test muscle spasm. In some embodiments, a reduction in a preselected amount, e.g., a reduction of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 50% indicates efficacy of alleviating the test muscle contraction.

In some embodiments, the testing comprises: a) inducing contraction of the first test muscle, for example, by applying electrical stimulation (e.g., transcutaneous or surface stimulation); b) administering to the subject a test aliquot of the composition; c) inducing a second test muscle contraction, for example, by applying electrical stimulation (e.g., transcutaneous or surface stimulation); d) evaluating the effect of the administered composition on testing for contractile spasm; e) providing a muscle contraction parameter value, such as a value of intensity or duration, for the first test muscle contraction, for example by evaluating the electrical activity of the test muscle (e.g. by EMG); and f) providing a muscle contraction parameter value, e.g. a value of intensity or duration, of the second test muscle contraction, e.g. by evaluating the electrical activity of the test muscle, e.g. by EMG. In some embodiments, step b is performed before step c. In some embodiments, steps b and c are performed within a preselected time of each other, e.g., they are performed in close enough time proximity that step b will adjust step c. In some embodiments, the test muscle contraction comprises contraction of a foot muscle (e.g., flexor hallucis brevis). In some embodiments, a decrease in the value of step f compared to the value of step e is indicative of efficacy of alleviating the test muscle contraction.

In some embodiments, the testing comprises: a) applying a first electrical stimulus to a test muscle of the subject to induce a test muscle contraction; b) measuring the electrical activity of the test muscle, for example by EMG, to provide a reference curve; c) administering a test aliquot of the composition; d) applying a second electrical stimulus to the test muscle of the subject after a preselected period of time after administration of the test aliquot of the composition; e) measuring electrical activity of the test muscle to generate a treatment curve; f) the treatment curve is compared to the reference curve to determine whether test muscle contraction is reduced or prevented following administration of the test aliquot. In some embodiments, the time period between step c and step d is at least about 10 minutes, 15 minutes, 30 minutes, 1 hour, and the like. In some embodiments, comprising determining the area under the curve of the reference curve and the treatment curve, wherein the test muscle contraction is reduced or prevented when the area under the curve of the treatment curve is reduced compared to the reference curve.

In some embodiments, the testing further comprises: a) determining a critical frequency for inducing contraction of a first test muscle; b) administering a test aliquot of a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof); c) determining a critical frequency for inducing contraction of a second test muscle; d) critical frequencies were compared to assess the effectiveness of the test aliquot of the composition for testing muscle contraction.

In some embodiments, the composition of the test aliquot comprises a plurality (e.g., two or three) of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof). In some embodiments, the composition of the test aliquot additionally comprises a pharmaceutically acceptable excipient. In some embodiments, the composition of the test aliquot comprises an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) and a plurality of pharmaceutically acceptable excipients.

In some embodiments, the composition of the test aliquot comprises a TRP channel activator or an ASIC channel activator. In some embodiments, the TRP channel activators comprise an activator of TRPV1 and an activator of TRPA 1. In some embodiments, the composition comprises a TRP activator and an ASIC channel activator. In certain embodiments, the TRPV1 agonist is a capsaicinoid, such as capsaicin. In some embodiments, the TRPV1 channel activated by the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or a combination thereof) is present on sensory neurons in the oral cavity, esophagus, and/or stomach. In some embodiments, the ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or a combination thereof) increases inhibitory signaling to alpha motor neurons.

In some embodiments, the composition is formulated as a liquid or a solid. In some embodiments, the liquid is selected from the group consisting of: emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), sweet syrups, drops, sprays, and elixirs. In some embodiments, the composition is formulated as a solid. In some embodiments, the solid is selected from the group consisting of: tablets, capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid-filled lozenges), gums, candies, chewable tablets, foods, dissolving strips, films, and semi-solid formulations. In some embodiments, the solid is a tablet or capsule. In some embodiments, the capsule is a hard or soft capsule.

In another aspect, the invention features a method of assessing abnormal or unwanted muscle contraction or the absence of normal muscle contraction in an individual, comprising: for example, indirectly or directly obtaining knowledge of test results regarding efficacy of administering a test aliquot of a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) to alleviate test muscle contraction in the individual; and classifying the individual in response to the result. In some embodiments, the subject has been diagnosed with or identified as having a disorder associated with muscle spasticity, e.g., any of the disorders disclosed herein, e.g., nocturnal spasticity, multiple sclerosis, spinal cord spasticity, or dystonia. In some embodiments, testing includes directly acquiring the knowledge. In some embodiments, testing additionally comprises performing the test.

In some embodiments, the results indicate a reduction in test muscle contraction by administering a preselected level of the test aliquot. In some embodiments, the results indicate that test muscle contraction was alleviated by administering a test aliquot.

In some embodiments, the testing comprises classifying the individual as a candidate for treatment with a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof). In some embodiments, the results indicate a failure to provide a preselected level of relief of test muscle contraction by administration of the test aliquot. In some embodiments, the results indicate that the test muscle contraction was not alleviated by administration of the test aliquot. In some embodiments, testing comprises classifying the individual as a candidate not being treated with a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof). In some embodiments, the method is computer-implemented.

In another aspect, the invention features a computer-implemented method of assessing an individual for an undesired or abnormal muscle contraction (e.g., spasticity, cramping, dystonia, or fasciculation) or absence of normal muscle contraction (e.g., gait abnormalities, such as foot drop), comprising: a) for example, directly or indirectly obtaining a parameter value associated with the effect of administering a test aliquot of a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) on a test muscle spasm, e.g., by assessing the electrical activity (e.g., by EMG) of the test muscle; b) assessing the effectiveness of the administration of the test aliquot on a computer, for example, by comparing the test value or curve to the treatment value or curve; c) in response to the evaluation, comprising classifying the individual as a candidate for treatment with a composition comprising a capsaicinoid, or a related analog, or a combination thereof.

In another aspect, the invention features a system that includes a memory; and a processing unit operable to: a) assessing the effectiveness of administering a test aliquot of a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof); b) in response to the assessment, comprising classifying the individual as a candidate for treatment with a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof).

In another aspect, the invention features a computer-readable medium containing computer-executable instructions that, when executed on a computer processor, perform a method comprising acts of: a) assessing the effectiveness of administering a test aliquot of a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof); b) in response to the assessment, comprising classifying the individual as a candidate for treatment with a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof).

In some embodiments, the subject has been diagnosed with or identified as having a disorder associated with muscle spasm, cramping, dystonia, or fasciculation, such as any of the disorders disclosed herein, e.g., nocturnal spasms, multiple sclerosis, spinal cord spasms, or dystonia.

In another aspect, the invention features a kit including a liquid-tight container including one or more of: one or more test aliquots of a composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof); one or more leads for conducting electrical current to a subject and inducing spasticity; and one or more leads for measuring electrical activity associated with the cramp. In some embodiments, the kit further comprises a plurality (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) of test aliquots of the composition.

In another aspect, the invention features a method of evaluating a composition for treating an undesired or abnormal muscle contraction (e.g., spasticity, cramping, dystonia, or fasciculation) or an absence of normal muscle contraction (e.g., gait abnormality) comprising: a) for example, indirectly or directly obtaining knowledge of test results showing that administration of a test aliquot of the composition alleviates test muscle contractions in a test subject; and b) obtaining, e.g., indirectly or directly, knowledge of the effectiveness of the administration of the composition to a subject in the treatment of the absence or absence of normal muscle contraction; wherein the effectiveness of the treatment of a muscle spasm in one or both of steps a and b indicates the utility of the composition for treating a muscle spasm. In some embodiments, the test aliquot is administered to alleviate the test muscle contraction. In some embodiments, step b is performed only when the composition relaxes the test muscle contraction in step a. In some embodiments, step a comprises performing the test. In some embodiments, step b comprises administering the composition to the subject. In some embodiments, step a comprises conducting the test and step b comprises administering the composition to the subject.

In some embodiments, the test subject and the administered subject are of the same species, e.g., both rodents or both primates, e.g., humans. In some embodiments, the test subject and the administered subject are the same subject. In some embodiments, the test subject and the administered subject are different subjects. In some embodiments, the test subject and the administered subject are of different species, e.g., the test species is a non-human, e.g., a rodent, and the administered subject is a primate, e.g., a human.

Drawings

Fig. 1 is a series of graphs of 6 sensory neurons isolated from the trigeminal ganglia of rats, illustrating their activation by extracts of capsicum, cinnamon and ginger used in human experiments.

Figure 2 shows the effect of TRP-Stim drink on Flexor Hallucis Brevis (FHB) spasms in subject a.

Figure 3 shows the effect of a TRP-Stim drink on FHB spasms in a second subject after the induction of spasms.

Figure 4 shows the effect of TRP-Stim drinks tested over a longer period of time on FHB cramps in a third subject.

Figure 5 shows the effect of TRP-Stim drink on FHB cramps in a fourth subject.

Fig. 6 is a graph showing the effect of a TRP-Stim beverage on gastrocnemius (calf muscle) spasms in a fifth subject.

Figure 7 shows the effect of a TRP-Stim drink on gastrocnemius (calf muscle) spasms in a sixth subject.

Fig. 8 is a graph showing the effect of a TRP-Stim drink on FHB muscle spasms in a seventh subject experiencing spontaneous spasms induced by the toe-tauteness.

Detailed Description

The methods and compositions of the invention are directed to the treatment of peripheral nervous system conditions (e.g., peripheral neuropathy), central nervous system conditions, muscle conditions and disorders (e.g., fibromyalgia, muscle cramps and spasms (e.g., nocturnal spasms), painful muscle contractions (e.g., muscle contractions of the head or neck), neuromuscular disorders (e.g., motor neuron disease) or dystonia (e.g., cervical dystonia, blepharospasm, back spasms, or leg spasms due to spinal stenosis)), connective tissue diseases (e.g., degenerative joint disease), throat conditions (e.g., dysphagia or spasmodic dysphonia), tactile sensitivity, electrolyte imbalance, and/or vitamin deficiency) with compositions of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof), Respiratory pathologies (e.g., asthma), cough, and sarcoidosis.

Definition of

As used herein, the term "acidulant" refers to an acidic compound (e.g., citric acid) that is used to lower the pH of the composition, e.g., the pH can be lowered in the range of 2.5-6.5 (e.g., pH 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or 6.5).

"acquiring" as the term is used herein refers to obtaining an owned value (e.g., a numerical value) or an image or physical entity (e.g., a sample) by "directly acquiring" or "indirectly acquiring" the value or physical entity. By "directly acquiring" is meant performing a method (e.g., applying an electrical current to or measuring an electrical current from an individual, or capturing a signal from an individual or sample or performing a synthetic or analytical method) to obtain a value or physical entity. "indirectly obtaining" refers to accepting a value or physical entity from another party or source (e.g., a third party laboratory that directly obtains the physical entity or value). Directly obtaining a value or physical entity includes performing a process that includes a physical change in a physical substance or using a machine or apparatus. Exemplary changes include applying an electrical current to or measuring an electrical current from an individual muscle. Directly obtaining a value includes performing a method using a machine or device (e.g., a device that induces a cramp or a device that measures a parameter associated with a cramp).

As used herein, the term "agonist" refers to a molecule that stimulates a biological response. In some embodiments, the agonist is an activator. For example, the activators or agonists mentioned herein activate a TRP ion channel (e.g., TRPV1 ion channel).

The use of the words "a" or "an" when used herein in connection with the term "comprising" may mean "one," but is also consistent with the meaning of "one or more," at least one, "and" one or more than one.

The term "administration" refers to a mode of delivery. The daily dose may be divided into one, two, three or more doses in a suitable form so that one, two, three or more doses are administered over the entire period. In a preferred embodiment of the invention, the compositions and solutions are administered orally. When the term "composition" is used to describe a formulation comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof), the term refers to an edible formulation suitable for oral ingestion by a subject (e.g., a human subject). Exemplary compositions comprising ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) include oral solid dosage forms (e.g., capsules, tablets, pills, dragees, crystals, pastes, gels, powders, gums, granules, chewable tablets, food products, films, and the like), oral liquid dosage forms (e.g., emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), syrups, drops, and elixirs), ready-to-drink beverages, dry compositions reconstitutable with a liquid (e.g., powders, granules, or tablets reconstitutable with water), gels, semi-solids (e.g., ice cream, pudding or yogurt), frozen liquids (e.g., popsicles), lozenges or hard candies, dissolving bars (e.g., edible bars containing pullulan and the compositions of the present invention), and chewing gums. Other compositions are described herein.

As used herein, the term "analog" or "related analog" refers to a substance that has a similar chemical structure as another compound, but differs therefrom with respect to a particular component.

As used herein, the term "derivative" refers to a substance that is made directly from another substance or made by modification or partial substitution.

As used herein, a "muscle spasm" is a muscle spasm treated with a composition described herein. In embodiments, it is not evoked, but is spontaneously produced by activity or underlying cause (e.g., physical activity or nocturnal cramping). In one embodiment, a muscle spasm comprises a spasm of a muscle other than the muscle that is tested for the muscle spasm. A muscle spasm can be a contraction of skeletal or smooth muscle. In one embodiment, muscle spasms occur most frequently in the feet, lower legs, anterior thigh (e.g., quadriceps), posterior thigh (e.g., popliteal), hands, arms (e.g., biceps or triceps), abdomen, and muscles along the rib cage. Muscle spasms that occur in the calf muscle are also commonly referred to as "charley horse". Other common muscle spasms include exercise-induced muscle spasms, menstrual spasms, "writer's spasms," "musician spasms," and nocturnal spasms. In one embodiment, a muscle spasm is a contraction of a muscle other than skeletal muscle (e.g., smooth muscle).

As used herein, "muscle cramp" refers to the involuntary contraction of a muscle or even several fibers of a muscle. The degree or duration of cramping is often less than cramping. If the cramp is intense and persistent, it becomes cramped.

As used herein, "dystonia" refers to a sustained muscle contraction that causes twisting and repetitive motion or abnormal posture.

As used herein, "fasciculation" refers to small local involuntary muscle contractions and relaxations. Fasciculation is also commonly referred to as "muscle twitching".

As used herein, the term "effective amount" of a compound is an amount sufficient to achieve a beneficial or desired result, such as an effective treatment of a peripheral nervous system condition (e.g., peripheral neuropathy), a central nervous system condition (e.g., amyotrophic lateral sclerosis), a muscle condition and disorder (e.g., fibromyalgia, muscle cramps and spasms, cervical dystonia, blepharospasm, back spasms, or leg spasms due to spinal stenosis), a connective tissue disease (e.g., degenerative joint disease), a laryngeal condition (e.g., dysphagia or spasmodic dysphonia), and sarcoidosis, and thus, an "effective amount" depends on the situation in which it is used. For example, in the case of administration of an agent that activates a TRP channel (e.g., TRPV1 or TRPA1) or an ASIC channel, an effective amount of the agent is an amount sufficient to achieve an increase in TRPV1, TRPA1, and/or ASIC channel activity, e.g., as compared to a response obtained in the absence of administration of the agent. The effective amount of the active compounds for practicing the present invention may also vary based on, for example, the age and weight or the nature of the individual exercising.

The composition may also include an excipient that is not an activator of TRPV1, TRPA1, or an ASIC channel, and that is non-toxic and non-inflammatory in an individual (e.g., in a human individual). In some embodiments, excipients can provide desirable or improved physical and/or chemical properties, such as stability, flow, viscosity, disintegration rate, taste, delivery, and the like. Exemplary, non-limiting excipients may be selected from: disintegrants (e.g., carboxymethylcellulose, starch, crystalline cellulose, low-substituted hydroxypropylcellulose, etc.), binders (e.g., acacia, carboxymethylcellulose, gelatin, crystalline cellulose, simple syrup, honey, hydroxypropylcellulose, povidone, methylcellulose, etc.), surfactants (e.g., polyethylene glycol 40 stearate, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc.), emulsifiers (e.g., polyethylene glycol 40 stearate, sorbitan sesquioleate, polysorbate 80, sodium lauryl sulfate, lauromacrogol, acacia, cholesterol, stearic acid, povidone, glyceryl monostearate, etc.), plasticizers (e.g., glycerin, propylene glycol, polyethylene glycol, etc.), lubricants (e.g., magnesium silicate, carboxymethylcellulose, light anhydrous silicic acid, stearic acid, calcium stearate, etc.), lubricants (e.g., magnesium silicate, carboxymethylcellulose, sodium lauryl sulfate, lauromacrogol, etc.), and the like, Magnesium stearate, talc, etc.), a sweetening agent (e.g., soft white sugar, honey, simple syrup, glucose, saccharin sodium, acesulfame potassium, disodium glycyrrhizinate, etc.), a pH adjuster (e.g., hydrochloric acid, citric acid, sodium bicarbonate, potassium hydroxide, sodium carbonate, etc.), a preservative (e.g., benzoic acid, benzalkonium chloride, ethyl paraben, butyl paraben, propyl paraben, methyl paraben, etc.), a flavoring agent (e.g., anise oil, orange oil, cinnamon oil, thymol, orange peel, dl-menthol, 1-menthol, eucalyptus, etc.) or a coloring agent (e.g., tincture) No. 2, No. 3, No. 40, No. 102, No. 104, No. 105 or 106, food yellow No. 4 or 5, food green No. 3, food blue No. 1 or No. 2, titanium dioxide, sodium copper chlorophyllin, No. 3, No. 102, Turmeric, gardenia red, annatto red, sorghum red, etc.) or antioxidants (e.g., ascorbic acid, sodium thiosulfate, tocopherol, sodium bisulfite, etc.), or any combination thereof.

As used herein, the term "subject" 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.

As used herein, and when used with respect to TRPV1, TRPA1, and/or ASIC channel activators, the term "substantially pure" refers to a composition comprising a channel activator, wherein the composition is free of organic and/or inorganic substances that do not activate TRPV1, TRPA1, and/or ASIC channels, and wherein 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 99.5% (w/w) of the composition is a particular channel activator compound. Substantially pure compositions can be prepared and analyzed using standard methods known in the art (e.g., chromatographic separation, extraction, etc.). A substantially pure composition may include isomeric impurities (e.g., geometric isomers) and/or salts or solvates of the channel activators.

As used herein, a "test muscle contraction" is a muscle contraction of an individual that is typically induced, for example, by application of an electric current. The stimulus may be applied to induce a muscle contraction that reproduces a naturally occurring muscle spasm, muscle cramp, dystonia, or fasciculation, such as testing a muscle spasm, testing a muscle cramp, testing a muscle dystonia, or testing a fasciculation. In an embodiment, the test muscle spasm comprises a flexor hallucis brevis spasm. In some embodiments, the efficacy of inducing a test muscle spasm in a subject is indicative of the efficacy of treating a muscle spasm, e.g., with a composition described herein. In other embodiments, the efficacy of the treatment to test a muscle spasm is indicative of the efficacy of the treatment to treat a muscle spasm, spasticity, dystonia, or fasciculation. As used herein, the term "treating" or "improving" refers to administering a composition for therapeutic purposes or administering a therapeutic agent to a subject already suffering from a disorder to improve the condition of the subject.

As used herein, the term "treating a condition or disorder" or "ameliorating a condition or disorder" refers to causing a condition or disorder (e.g., a peripheral nervous system condition (e.g., a peripheral neuropathy), a central nervous system condition, a muscle condition and disorder (e.g., fibromyalgia, muscle cramps and spasms (e.g., nocturnal spasms), painful muscle contractions (e.g., muscle contractions of the head or neck), neuromuscular disorders (e.g., motor neuron disease) or dystonia (e.g., cervical dystonia, blepharospasm, back spasms, or leg spasms due to spinal stenosis)), connective tissue disease (e.g., degenerative joint disease), laryngeal disease (e.g., dysphagia or spasmodic dysphonia), tactile sensitivity, electrolyte imbalance, and/or vitamin deficiency, a respiratory condition (e.g., asthma), Cough and sarcoidosis) and symptoms associated with the condition or disorder, e.g., are alleviated, reduced, cured, or in a state of remission. Such improvement 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 as compared to an equivalent untreated control.

As used herein, the term "viscosity" refers to a measure of the resistance to flow (e.g., "consistency") within a fluid. Viscosity is typically expressed in centipoise (cP) or pascal-seconds.

Other features and advantages of the invention will be apparent from the detailed description and from the claims.

Composition comprising a metal oxide and a metal oxide

The compositions described herein are edible formulations suitable for administration to a subject (e.g., a human) and include one or more ion channel activators (e.g., activators of TRPV1, TRPA1, or ASIC channels) and one or more optional excipients, as described herein. Exemplary, non-limiting compositions include oral solid dosage forms (e.g., tablets, capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid-filled lozenges), gums, candies, chewable tablets, foods, films, and the like), oral liquid dosage forms (e.g., emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), syrups, drops, sprays, elixirs, and the like), ready-to-drink beverages, dry compositions reconstitutable with a liquid (e.g., powders, granules, or tablets reconstitutable with water), gels, semisolids (e.g., ice cream, pudding, or yogurt), frozen liquids (e.g., ice lolly), lozenges or hard candies, dissolving bars (e.g., edible bars containing pullulan and the compositions of the present invention), and chewing gums.

TRP channel and ASIC channel

Transient Receptor Protein (TRP) channels are a family of ion channels that are typically expressed on the surface of cells. Members of the TRP channel family share some structural similarities and are organized into subfamilies, including TRPA, TRPC, TRPV, TRPM, TRPML, TRMPN, and TRPP. These subfamilies each comprise a subunit gene including, for example, TRPV1, TRPV2, TRPV4, TRPV3, TRPV5, TRPV6, TRPV1, TRPP3, TRPP2, TRPP5, TRPC4, TRPC5, TRPC1, TRPC3, TRPC7, TRPC6, TRPM1, TRPM3, TRPM6, TRPM7, TRPM4, TRPM5, TRPM2, TRPM8, TRPML1, TRPML3 and TRPML 2. The compositions described herein may comprise at least one activator or agonist of any TRP channel.

Acid-sensitive ion channels (ASICs) are neuronal voltage insensitive cation channels activated by extracellular protons. ASIC channels are mainly expressed in the nervous system and mostly conduct Na⁺. There are four ASIC channel genes ASIC1, ASIC2, ASIC3 and ASIC4 encoding at least six ASIC channel ASICs 3, ASCI4 and splice variants of ASIC1 and ASIC2, ASIC1a, ASIC1b, ASIC2a, ASIC2 b. The compositions described herein may comprise at least one agonist of any ASIC channel.

TRPV1 channel small molecule activator

Compounds that activate TRPV1 that may be used in the compositions of the present invention include naturally occurring and non-naturally occurring compounds (e.g., synthetic analogs and derivatives of naturally occurring compounds), including but not limited to those described below.

Naturally occurring small molecule activators of TRPV1

TRPV1 channel activators include naturally occurring compounds. Examples include: curcumin, piperine, piperyline (piperyline), piperine (piperettine), piperitoleine A (piperolein A), piperitoleine B, piperitoxine, xyloaldehyde (warburganal), N-arachidonoyl-dopamine (NADA), N-acylphenolamine, polygondialdehyde, lacteal aldehyde (isovalerral), guaiacol, eugenol, zingerone, triisopentenylphenol (e.g., scutigeral), gingerol, shogaol, N-oleoylethanolamine, oleoylethanolamide, N-oleoyl-dopamine, 3-methyl-N-oleoyl-dopamine, oleamide, N-arachidoylserine, N-acyltaurine (e.g., N-eicosyltaurine, N-acylsalsolinol (e.g., N-arachidonoyl salsolinol), miol, helioaldehyde, triglycerolyl-aldehyde, and triphenolic aldehyde, Polygonaldehydal, sanshool, evodiamine, arachidonic acid ethanolamide and 4-hydroxynonenal.

Non-naturally occurring small molecule activators of TRPV1

TRPV1 channel activators include non-naturally occurring compounds derived by synthetic means (e.g., by combining two or more naturally occurring small molecule activators as described above or by forming artificial compounds not occurring in nature). Examples of non-naturally occurring small molecule activators of TRPV1 include (but are not limited to): ricinoleic acid derivatives, including 12,4' -diphenylacetyl ricinoleate, 12-phenylacetyl ricinoleate, 2',2',2' -trichloroethyl ricinoleate, 12-phenylacetyl ricinoleate 2',2',2' -trichloroethyl ester, 12-phenylacetyl ricinoleate, 12-benzoylricinoleate 2',2',2' -trichloroethyl ester, 12-benzoyl ricinoleic acid, 12-benzoyl ricinoleic base, 9, 10-methylene-12, 4' -diphenylacetyl ricinoleic base, 9, 10-methylene-12-phenylacetyl ricinoleic base, 4' - (2-aminoethyl) -12-phenylacetyl ricinoleic base (hydrochloride salt), and 10-epoxy-12-phenylacetyl ricinoleic base; n-vanillyl myristamide; n- (3-methoxy-4-hydroxybenzyl) oleamide; n- [ (4- (2-aminoethoxy) -3-methoxyphenyl) methyl ] -9Z-octadecenamide; n- (9Z-octadecenyl) -3-methoxy-4-hydroxyphenylacetamide; octyl 3, 4-dihydroxybenzacetamides, octyl 4-hydroxybenzoacetamides; N-N' - (3-methoxy-4-aminoethoxy-benzyl) - (4-tert-butyl-benzyl) -urea; [1- [2- (1-adamantyl) ethyl ] -1-pentyl-3- [3- (4-pyridyl) propyl ] urea ], N-vanillyl-alkadienamide, N-vanillyl-alkadienyl; n-vanillyl-cis-monounsaturated enamide (e.g., N-vanillyl-9Z-octadecenamide (N-vanillyl oil amide) and N- [ (4-acetoxy-3-methoxyphenyl) methyl ] -9Z-octadecenamide); n- [ (4- (2-aminoethoxy) -3-methoxyphenyl) methyl ] -9Z-octadecenamide; n-oleyl-homovanillyl oxamide; acesulfame potassium; a cyclamate; flufenamic acid dopamine and other dopamine amides of fenamic acid; and urea derivatives (for example, 1- [2- (1-adamantyl) ethyl ] -1-pentyl-3- [3- (4-pyridyl) propyl ] urea, 1- [2- (1-adamantyl) ethyl ] -3- [3- (4-pyridyl) propyl ] -1- (3,3, 3-trifluoropropyl) urea, 1- [3- (1-adamantyl) propyl ] -1-propyl ] -3- [3- (4-pyridyl) propyl ] urea, 1- [2- (1-adamantyl) ethyl ] -3- [ 1-methyl-3- (4-pyridyl) propyl ] -1-pentylurea, urea derivatives such as, for example, urea, 1- [2- (1-adamantyl) ethyl ] -3- [ 2-methyl-3- (4-pyridyl) propyl ] -1-pentylurea, (+) -1- [2- (1-adamantyl) ethyl ] -3- [ 2-methyl-3- (4-pyridyl) propyl ] -1-pentylurea, and (E) -1- [2- (1-adamantyl) ethyl ] -1-pentyl-3- [3- (4-pyridyl) -2-propenyl ] urea).

Additional activators of the TRPV1 channel are described, for example, in U.S. patent No. 8,642,775; 8,546,352 No; 8,338,457 No; 8,263,093 No; 8,252,816 No; 7,632,519 No; 7,446,226 No; 7,429,673 No; 7,407,950 No; 6,872,748 No; 6,022,718 No; 5,962,532 No; 5,762,963 No; 5,403,868 No; 5,290,816 No; 5,221,692 No; 5,021,450 No; 4,812,446 No; 4,599,342 No; 4,564,633 No; 4,544,669 No; 4,544,668 No; 4,532,139 No; 4,493,848 No; 4,424,205 No; 4,313,958 No; U.S. patent application publication No. 2013/0090359; 2007/0293703 No; 2007/0167524 No; 2006/0240097 No. and 2005/0085652 No. C; and WO 00/50387; annex et al, Current pharmaceuticals (Curr. pharm. Des.) 2008,14: 2-17; huang et al, Proc Natl Acad of sciences USA (Proc Natl Acad Sci USA) 2002,299: 8400-;j BiolChem 2005,280(36) 31405-12; and Vriens et al, molecular pharmacology (Mol Pharmacol) 2009, 75-1262-; each of which is incorporated by reference.

Capsaicinoids, capsaicinoids and analogs thereof as TRPV1 channel activators

Capsaicinoids and analogs thereof, capsaicinoids and analogs thereof are compounds that can activate the TRPV1 channel and can be used in the compositions of the present invention. These compounds can be naturally occurring and non-naturally occurring compounds (e.g., synthetic analogs and derivatives of naturally occurring compounds), including but not limited to those described below.

Capsaicinoids, capsaicinoids and related analogs and derivatives and combinations thereof suitable for use in the compositions and methods of the invention may be naturally occurring and include: capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, nonivamide, pseudocapsaicin, resiniferatoxin, tintoxin, capsaicinoids, dihydrocapsaicin esters, nordihydrocapsaicin esters, norcapsaicin, coniferyl capsaicinoids, dihydrocapsaicin coniferyl esters and other coniferyl esters, capsaicinoid analogs, and 3-hydroxyacetanilide.

Capsaicinoids and related analogs and derivatives also include non-naturally occurring compounds that are derived by synthetic means (e.g., by combining two or more naturally occurring capsaicinoids as described above or by forming an artificial compound that does not occur in nature). Examples of non-naturally occurring capsaicinoids include (but are not limited to): esters of capsaicinoids (e.g., aliphatic esters, hydrophilic esters, etc.) including 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl formate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl acetate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl propionate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl butyrate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl 2, 2-dimethylpropionate, 4- [ ((6E) -8-methylnon-6-enoylamino) methyl ] -2-methoxyphenyl, 4- [ ((6E) -8-methylnon-6-enamido) methyl ] -2-methoxyphenyl octadecanoic acid and 4- [ ((6E) -8-methylnon-6-enamido) methyl ] -2-methoxyphenoxy } carboxylic acid 4- [ ((6E) -8-methylnon-6-enamido) methyl ] -2-methoxyphenyl, ester derivatives of capsicum esters (e.g., homovanillyl 8-methylnonanoate), 3- (3-methoxy-4-hydroxyphenyl) propyl 8-methylnonanoate, substituted benzyl ester derivatives of capsicum esters (e.g., substituted benzyl ester derivatives of 8-methylnonanoate), Isobutylamides (e.g., heptanoylisobutylamide), guaiacinamides (e.g., heptanoylguaiacinamide), halogenated capsaicin analogs, phenyl capsaicin (e.g., 7-phenyl hept-6-yne-acid-4-hydroxy-3-methoxybenzamide), N-vanillyl fatty acid amides (e.g., polyviny), denatonium capsaicin, capsaicin derivatives (e.g., N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (4-chlorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [2- (4-fluorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (2, 4-dichlorophenyl) ethyl ] thiourea, N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [2- (4-benzyloxyphenyl) ethyl ] thiourea, n- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N '- [2- (4- (N-octyloxy) phenyl) ethyl ] thiourea and N- [4- (2-aminoethoxy) -3-methoxybenzyl ] -N' - [ 4-N-octyloxybenzyl ] thiourea, N-phenylmethylalkynylamide capsaicin derivatives; ether-linked and relatively non-pungent analogs of N-nonanoyl vanillylamide (e.g., N- (4-O-glycerol-3-methoxybenzyl) nonanamide, N-nonanoyl vanillylamide-4-glyceryl ether, N- (4-O-sodium acetate) -3-methoxybenzyl-nonanamide, N-nonanoyl vanillylamide-4-O-sodium acetate and N- (4-O-diol-3-methoxybenzyl) -nonanamide), N-nonanoyl vanillyl amide-4-diol ether), compounds prepared by combining a phorbol-related diterpene with a homovanillic acid analog via esterification at the exocyclic hydroxyl of the diterpene (e.g., 20-homovanillyl-mellitoxin and 20-homovanillyl-12-deoxyphorbol- 13-phenylacetate), zucchini (N- [ (4-hydroxy-3-methoxyphenyl) -methyl ] -8-methyl- (Z) -6-nonanamide), novanib, casamantab, ovani, alfanib and pravannib (N-palmitoyl-vanillylamide).

Additional capsaicinoids are described, for example, in U.S. patent No. 8,652,497; 8,642,657 No; 8,420,600 No; 8,309,060 No; 8,212,068 No; 7,981,460 No; 7,943,666 No; 7,446,226 No; 7,034,058 No; 6,333,421 No; 5,891,919 No; 5,403,868 No; 5,290,816 No; 5,221,692 No; 5,021,450 No; 4,812,446 No; 4,493,848 No; 4,564,633 th and 4,313,958 th terms.

Additional capsaicinoids and capsaicinoids are exemplified in U.S. provisional applications No. 61/979,405 and No. 61/797,423, which are incorporated herein by reference. TRPV1 channel activators suitable for use in the compositions and methods described herein may also be identified using standard methods as described, for example, in U.S. patent application publication No. 2003/0104085, which is incorporated herein by reference. Exemplary assays for identifying activators of the TRPV1 channel include, but are not limited to, receptor binding assays; a functional assessment of stimulation of calcium influx or membrane potential in a cell expressing a TRPV1 receptor; analysis of the ability to induce cell death (e.g., selective ablation of C-fiber neurons) in such cells; and other assays known in the art.

Additionally, TRPV1 channel activators can be acidulants (e.g., acetic acid, phosphoric acid, citric acid, malic acid, succinic acid, tartaric acid, lactic acid, fumaric acid, or ascorbic acid) to maintain a low pH (e.g., pH 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or 6.5) in the range of 2.5-6.5.

The TRPV1 channel activators may be present in the compositions of the present invention at a concentration ranging from about 0.001% to 10% (e.g., 0.001, 0.005, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%) weight to weight (w/w) by total weight of the composition or from about 0.001% to 10% (e.g., 0.001, 0.005, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%) weight to volume (w/v) by total volume of the composition, however, TRPV1 channel activators may be present at lower or higher concentrations (e.g., less than 0.01%, e.g., 0.008%, 0.005%, 0.004%, 0.001% (w/w), or (w/v), or greater than 10%, e.g., 12%, 15%, 20%, 30%, 35%, 40%, 50% (w/w), or (w/v)). The TRPV1 channel activator may be present in a concentration range of about 20mg to 500mg (e.g., 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 70mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 420mg, or 450mg) per unit dose.

TRPA1 channel small molecule activator

Compounds that activate TRPA1 that may be used in the compositions of the present invention include naturally occurring and non-naturally occurring compounds (e.g., synthetic analogs and derivatives of naturally occurring compounds), including but not limited to those described below.

Naturally occurring small molecule activators of TRPA1

TRPA1 channel activators include mustard oil, isothiocyanate compounds (e.g., allyl isothiocyanate), acrolein, farnesylthiosalicylic acid, delta₉-Tetrahydrocannabinol (THC), eugenol, ginger, gingerol, shogaol, cinnamaldehyde, cinnamon oil, wintergreen oil, clove oil, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide, behenyl alcohol, farnesyl thiosalicylic acid, farnesyl thioacetic acid, thymol, limonene, bradykinin, enal 4-HNE, cyclopentenone prostaglandin (15dPGJ2, 15-deoxy-a 12, 14-prostaglandin J2), acetaldehyde, 4-hydroxy-2-nonenal, elacomal and o-cresol.

Non-naturally occurring small molecule activators of TRPA1

In another embodiment, TRPA1 channel activators include non-naturally occurring compounds derived by synthetic means (e.g., by combining two or more naturally occurring small molecule activators as described above or by forming artificial compounds not occurring in nature). Non-naturally occurring small molecule activators of TRPA1 include (but are not limited to): dibenzoazepines and dibenzooxazepine derivatives, dibenzo [ b, fJ-1,4] oxazepine, formalin (formalin), methyl 6, 11-dihydro-5H-dibenzo [ b, e ] azepine-10-carboxylate, propofol, irine (icilin), formalin, methyl 6, 11-dihydro-5H-dibenzo [ b, e ] azepine-10-carboxylate and 4-isobutylamino-2- [4- (tetrahydro-pyran-3-ylmethyl) -piperazin-1-yl ] -pyrimidine-5-carboxylic acid benzamide.

Other activators of TRPA1 are described, for example, in Harteneck et al, experimental medicine and biology evolution (AdvExp Med Biol.), (2011,704: 87-106; viana et al, expert opine, the term pat, 2009,19(12) 1787-99; bandell et al, Neuron (Neuron), 2004,41(6), 840-857; McNamara et al, journal of the national academy of sciences USA 2007,104(33), 13525-; trevisiani et al, Proc. Natl. Acad. Sci. USA 2007,104: 13519-13524; Cruz-Orengo et al, Molecular Pain (Molecular Pain) 2008,4: 30; ryckmans et al, Bioorg Med Chem Lett 2011,21: 4857-; macpherson et al Nature (Nature) 2007,445: 541-545; jordt et al, Nature 2004,427(6971) 260-265; escalera et al, J. Biochem., 2008,283: 24136-24144; and U.S. patent No. 8,623,880; 8,614,201 No; 8,461,145 No; 7,960,130 and 7,674,594, each of which is incorporated by reference.

Methods of identifying activators of the TRPA1 channel are known in the art and described, for example, in U.S. patent No. 7,674,594; 7,662,576 No; 7,465,581 No; and U.S. patent publication nos. 2014/0024725 and 2007/0196866.

The TRPA1 channel activators may be present in the compositions of the present invention at a concentration ranging from about 0.001% to 10% (e.g., 0.001, 0.005, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%) weight to weight (w/w) by total weight of the composition or from about 0.001% to 10% (e.g., 0.001, 0.005, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%) weight to volume (w/v) by total volume of the composition, however, the TRPA1 channel activator may be present at lower or higher concentrations (e.g., less than 0.001%, e.g., 0.0008%, 0.0005%, 0.0004%, 0.0001% (w/w) or (w/v), or greater than 10%, e.g., 12%, 15%, 20%, 30%, 35%, 40%, 50% (w/w) or (w/v)). The TRPA1 channel activator may be present in a concentration range of about 20mg to 500mg (e.g., 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 70mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 420mg, 450mg) per unit dose.

Other TRP channel activators

Other TRP channel activators or agonists suitable for use in the methods and compositions described herein are known in the art. In one embodiment, a TRP channel agonist may be non-selective and may activate more than one TRP channel. For example, carvacrol, a compound present in oregano (oregano), activates TRPA1 and TRPV 3. In another example, epstein and menthol activate TRPA1 and TRPM 8. Naturally occurring and synthetic derivatives and analogs of carvacrol, irinotecan, or menthol are suitable for use in the compositions and methods of the invention. Agonists or activators of TRP channels suitable for use in the compositions of the present invention or administered according to the methods of the present invention are disclosed herein. The various agonists of TRP channel family members listed below are not to be construed as comprising a complete list but are presented only to provide examples of additional TRP agonists.

Examples of TRPV4 agonists include, but are not limited to, 4- α -phorbol-12, 13 dicaprate (4 α -PDD), GSK1016790A, 5',6' -epoxyeicosatrienoic acid (5'6' -EET), 8',9' -epoxyeicosatrienoic acid (8'9' -EET), APP44-1, R1747, Arachidonic Acid (AA), 12-O-tetradecanoylphosphatephorol-13-acetate (TPA), phorbol 12-myristate 13-acetate (PMA), Bisandrographolide (BAA), arachidonic acid ethanolamide, and any of the compounds disclosed in WO 2006/029209 (e.g., compounds of formula I, II, IIa, or III, N- { (1S) -1- [ ({ (4R) -1- [ (4-chlorophenyl) sulfonyl ] -3-oxohexahydro-1H-aza Heptin-4-yl } amino) carbonyl ] -3-methylbutyl } -1-benzothiophene-2-carboxamide, N- { (1S) -1- [ ({ (4R) -1- [ (4-fluorophenyl) sulfonyl ] -3-oxohexahydro-1H-azepin-4-yl } amino) carbonyl ] -3-methylbutyl } -1-benzothiophene-2-carboxamide, N- { (1S) -1- [ ({ (4R) -1- [ (2-cyanophenyl) sulfonyl ] -3-oxohexahydro-1H-azepin-4-yl } amino) carbonyl ] -3-methylbutyl } -1-methyl-1H-indole-2-carboxamide N- { (1S) -1- [ ({ (4R) -1- [ (2-cyanophenyl) sulfonyl ] hexahydro-1H-azepin-4-yl } amino) carbonyl ] -3-methylbutyl } -1-methyl-1H-indole-2-carboxamide) or N- (4-hydroxyphenyl) -5Z,8Z,11Z, 14Z-eicosatetraenamide (AM 404).

Examples of TRPC6 agonists or activators include, but are not limited to, 1-oleoyl-2-acetyl-sn-glycerol (OAG), carbachol (carbachol), Diacylglycerol (DAG), 1, 2-didecanoyl glycerol, flufenamate/flufenamic acid, nifurate/niflumic acid, hyperforin (hyperforin), and the compounds disclosed in WO 2010/015965 (e.g., compounds of formula IV, compound IX, compound X, compound XI, compound XII).

Examples of TRPM6 agonists or activators include, but are not limited to, 2-aminoethoxydiphenyl borate (2-APB).

Examples of TRPV2 agonists or activators include, but are not limited to, diphenylboronic anhydride (DPBA), Δ -9-tetrahydrocannabinol (Δ -9)⁹-THC or THC), Cannabinol (CBN), Cannabidiol (CBP), 2-APB, probenecid (probenecid), 0-1821, 11-hydroxy- Δ⁹Tetrahydrocannabinol, cannabilone (nabilone), CPS5940, HU-210, HU-211/dexanabinol, HU-331, HU-308, JWH-015, WIN55, 212-2, 2-arachidonoyl glycerol (2-AG), Arvil, PEA, AM404, 0-1918 and JWH-133.

Examples of TRPV3 agonists or activators include, but are not limited to, eugenol (acenchol), eugenol acetate, the compounds disclosed in WO 2008/065666 (formula I or formula II, compound IA), menthol, eugenol, dihydrocarveol, carveol, thymol, vanillin (vanillin), ethyl vanillin, cinnamaldehyde, 2 aminoethoxydiphenyl borate (2-APB), Diphenylamine (DPA), diphenylboronic anhydride (DPBA), camphor, (+) -borneol, (-) -isopinocampheol, (-) -fenchylone, (-) -trans-abietyl alcohol, isoborneol, (+) -camphorquinone, (-) -a-thujonone, alpha-pinene oxide, 1, 8-cineole/eucalyptol, 6-tert-butyl-m-cresol, methyl ethyl phenol, methyl ethyl vanillin, ethyl cinnamaldehyde, diphenyl borate, diphenyl oxide, diphenyl borate, and/ethyl camphor, Carvacrol, p-xylenol, cresol, propofol, p-cymene, (-) -isopulegol, (-) -carvone, (+) -dihydrocarvone, (-) -menthone, (+) -linalool, vanillyl alcohol, farnesyl pyrophosphate, farnesyl diphosphate, isopentenyl pyrophosphate and 1-isopropyl-4-methyl-bicyclo [3.1.0] hex-4-ol.

The TRP channel agonist or activator may also be an analog or derivative of any of the TRP channel activators described herein.

TRP channel agonists or activators may be present in the compositions of the present invention at concentrations ranging from about 0.001% to 10% (e.g., 0.001, 0.005, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%) weight to weight based on the total volume of the composition, although TRP channel agonists or activators may be present at lower or higher concentrations.

TRP channel agonists or activators may also be identified using standard methods. Exemplary assays known in the art for identifying agonists of any TRP channel in the TRP family include, but are not limited to, receptor binding assays; a functional assessment of stimulation of calcium influx or membrane potential in a cell expressing a TRPV1 receptor; analysis of the ability to induce cell death (e.g., selective ablation of C-fiber neurons) in such cells; and other assays known in the art.

ASIC channel activator

ASIC channels are activated by low pH. The pH of the inventive composition including the ASIC channel activator can be in the range of 2.5-6.5 (e.g., pH 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or 6.5). The pH may be adjusted within this range by any means acceptable to the composition intended for ingestion by the individual. Exemplary acidulants are acetic acid, phosphoric acid, citric acid, malic acid, succinic acid, lactic acid, tartaric acid, fumaric acid, and ascorbic acid. Acidulants can be present in the compositions of the invention at a concentration ranging from about 0.001% to 10% by weight (e.g., about 0.001, 0.005, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%) based on the total volume of the composition, although acidulants can be present at lower or higher concentrations.

Additional Components of the compositions

The compositions of the present invention may additionally include, for example, electrolytes (e.g., potassium or other salts), sweeteners, flavoring and coloring agents, vitamins, minerals, preservatives, viscosity modifiers and antioxidants, as described below.

Other exemplary excipients are described in Handbook of Pharmaceutical excipients (Handbook of Pharmaceutical excipients), 6 th edition, edited by Rowe et al, Pharmaceutical Press (2009).

Viscosity and viscosity modifiers

Viscosity is the ratio of shear stress to shear rate, expressed in dynes-seconds/cm or poise. Centipoise (cP) is one hundredth of a poise.

The viscosity of the compositions of the present invention may be greater than water (i.e., about 1.0cP at 20 ℃), for example, about 100, 200, 300, 400, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 8000, 9000cP or greater. If a consistency of corn syrup is desired, a viscosity in the range of about 2500cP is suitable. If a soft gel or honey consistency is desired, a viscosity in the range of about 10000cP to about 15000cP is suitable. For pudding-like products, a viscosity in the range of about 30000cP to about 38000cP is desirable. The viscosity of the compositions of the present invention can be measured using, for example, a rheometer or viscometer, but additional methods of measuring viscosity are known in the art.

Viscosity modifiers may be added to the compositions of the present invention. Such viscosity modifiers include, for example, collagen, gellan gum, carbohydrate gel-forming polymers, carob gum, locust bean gum, carrageenan, alginates (e.g., alginic acid, sodium alginate, potassium alginate, ammonium alginate, and calcium alginate), agar, guar gum, xanthan gum, carboxymethyl cellulose, transparent starch, pectin, gelatin, arrowroot, corn starch, umbellate starch, potato starch, sago, tapioca, furcellaran, corn syrup (e.g., light corn syrup and dark corn syrup), and sodium pyrophosphate. The viscosity modifier can be present in the composition in an amount of about 0.01% to about 10% by weight (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%) based on the total volume of the composition, although the viscosity modifier can be present at 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 is present in the composition from about 40% to about 60% (e.g., about 50%).

Electrolyte

Exemplary electrolytes include potassium salts, chloride salts, bromine salts, sodium salts, magnesium salts, calcium salts, citrate salts, acetate salts, phosphate salts, salicylate salts, bicarbonate salts, lactate salts, sulfate salts, tartrate salts, benzoate salts, selenite salts, molybdate salts, iodine salts, oxides, and combinations thereof. The electrolyte may be present in the compositions of the present invention at a concentration ranging from about 0.01% to about 10% by weight (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%) based on the total volume of the composition, although the electrolyte may be present at lower or higher concentrations.

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

Sweetening agent

Sweeteners may be included in the compositions of the present invention. Exemplary sweeteners include corn syrup (e.g., high fructose corn syrup), mannose, maltose, glucose polymers, sucrose (e.g., cane sugar or beet sugar), glucose, dextrose, lactose, galactose, fructose, polysaccharides (e.g., maltodextrin), rice syrup, honey, and natural fruit juices (e.g., orange, papaya, pineapple, apple, grape, apricot, pear, tomato, agave, or cranberry juices). In addition, non-caloric or low-caloric sweeteners may be used in the compositions of the present invention. Examples of such non-caloric or low-caloric sweeteners include, but are not limited to, saccharin, cyclamate, acesulfame potassium, sorbitol, sucralose, xylitol, erythritol, stevia extracts, L-aspartyl-L-phenyl-alanine esters (e.g., aspartame), L-aspartyl-D-alanine alkylamides, L-aspartyl-L-1-hydroxymethylalkylamides, and L-aspartyl-1-hydroxyethylalkylamides. The sweetener may be present in the compositions of the present invention at a concentration ranging from about 2% to about 20% by weight (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%) based on the total volume of the composition, although the sweetener may be present at lower or higher concentrations.

Flavouring and colouring agents

Exemplary flavoring agents include almond oil, bitter almond oil, anethole, anise oil, benzaldehyde, blackberry, black walnut oil, blueberry, caraway oil, cardamom, cherry juice, cherry syrup, cinnamon oil, cinnamon water, citric acid syrup, clove oil, cocoa, coriander oil, dextrose, sage, ethyl acetate, ethyl vanillin, fennel oil, ginger, glucose, glycerin, licorice, grape, honey, lavender oil, lemon oil, lime, mannitol, methyl salicylate, nutmeg oil, orange oil, tangerine peel, orange peel syrup, peppermint oil, peppermint water, phenethyl alcohol, pineapple, raspberry juice, raspberry syrup, rosemary oil, rose water, chinarose syrup, sorbitol, spearmint oil, strawberry, sucrose, thyme oil, peppermint oil, corn, Turpentine, vanilla, vanillin, and wild cherry syrup. Additional flavoring agents may be found in food chemical Codex and the Handbook of flavor ingredients of fanaro (Fenaroli's Handbook of flavor ingredients).

Small amounts of colorants may be used in the compositions of the present invention. Colorants include, for example, 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, chlorophyll and chlorophyllin, caramel pigments, annatto, cochineal, turmeric, saffron, paprika, and fruit, vegetable, and/or plant extracts (e.g., grapes, blackcurrants, prunus mume, carrots, beetroot, red cabbage, elderberry, and hibiscus extracts). The amount of colorant used will vary depending on the agent used in the composition and the desired color intensity of the finished product. The amount of colorant to be used can be readily determined by one skilled in the art.

Vitamins and minerals

Non-limiting examples of vitamins and minerals that may be included in the compositions of the present invention include, for example, choline bitartrate, nicotinamide, thiamine, folic acid, calcium d-pantothenate, biotin, vitamin A, vitamin C, vitamin B₁Hydrochloride, vitamin B₂Vitamin B₃Vitamin B₆Hydrochloride, vitamin B₁₂Vitamin D, vitamin E acetate, vitamin K and calcium, potassium, magnesium, zinc, iodide, iron and copper salts. When included in the compositions of the present invention, the compositions 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) of such vitamins and minerals.

Preservative

Preservatives may additionally be used in the compositions described herein. Exemplary preservatives include, for example, sorbate, 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). When included in the compositions of the present invention, the preservative is included at a level of about 0.0005% to about 0.5% by weight (e.g., about 0.0005%, about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, or about 0.5%) based on the total volume of the composition, although the preservative may be present at lower or higher concentrations.

Antioxidant agent

Antioxidants can 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; anthocyanins, delphinidins, malvidins or other anthocyanidins; apigenin, luteolin, or other flavones; hesperetin, naringenin, or other flavanoids; isorhamnetin, quercetin, kaempferol or other flavonols; and epigallocatechin-3-gallate, epicatechin, thearubigin, or other flavan-3-ols. When included in the compositions of the present invention, the antioxidant is included at a level of from about 0.0005% to about 0.5% by weight (e.g., about 0.0005%, about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, or about 0.5%) based on the total volume of the composition, although the antioxidant may be present at lower or higher concentrations.

Additional components of the compositions described herein can include amino acids (e.g., leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine), stimulants (e.g., caffeine), emulsifiers, carbon dioxide (e.g., carbonate salts equivalent to liquid compositions), stabilizers, humectants, anti-caking agents, or herbal extracts. These components may be included at a level of about 0.0005% to about 25% by weight (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%) based on the total volume of the composition, although additional components may be present at lower or higher concentrations.

Formulations and methods of making compositions

The compositions and solutions of the present invention can be formulated as ready-to-drink beverages, concentrates (e.g., syrups), dry compositions (e.g., powders, granules, or tablets reconstitutable with a liquid (e.g., water)), gels, solids, semi-solids (e.g., ice cream, puddings, or yogurt), frozen liquids (e.g., popsicles), lozenges or hard candies, dissolving bars (e.g., edible bars containing pullulan and the compositions of the present invention), and chewing gums. The formulation of these compositions may require the use of a formulation base, which is a substance or material that is mixed with or added to the ion channel activator and pharmaceutically acceptable excipients in order to obtain the desired form.

In oral solid dosage forms (e.g., tablets, capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid-filled lozenges), gums, candies, chewable tablets, foods, 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 starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) adsorbents such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant. 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 excipients such as lactose and high molecular weight polyethylene glycols.

In some embodiments, the composition may be in the form of a dry powder, granules, tablets, or capsules that are reconstitutable in a specified amount of liquid. The dry components may be mixed together and milled (e.g., to form a homogeneous powder) or mixed in an aqueous solution and dried by using methods known to those skilled in the art. The dry powder or granules may be "loose" or molded into tablets.

In other embodiments, the compositions of the present invention may be in the form of a gel or paste, additionally comprising a humectant (e.g., glycerin, propylene glycol, lithium chloride, α hydroxy acids, glycols, urea, quillaja, polyols, sugar alcohols (e.g., sorbitol, glycerin, xylitol, mannitol), triacetin or neoagarobiose), gum (e.g., xanthan gum, guar gum), an abrasive (e.g., silica (e.g., sorbitol, glycerol, mannitol), a gum base) Plasticizers, additives (e.g., sweeteners, preservatives, buffers, osmotic agents, surfactants, colorants, flavors, detergents, etc.) or thickeners (e.g., silicon dioxide))). These additional components may be present in the compositions of the present invention from about 0.5% to about 99% by weight (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%) based on the total volume of the composition, although these components may be present at lower or higher concentrations.

The gel or paste may additionally be encapsulated on or within a delivery device such as a bioadhesive strip, patch, film, or may be provided for direct application to the oral cavity (e.g., mucosal surfaces (e.g., in the mouth, nose, or throat), teeth, gums, or lips). For example, the paste or gel may be packaged in a unit containing from about 0.1 ounces to about 16 ounces of paste or gel. For example, the package may 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 a pill containing the composition of the present invention, the powdered ingredients are mixed together with a binder such as acacia or tragacanth, and then a plastomer is made by incorporating any liquid drug and adding an inert liquid. The resulting mass is called a pellet, which is then rolled into a sphere and coated with talc, gelatin or sugar.

To manufacture a tablet, an ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or a combination thereof) is mixed with a suitable diluent (e.g., dextrin, lactose, salt, starch, or a synthetic substance) designed to ensure disintegration of the tablet in vivo. To prevent sticking in the machine, lubricants, such as liquid paraffin, stearic acid, talc or synthetic substances, are usually added. Furthermore, the tablet press must be supplied with the drug mixture in a free-flowing form to ensure complete filling of the die. For this reason, the composition mixture is conventionally granulated by mechanically forcing the mixture mass through perforated metal sheets. The granulated mixture is supplied to a tablet press, the correct dose is supplied into the cavity, and the mixture is then compressed by means of a punch fitted into the cavity. To be successful, the tablet press must select the proper diluent and lubricant, prepare the appropriate granulation and achieve the correct degree of compression in the tablet press. Over-compression may mean that the tablet will not disintegrate in vivo; insufficient compression produces friable tablets that may break, resulting in inaccurate dosing. Different types of coatings may be applied to the tablets to prevent ingredient degradation, to mask the taste of certain ingredients, to control the release of active ingredients from the tablets, or to create more attractive tablets. For sugar coating, a concentrated sucrose syrup containing suspended starch, calcium or magnesium carbonate or other suitable material is applied, and each successive layer is dried before the next layer is applied. After drying the last layer, it is highly polished to obtain a nice finished product. The sugar coating provides protection and sweetness. Film coatings may also be used, in which a very thin transparent film, usually a cellulose derivative, is applied. Enteric coatings are designed to resist gastric fluid and dissolve in more alkaline intestinal fluids. Many substances have been used for enteric coatings, one of which is cellulose acetate phthalate. In making layered tablets incorporating two or more drugs, the compressed tablet is supplied to a second machine, around which another layer is compressed. In this way, normally incompatible drugs can be formulated in the same tablet.

Other solid doses, such as lozenges, candies, dragees or pastilles, disintegrate or dissolve in the mouth, slowly releasing the active ingredient (e.g., any of TRPV1, TRPA1, or ASIC channel activators described herein). The matrix is usually composed of a mixture of sugar and gum or gelatin. Lozenges are generally manufactured by compression techniques, while lozenges are manufactured by fusion and using molds. The dry extract is prepared by fluid extraction followed by evaporation, usually under reduced pressure, to a pill consistency or to dryness. The dried extract is usually granulated by passing through a screen and can be used to prepare tablets.

Oral liquid dosage forms include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), syrups, drops and elixirs. In addition to the active ingredient (e.g., any of the TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof described herein), the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethanol, isopropanol, 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. In addition to the active agent, suspensions 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 can 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 paperboard containers, bags, pouches, envelopes, or any other packaging known to those of skill in the art. For example, a ready-to-drink beverage may be bottled or packaged in a unit containing about 10-1000mL of the beverage. For example, a package can contain about 10mL, 20mL, 50mL, 100mL, 200mL, 300mL, 400mL, 500mL, 600mL, 700mL, 800mL, 900mL, or 1000mL of a beverage. Alternatively, the package can contain 200mL, 250mL, 330mL, 350mL, 355mL, 375mL, 440mL, or 500mL of the beverage. The ready-to-drink beverage may also be bottled or packaged in a unit containing 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 shelf stable compositions or solutions are desired, the packaging is suitably sterilized prior to filling with the pasteurized, ultra-pasteurized, or sterilized composition or solution. Where two or more components are required to be stable to each other (e.g., if the components are not stable at low pH), the packaging may feature multiple containers that can be mixed shortly before ingestion or can be ingested continuously.

Formulations for oral use may also be provided in the form of chewable tablets, or hard gelatin capsules in which the active ingredient (e.g., any of the ion channel activators described herein (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof)) is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules and pellets may be prepared in conventional manner using the ingredients mentioned above under tablets and capsules using, for example, a mixer, a fluid bed apparatus or a spray drying apparatus.

Oil-based formulations

The compositions of the present invention may be formulated as oral oil-based formulations.

In one embodiment, an oil-based formulation includes a formulation base composition having an oil and a lipophilic additive, which may be solid or pasty at room temperature. The lipophilic additives may include waxes, fatty acid monoglycerides, diglycerides, or triglycerides, fatty acids and polyethylene glycols and polyethylene glycol fatty acid esters, and mixtures thereof, and may be present in the range of about 5% to 20% by weight of the composition (e.g., about 5%, about 6%, about 10%, about 15%, about 17%, about 18%, about 19%, or about 20%). The wax may be beeswax, candelilla wax, carnauba wax, polyethylene oxide wax, or petroleum wax (or microcrystalline wax). The fatty acid monoglycerides, diglycerides or triglycerides may have different degrees of esterification. The fatty acid may be selected from palmitic, stearic or behenic acid and the calcium, sodium, potassium or magnesium salts thereof. The molecular weight of the polyethylene glycol and fatty acid polyethylene glycol esters may be between about 600 and 6000. The oil may include vegetable oils such as soybean oil, sunflower oil, corn oil, olive oil or nut oil; and mineral oils, such as liquid paraffin; and mixtures thereof. Oil-based formulations may be present in the form of soft or hard capsules and may be prepared by conventional techniques known in the art. In one such technique, the lipophilic additive is incorporated into the oil, heated at a temperature high enough to completely melt the lipophilic additive and obtain a homogeneous mixture. After cooling to approximately 50 ℃, other components described herein, such as ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) are incorporated into this mixture with agitation. Cooling the mixture thus obtained to a temperature of from 25 ℃ to 40 ℃ and optionally filling soft or hard capsules with this mixture. For a detailed discussion of lipids and lipid-based formulations, see, e.g., Porter et al, Nat Rev Drug discovery 2007,6(3): 231-.

In another embodiment, an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) may be formulated as an oil for topical administration. Generally, the activators described herein are at about>In a concentration range of 20% to 95% (w/w) in a solvent capable of dissolving the ion channel activator. Solvents that may be used include volatile solvents (e.g., methanol, ethanol, acetone, isopropanol, n-propanol, cyclohexane, and alkanes having a molecular weight less than dodecane (C12)Hydrocarbons), semi-volatile solvents (e.g., volatile essential oils such as clove oil, tea tree oil, sesame oil, and eucalyptol) and non-volatile solvents (e.g., polyethylene glycol 400, water, ethanol,(polyethylene polyoxypropylene Block copolymer available from BASF), glyceryl monooleate, Glycerol, lanolin, Low melting wax, sesquiterpenes and>alkanes, alkenes, alkanoic and alkenoic acids of C28). The oil may additionally include crystallization inhibitors, such as polyvinylpyrrolidone,BD 10 p (basf), povidone, and derivatives thereof; dextrin derivatives, polyethylene glycols, polypropylene glycols, mannitol and glycerol, and monoglycerides and diglycerides of essential oils, polyglycerol fatty acid esters, sucrose palmitate, pentaerythritol esters of wood rosin ((R)) ) Andthe crystallization inhibitor may be in the range of about 0.1 to 10% w/w. The oil of the ion channel activators described herein can be administered orally in the form of an oil.

Controlled release formulations

It is also within the scope of the present invention to provide compositions formulated to modulate release (e.g., delayed release, long acting and/or slow release, extended release or rapid release) of an ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combinations thereof) to reduce gastrointestinal side effects. Such compositions are well known in the art and include, for example, diffusion-controlled drug delivery systems, osmotic pressure-controlled drug delivery systems, or erodible drug delivery systems. An exemplary delivery system is SQZgel^TM(MacroMed Corp.) containing a pH sensitive polymer mixture in combination with an external coating, where the acidic environment of the stomach causes the polymer to absorb water andswelling, thereby coating the ion channel activator. Upon entering the higher pH intestine, the polymer slowly shrinks or "squeezes" at a "pull-in" rate, releasing the active composition in a sustained manner);extrusion-based technology (Egalet a/S) comprising a biodegradable coating and a matrix comprising an ion channel activator, which is surface erodible, hydrophobic and consists of PEG-stearate; Diffucaps/Surecaps (small beads of approximately 1mm or less diameter that can be incorporated into hard gelatin capsules, where the ion channel activator release profile is formed by layering the drug on a neutral core such as a sugar sphere, crystal or particle, followed by a rate-controlling, functional membrane); and Which involves formulating the dissolved individual molecules into tablets).

Ion channel activators described herein (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) can be formulated for pH controlled release. Examples of suitable formulation principles are compositions such as enteric coatings or hydrogels of the type described in U.S. patent nos. 6,537,584 and 5,484,610, which are incorporated herein by reference.

Another suitable formulation includes a formulation of an ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combination thereof) along with a vitamin E concentrate in a soft or hard gelatin capsule. Another specific example of a suitable formulation includes a formulation of an ion channel activator (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combinations thereof) in a soft or hard gelatin capsule along with ethanol, tocopheryl ethylene glycol 1000 succinate (TPGS), corn oil, and wax. Variations of this formulation may include ethanol, TPGS, corn oil, and polyglycolized glycerides (e.g., Gelucire) in soft or hard gelatin capsules. The resulting product may be in a semi-solid or solid dosage form. The release rate of this formulation depends on the degradation in the intestinal tract by lipases.

Another example of a suitable formulation is an oral pulsed dose drug delivery system. This dosage form can be considered a modified form of the ScheringRepetab tablet. A portion of the composition of the present invention is disposed in the core of the tablet. The core may be manufactured, for example, by conventional wet granulation or continuous granulation (e.g., extrusion), followed by compression of the granules into tablets. The core is then coated by air suspension using a suitable technique, for example using an enteric coating polymer (e.g. Eudragits). The first release dose is compression coated on the core or air suspension coated with or on top of an enteric coating. In one embodiment of the invention, the first released dose is coated with an enteric coating in an air suspension. In another embodiment of the invention, the first release dose is compression coated on the core to avoid release of the composition according to the invention before degradation of the enteric coating, which typically occurs at a pH higher than that found in the gastric compartment (i.e., degradation of the enteric coating typically occurs after passage through the gastric compartment).

Another example of a suitable formulation is an oral sustained drug delivery system. In this delivery system, the core may be manufactured, for example, by conventional wet granulation or continuous granulation (e.g., extrusion), followed by compression of the granules into tablets. The core is then coated by air suspension using a suitable technique, for example using ethylcellulose and hydrophilic excipients such as hydroxypropyl cellulose (HPC).

In some embodiments, the compositions of the present invention may include an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) in a microcrystalline form having a hydrophilic surface. The microcrystals may be coated directly with a film in order to obtain a sustained release formulation. The compositions of the present invention may also be complexed with true cyclodextrins and cyclodextrin derivatives (e.g., alkyl and hydroxyalkyl derivatives or sulfobutyl derivatives). Compounding is achieved by methods known in the art. Complexation may result in higher solubility and higher dissolution rate as well as higher bioavailability.

In other embodiments, the composition may include a pharmaceutically acceptable excipient, i.e., a delayed or controlled release agent of an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof). In some aspects, the pharmaceutical agent is a water soluble polymer, including, but not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, Hydroxypropylmethylcellulose (HPMC), methylcellulose, and carboxymethylcellulose.

Ion channel activators described herein (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) can be targeted to the mucus/mucosal lining of the oral cavity, tongue, nose, or gastrointestinal tract (GIT) via the use of bioadhesives. Bioadhesives are defined as synthetic or biological materials that are capable of adhering to a biological substrate or tissue. When the biological substrate is mucus, the term "mucoadhesion" has been used. When the biological tissue involved is the oral cavity or the stomach, the terms "oral adhesion" or "gastric adhesion" have been used. The bioadhesive can remain adhered to the biological substrate for an extended period of time. The period of time for which the bioadhesive agent needs to remain adhered to the biological substrate will vary depending on the target site and the condition being treated. Other delivery systems that can target TRPs or ASIC channel activators described herein to the colon include (but are not limited to):

(a) The ion channel activator is covalently linked to a 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 conversion by the gut microflora; examples of such prodrugs include azo conjugates, cyclodextrin conjugates, glycoside conjugates, glucuronic acid conjugates, dextran conjugates, polypeptides, and polymer conjugates;

(b) methods of delivering intact molecules to the colon, such as coating with a pH-sensitive polymer to release the ion channel activator at neutral to alkaline pH, or coating with a biodegradable polymer that releases the ion channel activator upon degradation by bacteria in the colon;

(c) embedding ion channel activators in biodegradable matrices and hydrogels that release the ion channel activators in response to pH or biodegradation;

(d) a time release system, wherein once the multi-layer coating formulation passes through the stomach, the ion channel activator is released after a lag time of 3-5 hours (which corresponds to the small intestine transit time);

(e) using a redox sensitive polymer, wherein the combination of azo and disulfide polymers provides for the release of an ion channel activator in response to the redox potential of the colon;

(f) Osmotic controlled delivery, in which the ion channel activator is released across a semi-permeable membrane due to osmotic pressure.

Micro-and nanoparticle formulations

In one embodiment, the nano-and microparticles loaded with ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) for sustained release are formulated by nano-precipitation or oil-in-water single emulsion solvent evaporation/extraction methods. First, poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) are prepared by a nanoprecipitation method. The oil-to-water volume ratio can be adjusted (e.g., about 1:2 to 1:5, such as about 1:2, 1:3, 1:4, or 1:5), and the size of the nanoparticles (e.g., about 162+/-3nm to 153+/-3nm, such as about 154, 155, 156, 157, 158, 159, 160, 161, or 162) can be selected to increase drug loading efficiency and drug release time. To obtain a more sustained release, the modified single emulsion approach can be applied with biocompatible polymers such as polylactic acid (PLLA), Polyhydroxybutyrate (PHB), polyglycolic acid (PGA), PLGA, and poly-caprolactone (PCL).

In another embodiment, gastric-specific mucoadhesive nanoparticles (SSMNs) may be used to improve the controlled delivery of ion channel activators (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) by continuously releasing the activators to their site of uptake for an extended period of time to ensure optimal bioavailability. Ion channel activators with narrow absorption windows (e.g., TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) are primarily associated with improved absorption at the jejunum and ileum due to enhanced absorption characteristics (e.g., large surface area) at these sites or due to enhanced solubility in the stomach as compared to the more distal portions of the gastrointestinal tract. Ion channel activators that may benefit from the use of stomach-specific mucoadhesive nanoparticles include ion channel activators that function locally in the stomach, ion channel activators that have low solubility at high pH, ion channel activators that are absorbed primarily in the stomach, ion channel activators that have a narrow absorption window (e.g., ion channel activators that are absorbed primarily from the proximal portion of the small intestine), ion channel activators that are rapidly absorbed from the gastrointestinal tract, ion channel activators that degrade in the colon, and ion channel activators that are unstable in intestinal fluids. A longer residence time in the stomach may be advantageous for local effects, especially in the upper part of the small intestine. A list of micro-and nano-carriers for mucosal delivery applications is described in table 1.

TABLE 1 micro-and Nanoparries for mucosal delivery

Route of administration

The compositions described herein can be administered to a subject in various forms depending on the route of administration selected, as will be appreciated by those skilled in the art and relevant to the particular disease or condition being treated. The compositions used in the methods described herein can be administered, for example, by topical, enteral, or parenteral administration. Topical administration includes, but is not limited to, epicutaneous, inhalation, enema, eye drop, ear drop, and administration via the mucosa in the body. Enteral administration includes oral, rectal, vaginal and gastric feeding tubes. Parenteral administration includes intravenous, intraarterial, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, 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 invention, an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof) is administered orally to achieve a mucosal effect and a transmucosal effect. Exemplary administration includes buccal, nasal, intradermal, inhalation, topical, subcutaneous, sublingual, sublabial, and insufflation administration. The compositions of the present invention may include a penetration enhancer to increase the bioavailability of the ion channel activator in the oral cavity. Exemplary penetration enhancers include surfactants (e.g., anionic surfactants (e.g., sodium lauryl sulfate), cationic surfactants (e.g., cetylpyridinium chloride), and nonionic surfactants (e.g., poloxamers, 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., alpha-, beta-, or gamma-cyclodextrin, methylated cyclodextrins), chelating agents (e.g., EDTA, citric acid, sodium salicylate, methyl salicylate), polymers (e.g., positively charged polymers (e.g., chitosan, trimethylchitosan)), and cationic compounds (e.g., poly-L-arginine, poly-n-butyl-methyl salicylate, poly-n-methyl-one, poly-n-butyl-one, poly-n-butyl-one, poly-, L-lysine).

For intravenous or intrathecal delivery or direct injection, the composition must be sterile and mobile to the extent that the composition can be delivered by syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. For example, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol or sorbitol in the composition, and sodium chloride. Prolonged 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 route of administration will depend on whether a local or systemic effect is achieved. For example, for topical effects, the compositions can be formulated for topical administration and applied directly to the site where their effect is desired. For systemic, long-term effects, the compositions can be formulated for enteral administration and administered via the digestive tract. For systemic, immediate, and/or short-term effects, the compositions may be formulated for parenteral administration and administered by routes other than through the digestive tract.

Parenteral depot systems from biodegradable polymers are also within the scope of the invention. These systems are injected or implanted into muscle or subcutaneous tissue and release the incorporated drug over an extended period of time ranging from days to months. Both the characteristics of the polymer and the device structure can control the release kinetics, which can be continuous or pulsatile. Polymer-based parenteral depot systems can be classified as implants or microparticles. The former is a cylindrical device injected into the subcutaneous tissue, while the latter is defined as spherical particles in the range of 10-100 μm. Extrusion, compression or injection moulding is used to manufacture implants, whereas for microparticles phase separation methods, spray drying techniques and water-in-oil-in-water emulsion techniques are often employed. The most commonly used biodegradable polymers for forming microparticles are polyesters from lactic and/or glycolic acid, such as poly (glycolic acid) and poly (L-lactic acid) (PLG/PLA microspheres). Of particular interest are in situ formed reservoir systems such as thermoplastic pastes and gelling systems formed by solidification, by cooling or due to sol-gel transition, cross-linking systems and organogels formed by amphiphilic lipids. Examples of thermosensitive polymers used in the foregoing systems include N-isopropylacrylamide, poloxamers (block copolymers of ethylene oxide and propylene oxide, such as poloxamers 188 and 407), poly (N-vinylcaprolactam), poly (silicon glycol), polyphosphazene derivatives, and PLGA-PEG-PLGA.

Dosage form

The compositions of the present invention are formulated into acceptable dosage forms by conventional methods known to those skilled in the art. The actual dosage level of the active ingredient in the compositions of the invention can 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, and which is non-toxic to the subject. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular composition of the invention employed, the route of administration, the time of administration, the rate of absorption of the particular agent employed, the duration of the treatment, other drugs, substances and/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and prior medical history of the individual being treated, and like factors well known in the medical arts. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the composition required. For example, a physician or veterinarian can start doses of the agents of the invention employed in compositions at levels below those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dosage of a composition of the invention will be that amount of material which is the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above. Preferably, an effective daily dose of the therapeutic composition may be administered in two, three, four, five, six or more sub-doses, optionally administered separately in unit dosage form at appropriate intervals throughout the day.

Preferred therapeutic dosage levels are oral administration of from about 500mg to about 1000mg (e.g., about 500mg, 520mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, or 1000mg) of the composition per day, relative to an adult suffering from the average weight of most of the symptoms, syndromes, and conditions described herein. Preferred prophylactic dose levels are from about 100mg to about 1000mg (e.g., about 110mg, 140mg, 200mg, 250mg, 300mg, 350mg, 400mg, 460mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, or 1000 mg). The dose may also be titrated (e.g., the dose may be escalated until evidence of gastrointestinal toxicity, such as diarrhea or nausea, occurs).

The frequency of treatment may also vary. An individual may be treated one or more times per day (e.g., once, twice, three times, four times or more) or every few hours (e.g., about every 2, 4, 6, 8, 12, or 24 hours). The composition may be administered 1 or 2 times every 24 hours. The treatment schedule can have varying durations, such as two days, three days, four days, five days, six days, seven days, eight days, nine days, 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, treatment may be twice a day for three days, twice a day for seven days, twice a day for ten days. The treatment cycle may be repeated at intervals, such as once per week, once per month, or once per month, separated by periods of no treatment. The treatment may be a single treatment or may last as long as the life of the subject (e.g., many years).

Food and food supplement

The invention also relates to the use of said composition as a food, food supplement or dietary product (food intended for a specific diet). In particular, the composition may be incorporated into industrially produced or craftsman prepared food products such as oils, butter, margarine, bread spreads or baked goods. It may also be provided in powder form for dilution in water or food bars.

The compositions of the present invention may additionally be administered in combination with dietary supplements to enhance and/or maintain general health. Examples of dietary supplements include, but are not limited to, vitamins (e.g., vitamin a, vitamin B)₁、B₂、B₃、B₅、B₆、B₇、B₉、B₁₂Vitamin C, vitamin D, vitamin E and vitamin K), minerals (e.g., potassium, chloride, sodium, calcium, magnesium, phosphorus, zinc, iron, manganese, copper, iodine, selenium and molybdenum), herbs or plants (e.g., hypericum perforatum (st. john's-world), piper methysticum (ka)va), Shilajit (Shilajit), and herbs), amino acids (e.g., glycine, serine, methionine, cysteine, aspartic acid, glutamic acid, glutamine, tryptophan, and phenylalanine), and concentrates, ingredients, extracts, and/or combinations of any of the above.

Conditions and disorders

The compositions of the present invention may be used to treat any of the conditions and disorders described herein.

Peripheral Nervous System (PNS) pathologies

The compositions of the present invention may be used to treat conditions affecting the Peripheral Nervous System (PNS). These conditions include: a disease, disorder or injury of the peripheral nervous system, including (but not limited to): spasmodic fasciculation syndrome, assam syndrome or neuromuscular rigidity (NMT), peripheral neuropathy (e.g. diabetic neuropathy), carpal tunnel syndrome or EBV infection. Other peripheral nervous system diseases and conditions include (but are not limited to): amyloidosis, diabetic neuropathy, nerve compression syndrome, neoplasms of the peripheral nervous system, brachial plexus neuropathy, Guillain-Barre syndrome (Guillain-Barresyndrome), neuralgia, polyneuropathy, complex regional pain syndrome, mononeuropathy, neuritis, acrodynia, neurofibroma, arm vibration syndrome, absence of pain sensation, and talov cysts (Tarlov cysts).

Central Nervous System (CNS) conditions

The compositions of the invention may be used to treat conditions affecting the Central Nervous System (CNS). These conditions include: diseases, disorders and injuries of the central nervous system caused by tumors, multiple sclerosis, spasticity due to cerebral palsy, stroke, motor neuron disease, spinal cord injury or stenosis. There are many other central nervous system diseases and conditions, including central nervous system infections (such as encephalitis and poliomyelitis), early-onset neurological disorders (including ADHD and autism), late-onset neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease and essential tremor), autoimmune and inflammatory diseases (such as multiple sclerosis and acute disseminated encephalomyelitis), genetic diseases (such as Krabbe's disease and Huntington's disease), and amyotrophic lateral sclerosis and adrenoleukodystrophy. Other CNS diseases include (but are not limited to): catalepsy, epilepsy, meningitis, migraine, tropical spastic paraparesis, arachnoid cyst, atresia syndrome and Tourette's syndrome. Anxiety disorders may also be characterized as CNS conditions. Anxiety disorders can be classified as: generalized anxiety disorder, phobia, panic disorder, agoraphobia, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress disorder, separation anxiety disorder, and contextual anxiety disorder.

Tactile sensitivity

The compositions of the invention may be used to treat tactile sensitivity or Tactile Defense (TD). TD refers to observable behavioral and emotional response patterns that are aversive, negative, and incompatible with certain types of tactile stimuli that are often viewed by most people as not painful. TD is a sensory integration disorder in which the brain cannot process and use information via senses. Haptic sensitivity may be caused by conditions such as autism, malaise, neuralgia, panic disorder, or anxiety disorder, or by a noxious bite or sting.

Electrolyte imbalance and/or vitamin deficiency

The compositions of the invention may be used to treat conditions associated with electrolyte imbalance and/or vitamin deficiency. Examples of such conditions include (but are not limited to): hyponatremia, hypernatremia, hyperkalemia, hypokalemia, hypercalcemia, hypocalcemia, hyperchloremia, hypochloroemia, hypermagnesemia, hypomagnesemia, hyperphosphatemia, hypophosphatemia, nephropathy, rickets, scurvy, pellagra, calcium deficiency, eating disorders, vitamin D deficiency, vitamin a deficiency, biotin deficiency, riboflavin deficiency, vitamin K deficiency, hypocyanocobalmia, paresthesia, nyctasia, nyctalopia, magnesium or thiamine deficiency, hypoparathyroidism, myelocystic disease, and adrenocortical carcinoma.

Muscle conditions and disorders

The compositions and methods described herein include treating an individual who has been diagnosed or identified as having a muscle condition or disorder. Exemplary disorders include nocturnal spasms, multiple sclerosis, dystonia, spinal cord spasms, neuromuscular disorders (including muscle pain and spasms associated with neuromuscular disorders), central nervous system disorders or injuries (e.g., spinal cord injury, brain injury, or stroke), muscle spasms, and fasciculations.

In some embodiments, the compositions of the present invention are also useful for treating painful muscle contractions in the head or neck when stretched, cluster or migraine headaches, back spasms, leg spasms due to spinal stenosis, skeletal muscle pain, muscle pain (e.g., fibromyalgia) and cramping (e.g., nocturnal spasms), cramping and spasms due to treatment with dialysis, diuretics, beta-blockers, statins, fibrates, beta 2-agonists, ACE inhibitors, ARBs, and antipsychotics, such as "economy class syndrome", paralysis, muscle claudication pain due to inactivity or binding seen in peripheral arterial disease or immobilization, and neuromuscular disease.

Neuromuscular diseases can be caused by circulatory problems, stroke, immune and autoimmune disorders, electrical insulation failure around the myelin sheath of nerves, genetic/genetic disorders (e.g. huntington's disease), certain rare tumors, failure of the connection between nerves and muscle fibers and exposure to chemicals in harmful environments, poisoning (e.g. heavy metal poisoning). Some neuromuscular diseases are caused by viral infection or by the invasion of a less well known harmful protein called prion. Motor endplate diseases include myasthenia gravis, forms of muscle weakness due to antibodies to acetylcholine receptors, and its associated condition langerhans myasthenia syndrome (LEMS). Tetanus and botulism are bacterial infections in which bacterial toxins cause an increase or decrease in muscle tone, respectively. Myopathies are all diseases that cause mainly muscle degeneration without affecting the nerves themselves (e.g., linear myopathy, centronuclear myopathy, mitochondrial myopathy, inflammatory myopathy, familial periodic paralysis or drug induced myopathy). Muscular dystrophies, including Duchenne's and Becker's, are a large group of diseases, many of which are inherited or caused by genetic mutations, in which muscle integrity is disrupted. Which results in a gradual loss of strength and a shortened life span. Also within the scope of the invention are the treatments of Guillain-Barre syndrome and inflammatory muscle disorders such as polymyalgia rheumatica, polymyositis, dermatomyositis, inclusion body myositis, and rhabdomyolysis. Additional neuromuscular disorders include, but are not limited to, multiple sclerosis, spinal cord spasm, spinal muscular atrophy, myasthenia gravis, spinal cord injury, traumatic brain injury, cerebral palsy, hereditary spastic paraplegia, motor neuron disease (e.g., amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive bulbar muscular atrophy (e.g., kennedy's disease) or post-polio syndrome), neuralgia, fibromyalgia, machado-joseph disease, spasmodic fasciculation syndrome, carpal tunnel syndrome, acrodynia, neurofibromatosis, neuromyotonia (e.g., focal neuromyotonia, assayaki syndrome), peripheral neuropathy, piriformis syndrome, plexus disease (e.g., brachial plexus disease or lumbosacrassa disease), Radiculopathy (e.g., lower lumbar radiculopathy) and encephalitis.

Dystonia is a neurological condition that affects a muscle or muscle group of a particular part of the body, causing involuntary muscle contractions and abnormal posture. Types of dystonia include: focal dystonia, multifocal dystonia, segmental dystonia, systemic dystonia (e.g., torsion dystonia or idiopathic torsion dystonia), hemidystonia, blepharospasm, psychodystonia, cervical dystonia, acute dystonic response, and nutritional vascular dystonia. The methods and compositions described herein may be applicable to cervical dystonia, cranial dystonia, laryngeal dystonia, and hand dystonia. The etiology of the disorder includes, but is not limited to, genetic, birth-related or physical trauma, infection, intoxication (e.g., lead intoxication) or response to some pharmaceutical agent (e.g., neuroleptic). Treatment is difficult and has been limited to minimizing symptoms of the disorder (e.g., muscle spasms). The methods and compositions described herein may be applicable to focal dystonia, blepharospasm, cervical dystonia, cranial dystonia, laryngeal dystonia, and hand dystonia.

In one embodiment, the subject has been diagnosed with or identified as having multiple sclerosis. Multiple Sclerosis (MS) is also known as disseminated sclerosis and disseminated encephalomyelitis. MS is an inflammatory disease in which the insulating sheaths of nerve cells in the brain and spinal cord are damaged, thereby disrupting the ability of the nervous system to communicate. Three major features of MS are lesion formation (also known as plaque), inflammation, and destruction of the myelin sheath of neurons in the central nervous system. Symptoms of MS may include muscle cramps and muscle weakness.

In some embodiments, the subject has been diagnosed with or identified as having nocturnal cramps. Nocturnal cramps are spontaneous muscle contractions that occur during sleep, can be very painful, and often recur throughout the night. The higher the risk that an elderly person (e.g. over the age of 50) experiences nocturnal cramps.

In one embodiment, the subject has been diagnosed with or identified as having spinal cord spasm. Spasticity is uncontrolled muscle tension or contraction that is common in individuals with spinal cord injuries and various neurological disorders. Spasticity is generally defined as the increase in velocity-related tone stretch reflex (muscle tone) with exaggerated tendon spasms, clonus and cramps caused by hyperexcitability of the stretch reflex. About 65% -78% of the spinal cord injury population have some degree of spasticity and are more common in neck (neck) injuries than chest (chest) and waist (lower back) injuries. In one embodiment, the subject has suffered a central nervous system injury, such as brain injury, stroke, or traumatic spinal cord injury. For example, central nervous system injury is associated with an undesired or abnormal muscle contraction or cramping or the absence of normal muscle contraction.

In some embodiments, the subject has been diagnosed with or identified as suffering from a muscle spasm, cramp, dystonia, or fasciculation (e.g., an undesired or abnormal muscle spasm, cramp, dystonia, or fasciculation). Muscle spasms, cramps, dystonia, or fasciculations may also occur as a result of other diseases or disorders, such as diabetes (e.g., diabetic neuropathy), Addison's disease, peripheral arterial disease, hypertension, alcoholism, cirrhosis, renal failure, hypothyroidism, neuromuscular diseases (e.g., amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscle atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal bulbar muscular atrophy (e.g., kennedy's disease), or post-polio syndrome), and metabolic disorders (e.g., adrenoleukodystrophy, phenylketonuria, or krabbe's disease). Thus, the methods described herein are also applicable to treating or evaluating individuals who have been diagnosed with other diseases or conditions associated with muscle spasms as described herein.

Muscle spasms, cramps, dystonia, or fasciculations may occur as a side effect of some drugs. Drugs that may cause muscle spasms include: diuretics, oral contraceptives, blood pressure medications. The methods described herein may also be applicable to treating or evaluating an individual prescribed or taking medications that cause muscle spasms. Exemplary drugs that may induce muscle spasms include (but are not limited to): diuretics such as Lasix (furanilide), microside (hydrochlorothiazide); alzheimer's disease drugs, such as Aricept (donepezil); myasthenia gravis drugs such as Prostigmine (neostigmine); cardiovascular drugs such as procandia (nifedipine); osteoporosis drugs, such as Evsta (Raloxifene); asthma drugs such as Brethine (terbutaline), profentil and Ventolin (albuterol); parkinson's disease agents, such as Tasmar (tolcapone); cholesterol drugs, for example statins, such as Crestor (rosuvastatin), Lescol (fluvastatin), Lipitor (atorvastatin), Mevacor (lovastatin), pravastatin (pravastatin), or simvastatin (simvastatin).

In one embodiment, the compositions and methods disclosed herein are suitable for treating or evaluating an individual in the absence of normal muscle contraction (e.g., gait abnormalities). Gait is abnormal and deviates from normal walking or abnormal and uncontrollable walking pattern. Examples of gait anomalies include a prepulse gait, a scissors gait, a spastic gait, a trans-threshold gait and a gnaw gait. For example, the gait disorder is "foot drop" in which the forefoot drops due to muscle weakness, nerve damage, or muscle paralysis. Gait abnormalities are often associated with neuromuscular diseases or disorders.

Connective tissue disease

The compositions of the invention are also useful for treating connective tissue disorders. Examples of diseases include (but are not limited to): degenerative Joint Disease (DJD), Marfan syndrome, Ehless-Dullos syndrome, osteogenesis imperfecta, Steckel syndrome (Sticklersyndrome), Alport syndrome, congenital contracture long and thin fingers, psoriatic arthritis, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren's syndrome, and mixed connective tissue disease.

Symptoms of larynx

The compositions of the invention may also treat throat disorders or throat injuries (e.g., from chemicals, cancer, surgery or infection). Examples of throat conditions include, but are not limited to, acid reflux, tonsillitis, pharyngitis, laryngeal spasm due to laryngeal surgery, laryngitis, dysphagia, and spasmodic dysphonia.

Sarcoidosis

The compositions of the present invention are also useful for treating sarcoidosis. Sarcoidosis is a disease involving abnormal pooling of inflammatory cells (granulomas) that may form in nodular form in multiple organs. Granulomas are most often located in or on the lungsIn the associated lymph nodes, but any organ may be diseased. The compositions of the present invention are suitable for treating different types of sarcoidosis, including (but not limited to): sarcoidosis annulata, erythrodermic sarcoidosis, ichthyoid sarcoidosis, hypopigmented sarcoidosis, lofgren's syndrome (syndrome), lupus erythematosus, scleroderma sarcoidosis, mucosal sarcoidosis, sarcoidosis of the nervous system, papulosarcoma, sarcoidosis of the scar, subcutaneous sarcoidosis, systemic sarcoidosis, and ulcerative sarcoidosis.

Respiratory pathologies

The compositions of the present invention may also be used to treat respiratory conditions or diseases. Respiratory pathologies involve organs and/or tissues involved in breathing, including the lungs, trachea, bronchi, bronchioles, alveoli, pleura, pleural cavity. Without wishing to be bound by theory, activation of TRPA1 and/or TRPV1 ion channels via administration of an ion channel activator of the present invention (e.g., TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or a combination thereof) may affect airway sensory nerve reactivity, thus causing bronchodilation of airway smooth muscle. Exemplary respiratory conditions that the compositions of the invention may be used to treat include, but are not limited to, asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pneumonia, cystic fibrosis, pleural cavity disease, influenza or the common cold.

Cough with asthma

The compositions of the present invention may also be used to treat or reduce cough in an individual. Coughing is a frequently repetitive reflex in nature and can help clear the respiratory tract of particles, irritants, secretions, and the like. Coughing may be voluntary or involuntary. Exemplary conditions associated with cough include respiratory conditions (e.g., asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pneumonia, cystic fibrosis, pleural cavity disease, influenza, or cold), exposure to allergens or chemical irritants, or inflammation. In some embodiments, the present compositions may be a cough suppressant.

Anxiety disorder

In some embodiments, the subject has been diagnosed with or identified as suffering from anxiety. Anxiety disorders can be characterized as pathologies involving the central nervous system and can cause feelings of anxiety and distress to an individual. These conditions can result in undesirable or abnormal muscle spasms, dystonia, and fasciculations that can be treated by the compositions of the present invention. Exemplary anxiety disorders include generalized anxiety disorder, phobias, panic disorder, agoraphobia, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress disorder, separation anxiety disorder, and contextual anxiety.

Method of evaluating an individual

The present invention provides various methods of assessing an individual for efficacy of a muscle spasm treatment or for treating an undesired or abnormal muscle contraction (e.g., a muscle spasm, spasticity, dystonia, or fasciculation). In the methods described herein, a test muscle of an individual is electrically induced to have a test muscle spasm, and the electrical activity of the test muscle is recorded. In some embodiments, a test aliquot of a composition for treating muscle spasm, cramping, dystonia, or fasciculation is administered to a subject and a second test muscle spasm is induced. The electrical activity of the second test seizure was also recorded. Comparison and analysis of the first and second test seizure records may indicate the efficacy of the test aliquot for reducing, alleviating, or preventing seizures. The comparison and analysis of the records may also be used to classify individuals or identify individuals for certain muscle spasm treatments.

Alpha motor neurons project from the brain stem and spinal cord and innervate muscles. Stimulation of the alpha motor neurons results in the transmission of electrical signals to the muscle that result from the movement of ions across cell membranes. Electrical stimulation from motor neurons causes muscle movement or contraction, such as muscle spasm or cramping. When the muscle is at rest, there is minimal or no electrical signal. The activity of alpha motor neurons can be modulated by signal transduction from primary sensory neurons activated by sensory input. Non-taste primary sensory neurons with nerve endings in the mouth, esophagus and stomach, for example, via activation of specific ion channels, can induce upregulation of inhibitory signals that cause alpha motor neurons. Via this inter-neuron negative feedback mechanism, activation of primary sensory neurons inhibits or prevents alpha motor neuron excitation via inhibition of signaling, and thereby inhibits muscle spasm or cramped muscle contraction.

Electrical stimulation can induce muscle contraction that reproduces muscle spasms, dystonias, or fasciculations in the methods described herein, electrical stimulation is used to induce a test muscle spasm. Electrical activity of the test muscle before, during, and after the test muscle spasm is detected, measured, and recorded. Analysis of the record of electrical activity of a muscle experiencing electrically induced spasms can be used to determine the efficacy of treatment for relieving muscle spasms.

Electromyography is a technique for measuring and recording the electrical activity of muscles during rest and exercise. The instrument that detects and records the electrical signals produced by the muscle is called a myoelectrogram. The record of electrical activity obtained by a electromyograph is called an electromyogram (or electromyogram). The electromyograph may comprise at least one recording electrode, at least one reference electrode, an amplifier component, means for converting an analog signal to a digital signal, and means for generating and displaying a recording. Optionally, the apparatus may further comprise at least one mechanical device for detecting additional biofeedback, such as body or skin temperature by a skin thermistor.

Electrical activity of a muscle (e.g., a test muscle) is recorded and detected by electrodes or leads. There are two main types of electrodes: a surface electrode and an insertion electrode. The surface electrode is non-invasive and is placed on the skin. The insertion electrode includes a needle and a thin wire electrode, and is inserted directly into the muscle tissue. In a preferred embodiment, the electrodes used in the present invention are surface electrodes.

The recording electrode is preferably placed on the test muscle and the reference electrode is placed nearby, e.g., within 2-6 inches of the active electrode. Preferably, the reference electrode is placed on the cooperating muscle. A synergistic muscle is a muscle that assists or participates in exercise with a test muscle, but does not cramp with the test muscle when electrically induced. In some preferred embodiments, a series or array of multiple recording electrodes is used. For example, a linear array of 8 recording electrodes is applied on the test muscle, and optionally a linear array of 4-8 recording electrodes is used on the cooperative muscle. In other embodiments, a grid array of recording electrodes is applied to the target muscle, for example using a 6 x 5 grid array of electrodes.

In the methods described herein, an electrical stimulus is applied to a test muscle to induce a test muscle contraction. The electrical stimulation is delivered by stimulation electrodes. The stimulation electrodes are preferably placed directly on the skin over the test muscle. Electrical stimulation is defined by a number of parameters, such as stimulation frequency (hertz or Hz), current intensity (milliamps or mA), pulse frequency (pulses per second or pps) and duration of stimulation. The electrical stimulation may be delivered by transcutaneous electrical stimulation or surface electrical stimulation.

Preferred test muscles for electrically induced muscle spasms include the flexor hallucis brevis (FHB or digitorum hallucis) and gastrocnemius (calf muscle). Other target muscles may include the Abductor Hallucis (AH), the biceps brachii (biceps), the triceps surae (triceps), or the quadriceps femoris (quadriceps).

The appropriate stimulation frequency of the electrical stimulation to induce the test muscle spasm may vary depending on the size or location of the muscle or the individual. For example, the electrical stimulation may be at least 1Hz, at least 2Hz, at least 3Hz, at least 4Hz, at least 5Hz, at least 6Hz, at least 7Hz, at least 8Hz, at least 9Hz, at least 10Hz, at least 11Hz, at least 12Hz, at least 13Hz, at least 14Hz, at least 15Hz, at least 20Hz, at least 25Hz, at least 30Hz, at least 35Hz, at least 40Hz, at least 50Hz, at least 60Hz, at least 70Hz, at least 80Hz, at least 90Hz, or at least 100 Hz. In some preferred embodiments, the stimulation frequency of the FHB is 8Hz, 10Hz, 12Hz, 14Hz or 18 Hz. In some embodiments, the stimulation frequency may change over time. For example, the stimulation frequency increases over time, such as from 2Hz to 24Hz in 2Hz increments.

The minimum frequency of electrical stimulation that is capable of inducing a spasm has been referred to as the "critical frequency". Studies have shown that the critical frequency of inducing spasticity is lower in spasmodic individuals compared to individuals without a history of spasticity. (Bertolasi et al, Ann. neuron.) -1993, 133: 303-6; Miller and Knight, Muscle Nerve (Muscle Nerve.) -2009, 39: 364-8; and Minetto et al, Muscle Nerve 2009; 40: 535-44). For example, Miller and Knight (muscular nerve 2009; 39:364-8) found that the critical frequency of the flexor hallucis brevis was approximately 15Hz in individuals with a history of spasticity and approximately 25Hz in spasticity individuals.

The amplitude or current intensity of the electrical stimulation may also vary depending on the size or location of the muscle or the individual. The maximum current intensity refers to the current intensity required to achieve a flat region in the peak amplitude of the M-wave. M-waves refer to the detected EMG signal. In a preferred embodiment, the current intensity exceeds the maximum current intensity by 30% or more. In some embodiments, the maximum amperage of each individual is determined prior to testing the individual. For example, the current intensity is 5mA, 10mA, 15mA, 20mA, 25mA, 30mA, 40mA, 50mA or 60 mA.

The electrical stimulation may be applied in the form of a series of pulses for a duration of time. For example, the stimulus may be applied in the form of a series of at least 100 microsecond pulses, at least 120 microsecond pulses, at least 150 microsecond pulses, at least 180 microsecond pulses, at least 200 microsecond pulses, at least 300 microsecond pulses, at least 400 microsecond pulses, at least 500 microsecond pulses, or at least 600 microsecond pulses. The stimulus may be applied for 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, or more. Preferably, to induce spasticity in the FHB, the stimulus is applied in a series of 180 microsecond pulses for 7 seconds.

In some embodiments, the parameters of the electrical stimulation to be applied to the test muscle may be adjusted to reduce or increase the amplitude of the test muscle contraction to better reproduce muscle spasms, dystonias, or fasciculations. For example, the frequency or intensity of the current applied to the test muscle may be varied according to the type of test muscle contraction desired, such as increasing the stimulation frequency compared to the test muscle cramp to induce a test muscle spasm.

In the methods described herein, the electrical activity of the target muscle is detected and recorded by recording electrodes before, during, and after the induced cramp. The electrical activity is recorded and displayed in the form of a graph or electromyogram. Preferably, the profile contains electrical activity before, during and after application of the electrical stimulation to induce a muscle spasm. In some embodiments, the profile contains electrical activity during and after application of the electrical stimulus. In some embodiments, the electrical activity is converted to Root Mean Square (RMS) values and displayed as a function of time. Where more than one recording electrode is used to measure the electrical activity of the target muscle, the curve contains the average electrical activity detected by all recording electrodes as a function of time.

The pattern of recorded electrical activity or signals may indicate the presence or absence of an induced muscle spasm. The indication of an induced muscle spasm comprises an involuntary electrical signal of the stimulated muscle, preferably while no electrical signal of the synergistic muscle is present, after the electrical stimulation is stopped. Alternatively, a signal amplitude that is 2 or 3 standard deviations greater than the 1 second baseline signal amplitude of the target muscle before stimulation or the synergistic muscle after stimulation indicates an induced cramp. The induced muscle spasm can last for at least 5 seconds, at least 10 seconds, at least 15 seconds, at least 20 seconds, at least 25 seconds, at least 30 seconds, at least 35 seconds, at least 40 seconds, at least 45 seconds, at least 50 seconds, at least 55 seconds, at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, or at least 5 minutes.

In some embodiments, a first muscle spasm is electrically induced in the subject prior to administration of the composition for treating muscle spasm, and a second muscle spasm is electrically induced in the subject after administration of the composition after a rest period. The first spasm-inducing curve obtained prior to administration of the composition is referred to as the reference curve. The second spasm-inducing profile obtained after administration of the composition is referred to as the treatment profile. Comparison of the treatment profile to the reference profile can be used to select individuals for treatment with the composition or to identify individuals that will respond to treatment with the composition. Specifically, the characteristics of the induced cramp in the reference curve and the treatment curve are compared to determine whether the administered composition reduces or prevents a second induced cramp.

Alternatively, a value (e.g., a reference value) may be determined from a reference curve and a value (e.g., a treatment value) may be determined from a treatment curve. The reference value and the treatment value can be compared to determine a reduction or prevention of spasticity. In one embodiment, the values determined from the reference curve and/or the treatment curve represent parameters of a muscle spasm. A decrease in the therapeutic value compared to the reference value indicates that the administered test aliquot is effective in alleviating or preventing muscle spasms.

The parameters of the muscle spasm can be compared to determine the efficacy of a treatment to alleviate spasm or a spasm prevention, e.g., by a decrease in the parameters of the muscle spasm. Muscle spasm parameters that may be determined from electromyography include the area under the curve, peak amplitude, duration of spasm, and changes in the critical frequency for initiating the test muscle spasm.

The area under the curve values for the reference curve and the treatment curve can be calculated using standard methods known in the art. A decreased or absent value of the area under the curve for the treatment curve as compared to the reference curve indicates that electrically-induced cramps have been reduced or prevented. For example, the area under the curve of the treatment curve may be reduced by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 50% as compared to the area under the curve of the reference curve.

The peak amplitude after cessation of electrical stimulation between the reference curve and the treatment curve can be compared. A decrease or absence of the peak amplitude of the treatment curve compared to the reference curve indicates that electrically-induced spasms have been reduced or prevented. For example, the peak amplitude of the treatment curve may be reduced by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 50% compared to the peak amplitude of the reference curve.

The duration of the test cramp between the reference curve and the treatment curve may be compared. A decrease or absence of the duration of the spasm is indicative of a decrease or prevention of electrically induced spasm. For example, the seizure duration may be reduced by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 50% as compared to the seizure duration of the reference curve.

The critical frequency refers to the minimum frequency of electrical stimulation required to induce a spasm. In one embodiment, an alteration in the critical frequency required to trigger a test muscle spasm is indicative of the efficacy of the treatment to relieve the spasm. For example, the change in critical frequency may be an increase of at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35% or 50%, 100%, 200% compared to the critical frequency required prior to treatment, e.g. in the reference curve. For example, the change in critical frequency may be a decrease of at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35% or 50% compared to the critical frequency required prior to treatment, for example, in the reference curve.

In certain embodiments, the rest period between the first test cramp and the second test cramp is at least 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 16 hours, 20 hours, or 24 hours. In certain embodiments, the electrical stimulus is applied again at least 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 16 hours, 20 hours, or 24 hours after administration of the composition for treating muscle spasm to induce a second muscle spasm.

In one embodiment, the test comprises determining that a spasm can be induced in the subject by applying the stimulus. For example, the stimulation is transcutaneous electrical stimulation or surface electrical stimulation. In some embodiments, the magnitude of the parameter that induces muscle spasm, e.g., as determined from an EMG curve, relative to the selection of a treatment regimen identifies or classifies the individual, or predicts the individual's response to a particular treatment regimen.

Combination therapy

In certain embodiments, additional therapeutic agents may be administered with the compositions of the invention for use, for example, in the treatment of peripheral nervous system conditions (e.g., peripheral neuropathy), central nervous system conditions, muscle conditions and disorders (e.g., fibromyalgia, muscle cramps and spasms (e.g., nocturnal spasms), painful muscle contractions (e.g., muscle contractions of the head or neck), neuromuscular disorders (e.g., motor neuron disease) or dystonia (e.g., cervical dystonia, blepharospasm, back spasms, or leg spasms due to spinal stenosis)), connective tissue diseases (e.g., degenerative joint disease), throat conditions (e.g., dysphagia or spasmodic dysphonia), tactile sensitivity, electrolyte imbalance and/or vitamin deficiency, respiratory conditions (e.g., asthma), cough, and sarcoidosis. In one embodiment, the candidate therapeutic agent is an agent known in the art for other conditions or disorders, such as a neuromuscular therapeutic agent. When combination therapy is employed, the additional therapeutic agent may be administered as another formulation or may be combined with any of the compositions described herein.

For example, any of the compositions described herein can be used to treat nocturnal cramps. In some embodiments, the composition may be used in combination with a sleep aid. Sleep aids that may be used in combination with the compositions and methods described herein include: antihistamines (e.g., diphenhydramine (diphenhydramine) and antihistaminic (doxylamine)); benzodiazepines (e.g., estazolam (ProSom), flurazepam (dalman), quazepam (Doral), temazepam (restoram), and triazolam (halcinon)); non-benzodiazepine sedative hypnotics (e.g., eszopiclone, Funesta), zaleplon (zalepon, Sonata), and zolpidem (Ambien)); and melatonin receptor agonists hypnotics (e.g., ramelteon, Rozerem). Other sleep aids that may also be used in combination with the compositions and methods described herein include: chamomile, valerian root, kava, lemon balm, passion flower, lavender, hypericum perforatum, melatonin, tryptophan (e.g., L-tryptophan), 5-hydroxytryptophan (5-HTP), catnip, hops, rhodiola rosea, oat straw, lavender, GABA, L-theanine, linden tree, ginseng (e.g., siberian ginseng), honey, nutmeg, wormwood, coltsfoot, rauwolfia, thauma (tamuginelch), veratrum, quassia, tulip, brewer's yeast, inositol, scutellaria, phosphatidylserine, calcium, magnesium, vitamin B6, vitamin B12, and pantothenic acid (B5).

In another embodiment, any of the compositions described herein can be used to treat painful muscle contractions, cluster headaches, or migraine headaches in the head or neck when stretched. In some embodiments, the composition may be used with: analgesics including aspirin, ibuprofen (ibruprofen), acetaminophen (acetaminophen), or naproxen (naproxen); triptans including sumatriptan, rizatriptan, naratriptan; mild sedatives, including butalbital; anti-depressants, including amitriptyline (amitriptyline); dihydroergotamine mesylate (dihydroergotamine mesylate); or ketorolac (ketorolac).

Any of the compositions described herein may also be used to treat focal dystonia. In some embodiments, the composition may be used with: botulinum toxin; anticholinergics, including trihexyphenidyl (trihexyphenidyl) and benztropine (benztropine); gabaergic agents, including benzodiazepines; and dopaminergic agents, including tetrabenazine and levodopa (levodopa).

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

In other embodiments, any of the compositions described herein can also be used in combination with a therapeutic agent for oral-related pain or disorder (e.g., oral lesions, oral ulcers, cold sores, thrush, gingivitis, leukoplakia, halitosis, or dry mouth). In some embodiments, the composition may be used with an antibacterial or antiviral agent to treat or prevent dental caries or caries.

In other embodiments, any of the compositions described herein can also be used in combination with a therapeutic agent for stomach or gastrointestinal related pain or disorder (e.g., dyspepsia, heartburn, colitis, irritable bowel syndrome, constipation, diarrhea, lactose intolerance, gastroesophageal reflux disease, ulcers, nausea, or stomach cramps). In some embodiments, the composition may be combined with an antacid (e.g., simethicone, magaldrate), aluminum salt, calcium salt, sodium salt, magnesium salt, alginic acid) laxative, H₂Antagonists (e.g., ranitidine (ranitidine), famotidine (famotidine), nisatidine (nizatidine), cimetidine (cimetidine)) or proton pump inhibitors (e.g., omeprazole (omeprazole), lansoprazole (lansoprazole), esomeprazole (esomeprazole), dexlansoprazole (dexlansoprazole), rabeprazole (rabeprazole) or pantoprazole (pentoprazole)) are used with an antidiarrheal agent (e.g., bismuth subsalicylate).

In other embodiments, any of the compositions described herein can also be used to treat a disease, disorder, or injury of the peripheral nervous system, such as spasmodic fasciculation syndrome, peripheral neuropathy, carpal tunnel syndrome, or EBV. In some embodiments, the composition may be used to treat spasmodic fasciculation syndrome with: a beta-blocker; analgesics, including ibuprofen and acetaminophen; magnesium; or carbamazepine (carbamazepine). In some embodiments, the composition may be used to treat peripheral neuropathy with: tricyclic antidepressants including amitriptyline (amitriptyline); anti-epileptic therapeutic agents including gabapentin (gabapentin) and sodium valproate (sodium valproate); synthetic cannabinoids, including nabilone; pregabalin (pregabalin); or serotonin-norepinephrine reuptake inhibitors (SNRI), including duloxetine (duloxetine). In some embodiments, the composition may be used with a corticosteroid to treat carpal tunnel syndrome.

Examples of the invention

General procedure

TRP-Stim solution

The solution ("TRP-Stim") administered to the volunteers contained: a base of a 1:1 mixture of water and corn syrup (for viscosity enhancement); 0.075% pepper preparation intended for human use (clear Super solublecaspsium, alsec Inc.); 1% Cinnamon essential oil (Aquaresin cinmamon, KalsecInc) intended for human consumption; and 1.5% Ginger oleoresin intended for human use (Aquaeresin Ginger, Kalsec Inc).

Electromyography (EMG) measurement of spasticity

The method of placing the stimulation electrodes on the Flexor Hallucis Brevis (FHB) or gastrocnemius muscles follows the procedure described by Minetto et al, muscular nerve, 40:535- > 544,2009, the contents of which are incorporated herein by reference in their entirety. The active stimulation electrode (negative electrode) was a 1.25 "circular mesh backed silver patch electrode (Bio-Flex manufactured by Lead-Lok) and was placed so as to cause FHB contraction at the minimum stimulation amplitude. The stimulation reference electrode was a 2 "square patch electrode (Bio-Flex manufactured by Fead-Fok) placed on the opposite side of the foot, for example, under the lateral malleolus. As described by Minetto et al (supra), FHB spasms were induced by delivering pulses using a battery-powered electrical muscle stimulator (EMS-7500, Current Solutions LLC). A series of 180 microsecond biphasic rectangular pulsed voltages were applied at various frequencies to stimulate the muscles. First, using a slow (2Hz) stimulation, the amplitude is adjusted to exceed the critical amplitude by-30% to initiate a strong contraction of the muscle. The muscle is then stimulated by delivering a series of 180 microsecond pulses of this amplitude at various frequencies for 7 seconds. The stimulation delivered by the stimulator includes "ramp up" and "ramp down" periods 1 second before and after the primary 7 second stimulation period, during which the pulse amplitude ramps up to or down from a final value.

It has been shown previously that sensitivity to FHB spasms using similar electrical stimulation protocols is highly reproducible in every body (Minetto et al, muscular nerve 2008,37:90-100,2008) and correlates with sensitivity to "normal muscle spasms" (Miller et al, muscular nerve 2009,39: 364-.

Cramps were quantified by EMG recordings from the abdomen of FHB. Two external EMG recording electrodes (Vermed silverreset) were placed along the abdomen of the FHB. The differential voltage with respect to the third ground electrode placed at the ankle WAs expanded, digitized and stored for calculation using a 1-330-C2+ EMG unit with PhysioFab software (J & J Engineering, Poulsbo, WA). The raw broadband EMG signal (10-400Hz) was processed by calibration and integration to provide the area under the curve (RMS). Seizure duration was quantified by the time required for the RMS EMG to return to an amplitude of 3 standard deviations above the baseline value. This will be well correlated with the duration of the cramp observed by returning to the toe rest position.

Spasm recording of the calf muscle (medial gastrocnemius) was performed using a similar procedure, with the placement of the stimulation and recording electrodes following Minetto et al, muscular nerve 2009,40: 535-. The amplitude of stimulation by a single 180 microsecond biphasic rectangular pulse was adjusted to-30% of the amplitude required for maximum muscle contraction. After a short slow stimulation (2Hz), the stimulation frequency was ramped up to 22-24Hz over-5 seconds and held at this frequency for an additional 5 seconds, after which the stimulation was terminated. This protocol reliably induced 30-90 seconds of cramping.

Activation assay for rat sensory neurons

Methods for monitoring activation of primary sensory neurons isolated from rat trigeminal ganglia followed those disclosed by Park et al (J. Biochem. 2006,281: 17304-17311). Cells isolated from rat trigeminal ganglia were loaded with the fluorescent calcium indicator Fura-2AM (Fura-2-acetoxymethyl ester) and measured for an increase in intracellular calcium reflecting neuronal activation with an increase in Fura-2 fluorescence measured by digital video microscopy fluorimetry with an enhanced CCD camera. Adding the same Capsici fructus extract, Cinnamomi cortex extract and Zingiberis rhizoma extract used in TRP-Stim beverage in balanced salt solution (in mM: 145NaCl, 5KCl, 2 CaCl)₂、1MgCl₂10HEPES and 10 glucose) were applied to the neurons after dilution. The capsicum extract was used at a dilution of 1/800,000, the cinnamon extract was used at a dilution of 1/5,000, and the ginger extract was used at a dilution of 1/12,000. In some experiments, after testing with the extract, the calcium ionophore ionomycin (ionomycin) was added to produce a large amount of calcium ingress as an indicator of the maximum possible signal, thus illustrating the intensity of activation by the highly diluted extract.

Example 1: activation of rat sensory neurons by extracts of Capsicum, Cinnamomum cassia and Zingiber officinale

Figure 1 shows a graph of six sensory neurons isolated from the trigeminal ganglia of rats, illustrating their activation by extracts of capsicum, cinnamon and ginger used in human experiments. Activation was quantified as an increase in intracellular free calcium monitored by a fluorescent calcium indicator. Considering that the concentration of nerve endings present in the oral cavity, esophagus or stomach is expected to be lower than in drinks due to dilution in the mucosa and interstitial fluid, the extract was diluted in extracellular saline (Tyrode's solution) and tested at a lower concentration than used in drinks. All three extracts were able to activate individual neurons when applied at concentrations 50-fold to 15,000-fold lower than those used in beverages. Each trace shows the recordings of different neurons, suggesting that some neurons can be activated by each extract and that the intensity of activation by each extract is different in specific neurons. These records indicate that each agent can act alone to activate some neurons and that the combination of agents can produce a greater portion of neurons with greater activation. In addition, the bottom two records show that when applied in combination, strong synergistic neuronal activation can be produced by the capsicum extract and the zingiber officinale extract.

Example 2: effect of TRP-Stim administration to human subjects

The in vitro data of example 1 shows that each individual component of the TRP-Stim solution is itself capable of activating sensory neurons. In line with this, human experiments showed that the efficacy of a drink with only capsicum (ClearCap capsicum at a dilution of 1/2000) to inhibit spasticity was achieved within 5 minutes.

The following experiments, illustrated by figures 2-8, show that spasticity is alleviated by administering a homogeneous drink composition containing capsicum, cinnamon extract and ginger extract designed to maximize TRP stimulation and wherein physiological effects are monitored by EMG recordings. These experiments demonstrate the utility of using EMG to evaluate individuals to determine the efficacy of a composition to alleviate electrically-induced cramps. The methods presented in this example can also be used in subjects who have been diagnosed or identified as having a disorder associated with muscle spasticity (e.g., a disorder disclosed herein, such as nocturnal spasticity or a neuromuscular disorder, such as multiple sclerosis, spinal cord spasticity, and dystonia).

Fig. 2-8 are graphs of EMG recordings of muscle contractions in seven human volunteers (four females and three males) showing the efficacy of ingesting 50mL of a solution designed to stimulate TRP VI and TRPA1 receptors in the mouth, esophagus, and stomach in preventing and treating spasticity. Muscle spasms are induced (fig. 2-7) or occur spontaneously (fig. 8) by simple stimulation of the toe or calf muscles. After recording cramps in the controls, the individuals consumed 50mL of TRP-Stim solution containing capsaicin and capsaicinoids (TRPV1 agonists), cinnamaldehyde (TRPA1 agonists), and gingerols (TRPA1 and TRPV1 agonists). Following ingestion of the solution, the subject is tested for muscle cramps at a time ranging from 4 minutes to 11 hours following ingestion using the same procedure as in the control.

Eight human volunteers were tested using TRP-Stim drinks. Seven of the eight showed a disappearance or significant reduction of cramps after ingestion of the drink (fig. 2-8). Complete onset of action and duration of 2 in different individuals, usually within 4-15 minutes¹/₂To 4 hours. The eighth subject showed that FHB cramps were not significantly affected by TRP-Stim drinks. Spasticity in this individual has much lower EMG amplitude than other individuals and appears to involve repeated contractions of only a few motor units.

Figure 2 is a graph showing the effect of a TRP-Stim drink on flexor hallucis brevis spasm in individual a. Under control conditions, spasticity was reliably induced by stimulation of the muscle using an electrical muscle stimulator (EMS-7500, CurrentSolutions LLC) placed with external electrodes for FHB stimulation. Using placement on the muscular abdomen and attachment to EMG amplifier (J)&J Engineering I-330C2+), the external electrodes record muscle activity. In the control, muscle spasms were reliably and reproducibly produced using 180 microsecond biphasic pulse stimulation delivered at 18Hz for 5 seconds, which continued activity as evident by EMG after stimulation ceased. After ingestion of the TRP-Stim drink, the cramps are very short after 11 minutes and 20 minutes and 2 after ingestion ¹/₂Essentially absent when tested hourly.

Fig. 3 is a graph showing the effect of a TRP-Stim drink on flexor hallucis brevis spasm in a second subject. Under control conditions, spasms were induced by stimulation at 10Hz for 5 seconds (180 microsecond pulses, amplitude set to-30% above muscle contraction threshold), and longer spasms were induced by increasing the frequency to 12 Hz. In the recordings starting 12 minutes after ingestion of the TRP-Stim drink, stimulation at 10Hz or 12Hz produced substantially no cramps, and increasing the stimulation frequency to 14Hz did not induce cramps. In this subject, a significant reduction in spasticity was still present at the later 4 hours.

Figure 4 is a graph showing the effect of a TRP-Stim drink tested over a longer period of time on flexor hallucis brevis spasms in a third subject. Under control conditions, spasms lasting 58 seconds were induced by stimulation at 18Hz for 5 seconds (180 microsecond pulses, amplitude set to-30% above muscle contraction threshold). After ingestion of the TRP-Stim drink, the duration of cramping decreased to 27 seconds after 8 minutes and to 8 seconds after 15 minutes. The cramps were eliminated after 20 minutes and tested after 2 hours. Reliable spasms were recovered in a test 11 hours after ingestion. After the subject had drunk the 50mL TRP-Stim drink again, the cramps were completely eliminated in the test started after 10 minutes.

Fig. 5 is a graph showing the effect of a TRP-Stim drink on flexor hallucis brevis spasm in a fourth subject. This individual participated in intense exercise (triathlon) four hours earlier and experienced muscle twitching. This subject had an unusual low frequency threshold (8Hz) that induced FHB muscle spasms, and the resulting spasms were unusually long (172 seconds after 8Hz stimulation and 222 seconds after 10Hz stimulation). In tests starting 13 minutes after ingestion of the TRP-Stim drink, spasticity completely disappeared even when the stimulation frequency increased to 12 Hz. The cramps disappeared after 3 hours. After 4 hours, spasms were recovered at an increased frequency threshold (10Hz) and the spasms were shorter compared to the control. After the subject again drunk 50mL of TRP-Stim drink, the cramps were completely eliminated again.

Fig. 6 is a graph showing the effect of a TRP-Stim beverage on gastrocnemius muscle (calf muscle) cramping in a fifth individual. The muscle was stimulated by a protocol that ramps the stimulation frequency from 2Hz to 28Hz (180 microsecond pulses, with amplitude set to-30% above the muscle contraction threshold). After stimulation ceased, the muscle underwent prolonged spasms lasting 59 seconds. In a test 3 minutes after ingestion of 50mL of TRP-Stim, the cramps disappeared.

Fig. 7 is a graph showing the effect of a TRP-Stim beverage on gastrocnemius muscle (calf muscle) cramping in a sixth individual. The muscle was stimulated by a protocol that ramps the stimulation frequency from 2Hz to 24Hz (180 microsecond pulses, with amplitude set to-30% above the muscle contraction threshold). After stimulation ceased, the muscle underwent prolonged spasms lasting 96 seconds. In a test of 4 minutes after ingestion of 50mL of TRP-Stim, the cramps disappeared. In a test performed 40 minutes later, the cramps still disappeared.

Figure 8 is a graph showing the effect of TRP-Stim drinks on FHB muscle cramping in a seventh individual experiencing spontaneous cramping induced by the tight toes. In the control condition, voluntary toe flexion lasting-5 seconds reliably produced FHB cramps lasting 5-8 seconds in different trials. The spasm disappeared ten minutes after the subject ingested 50mL of the TRP-Stim drink.

The methods described in this example can be used to assess a subject having a disorder associated with muscle spasms, such as a subject suffering from nocturnal spasms or who has been diagnosed or identified as having a neuromuscular disease (e.g., multiple sclerosis, spinal cord spasms, or dystonia). For example, the methods described in this example can be used to assess the efficacy of any of the compositions described herein to alleviate an electrically-induced muscle spasm in an individual diagnosed with or identified as having a disorder associated with muscle spasm. In addition, the methods described in this example can also be used to assess and classify individuals diagnosed with or suffering from a disorder associated with muscle spasm.

OTHER EMBODIMENTS

From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein to adapt it to various usages and conditions. Such embodiments are also within the scope of the following claims.

All publications, patent applications, and patents mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent application, or patent was specifically and individually indicated to be incorporated by reference.

Claims

1. A composition formulated for oral administration comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient, wherein the composition is a liquid or a solid, and wherein the composition is formulated for delayed release of the ion channel activator.

2. The composition of claim 1, wherein the composition comprises a plurality of ion channel activators and a pharmaceutically acceptable excipient.

3. The composition of claims 1 and 2, wherein the composition comprises two ion channel activators and a pharmaceutically acceptable excipient.

4. The composition of any one of claims 1-3, wherein the composition comprises an ion channel activator and a plurality of pharmaceutically acceptable excipients.

5. The composition of any one of claims 1-4, wherein the pharmaceutically acceptable excipient comprises a delayed release agent of an ion channel activator such that, when orally administered to a subject, the ion channel activator is not substantially released in the stomach of the subject.

6. The composition of claim 5, wherein the delayed release agent is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and mixtures thereof.

7. The composition of any one of claims 5-76, wherein the pharmaceutically acceptable excipient comprises a coating.

8. The composition of claim 7, wherein the coating is selected from the group consisting of: enteric coatings, sugar coatings, and polymeric coatings.

9. The composition of any one of claims 1-8, wherein the ion channel activator is embedded in biodegradable microparticles or nanoparticles for sustained release.

10. The composition of any one of claims 1-9, wherein the composition further comprises a formulation base.

11. The composition of claim 10, wherein the formulation base comprises an oil and a lipophilic additive.

12. The composition of claim 12, wherein the oil is selected from the group consisting of: vegetable oil, mineral oil, soybean oil, sunflower seed oil, corn oil, olive oil, nut oil and liquid paraffin.

13. The composition of claim 12, wherein the lipophilic additive is selected from the group consisting of: polyethylene glycol, fatty acid monoglycerides, diglycerides or triglycerides, palmitic acid, stearic acid, behenic acid, polyethylene glycol fatty acid esters, candelilla wax, carnauba wax, polyethylene oxide wax and petroleum wax.

14. The composition of any one of claims 1 to 13, wherein the composition further comprises a coloring agent, a dissolving agent, a flavoring agent, a sweetener, a viscosity modifier, an electrolyte, a vitamin, a mineral, an antioxidant, or a preservative.

15. The composition of any one of claims 1-14, wherein the composition is formulated as a liquid.

16. The composition of claim 15, wherein the liquid is selected from the group consisting of: emulsions, microemulsions, solutions, suspensions, syrups, drops, sprays and elixirs.

17. The composition of any one of claims 1-14, wherein the composition is formulated as a solid.

18. The composition of claim 17, wherein the solid is selected from the group consisting of: tablets, capsules, powders, crystals, pastes, gels, lozenges, gums, candies, chewable tablets, foods, dissolving strips, films, and semi-solid formulations.

19. The composition of claim 18, wherein the capsule is a hard or soft capsule.

20. The composition of any one of claims 1-19, wherein the ion channel activator comprises a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof.

21. The composition of claim 20, wherein said TRPV1 channel activator is a capsaicinoid (capsaicinoid), a capsicum ester (capsinoid), oleoylethanolamide, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsaicinoid (capsiate), a 1-monoacylglycerol having C18 and C20 unsaturation and C8-C12 saturated fatty acids, a 2-monoacylglycerol having C18 and C20 unsaturated fatty acids, mioga dialdehyde (miogladiol), mioga trifolia (miogrital), polygodial (polygodial), a terpenoid having α -unsaturated 1, 4-dialdehyde moiety, sanshonol (sanshool), evodiamine (evodine), acesulfame potassium (acesulfame-K), cyclamate (cyclamate), CuSO₄、ZnSO₄、FeSO₄Arfanil (arvanil), arachidonic acid ethanolamide (anandamide), N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynonenal, 1- [2- (1-adamantyl) ethyl]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea or gingerol (gingerol).

22. The composition of claim 21, wherein the capsaicinoid is selected from the group consisting of: capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, nonivamide (nonivamide), pseudocapsaicin, resiniferatoxin (resiniferatoxin), tinyatoxin (tinyatoxin), capsaicinoid, dihydrocapsaicinoid, nordihydrocapsaicinoid, norcapsaicin, coniferyl capsaicinoid (capsicinate), dihydroconiferyl capsaicinoid and other coniferyl esters, capsaicinoid analogs (capsicinoninids), and 3-hydroxyacetanilide.

23. The composition of claim 20, wherein the TRPA1 channel activator is allyl isothiocyanate, gingerol, cinnamaldehyde (cinnamyl), acrolein (acrolein), farnesyl thiosalicylic acid, Δ ∑ a₉-tetrahydrocannabinol (Δ)₉-tetrahydrocanabinol), eugenol (eugenol), shogaol (shogaol), behenyl alcohol, methyl salicylate, allicin (allicin), diallyl sulfide, diallyl disulfide, diallyl trisulfide or farnesyl thioacetic acid.

24. The composition of claim 20, wherein the ASIC channel activator comprises acetic acid, phosphoric acid, citric acid, malic acid, succinic acid, lactic acid, tartaric acid, fumaric acid, or ascorbic acid.

25. The composition of any one of claims 20 to 24, wherein said TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combination thereof is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).

26. The composition of any one of claims 1-25, wherein the composition is capable of reducing gastrointestinal side effects.

27. A composition formulated for oral administration to a subject, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient, wherein upon administration, the residence time of the ion channel activator in the oral cavity of the subject is greater than about 5 seconds.

28. The composition of claim 27, wherein the composition comprises a plurality of ion channel activators.

29. The composition of any one of claims 27-28, wherein the composition comprises two ion channel activators.

30. The composition of any one of claims 27-29, wherein the composition comprises an ion channel activator and a plurality of pharmaceutically acceptable excipients.

31. The composition of any one of claims 27-30, wherein the residence time of the ion channel activator in the oral cavity of a subject is greater than about 60 seconds.

32. The composition of any one of claims 27-31, wherein the composition further comprises a formulation base.

33. The composition of claim 32, wherein the formulation base comprises an oil and a lipophilic additive.

34. The composition of claim 33, wherein the oil is selected from the group consisting of: vegetable oil, mineral oil, soybean oil, sunflower seed oil, corn oil, olive oil, nut oil and liquid paraffin.

35. The composition of claim 33, wherein the lipophilic additive is selected from the group consisting of: polyethylene glycol, fatty acid monoglycerides, diglycerides or triglycerides, palmitic acid, stearic acid, behenic acid, polyethylene glycol fatty acid esters, candelilla wax, carnauba wax, polyethylene oxide wax and petroleum wax.

36. The composition of any one of claims 27 to 35, wherein the composition further comprises a coloring agent, a dissolving agent, a flavoring agent, a sweetener, a viscosity modifier, an electrolyte, a vitamin, a mineral, an antioxidant, or a preservative.

37. The composition of any one of claims 27-36, wherein the composition is formulated as a liquid.

38. The composition of claim 37, wherein the liquid is selected from the group consisting of: emulsions, microemulsions, solutions, suspensions, syrups, drops, sprays and elixirs.

39. The composition of any one of claims 27-36, wherein the composition is formulated as a solid.

40. The composition of claim 39, wherein the solid is selected from the group consisting of: tablets, capsules, powders, crystals, pastes, gels, lozenges, gums, candies, chewable tablets, foods, dissolving strips, films, and semi-solid formulations.

41. The composition of claim 40, wherein the capsule is a hard or soft capsule.

42. The composition of any one of claims 27-41, wherein the ion channel activator comprises a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof.

43. The composition of claim 42, wherein said TRPV1 channel activator is a capsaicinoid, a capsicester, an oleoylethanolamide, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsaicinoid ester, a 1-monoacylglycerol having C18 and C20 unsaturation and C8-C12 saturated fatty acids, a 2-monoacylglycerol having C18 and C20 unsaturated fatty acids, mioga dialdehyde, polygodial dialdehyde, a terpenoid having α -unsaturated 1, 4-dialdehyde moiety, sanshool, evodiamine, acesulfame potassium, a cyclamate, CuSO₄、ZnSO₄、FeSO₄Avanib, arachidonic acid ethanolamide, N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynonenal, 1- [2- (1-adamantyl) ethyl]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea or gingerol.

44. The composition of claim 43, wherein said capsaicinoid is selected from the group consisting of: capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, nonivamide, pseudocapsaicin, resiniferatoxin, tintoxin, capsaicinoids, dihydrocapsaicin esters, nordihydrocapsaicin esters, norcapsaicin, coniferyl capsaicinoids, dihydrocapsaicin coniferyl esters and other coniferyl esters, capsaicinoid analogs, and 3-hydroxyacetanilide.

45. The composition of claim 42, wherein the TRPA1 channel activator is allyl isothiocyanate, gingerol, cinnamaldehyde, acrolein, farnesyl thiosalicylic acid, Δ ™₉-tetrahydrocannabinol, eugenol, shogaol, sanshool, methyl salicylate, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide or farnesylthioacetic acid.

46. The composition of claim 42, wherein the ASIC channel activator comprises acetic acid, phosphoric acid, citric acid, malic acid, succinic acid, lactic acid, tartaric acid, fumaric acid, or ascorbic acid.

47. The composition of any one of claims 27 to 46, wherein said TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combination thereof is present at about 0.001% to about 10% (w/w), or about 0.001% to about 10% (v/v).

48. The composition of any one of claims 27 to 47, wherein the ion channel activator is ingested by the subject.

49. The composition of any one of claims 27-48, wherein the ion channel activator is contained in the oral cavity by the subject.

50. The composition of any one of claims 27 to 49, wherein the ion channel activator is dissolved in the oral cavity of the subject or chewed by the subject prior to swallowing.

51. A composition for use in a method of treating painful muscle contractions in a subject in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

52. The composition according to claim 51, wherein the painful muscle contraction is a muscle contraction of the head or neck.

53. The composition of any one of claims 51-52, wherein the painful muscle contraction is associated with a tension headache, a cluster headache, or a migraine.

54. A composition for use in a method of treating tactile sensitivity in an individual in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

55. The composition of claim 54, wherein the tactile sensitivity is associated with autism, dysmotility, neuropathic pain, anxiety, a toxic bite, or a toxic bite.

56. The composition of claim 55, wherein the anxiety disorder is selected from the group consisting of: panic disorder, Obsessive Compulsive Disorder (OCD), post-traumatic stress disorder (PTSD), social anxiety disorder, phobia, and Generalized Anxiety Disorder (GAD).

57. A composition for use in a method of treating dystonia in a subject in need thereof, said composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

58. The composition of claim 57, wherein the dystonia is selected from the group consisting of: focal dystonia, blepharospasm, cervical dystonia, cranial dystonia, laryngeal dystonia and hand dystonia.

59. A composition for use in a method of treating a Peripheral Nervous System (PNS) condition in a subject in need thereof, the composition comprising an effective amount for the subject of an ion channel activator and a pharmaceutically acceptable excipient.

60. The composition of claim 59, wherein the PNS condition is selected from the group consisting of: spasmodic fasciculation Syndrome, Isaacs' Syndrome, or neuromuscular rigidity, peripheral neuropathy, carpal tunnel Syndrome, and Epstein-Barr virus (Epstein-Barr virus) infections.

61. A composition for use in a method of treating a laryngeal condition in a subject in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

62. The composition of claim 61, wherein the laryngeal condition is associated with chemical injury, cancer, surgical injury, or a pathogen infection.

63. The composition of any one of claims 61-62, wherein the laryngeal disease is selected from the group consisting of: acid reflux, laryngeal spasm, dysphagia, and spasmodic dysphonia.

64. A composition for use in a method of treating a condition associated with electrolyte imbalance or vitamin deficiency in a subject in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

65. The composition of claim 64, wherein the condition is selected from the group consisting of: hyponatremia, hypocalcemia, hypomagnesemia, nephropathy, rickets, calcium or magnesium deficiency, thiamine deficiency, hypoparathyroidism, medullary cystic disease and adrenocortical carcinoma.

66. A composition for use in a method of treating a Central Nervous System (CNS) condition in an individual in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

67. The composition of claim 68, wherein the CNS condition is associated with a tumor.

68. The composition of any one of claims 66-67, wherein the CNS condition is selected from the group consisting of: multiple sclerosis, cerebral palsy, stroke, motor neuron disease, spinal cord injury and stenosis.

69. A composition for use in a method of treating a muscle condition or disorder in a subject in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

70. The composition of claim 69, wherein the muscle condition or disorder is associated with muscle pain, muscle cramping, muscle spasm, fasciculation, or any combination thereof.

71. The composition of any one of claims 69-70, wherein the muscle condition or disorder is a neuromuscular disorder.

72. The composition of any one of claims 69-71, wherein the muscle condition or disorder is muscle pain, muscle cramping, spasticity, or fasciculation associated with a motor neuron disease.

73. The composition of claim 72, wherein the motor neuron disease is selected from the group consisting of: amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar paralysis, pseudobulbar paralysis, spinal muscular atrophy, progressive spinal bulbar muscular atrophy, and post polio syndrome.

74. The composition of any one of claims 69-73, wherein the muscle condition or disorder is associated with treatment of the subject with dialysis, diuretics, beta-blockers, statins, fibrates, beta 2-agonists, ACE inhibitors, ARBs, antipsychotics, or any combination thereof.

75. The composition of claim 74, wherein the muscle condition or disorder is associated with treatment of the subject with a statin and a fibrate.

76. The composition of any one of claims 69-75, wherein the muscle condition or disorder occurs in one or more skeletal muscles.

77. The composition of any one of claims 69-76, wherein the muscle condition or disorder is refractory to approved treatment.

78. The composition of claim 77, wherein the approved treatment is botulinum (botox), cyclobenzaprine (cyclopenaprine), oxyphenamine (orphenadrine), baclofen (baclofen), or any combination thereof.

79. The composition of any one of claims 69-78, wherein the muscle condition or disorder involves muscle claudication pain.

80. The composition of claim 79, wherein said muscle claudication pain is associated with inactivity, immobilization, economy class syndrome, paralysis, peripheral arterial disease, or immobilization.

81. A composition for use in a method of treating a respiratory condition in a subject in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

82. The composition of claim 78, wherein the respiratory condition comprises asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pneumonia, cystic fibrosis, pleural cavity disease, influenza, or cold.

83. A composition for use in a method of treating cough in a subject in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

84. The composition of claim 83, wherein the cough results from a respiratory pathology, exposure to an allergen or chemical irritant, or inflammation.

85. A composition for use in a method of treating sarcoidosis in an individual in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

86. A composition for use in a method of treating connective tissue disease in an individual in need thereof, the composition comprising an effective amount of an ion channel activator and a pharmaceutically acceptable excipient.

87. The composition of claim 86, wherein the connective tissue disease is selected from the group consisting of: Ehlers-Danlos syndrome, epidermolysis bullosa, Marfang's syndrome, osteogenesis imperfecta, arthritis, scleroderma, Sjogren's syndromeLupus, vasculitis, mixed connective tissue disease, cellulitis, polymyositis, and dermatomyositis.

88. The composition of claim 87, wherein the arthritis is rheumatoid arthritis, osteoarthritis, gout, or psoriatic arthritis, or wherein the vasculitis is Wegener's granulomatosis or Charger-Schtelus Syndrome (Churg-Strauss Syndrome).

89. The composition of any one of claims 51 to 88, wherein said TRPV1 channel activator is a capsaicinoid, a capsicum ester, oleoylethanolamide, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsaicinoid ester, 1-monoacylglycerol having C18 and C20 unsaturation and C8-C12 saturated fatty acids, 2-monoacylglycerol having C18 and C20 unsaturated fatty acids, mioga dialdehyde, polygodial, terpenoid having a α -unsaturated 1, 4-dialdehyde moiety, xanthoxylol, evodiamine, acesulfame potassium, cyclamate, CuSO ₄、ZnSO₄、FeSO₄Avanib, arachidonic acid ethanolamide, N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynonenal, 1- [2- (1-adamantyl) ethyl]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea or gingerol.

90. The composition of any one of claims 51-88, wherein the TRPA1 channel activator is allyl isothiocyanate, gingerol, cinnamaldehyde, acrolein, farnesylthiosalicylic acid, Δ ™₉-tetrahydrocannabinol, eugenol, shogaol, sanshool, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide or farnesylthioacetic acid.

91. The composition of any one of claims 51-88, wherein the ASIC channel activator comprises acetic acid, phosphoric acid, citric acid, malic acid, succinic acid, lactic acid, tartaric acid, fumaric acid, or ascorbic acid.

92. The composition of any one of claims 51-88, wherein the composition is formulated as a liquid.

93. The composition of claim 93, wherein the liquid is selected from the group consisting of: emulsions, microemulsions, solutions, suspensions, syrups, drops, sprays and elixirs.

94. The composition of any one of claims 51-88, wherein the composition is formulated as a solid.

95. The composition of claim 94, wherein the solid is selected from the group consisting of: tablets, capsules, powders, crystals, pastes, gels, lozenges, gums, candies, chewable tablets, foods, dissolving strips, films, and semi-solid formulations.

96. The composition of claim 95, wherein said capsule is a hard or soft capsule.

97. A composition for use in a method of treating an individual for an undesired or abnormal muscle contraction or an absence of normal muscle contraction comprising:

obtaining knowledge of test results regarding efficacy of administering a test aliquot of a composition comprising an ion channel activator to alleviate test muscle contraction in the subject;

administering a composition comprising an ion channel activator in an amount sufficient to alleviate an undesired or abnormal muscle contraction or the absence of normal muscle contraction in the subject.

98. The composition of claim 97, wherein the muscle contraction comprises a muscle spasm, muscle cramp, dystonia, or fasciculation.

99. The composition of any one of claims 97-98, wherein the muscle contraction occurs in skeletal or smooth muscle.

100. The composition of claim 97, wherein the test muscle contraction is a test muscle spasm or a test muscle cramp.

101. The composition of claim 97, wherein the subject has a central nervous system disorder or injury.

102. The composition of claim 97, wherein the subject has been diagnosed with or identified as having multiple sclerosis.

103. The composition of claim 97, wherein the subject has been diagnosed with or identified as having dystonia.

104. The composition of claim 97, wherein the subject has been diagnosed with or identified as having spinal cord spasm.

105. The composition of claim 97, wherein the subject has been diagnosed with or identified as having a disorder associated with muscle spasm, muscle pain, muscle cramping, spasticity, or fasciculation.

106. The composition of claim 97, comprising directly acquiring the knowledge.

107. The composition of claim 97, further comprising performing the test.

108. The composition of claim 97, wherein the muscle contraction selected, treated, or diagnosed comprises contraction of a muscle other than the muscle contracted in the test muscle contraction.

109. The composition of claim 97, wherein said test muscle contraction comprises a foot muscle contraction and said muscle spasm comprises a spasm of a muscle other than foot.

110. The composition of claim 97, wherein the muscle contraction is not induced by an applied electrical stimulus.

111. The composition of claim 97, wherein the muscle contraction is nocturnal cramps.

112. The composition of claim 97, wherein the muscle contraction is associated with multiple sclerosis.

113. The composition of claim 97, wherein the muscle contraction is associated with spinal cord spasm.

114. The composition of claim 97, wherein the muscle contraction is associated with dystonia.

115. The composition of claim 97, wherein the test comprises inducing the test muscle spasm by application of electrical stimulation.

116. The composition of claim 97, wherein the testing comprises determining muscle contraction that can be induced in an individual by application of electrical stimulation.

117. The composition of claim 97, wherein the test comprises:

a) administering to the subject the test aliquot of the composition;

b) Inducing a test muscle contraction; and

c) evaluating the effect of the composition administered to the test aliquot on the test muscle contraction.

118. The composition of claim 117, wherein step a is performed before step b.

119. The composition of claim 117, wherein step a is performed after step b.

120. The composition of any one of claims 97-119, wherein the ion channel activator comprises a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or a combination thereof.

121. The composition of claim 120, wherein said TRPV1 channel activator is a capsaicinoid, a capsicester, oleoylethanolamide, N-oleoyl dopamine, 3-methyl-N-oleoyl dopamine, oleamide, capsaicinoid ester, having C18 and C20 unsaturation and C181-monoacylglycerol of 8-C12 saturated fatty acid, 2-monoacylglycerol with C18 and C20 unsaturated fatty acid, mioga ginger dialdehyde, mioga ginger trialdehyde, polygodial, terpenoid with α -unsaturated 1, 4-dialdehyde part, sanshool, evodiamine, acesulfame potassium, cyclamate, CuSO ₄、ZnSO₄、FeSO₄Avanib, arachidonic acid ethanolamide, N-arachidoyl-dopamine, flufenamic acid dopamine, fenamic acid dopamine amide, 4-hydroxynonenal, 1- [2- (1-adamantyl) ethyl]-1-pentyl-3- [3- (4-pyridyl) propyl group]Urea or gingerol.

122. The composition of claim 120, wherein the TRPA1 channel activator is allyl isothiocyanate, gingerol, cinnamaldehyde, acrolein, farnesyl thiosalicylic acid, Δ ∑ a₉-tetrahydrocannabinol, eugenol, shogaol, sanshool, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide or farnesylthioacetic acid.

123. The composition of claim 120, wherein the ASIC channel activator comprises acetic acid, phosphoric acid, citric acid, malic acid, succinic acid, lactic acid, tartaric acid, fumaric acid, or ascorbic acid.

124. The composition of claim 120, wherein said TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combination thereof is present at about 0.001% to about 10% (w/w) or about 0.001% to about 10% (v/v).