U.S. patent application number 16/727508 was filed with the patent office on 2020-12-03 for methods of treating muscle cramping and related compositions.
The applicant listed for this patent is Cliff-Cartwright Corporation. Invention is credited to Bruce P. Bean, Donald MacKinnon, Roderick MacKinnon.
Application Number | 20200375925 16/727508 |
Document ID | / |
Family ID | 1000005021363 |
Filed Date | 2020-12-03 |
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United States Patent
Application |
20200375925 |
Kind Code |
A1 |
Bean; Bruce P. ; et
al. |
December 3, 2020 |
METHODS OF TREATING MUSCLE CRAMPING AND RELATED COMPOSITIONS
Abstract
Described herein are compositions comprising capsaicin and
methods of treating muscle cramping in a subject, comprising orally
administering to the subject a composition comprising capsaicin and
an excipient.
Inventors: |
Bean; Bruce P.; (Waban,
MA) ; MacKinnon; Donald; (New York, NY) ;
MacKinnon; Roderick; (New York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cliff-Cartwright Corporation |
Wellesley Hills |
MA |
US |
|
|
Family ID: |
1000005021363 |
Appl. No.: |
16/727508 |
Filed: |
December 26, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15241986 |
Aug 19, 2016 |
10568853 |
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16727508 |
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14450384 |
Aug 4, 2014 |
9937135 |
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15241986 |
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13191941 |
Jul 27, 2011 |
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14450384 |
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61368059 |
Jul 27, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/06 20130101; A61K
31/19 20130101; A61K 31/12 20130101; A23L 2/52 20130101; A61K
9/0095 20130101; A61K 36/9068 20130101; A61K 33/42 20130101; A61K
31/194 20130101; A61K 36/906 20130101; A61K 9/08 20130101; A23V
2002/00 20130101; A61K 31/165 20130101; A61K 9/0053 20130101; A61K
31/375 20130101; A61K 36/81 20130101; A61K 36/54 20130101; A61K
31/16 20130101 |
International
Class: |
A61K 31/165 20060101
A61K031/165; A61K 9/00 20060101 A61K009/00; A61K 9/06 20060101
A61K009/06; A61K 9/08 20060101 A61K009/08; A61K 31/12 20060101
A61K031/12; A61K 31/16 20060101 A61K031/16; A61K 31/19 20060101
A61K031/19; A61K 31/194 20060101 A61K031/194; A61K 31/375 20060101
A61K031/375; A61K 33/42 20060101 A61K033/42; A61K 36/906 20060101
A61K036/906; A23L 2/52 20060101 A23L002/52; A61K 36/54 20060101
A61K036/54; A61K 36/81 20060101 A61K036/81; A61K 36/9068 20060101
A61K036/9068 |
Claims
1-74. (canceled)
75. A method of treating a menstrual cramp in a subject in need
thereof, the method comprising orally administering to the subject
a liquid composition comprising capsaicinoid, cinnamaldehyde, a
gingerol, and an excipient, wherein the liquid composition
comprises 0.001% to 1% weight/weight (w/w) capsaicinoids per weight
of the liquid composition or 0.0001-0.01 mgs of total
capsaicinoids/mL of the liquid composition and a total of 0.001% to
1% weight/weight (w/w) of a gingerol per weight of the liquid
composition.
76. The method of claim 75, wherein the liquid formulation is
administered prior to, during, or after the menstrual cramp.
77. The method of claim 75, wherein the liquid formulation
comprises a beverage or a spray.
78. The method of claim 75, wherein the liquid formulation
comprises a beverage.
79. The method of claim 75, wherein the capsaicinoid comprises
capsaicin.
80. The method of claim 75, wherein the liquid composition further
comprises an electrolyte.
81. The method of claim 75, wherein the excipient comprises a
disintegrant, a binder, a surfactant, an emulsifier, a viscosity
modifier, a lubricant, a sweetener, a pH-adjusting agent, a
preservative, a flavoring agent, a coloring agent, or an
antioxidant.
82. The method of claim 75, wherein the excipient is selected from
gellan gum, carob bean gum, locust bean gum, carrageenan,
alginates, agar, guar gum, xanthan gum, carboxymethyl cellulose,
clear starch, pectin, gelatin, cornstarch, katakuri starch, potato
starch, and gum arabic.
83. The method of claim 75, wherein the excipient comprises a
sweetener selected from high fructose corn syrup, mannose, maltose,
glucose polymers, sucrose, glucose, dextrose, lactose, galactose,
fructose, polysaccharides, rice syrup, honey, saccharin,
cyclamates, acetosulfam, sorbitol, sucralose, xylitol, erythritol,
Stevia extract, L-aspartyl-L-phenyl-alanine ester,
L-aspartyl-D-alanine alkyl amides,
L-aspartyl-L-1-hydroxymethylalkaneamide, and
L-aspartyl-1-hydroxyethylalkaneamide.
84. The method of claim 75, wherein the excipient comprises a
pH-adjusting agent selected from hydrochloric acid, citric acid,
sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide,
and sodium carbonate.
85. The method of claim 75, wherein the excipient comprises a
preservative selected from sorbic acid, benzoic acid, sodium
benzoate, calcium benzoate, potassium benzoate, potassium sorbate,
calcium sorbate, and sodium sorbate.
86. The method of claim 75, wherein the excipient comprises a
flavoring agent selected from almond oil, amaretto oil, anethole,
anise oil, benzaldehyde, blackberry, black walnut oil, blueberry,
caraway, caraway oil, cardamom oil, cardamom seed, cherry juice,
cherry syrup, cinnamon, cinnamon oil, cinnamon water, citric acid,
citric acid syrup, clove oil, cocoa, coriander oil, dextrose,
eriodictyon, ethyl acetate, ethyl vanillin, fennel oil, ginger,
glucose, glycerin, glycyrrhiza, grape, honey, lavender oil, lemon
oil, lime, mannitol, methyl salicylate, myristica oil, orange oil,
orange peel, orange syrup, peppermint, peppermint oil, peppermint
water, phenylethyl alcohol, pineapple, raspberry juice, raspberry
syrup, rosemary oil, rose oil, rose water, sarsaparilla syrup,
sorbitol, spearmint, spearmint oil, strawberry, sucrose, thyme oil,
tolu balsam, vanilla, vanillin, and wild cherry syrup.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. application Ser. No.
14/450,384, filed Aug. 4, 2014, which is a continuation of U.S.
application Ser. No. 13/191,941, filed Jul. 27, 2011, now
abandoned, which claims the benefit of U.S. Provisional Application
No. 61/368,059, filed Jul. 27, 2010. The contents of each of the
foregoing applications are hereby incorporated by reference in
their entirety.
BACKGROUND OF THE INVENTION
[0002] In general, the invention relates to methods and
compositions for preventing, treating or ameliorating muscle
cramping and/or accelerating nerve-muscle recovery from exercise
fatigue.
[0003] Muscle cramps, the involuntary and forceful contraction of
muscles, are often painful and can last for a prolonged period of
time. Muscle contractions and cramping can be triggered by exercise
and can also occur spontaneously (e.g., nocturnal or night cramps).
The underlying physiological mechanism of muscle cramping is
unknown. Recent understanding has led to the hypothesis that
cramping results from excessive electrical firing of the neurons
(motor neurons) that project from the spinal cord and trigger
contraction of skeletal muscles (Schwellnus, Br J Sports Med.
43:401-8, 2009; Miller et al, Med Sci Sports Exerc. 42:953-61,
2010). Recovery from strenuous exercise can be associated with
neuromuscular irritability, associated with neuromuscular fatigue,
that may or may not be associated with the development of frank
cramps. Few treatments and therapeutic regimens are available to
alleviate this neuromuscular irritability.
[0004] There exists a need in the art for improved methods and
compositions for preventing, treating, and ameliorating muscle
cramping and/or accelerating nerve-muscle recovery from exercise
fatigue by reducing neuromuscular irritability. As shown herein,
compositions that include activators of TRP and ASIC channels may
be useful to prevent, treat, or ameliorate muscle cramping and/or
accelerate nerve-muscle from, e.g., exercise fatigue. Further,
these compositions can be useful in treating neuromuscular
irritability that may or may not be associated with the development
of frank cramps.
SUMMARY OF THE INVENTION
[0005] The present invention is directed to the prevention,
treatment or amelioration of muscle cramps and/or accelerating
nerve-muscle recovery from exercise fatigue using a composition
with an activator of TRPV1 channels, an activator of TRPA1
channels, and/or an activator of ASIC channels.
[0006] In a first aspect, the invention features a method for
treating muscle cramps in a subject in need thereof (e.g., a
human), the method including the step of administering to the
subject a composition that includes an effective amount of one or
more TRPV1 channel activators, TRPA1 channel activators, or ASIC
channel activators, or any combination thereof.
[0007] The invention also features a method for treating
musculoskeletal irritability in a subject in need thereof. The
method includes administering to the subject a composition that
includes an effective amount of one or more TRPV1 channel
activators, TRPA1 channel activators, or ASIC channel activators,
or any combination thereof.
[0008] In still another aspect, the invention features a method for
improving muscle recovery (e.g., muscle recovery following
exercise) in a subject in need thereof, where the method includes
administering to the subject a composition that includes an
effective amount of one or more TRPV1 channel activators, TRPA1
channel activators, or ASIC channel activators, or any combination
thereof.
[0009] In any of the foregoing methods, the composition can be,
e.g., an oral formulation (e.g., a liquid, beverage, gel,
semi-solid, frozen liquid, lozenge, hard candy, dissolving strip,
or spray).
[0010] In certain embodiments of any of the methods described
herein, the composition is administered to the subject prior to
exercise, during exercise, or following exercise (e.g., within
0-120 minutes prior to exercise, or within 0-360 minutes, 0-15
minutes, or 2-6 hours following exercise.
[0011] Muscle cramps that can be treated or prevented using the
methods and compositions described herein include, e.g., muscle
cramps resulting from exercise, nocturnal cramps, and menstrual
cramps.
[0012] In particular embodiments of any of the methods described
herein, the composition includes an effective amount of two or
three different TRP channel activators independently selected
from:
[0013] (a) capsaicin or other capsaicinoids;
[0014] (b) cinnamaldehyde or cinnamon oil; and
[0015] (c) gingerols.
[0016] In other embodiments of any of the methods described herein,
each channel activator, independently, includes between 0.001% to
1% weight percent of a composition that is a solid, semi-solid,
gel, or chewing gum, or 0.001 to 1% (v/v) of a composition that is
a liquid, beverage, or spray.
[0017] In still other embodiments of any of the methods described
herein, the composition is any of the compositions described
herein.
[0018] The invention also features a composition formulated for
oral ingestion by a subject. The composition includes an effective
amount of one or more channel activators (e.g., one or more
substantially pure channel activators) selected from TRPV1 channel
activators, TRPA1 channel activators, and ASIC channel activators.
Desirably, the composition is a liquid, beverage, gel, semi-solid,
frozen liquid, lozenge, hard candy, dissolving strip, or spray.
[0019] Desirably, the channel activator is capable of activation of
a channel in a gastroesophogeal neuron when administered to a
subject
[0020] The channel activators can be substantially pure or not
substantially pure (e.g., part of a crude extract).
[0021] In certain embodiments, the channel activators are capable
of activation of a channel in a gastroesophogeal neuron when
administered to a subject.
[0022] The TRPV1 channel activator can be is a capsaicinoid (e.g.,
capsaicin). In one example embodiments, the composition contains
capsaicin but is substantially free of dihydrocapsaicin.
[0023] The TRPV1 channel activator can also be, e.g.,
oleoylethanolamide, N-oleoyldopamine, 3-methyl-N-oleoyldopamine,
oleamide, capsiate, a 1-monoacylglycerol having C18 and C20
unsaturated and C8-C12 saturated fatty acid, a 2-monoacylglycerol
having C18 and C20 unsaturated fatty acids, miogadial, miogatrial,
polygodial, a terpenoid with an alpha,beta-unsaturated
1,4-dialdehyde moiety, sanshool, evodiamine, acesulfame-K,
cyclamate, CuSO.sub.4, ZnSO.sub.4, FeSO.sub.4, arvanil, anandamide,
N-arachidonoyl-dopamine, flufenamic acid dopamide, a dopamine amide
of fenamic acid, 4-hydroxynonenal, or
1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea, or
gingerol.
[0024] Suitable TRPA1 channel activators include, e.g., allyl
isothiocyanate, gingerols, cinnamaldehyde, acrolein, farnesyl
thiosalicylic acid, A-tetrahydrocannabinol, eugenol, shogaols,
nicotine, nicotine derivatives or analogs, methyl salicylate,
cinnamaldehyde, allicin, diallyl sulfide, diallyl disulfide,
diallyl trisulfide, sanshools, and farnesyl thioacetic acid.
[0025] Each channel activator can be present, e.g., between 0.001%
to 1% (w/w) or 0.001 to 1% (v/v) of a composition.
[0026] In certain embodiments, the composition includes no more
than one TRPV1 channel activator, TRPA1 channel activator, or ASIC
channel activator. In still other embodiments, the composition
includes a TRPV1 channel activator and a TRPA1 channel activator
(e.g., a substantially pure TRPA1 channel activator and/or a
substantially pure TRPV1 channel activator). In yet other
embodiments, the composition includes no more than one TRPV1
channel activator and no more than one TRPA1 channel activator. And
in still other embodiments, the composition includes a second TRPV1
channel activator and/or a second TRPA1 channel activator.
[0027] The composition includes can include an effective amount of
an ASIC channel activator (e.g., a substantially pure ASIC channel
activator). In some embodiments, the ASIC channel activator (e.g.,
a substantially pure ASIC channel activator) is capable of
activation of an ASIC channel in a gastroesophogeal neuron when
administered to a subject.
[0028] In certain embodiments, the ASIC channel activator is an
acidulant that is acetic acid. In further embodiments, the
composition is a liquid or beverage that has an acetic acid
concentration ranging from 0 M to 0.1 M (e.g., from 0 M to 0.001
M). In other embodiments, the ASIC channel activator is an
acidulant selected from phosphoric acid, citric acid, malic acid,
succinic acid, tartaric acid, fumaric acid, and ascorbic acid.
[0029] The invention also features a composition that includes an
effective amount of two or three different TRP channel activators
independently selected from capsaicin or another capsaicinoid;
cinnamaldehyde or cinnamon oil; and gingerols, where the
composition is an oral formulation that is a liquid, beverage, gel,
solid, semi-solid, chewing gum, or spray.
[0030] In certain embodiments, the composition includes an
effective amount of two or three different TRP channel activators
independently selected from: capsicum; cinnamon volatile oil; and
ginger oleoresin. For example, the the composition can include each
of the components.
[0031] In some embodiments the capsaicinoid is present in 0.001% to
1% (w/w) or 0.001% to 1% (v/v); and/or the cinnamaldehyde or
cinnamon oil is present in 0.001% to 10% (w/w) or 0.001% to 10%
(v/v); and/or the gingerols are present in 0.001% to 10% (w/w) or
0.001% to 10% (v/v).
[0032] In one example, the composition is a beverage that
optionally includes a sweetener.
[0033] A composition of the invention can also include an acidulant
selected from acetic acid, phosphoric acid, citric acid, malic
acid, succinic acid, tartaric acid, fumaric acid, acetic acid, and
ascorbic acid.
[0034] The composition can also include a potassium salt at a
concentration of between about 0.02% and about 7% by weight based
on total volume of the liquid, beverage, or gel.
[0035] The composition can be a liquid, beverage, or gel that also
includes a viscosity modifier, such as collagen, gellan gum,
carbohydrate gel-forming polymers, carob bean gum, locust bean gum,
carrageenan, alginic acid, sodium alginate, potassium alginate,
ammonium alginate, calcium alginate, agar, guar gum, xanthan gum,
carboxymethyl cellulose, clear starch, pectin, gelatin, arrowroot,
cornstarch, katakuri starch, potato starch, sago, tapioca,
furcellaran, or sodium pyrophosphate. In certain embodiments, the
composition has a viscosity between about 1000 and about 10000 cP
(e.g., 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or
10000 cP).
[0036] In some embodiments of any compositions described herein,
the composition also includes one or more of electrolytes,
sweeteners, flavoring agents, vitamins, minerals, amino acids, or
preservatives.
[0037] In certain embodiments of any compositions described herein,
the composition is a beverage or gel that is made by reconstituting
a dry powder with an aqueous fluid (e.g., water).
[0038] In other embodiments of any compositions described herein,
the composition is a packaged beverage. In some embodiments, the
packaged beverage is provided in a unit that contains between
10-1000 mL (e.g., between 10-500 mL) of the beverage.
[0039] In still other embodiments of any compositions described
herein, the composition is a gel. In certain embodiments, the
composition is a packaged gel. In further embodiments, the packaged
gel is provided in a unit that contains between 5-100 grams (e.g.,
between 30-40 grams) of the gel.
[0040] In some embodiments of any of the methods described herein,
the composition of (1) or (2) has a pH that is greater than about
2.5 (e.g., the pH of the composition is greater than about 2.5,
2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,
3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1,
5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or
6.5). For example, the composition of (1) or (2) can have a pH of
about 4 to about 9, about 5 to about 9, or 6.5 to about 7.5.
[0041] In certain embodiments, the composition is a liquid or
beverage that does not include acetic acid or a salt thereof, or
that has an acetic acid concentration ranging from 0 M to 0.1 M, 0
M to 0.001 M, is substantially 0 M.
[0042] In some embodiments of any of the compositions described
herein, the TRPV1 channel activator is a proton concentration of
10.sup.-7 M to 10.sup.-2 M (pH 2-pH 7), e.g. produced by inclusion
of acidulants such as acetic acid, phosphoric acid, citric acid,
malic acid, succinic acid, tartaric acid, fumaric acid, and
ascorbic acid.
[0043] In some embodiments of any of the methods or compositions
described herein, where the composition includes vinegar (e.g.,
apple cider vinegar), the composition includes no more than one of
garlic (e.g., garlic extracts) or ginger (e.g., ginger
extracts).
[0044] In other embodiments of any of the methods or compositions
described herein, where the composition includes garlic (e.g.,
garlic extracts), the composition includes no more than one of
vinegar (e.g., apple cider vinegar) or ginger (e.g., ginger
extracts).
[0045] In some embodiments of any of the methods or compositions
described herein, where the composition includes ginger (e.g.,
ginger extracts), the composition includes no more than one of
garlic (e.g., garlic extracts) or vinegar (e.g., apple cider
vinegar).
[0046] Any of the compositions described herein can be used in any
of the methods described herein (e.g., to treat muscle cramps such
as nocturnal cramps or menstrual cramps, or muscle cramps resulting
from exercise, to treat musculoskeletal irritability, or to improve
muscle recovery). The compositions used in the methods can include
substantially pure channel activators. In other embodiments of any
of the compositions or methods described herein, the TRP channel
(e.g., a TRPV1 or TRPA1 activator) activator and/or the ASIC
channel activator is not substantially pure. For example, a
composition can include a mixture of capsaicinoids (e.g., as
capsicum or between 0.0001-0.01 mgs/mL of total capsaicinoids). In
some embodiments, the channel activators are provided as extracts
suitable for human consumption.
[0047] In still another aspect; the invention features a method of
preparing any of the compositions described herein for treating or
ameliorating muscle cramps in a subject in need thereof, or for
treating musculoskeletal irritability in a subject in need thereof,
the method including the use of TRP or ASIC channel activator
compounds that are substantially pure with an excipient to provide
a composition that is a liquid, beverage, gel, solid, semi-solid,
chewing gum, or spray.
[0048] By "ASIC channel" is meant an acid sensing ion channel that
is opened by low pH and can excite certain neurons or muscle fibers
or other cells.
[0049] By "acidulant" is meant an acidic compound (e.g., citric
acid) used to lower the pH of a composition, e.g., the pH can be
lowered in the range of 2.5-6.5 (e.g., pH of 2.5, 3.0, 3.5, 4.0,
4.5, 5.0, 5.5, 6.0, or 6.5).
[0050] By "activator," "compound that activates," or "agonist" is
meant a molecule that stimulates a biological response.
[0051] By "administering" and "administration" is meant a mode of
delivery. A daily dosage can be divided into one, two, three or
more doses in a suitable form to be administered one, two, three or
more times throughout a time period. In preferred embodiments of
the present invention, compositions and solutions are administered
orally.
[0052] By "beverage" is meant a composition that is not in solid or
gas form, such as a liquid or semi-liquid that is designed to enter
into the mouth of a subject and be orally consumed or ingested. A
beverage may be in a ready-to-drink liquid form (e.g., may be
consumed without modification) or in a liquid, solid, or
concentrated form, which can be transformed into a ready-to-drink
liquid form with an addition of another liquid (e.g., water). See,
e.g., Sports Drinks: Basic Science and Practical Aspects, Ed.
Ronald J. Maughan, CRC Press, 2000.
[0053] Where the term "composition" is used to describe a
formulation that includes an activator of TRPV1 channels, and/or an
activator of TRPA1 channels, and/or an activator of ASIC channels,
the term refers to a comestible formulation that is suitable for
oral ingestion by the subject (e.g., the human subject). Exemplary
compositions that include an activator of TRPV1, TRPA1, and ASIC
channels include sprays (e.g., aerosols), powders, chewing gum,
ingestible solids, gels, aqueous beverages, dry powder (e.g., a
powder that can be directly consumed or that can be reconstituted
with liquid to provide a beverage as defined herein), nutritional
bars, lozenges, tablets, capsules, wafers, pastes, and the like.
Other compositions are described herein.
[0054] The term an "effective amount" of a compound as used herein,
is that amount sufficient to effect beneficial or desired results,
such as the effective treatment of muscle cramps or musculoskeletal
irritability or the improvement of muscle recovery following
exercise, and, as such, an "effective amount" depends upon the
context in which it is being applied. For example, in the context
of administering an agent that activates a TRP channel (e.g., TRPV1
or TRPA1) or an ASIC channel, an effective amount of an agent is,
for example, an amount sufficient to achieve an increase in TRPV1,
TRPA1, or ASIC activity as compared to the response obtained
without administration of the agent. The effective amount of active
compound(s) used to practice the present invention can also be
varied based on, for example, the age, and body weight, of the
subject or the nature of the exercise.
[0055] The compositions can also include one more excipients that
are not activators of TRPV1, TRPA1, and ASIC channels and that are
non-toxic and non-inflammatory in a subject (e.g., in a human
subject). In some embodiments, the excipient(s) can provide
desirable or improved physical and/or chemical properties such as
stability, flow, viscosity, rate of disintegration, taste,
delivery, etc. Exemplary, non-limiting excipients that can be
selected from: a disintegrant (e.g., carmellose, starch,
crystalline cellulose, low-substituted hydroxypropyl cellulose, and
the like), a binder (e.g., gum acacia, carmellose, gelatin,
crystalline cellulose, simple syrup, honey, hydroxypropyl
cellulose, povidone, methylcellulose, and the like), a surfactant
(e.g., polyoxyl 40 stearate, polysorbate 80, polyoxyethylene
hydrogenated castor oil, and the like), an emulsifier (e.g.,
polyoxyl 40 stearate, sorbitan sesquioleate, polysorbate 80, sodium
lauryl sulfate, lauromacrogol, gum arabic, cholesterol, stearic
acid, povidone, glyceryl monostearate, and the like), a plasticizer
(e.g., glycerin, propylene glycol, macrogol, and the like), a
lubricant (e.g., magnesium silicate, carmellose, light anhydrous
silicic acid, stearic acid, calcium stearate, magnesium stearate,
talc, and the like), a sweetener (e.g., white soft sugar, honey,
simple syrup, glucose, saccharin sodium, acesulfame potassium,
disodium glycyrrhizinate, and the like), a pH-adjusting agent
(e.g., hydrochloric acid, citric acid, sodium hydrogen carbonate,
potassium hydroxide, sodium hydroxide, sodium carbonate, and the
like), a preservative (e.g., benzoic acid, benzalkonium chloride,
ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl
parahydroxybenzoate, methyl parahydroxybenzoate, and the like), a
flavor (e.g., fennel oil, orange oil, cinnamon oil, thymol, orange
peel tincture, dl-menthol, 1-menthol, eucalyptus oil, and the
like), or a coloring agent (e.g., Food Red No. 2, No. 3, No. 40,
No. 102, No. 104, No. 105 or No. 106, Food Yellow No. 4 or No. 5,
Food Green No. 3, Food Blue No. 1 or No. 2, titanium dioxide,
sodium copper chlorophyllin, turmeric, gardenia, annatto dye,
kaoliang dye, and the like), or an antioxidant (e.g., ascorbic
acid, sodium thiosulfate, tocopherol, sodium hydrogen sulfite, and
the like), or any combination thereof.
[0056] By "ingestible solid" is meant a solid formulation that can
be ingested by a subject (e.g., a human) without toxic effects.
[0057] By "muscle cramp" is meant a spontaneous contraction of one
or more muscles. A muscle cramp may be associated with strenuous
exercise or fatigue or may occur during rest (e.g., a nocturnal
cramp). Menstrual cramps are also muscle cramps By "nerve-muscle
recovery" or "muscle recovery" is meant the recovery from
spontaneous muscle contractions and fatigue following exercise that
may or may not be associated with the development of frank
cramps.
[0058] By "neuromuscular irritability" is meant spontaneous muscle
contractions (e.g. associated with muscle fatigue) which may or may
not be associated with frank cramps.
[0059] By "preventing" or "reducing the likelihood of" is meant
reducing the severity, the frequency, and/or the duration of a
condition or disorder (e.g., muscle cramping) or the symptoms
thereof. For example, reducing the likelihood of or preventing
muscle cramping is synonymous with prophylaxis of muscle
cramping.
[0060] By "subject" is meant a mammal, including, but not limited
to, a human or non-human mammal, such as a bovine, equine, canine,
ovine, or feline.
[0061] As used herein, and when used in reference to TRPA1, TRPV1,
and/or ASIC channel activators, the term "substantially pure"
refers to a composition that includes a channel activator in which
the composition is free of organic and/or inorganic species that do
not activate the TRPA1, TRPV1, and/or ASIC channels, and where 60%,
65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 99.5% (w/w) of
the composition is a particular channel activator compound.
Substantially pure compositions can be prepared and analyzed using
standard methods known in the art (e.g., chromatographic
separation, extractions, and the like). Substantially pure
compositions can include isomeric impurities (e.g., geometric
isomers) and/or salts or solvates of a channel activator.
[0062] By "treating" or "ameliorating" is meant administering a
composition for therapeutic purposes or administering treatment to
a subject already suffering from a disorder to improve the
subject's condition. By "treating a condition or disorder" or
"ameliorating a condition or disorder" is meant that the condition
or disorder (e.g., muscle cramping) and the symptoms associated
with the condition or disorder are, e.g., alleviated, reduced,
cured, or placed in a state of remission. As compared with an
equivalent untreated control, such amelioration 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.
[0063] By "transient receptor potential cation channel, subfamily
V, member 1" or "TRPV1" is meant a nonselective cation channel that
may be activated by physical and/or chemical stimuli. TRPV1 channel
activators include, e.g., capsaicinoids and capsaicinoid analogs or
derivatives and certain endocannabinoids.
[0064] By "transient receptor potential cation channel, subfamily
A, member 1" or "TRPA1" is meant a cation channel that is a member
of the transient receptor potential channel family. TRPA1 channel
activators include, e.g., ally isothiocyanate, cinnamaldehyde,
farnesyl thiosalicylic acid, nicotine and its structural analogues,
formalin, hydrogen peroxide, 4-hydroxynonenal, and acrolein.
[0065] By "viscosity" is meant a measurement of a fluid's internal
resistance to flow (e.g., "thickness"). Viscosity is generally
expressed in centipoise (cP) or pascal-seconds.
[0066] Other features and advantages of the invention will be
apparent from the detailed description and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0067] FIG. 1 shows graphs from 6 sensory neurons isolated from the
trigeminal ganglia of rats that illustrate their activation by the
capsicum, cinnamon, and ginger extracts that were used in the human
experiments. These data show that each agent is capable of acting
alone to activate some neurons but also that a combination of
agents can produce stronger activation of a larger fraction of
neurons. Further, the bottom two records suggest that there can be
strongly synergistic activation of neurons by the capsicum extract
and the ginger extract when applied in combination.
[0068] FIG. 2 shows the effect of the TRP-Stim beverage on cramping
of the flexor hallucis brevis (FHB) of Subject A. Under control
conditions, cramping was reliably induced by stimulating the muscle
using an electrical muscle stimulator. After ingestion of 50 mL of
a TRP-Stim beverage containing capsaicin and capsaicinoids (TRPV1
agonists), cinnamaldehyde (TRPA1 agonist), and gingerols (TRPA1 and
TRPV1 agonists), cramping was very brief after 11 minutes and
essentially absent at tests at 20 minutes and 21/2 hours after
ingestion.
[0069] FIG. 3 shows the effect of the TRP-Stim beverage on cramping
of the FHB of a second subject after cramping was induced. In
recordings beginning 12 minutes after ingestion of the TRP-Stim
beverage, stimulation at 10 Hz or 12 Hz produced essentially no
cramping, and increasing the frequency of stimulation to 14 Hz also
did not induce cramping. The dramatic reduction in cramping was
still present 4 hours later in this subject.
[0070] FIG. 4 shows the effect of the TRP-Stim beverage on cramping
of the FHB of a third subject tested over longer times. Under
control conditions, a cramp lasting 58 seconds was induced. After
ingestion of the TRP-Stim beverage, the duration of the cramp was
reduced to 27 seconds after 8 minutes, to 8 seconds after 15
minutes, and cramping was abolished after 20 minutes and in a test
after 2 hours. In tests 11 hours after ingestion, reliable cramping
had returned. After the subject again drank 50 mL of the TRP-Stim
beverage, cramping was completely abolished in tests beginning
after 10 minutes.
[0071] FIG. 5 shows the effect of the TRP-Stim beverage on cramping
of the FHB of a fourth subject. This subject had engaged in
strenuous exercise (triathlon) four hours earlier and was
experiencing muscle twitchiness. This subject had an unusually low
frequency threshold (8 Hz) for induction of cramping in the FHB
muscle, and the resulting cramps were unusually long (172 seconds
after 8 Hz stimulation and 222 seconds after 10 Hz stimulation).
Cramping was completely gone in tests starting 13 minutes after
ingestion of the TRP-Stim beverage, even when increasing the
stimulation frequency to 12 Hz. Cramping was still abolished 3
hours later. After 4 hours, cramping returned, but with an
increased frequency threshold (10 Hz). After the subject again
drank 50 mL of the TRP-Stim beverage, cramping was again completely
abolished.
[0072] FIG. 6 is a graph showing the effect of the TRP-Stim
beverage on cramping of the gastroenemius (calf) muscle of a fifth
subject. The muscle was stimulated, and after cessation of
stimulation, the muscle went into a prolonged cramp lasting 59
seconds. In a test 3 minutes after ingestion of 50 mL of TRP-Stim,
cramping was abolished.
[0073] FIG. 7 shows the effect of the TRP-Stim beverage on cramping
of the gastroenemius (calf) muscle of a sixth subject. The muscle
was stimulated, and after cessation of stimulation, the muscle went
into a prolonged cramp lasting 96 seconds. In a test 4 minutes
after ingestion of 50 mL of TRP-Stim, cramping was abolished.
Cramping was still abolished in a test conducted 40 minutes
later.
[0074] FIG. 8 is a graph showing the effect of the TRP-Stim
beverage on cramping of an FHB muscle in a seventh subject who
experienced spontaneous cramping induced by pointing her toe. Ten
minutes after the subject ingested 50 mL of the TRP-Stim beverage,
cramping was abolished.
DETAILED DESCRIPTION
[0075] The methods and compositions of the present invention are
directed to the treatment or amelioration of muscle cramps using a
composition that includes one or more TRPV1 channel activators
and/or TRPA1 channel activators and/or ASIC channel activators.
Muscle Cramping
[0076] Few treatments and therapeutic regimens are available to
alleviate muscle cramping and associated symptoms. Recent work
suggests that ingestion of pickle juice can alleviate cramping
(Miller et al., Med. Sci. Sports. Exerc. 42:953-61, 2010). The
mechanism for the efficacy of pickle juice is unknown, although it
has been recently proposed (Miller et al., Med Sci Sports Exerc.
42:953-61, 2010) that it involves an oropharangeal reflex induced
by the sour taste of acetic acid stimulating taste receptors (Kajii
et al. Physiol Behav. 77:321-5, 2002). Without being bound by
theory, we instead hypothesize that pickle juice's efficacy results
from the activation of a specific class of non-taste primary
sensory neurons that contain nerve endings in the mouth, esophagus,
and stomach. These neurons, polymodal C-fiber and A-delta neurons,
are distinct from taste neurons, are activated by diverse
(polymodal) stimuli, including noxious mechanical, chemical, and
thermal stimuli, and are known to contain specific ion channel
receptors called Transient Receptor Potential (TRP) ion channels
and acid sensing (ASIC) ion channels (Beilefeldt et al., Am J
Physiol Gastrointest Liver Physiol 294: G130-G138, 2008; Yu et al.,
Am J Physiol Gastrointest Liver Physiol 297: G34-G42, 2009).
[0077] We hypothesize that cramps result from excessive firing of
motor neurons in the spinal cord, in accordance with recent
understanding (Schwellnus, Br J Sports Med. 43:401-8, 2009). We
further hypothesize that stimulating TRPV1 or TRPA1 or ASIC
channels in the nerve endings of primary sensory neurons present in
the mouth, esophagus and/or stomach, which project to the spinal
cord and brain stem, influence neuromuscular activity by altering
activity of neural circuits in the spinal cord or brainstem. TRPV1,
TRPA1, and ASIC channels are known to be present in
gastroesophageal polymodal sensory neurons that mediate
transmission of a variety of noxious stimuli, including mechanical,
chemical, and thermal stimul (Beilefeldt et al., Am J Physiol
Gastrointest Liver Physiol 294: G130-G138, 2008; Yu et al., Am J
Physiol Gastrointest Liver Physiol 297: G34-G42, 2009). These
primary sensory neurons project to the spinal cord and brain stem,
where they release glutamate and a variety of neuropeptides (e.g.,
calcitonin gene-related peptide (CGRP) and substance P). These
transmitters act broadly on other types of neurons within the
spinal cord and brain stem circuitry, including neurons that
release GABA, glycine, and serotonin in the spinal cord, which can
in turn inhibit firing of motor neurons. Activity of inhibitory
neurons in the spinal cord and brain stem may thus be triggered by
stimulation of molecular targets (e.g., TRPV1 and TRPA1 and ASIC
channels) present in primary sensory nerve endings in the mouth,
esophagus and/or stomach, resulting in inhibition of the motor
neurons whose excessive firing is responsible for muscle cramping.
In support of this hypothesis, some cramps can be prevented by
local nerve block and appear to result from impairment of function
of GABAergic interneurons in the spinal cord (Obi et al., Muscle
and Nerve 6:1228-1231, 1993).
[0078] We also hypothesize that spontaneous muscle contractions
during recovery from exercise fatigue also arise from excessive
firing of motor neurons in the spinal cord and can similarly be
reduced by stimulating TRPV1, TRPA1, and/or ASIC channels in the
nerve endings of primary sensory neurons present in the mouth,
esophagus and/or stomach, which project to the spinal cord and
brain stem. By reducing spontaneous muscle contractions stimulation
of TRPV1, TRPA1, and/or ASIC channels in nerve endings within the
esophagus and/or stomach can accelerate neuromuscular recovery
following exercise fatigue.
Compositions
[0079] The compositions described herein are comestible
formulations suitable for oral consumption by a subject (e.g., by a
human) and include one or more activators of TRPV1, TRPA1, and/or
ASIC channels as well as one or more optional excipients as
described herein. Exemplary, non-limiting compositions include
those that are solids (e.g., chews or chewing gums), liquids (e.g.,
beverages), and gels.
TRPV1 Channel Activators
[0080] Compounds that activate TRPV1 that may be used in the
compositions of the present invention include, for example,
capsaicin, capsaicin analogs and derivatives (e.g., capsaicinoids),
and any other compound that activates TRPV1, examples of which are
described herein. Modulators of TRPV1 activity are known in the art
(see, e.g., Harteneck et al., "Synthetic modulators of TRP channel
activity," Adv Exp Med Biol. 704:87-106, 2011, and other references
described herein).
[0081] In one embodiment, the TRPV1 channel activator is a
capsaicinoid (e.g., capsaicin
(8-methyl-N-vanillyl-trans-6-nonenamide)). Exemplary capsaicinoids
are provided in Table 1.
TABLE-US-00001 TABLE 1 Exemplary capsaicinoids Capsaicin
##STR00001## Dihydrocapsaicin ##STR00002## Nordihydrocapsaicin
##STR00003## Homodihydrocapsaicin ##STR00004## Homocapsaicin
##STR00005## Nonivamide ##STR00006##
[0082] Suitable capsaicinoids and capsaicinoid analogs and
derivatives for use in the compositions and methods of the present
invention include naturally occurring and synthetic capsaicin
derivatives and analogs including, e.g., vanilloids (e.g.,
N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, and
N-vanillyl-cis-monounsaturated alkenamides), capsiate,
dihydrocapsiate, nordihydrocapsiate and other capsinoids,
capsiconiate, dihydrocapsiconiate and other coniferyl esters,
capsiconinoid, resiniferatoxin, tinyatoxin, civamide,
N-phenylmethylalkenamide capsaicin derivatives, olvanil,
N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide,
N-oleyl-homovanillamide, triprenylphenols (e.g., scutigeral),
gingerols, piperines, shogaols, guaiacol, eugenol, zingerone,
nuvanil, NE-19550, NE-21610, and NE-28345.
[0083] Other suitable TRPV1 channel activators include
oleoylethanolamide, N-oleoyldopamine, 3-methyl-N-oleoyldopamine,
oleamide, capsiate, 1-monoacylglycerols having C18 and C20
unsaturated and C8-C12 saturated fatty acid, 2-monoacylglycerols
having C18 and C20 unsaturated fatty acids, miogadial, miogatrial,
polygodial, and other terpenoids with an alpha,beta-unsaturated
1,4-dialdehyde moiety, sanshools, evodiamine, acesulfame-K,
cyclamate, sulfates (e.g., CuSO.sub.4, ZnSO.sub.4, and FeSO.sub.4),
arvanil, anandamide, N-arachidonoyl-dopamine, flufenamic acid
dopamide and other dopamine amides of fenamic acids,
4-hydroxynonenal, SA 13353 (i.e.,
1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea),
gingerol or salts of magnesium.
[0084] In addition, the TRPV1 channel activator may be an analog or
derivative of any of the TRPV1 channel activators described
herein.
[0085] Additional TRPV1 channel activators are described, for
example, in U.S. Pat. Nos. 7,632,519; 7,446,226; 7,429,673;
7,407,950; 6,022,718; 5,962,532; 5,762,963; 5,403,868; 5,290,816;
5,221,692; 4,812,446; 4,599,342; 4,564,633; 4,544,669; 4,544,668;
4,532,139; 4,493,848; 4,424,205; 4,313,958; in U.S. Patent
Application Publication Nos. 2007/0293703; 2007/0167524;
2006/0240097; and 2005/0085652; and in WO 00/50387, each of which
is incorporated by reference.
[0086] In addition, the TRPV1 channel activator may be an acidulant
(e.g., acetic acid, phosphoric acid, citric acid, malic acid,
succinic acid, tartaric acid, fumaric acid, or ascorbic acid)
maintaining a low pH in the range of 2.5-6.5 (e.g., pH of 2.5, 3.0,
3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or 6.5).
[0087] TRPV1 channel activators for use in the compositions and
methods described herein can be identified using standard
methodology, as described, for example, in U.S. Patent Application
Publication No. 2003/0104085, which is hereby incorporated by
reference. Exemplary assays for identification of TRPV1 channel
activators include, without limitation, receptor binding assays;
functional assessments of stimulation of calcium influx or membrane
potential in cells expressing the TRPV1 receptor; assays for the
ability to induce cell death in such cells (e.g., selective
ablation of C-fiber neurons); and other assays known in the
art.
[0088] A TRPV1 channel activator may be present in a composition of
the invention at a concentration range of about 0.01% to 10% by
weight by weight based on the total volume of the composition
(e.g., 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%), though a
TRPV1 channel activator may be present in lower or higher
concentrations.
TRPA1 Channel Activators
[0089] TRPA1 channels are activated by naturally occurring
substances including, e.g., mustard oil, isothiocyanate compounds
(e.g., allyl isothiocyanate), acrolein, farnesyl thiosalicylic
acid. A-tetrahydrocannabinol (THC), eugenol, ginger, gingerol,
gingerols, shogaols, nicotine, nicotine derivatives and analogs,
methyl salicylate, cinnamaldehyde, cinnamon oil, wintergreen oil,
clove oil, allicin, diallyl sulfide, diallyl disulfide, diallyl
trisulfide, sanshools, farnesyl thiosalicylic acid, and farnesyl
thioacetic acid. The TRPA1 channel activator may also be an analog
or derivative of any of the TRPA1 channel activators described
herein, and additional TRPA1 channel activators are identified in
WO 2009/071631, hereby incorporated by reference. Still other
modulators of TRPA1 are described in, e.g., Harteneck et al.,
"Synthetic modulators of TRP channel activity," Adv Exp Med Biol.
704:87-106, 2011; Viana et al. "TRPA1 modulators in preclinical
development," Expert Opin. Ther. Pat. 19(12):1787-99.2009).
[0090] Methods for identifying TRPA1 channel activators are known
in the art and are described, for example, in U.S. Pat. No.
7,674,594.
[0091] A TRPA1 channel activator may be present in a composition of
the invention at a concentration range of about 0.01% to 10% by
weight by weight based on the total volume of the composition
(e.g., 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%), though a
TRPA1 channel activator may be present in lower or higher
concentrations.
ASIC Channel Activators
[0092] ASIC channels are activated by low pH. The pH of a
composition of the present invention that includes an ASIC channel
activator may be in the range of 2.5-6.5 (e.g., pH of 2.5, 3.0,
3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or 6.5). The pH may be adjusted
within this range by any means acceptable for compositions that are
intended to be ingested by a subject. Exemplary acidulants are
acetic acid, phosphoric acid, citric acid, malic acid, succinic
acid, tartaric acid, fumaric acid, and ascorbic acid. The acidulant
may be present in a composition of the invention at a concentration
range of about 0.01% to 10% by weight based on the total volume of
the composition (e.g., 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,
or 10%), though the acidulant may be present in lower or higher
concentrations.
Additional Components of the Composition
[0093] The composition of the present invention may additionally
include, for example, electrolytes (e.g., potassium salt or other
salts), sweeteners, flavoring and coloring agents, vitamins,
minerals, preservatives, and antioxidants.
[0094] Viscosity and Viscosity Modifiers
[0095] Viscosity is the ratio of shear stress to shear rate,
expressed as dynes-second/cm.sup.2, or poise. A centipoise (cP) is
one one-hundredth of a poise.
[0096] The composition of the present invention may have a
viscosity greater than water (i.e., about 1.0 cP at 20.degree. C.),
e.g., about 100, 200, 300, 400, 500, 1000, 1500, 2000, 2500, 3000,
3500, 4000, 4500, 5000, 6000, 7000, 8000, 9000 cP or more. If a
consistency of corn syrup is desired, viscosities in the range of
about 2500 cP are suitable. If a consistency of a soft gel or honey
is desired, viscosities in the range of about 10000 cP to about
15000 cP are suitable. For pudding-like products, viscosities in
the range of about 30000 cP to about 38000 cP are desirable.
Viscosity of the compositions of the present invention may be
measured with, e.g., a rheometer or viscometer, though additional
methods of measuring viscosity are known in the art.
[0097] Viscosity modifiers may be added to compositions of the
present invention. Such viscosity modifiers include, for example,
collagen, gellan gum, carbohydrate gel-forming polymers, carob bean
gum, locust bean gum, carrageenan, alginates (e.g., alginic acid,
sodium alginate, potassium alginate, ammonium alginate, and calcium
alginate), agar, guar gum, xanthan gum, carboxymethyl cellulose,
clear starch, pectin, gelatin, arrowroot, cornstarch, katakuri
starch, potato starch, sago, tapioca, furcellaran, and sodium
pyrophosphate. A viscosity modifier may be present in the
composition in an amount of from about 0.01% to 10% by weight based
on the total volume of the composition (e.g., 0.01, 0.1, 0.5, 1, 2,
3, 4, 5, 6, 7, 8, 9, or 10%), though the viscosity modifier may be
present in lower or higher concentrations.
[0098] Electrolytes
[0099] Exemplary electrolytes include potassium salts, chloride
salts, bromide salts, sodium salts, magnesium salts, calcium salts,
citrate salts, acetate salts, phosphate salts, salicylates,
bicarbonate salts, lactate salts, sulphate salts, tartrate salts,
benzoate salts, selenite salts, molybdate salts, iodide salts,
oxides, and combinations thereof. An electrolyte may be present in
a composition of the invention at a concentration range of about
0.01% to 10% by weight based on the total volume of the composition
(e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7,
8, 9, or 10%), though an electrolyte may be present in lower or
higher concentrations.
[0100] In certain embodiments, the compositions of the present
invention include high concentrations of potassium (e.g., potassium
chloride). The concentration of potassium in the composition may
be, e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6,
or 7% or more by weight based on the total volume of the
composition.
[0101] In certain embodiments, the compositions of the present
invention include high concentrations of magnesium (e.g., magnesium
chloride). The concentration of magnesium in the composition may
be, e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6,
or 7% or more by weight based on the total volume of the
composition.
[0102] Sweeteners
[0103] Sweeteners may be included in the compositions of the
invention. Exemplary sweeteners include high fructose corn syrup,
mannose, maltose, glucose polymers, sucrose (e.g., cane sugar or
beet sugar), glucose, dextrose, lactose, galactose, fructose,
polysaccharides (e.g., malodextrins), rice syrup, honey, and
natural fruit juices (e.g., orange juice, papaya juice, pineapple
juice, apple juice, grape juice, apricot juice, pear juice, tomato
juice, agave nectar, or cranberry juice). Additionally, non- or
low-caloric sweeteners can be used in the compositions of the
invention. Examples of such non-caloric or low-caloric sweeteners
include, but are not limited to, saccharin, cyclamates,
acetosulfam, sorbitol, sucralose, xylitol, erythritol, Stevia
extract, L-aspartyl-L-phenyl-alanine ester (e.g., aspartame),
L-aspartyl-D-alanine alkyl amides,
L-aspartyl-L-1-hydroxymethylalkaneamide, and
L-aspartyl-1-hydroxyethylalkaneamide. Sweeteners may be present in
a composition of the invention at a concentration range of about 2%
to 20% by weight based on the total volume of the composition
(e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, or 20%), though sweeteners may be present in lower or higher
concentrations.
[0104] Flavoring and Coloring Agents
[0105] Exemplary flavoring agents include almond oil, amaretto oil,
anethole, anise oil, benzaldehyde, blackberry, black walnut oil,
blueberry, caraway, caraway oil, cardamom oil, cardamom seed,
cherry juice, cherry syrup, cinnamon, cinnamon oil, cinnamon water,
citric acid, citric acid syrup, clove oil, cocoa, coriander oil,
dextrose, eriodictyon, ethyl acetate, ethyl vanillin, fennel oil,
ginger, glucose, glycerin, glycyrrhiza, grape, honey, lavender oil,
lemon oil, lime, mannitol, methyl salicylate, myristica oil, orange
oil, orange peel, orange syrup, peppermint, peppermint oil,
peppermint water, phenylethyl alcohol, pineapple, raspberry juice,
raspberry syrup, rosemary oil, rose oil, rose water, sarsaparilla
syrup, sorbitol, spearmint, spearmint oil, strawberry, sucrose,
thyme oil, tolu balsam, vanilla, vanillin, and wild cherry syrup.
Additional flavoring agents may be found in Food Chemicals Codex
and Fenaroli's Handbook of Flavor Ingredients.
[0106] Small amounts of one or more coloring agents may be utilized
in the compositions of the present invention. Coloring agents
include, e.g., beta-carotene, riboflavin dyes, FD&C dyes (e.g.,
Yellow No. 5, Blue No. 1, Blue No. 2, and Red No. 40), FD&C
lakes, chlorophylls and chlorophyllins, caramel coloring, annatto,
cochineal, turmeric, saffron, paprika, and fruit, vegetable, and/or
plant extracts (e.g., grape, black currant, aronia, carrot,
beetroot, red cabbage, elderberry, and hibiscus extracts). The
amount of coloring agent used will vary depending on the agents
used in the composition and the color intensity desired in the
finished product. The amount of coloring agent to be used can be
readily determined by one skilled in the art.
[0107] Vitamins and Minerals
[0108] Non-limiting examples of vitamins and minerals that may be
included in the compositions of the present invention include,
e.g., choline bitartate, niacinamide, thiamin, folic acid,
d-calcium pantothenate, biotin, vitamin A, vitamin C, vitamin
B.sub.1 hydrochloride, vitamin B.sub.2, vitamin B.sub.3, vitamin
B.sub.6 hydrochloride, vitamin B.sub.12, vitamin D, vitamin E
acetate, vitamin K, and salts of calcium, potassium, magnesium,
zinc, iodine, iron, and copper. When included in a composition of
the invention, the composition contains at least 5, 10, 15, 20, 25,
30, 35, 40, 45, or 50% of the U.S. recommended daily intake (RDI)
for such vitamins and minerals.
[0109] Preservatives
[0110] One or more preservatives may additionally be utilized 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 a composition of
the invention, the preservative is included at levels from about
0.0005% to about 0.5% (e.g., 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1,
or 0.5%) by weight based on the total volume of the composition,
though preservatives may be present in lower or higher
concentrations.
[0111] Antioxidants
[0112] One or more antioxidant agents may also be included in the
compositions to, for example, reduce exercise-induced oxidative
stress. Exemplary antioxidants include vitamin C and vitamin E;
beta-carotene, lutein, or other carotenoids; cyanidin, delphinidin,
malvidin, or other anthocyanidins; apigenin, luteolin, or other
flavones; hesperitin, naringenin, or other flavonones;
isorhamnetin, quercetin, kaempferol or other flavonols; and
epigallocatechin-3-gallate, epicatechin, thearubigins, or other
flavan-3-ols.
[0113] Additional components of the compositions described herein
may include amino acids (e.g., leucine, isoleucine, lysine,
methionine, phenylalanine, threonine, tryptophan, and valine),
stimulants (e.g., caffeine), emulsifying agents, carbon dioxide
(e.g., to carbonate a liquid composition), stabilizers, humectants,
anticaking agents, or herbal extracts.
Combination Therapies
[0114] In certain embodiments, additional therapeutic agent(s) may
be administered with compositions of the present invention for,
e.g., the treatment or amelioration of muscle cramps and/or the
recovery of muscles from exercise fatigue. Such therapeutic agents
include, for example, muscle relaxants (e.g., diazepam) or
anti-inflammatory agents (e.g., ibuprofen). When combination
therapy is employed, the additional therapeutic agent(s) can be
administered as a separate formulation or may be combined with any
of the compositions described herein.
[0115] For example, any of the compositions described herein can be
used for the treatment of nocturnal (or night) cramps. In some
embodiments, the compositions can be used in combination with one
or more sleep aids. Sleep aids that can be used in combination with
the compositions and methods described herein include:
antihistamines (e.g., diphenhydramine and doxylamine);
benzodiazepines (e.g., estazolam (ProSom), flurazepam (Dalmane),
quazepam (Doral), temazepam (Restoril), and triazolam (Halcion));
non-benzodiazepine sedative hypnotics (e.g., eszopiclone (Lunesta),
zalepon (Sonata), and zolpidem (Ambien)); and melatonin receptor
agonist hypnotics (e.g., ramelteon (Rozerem). Still other sleep
aids that can be used in combination with the compositions and
methods described herein include: chamomile, valerian root, kava
kava, lemon balm, passionflower, lavender, St. John's Wort,
melatonin, tryptophan (e.g., L-tryptophan), 5-hydroxytryptophan
(5-HTP), catnip, hops, rhodiola, oatstraw, lavender, GABA,
L-theanine, linden, ginseng (e.g., Siberian ginseng), honey,
nutmeg, mugwort, butterbur, rauwolfia, taumelloolch, American
hellebore, quassia, tulip tree, brewer's yeast, inositol, skullcap,
phosphatidylserine, calcium, magnesium, vitamin B6, vitamin B12,
and pantothenic acid (B5).
Formulations and Methods of Preparing Compositions
[0116] The compositions and solutions of the present invention may
be formulated as ready-to-drink beverages, concentrates (e.g.,
syrups), dry compositions (e.g., powders, granules, or tablets that
may be reconstituted with a liquid (e.g., with water), gels,
solids, semi-solids (e.g., ice cream, pudding, or yogurt), frozen
liquids (e.g., ice pops), lozenges or hard candies, dissolving
strips (e.g., an edible strip containing pullulan and compositions
of the invention), and chewing gum.
[0117] In some embodiments, the compositions may be in the form of
a dry powder, granule, or tablet that may be reconstituted in a
specified amount of a liquid. The dried components may be mixed
together and milled (e.g., to create a homogenous powder) or mixed
in aqueous solution and dried by using methods known to one of
skill in the art. Dried powders or granules may be "loose" or
fashioned into tablets.
[0118] The compositions described herein can be ingested, for
example, by a subject before, during, or after exercise. The
compositions and solutions described herein can be ingested (e.g.,
through eating or drinking) before the onset of muscle cramping,
when muscle cramping begins, any time after the onset of muscle
cramping, or after muscle cramping has subsided. The compositions
of the solution can also be ingested after exercise to accelerate
nerve-muscle recovery from exercise fatigue. When the compositions
and solutions of the present invention are in the form of a
ready-to-drink beverage, e.g., 1, 2, 4, 8, 10, 12, 14, 16, 18, 20,
24, 26, 28, 30, or 32 ounces of the beverage may be consumed as
needed (e.g., once, twice, three, four, five, six times per day;
once per week; or once per month).
[0119] The compositions and solutions of the present invention may
be prepared using methods known to one of skill in the art. Such
methods include dissolving, dispersing, or otherwise mixing all
components singularly or in suitable combinations and agitating
with, for example, a mechanical stirrer until all of the
ingredients have been solubilized or adequately dispersed. Where a
shelf-stable composition or solution is desired, the final mixture
can be pasteurized, ultra-pasteurized, sterilized, or filled
aseptically at appropriate process conditions. Where required for
mutual stability of two or more components (for example if a
component is unstable at low pH), multiple components can be mixed
shortly before ingestion.
[0120] The compositions and solutions described herein may be
bottled or packaged in, for example, glass bottles, plastic bottles
and containers (e.g., polyethylene terephthalate or foil-lined
ethylene vinyl alcohol), metal cans (e.g., coated aluminum or
steel), lined cardboard containers, pouches, packs, wrappers, or
any other packaging known to one of skill in the art. For example,
a ready-to-drink beverage can be bottled or packaged in a unit that
contains between 10-1000 mL of the beverage. For example, the
packaging can contain 10, 20, 50, 100, 200, 300, 400, 500, 600,
700, 800, 900, or 1000 mL of the beverage. Alternatively, the
packaging can contain 200.250, 330, 350, 355.375, 440, or 500 mL of
the beverage. A ready-to-drink beverage can also be bottled or
packaged in a unit that contains between 1-32 fluid ounces of
beverage (e.g., the unit may contain 1, 2, 5, 6.75, 8, 8.3.8.4,
8.45, 9.6, 10, 12, 15, 15.5, 16, 18.6, 20, 23, 24, or 32 fluid
ounces). Where a shelf-stable composition or solution is desired,
the packaging is appropriately sterilized before being filled by
the pasteurized, ultra-pasteurized, or sterilized composition or
solution. Where required for mutual stability of two or more
components (for example if a component is unstable at low pH), the
packaging may feature multiple containers that can be mixed shortly
before ingestion or that can be consumed serially.
EXAMPLES
General Procedures
TRP-Stim Solution
[0121] The solution ("TRP-Stim") administered to the volunteers
contained: a base of a 1:1 mixture of water and light karo syrup
(for increased viscosity); 0.075% of a capsicum preparation
intended for human use (Clearcap Super Soluble Caspsicum, Kalsec
Inc.); 1% of a cinnamon volatile oil intended for human consumption
(Aquaresin Cinnamon, Kalsec inc); and 1.5% of a ginger oleoresin
intended for human use (Aquaeresin Ginger, Kalsec Inc).
Electromyography (EMG) Measurements of Cramps
[0122] Methods for placing stimulating electrodes on the flexor
hallucis brevis (FHB) or gastroenemius muscles followed the
procedures described by Minetto et al., Muscle Nerve, 40: 535-544,
2009. The active stimulation electrode (cathode) was a 1.25''
circular mesh-backed silver patch electrode (Reliamed) and was
placed so as to produce contraction of the FHB with minimal
stimulation amplitude. The stimulation reference electrode was a
2'' square patch electrode (Reliamed) placed on the opposite side
of the foot. Cramping of the FHB was induced as described by
Minetto et al. (ibid.) using a battery-powered electrical muscle
stimulator (EMS-7500, Current Solutions LLC) to deliver pulses. A
series of 180 microsecond biphasic square pulses of voltages were
applied at various frequencies to stimulate the muscle. First,
using slow (2 Hz) stimulation, the amplitude was adjusted to
.about.30% more than the threshold amplitude for eliciting strong
contraction of the muscle. The muscle was then stimulated by a
train of 180 microsecond pulses of this amplitude delivered for 5
seconds at various frequencies. The stimulation delivered by the
stimulator also including "ramp up" and "ramp down" periods of 1
second preceding and following the main 5-sec stimulation period
during which the amplitude of the pulses was ramped up or down to
and from the final value.
[0123] It has been previously shown that susceptibility to cramping
of the FHB using similar electrical stimulation protocols is highly
reproducible within each subject (Minetto et al., Muscle Nerve,
37:90-100, 2008) and is correlated with susceptibility to "ordinary
muscle cramps" (Miller et al., Muscle Nerve, 39:364-368, 2009).
[0124] Cramping was quantified by making EMG recordings from the
belly of the FHB. Two external EMG recording electrodes (Vermed
SilveRest) were placed along the belly of the FHB. The differential
voltage relative to a third ground electrode placed at the ankle
was amplified, digitized, and saved to computer using an I-330-C2+
EMG unit with PhysioLab software (J&J Engineering. Poulsbo,
Wash.). The raw wide-band EMG signal (10-400 Hz) was processed by
being rectified and integrated to provide the area under the curve
(RMS). The duration of cramp was quantified by the time required
for the RMS EMG to return to an amplitude of 3 standard deviations
above the baseline value. This correlated well with duration of the
cramp as observed by the return to the toe to resting position.
[0125] Recordings of cramps in calf muscles (medial gastroenemius)
were made using similar procedures, with placement of stimulation
and recording electrodes following that by Minetto et al., Muscle
Nerve, 40:535-544, 2009. The amplitude of stimulation by a single
180 microsecond biphasic square pulses was adjusted to be
.about.30% of the amplitude required for maximal contraction of the
muscle. After a short period of slow stimulation (2 Hz), the
frequency of stimulation was ramped up to 22-24 Hz over .about.5
seconds and held at this frequency for an additional 5 seconds
before terminating the stimulation. This protocol reliably induced
cramping of 30-90 seconds.
[0126] Assay of Activation of Rat Sensory Neurons Methods to
monitor activation of primary sensory neurons isolated from the
trigeminal ganglion of rats followed those published by Park et
al., Journal of Biological Chemistry, 281:17304-17311, 2006). Cells
isolated from rat trigeminal ganglia were loaded with the
fluorescent calcium indicator Fura-2AM (Fura-2-acetoxymethyl
ester), and increases in intracellular calcium reflecting
activation of the neurons were measured as an increase in Fura-2
fluorescence as measured by digital video micro-fluorometry with an
intensified CCD camera. The same capsicum extract, cinnamon
extract, and ginger extract used in the TRP-Stim beverage were
applied to the neurons after being diluted in balanced salt
solution (in mM: 145 NaCl. 5 KC, 2 CaCl.sub.2, 1 MgCl.sub.2, 10
HEPES, and 10 glucose) which perfused the neurons. Caspicum extract
was applied at a dilution of 1/800,000, cinnamon extract at a
dilution of 1/5,000, and ginger extract at a dilution of 1/12,000.
In some experiments the calcium ionophore ionomycin was added
following the tests with extracts to produce a large entry of
calcium as an index of the maximal possible signal, illustrating
the strength of activation by the heavily diluted extracts.
Example 1: Activation of Rat Sensory Neurons by Capsicum, Cinnamon,
and Ginger Extracts
[0127] FIG. 1 shows graphs from six sensory neurons isolated from
the trigeminal ganglia of rats, illustrating their activation by
the capsicum, cinnamon, and ginger extracts that were used in the
human experiments. Activation was quantified as an increase in
intracellular free calcium, monitored by a fluorescent calcium
indicator. Extracts were diluted into normal extracellular saline
(Tyrode's solution) and were tested at lower concentrations than
used in the beverage, taking account that concentrations present at
nerve endings in mouth, esophagus, or stomach are expected to be
lower than the beverage as a result of dilution into mucosa and
interstitial fluid. All three extracts were capable of activating
individual neurons when applied at concentrations 50-fold to
15,000-fold lower than used in the beverage. Each trace shows a
record from a different neuron, illustrating that some neurons
could be activated by each of the extracts and that the strength of
activation by each extract varied among particular neurons. These
records illustrate that each agent is capable of acting alone to
activate some neurons and that a combination of agents can produce
stronger activation of a larger fraction of neurons. Further, the
bottom two records show that there can be strongly synergistic
activation of neurons by the capsicum extract and the ginger
extract when applied in combination.
Example 2: Effect of TRP-Stim Administration to Human Subjects
[0128] The in vitro data of Example 1 show that each individual
component of the TRP-Stim solution by itself was capable of
activating sensory neurons. Consistent with this, human experiments
showed the efficacy of a beverage with capsicum alone (ClearCap
capsicum at 1/2000 dilution) to inhibit cramping, achieved within 5
minutes.
[0129] The in vitro data also show that combinations of channel
activators can not only show the desired activity, but can also
provide synergistic effects. The following experiments, illustrated
by FIGS. 2-8, show cramp relief by the administration of a uniform
beverage composition designed for maximal TRP stimulation
containing capsicum, cinnamon extract, and ginger extract, and
where the physiological effects were monitored by EMG
recording.
[0130] FIGS. 2-8 are graphs of EMG recordings of muscle
contractions in seven human volunteers (four females and three
males) that show the efficacy in preventing and treating cramps of
ingesting 50 mL of a solution designed to stimulate TRPV1 and TRPA1
receptors in the mouth, esophagus, and stomach. Muscle cramps were
induced by brief stimulation of toe or calf muscles (FIGS. 2-7) or
occurred spontaneously (FIG. 8). After recording cramping in
control, subjects drank 50 mL of the TRP-Stim solution containing
capsaicin and capsaicinoids (TRPV1 agonists), cinnamaldehyde (TRPA1
agonist), and gingerols (TRPA1 and TRPV1 agonists). After ingestion
of the solution, subjects were tested for muscle cramping using the
same procedures as in control at times ranging from 4 minutes to 11
hours after ingestion.
[0131] Eight human volunteers were tested using the TRP-Stim
beverage. Seven of the eight showed a complete abolition or
dramatic reduction in cramping following ingestion of the beverage
(FIGS. 2-8). The effect was typically complete within 4-15 minutes
and lasted for 21/2 to 4 hours in different subjects. An eighth
subject showed cramping of the FHB that was not dramatically
affected by the TRP-Stim beverage. The cramping in this subject was
of much lower EMG amplitude that the other subjects and appeared to
involve repetitive contraction of only a few motor units.
[0132] FIG. 2 is a graph showing the effect of the TRP-Stim
beverage on cramping of the flexor hallucis brevis of Subject A.
Under control conditions, cramping was reliably induced by
stimulating the muscle using an electrical muscle stimulator
(EMS-7500, Current Solutions LLC) placed with external electrodes
for FHB stimulation. Muscle activity was recorded using external
electrodes placed over the belly of the muscle attached to an EMG
amplifier (J&J Engineering I-330C2+). In control, stimulation
using 180 microsecond biphasic pulses delivered at 18 Hz for 5
seconds reliably and reproducibly produced cramping of the muscle,
which was evident by EMG activity continuing after the cessation of
stimulation. After ingestion of the TRP-Stim beverage, cramping was
very brief after 11 minutes and essentially absent at tests at 20
minutes and 2% hours after ingestion.
[0133] FIG. 3 is a graph showing the effect of the TRP-Stim
beverage on cramping of the flexor hallucis brevis of a second
subject. Under control conditions, cramping was induced by
stimulation at 10 Hz for 5 seconds (180 microsecond pulses,
amplitude set to .about.30% higher than threshold for muscle
contraction), and a longer cramp was induced by increasing the
frequency to 12 Hz. In recordings beginning 12 minutes after
ingestion of the TRP-Stim beverage, stimulation at 10 Hz or 12 Hz
produced essentially no cramping, and increasing the frequency of
stimulation to 14 Hz also did not induce cramping. The dramatic
reduction in cramping was still present 4 hours later in this
subject.
[0134] FIG. 4 is a graph showing the effect of the TRP-Stim
beverage on cramping of the flexor hallucis brevis of a third
subject tested over longer times. Under control conditions, a cramp
lasting 58 seconds was induced by stimulation at 18 Hz for 5
seconds (180 microsecond pulses, amplitude set to .about.30% higher
than threshold for muscle contraction). After ingestion of the
TRP-Stim beverage, the duration of the cramp was reduced to 27
seconds after 8 minutes and to 8 seconds after 15 minutes. Cramping
was abolished after 20 minutes and in a test after 2 hours. In
tests 11 hours after ingestion, reliable cramping had returned.
After the subject again drank 50 mL of the TRP-Stim beverage,
cramping was completely abolished in tests beginning after 10
minutes.
[0135] FIG. 5 is a graph showing the effect of the TRP-Stim
beverage on cramping of the flexor hallucis brevis of a fourth
subject. This subject had engaged in strenuous exercise (triathlon)
four hours earlier and was experiencing muscle twitchiness. This
subject had an unusually low frequency threshold (8 Hz) for
induction of cramping in the FHB muscle, and the resulting cramps
were unusually long (172 seconds after 8 Hz stimulation and 222
seconds after 10 Hz stimulation). Cramping was completely gone in
tests starting 13 minutes after ingestion of the TRP-Stim beverage,
even when increasing the stimulation frequency to 12 Hz. Cramping
was still abolished 3 hours later. After 4 hours, cramping returned
with an increased frequency threshold (10 Hz) and shorter cramps
than in control. After the subject again drank 50 mL of the
TRP-Stim beverage, cramping was again completely abolished.
[0136] FIG. 6 is a graph showing the effect of the TRP-Stim
beverage on cramping of the gastroenemius (calf) muscle of a fifth
subject. The muscle was stimulated by a protocol ramping the
frequency of stimulation from 2 Hz to 28 Hz (180 microsecond
pulses, amplitude set to .about.30% higher than threshold for
muscle contraction). After cessation of stimulation, the muscle
went into a prolonged cramp lasting 59 seconds. In a test 3 minutes
after ingestion of 50 mL of TRP-Stim, cramping was abolished.
[0137] FIG. 7 is a graph showing the effect of the TRP-Stim
beverage on cramping of the gastroenemius (calf) muscle of a sixth
subject. The muscle was stimulated by a protocol ramping the
frequency of stimulation from 2 Hz to 24 Hz (180 microsecond
pulses, amplitude set to .about.30% higher than threshold for
muscle contraction). After cessation of stimulation, the muscle
went into a prolonged cramp lasting 96 seconds. In a test 4 minutes
after ingestion of 50 mL of TRP-Stim, cramping was abolished.
Cramping was still abolished in a test conducted 40 minutes
later.
[0138] FIG. 8 is a graph showing the effect of the TRP-Stim
beverage on cramping of an FHB muscle in a seventh subject, who
experienced spontaneous cramping induced by pointing her toe. In
control conditions, voluntary toe flexes lasting .about.5 seconds
reliably produced cramping of the FHB lasting 5-8 seconds in
different trials. Ten minutes after the subject ingested 50 mL of
the TRP-Stim beverage, cramping was abolished.
OTHER EMBODIMENTS
[0139] From the foregoing description, it is apparent that
variations and modifications may be made to the invention described
herein to adopt it to various usages and conditions. Such
embodiments are also within the scope of the following claims.
[0140] All publications, patent applications, and patents mentioned
in this specification are herein incorporated by reference to the
same extent as if each independent publication, patent application,
or patent was specifically and individually indicated to be
incorporated by reference.
* * * * *