Note: Descriptions are shown in the official language in which they were submitted.
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VETERINARY SUPPLEMENTS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. 119(e) of U.S.
Provisional
Application No. 61/753,544 filed January 17, 2013, the entire contents of
which are incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] Oxidative stress is a condition characterized by elevated levels of
free radicals and
reactive oxygen species in the blood stream. Oxidative stress occurs in a
variety of animals, and
is associated with a variety of diseases and conditions, including
inflammation, joint disorders,
arthritis, cognitive dysfunction, diabetes, pancreatitis, respiratory
diseases, and cardiac and
vision disorders. Symptoms of oxidative stress in animals include
disorientation, decreased
social interaction, loss of prior house training, sleep disturbance, and
decreased mobility.
Oxidative stress is also thought to contribute to certain illnesses, such as
viral infections,
including feline immunodeficiency virus, and to genetically predisposed
conditions, including
canine hip dysplasia and asthma. Accordingly, a need exists for veterinary
supplements that treat
or prevent oxidative stress and the associated diseases and conditions.
[0003] Nuclear factor erythroid-2-related factor 2 (Nr12) is a transcription
factor that plays a
central role in the Nrf2 antioxidant response pathway. Nr12 regulates the
expression of several
antioxidant enzymes. Under normal conditions, Nrf2 is kept in the cytoplasm by
a cluster of
proteins that degrade it quickly. Under oxidative stress, Nrf2 is not
degraded, but instead travels
to the nucleus where it binds to DNA and activates transcription of
antioxidative and
cytoprotective genes and ultimately their protein products, which enable cells
to survive in the
face of stress from free radicals and other antioxidants. Nr12 also down-
regulates other genes
that promote inflammation and fibrosis.
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SUMMARY OF THE INVENTION
[0004] Disclosed herein are veterinary supplements comprising one or more Nrf2-
activating
agents. In some embodiments, the veterinary supplements further comprise omega-
3 fatty acids.
In some embodiments, the veterinary supplements further comprise collagen. In
some
embodiments, the veterinary supplements further comprise omega-3 fatty acids
and collagen.
[0005] In some embodiments, the one or more Nrf2-activating agents are
selected from the
group consisting of Bacopa extract, thistle
extract, Ashwagandha extract, green tea extract,
turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf
extract, N-Acetyl
Cysteine, piperine, resveratrol, pterostilbene, sulfurophane, ginger,
cinnamon, wasabi, carnosic
acid, lipoic acid, licorice, lycopene, and combinations thereof.
[0006] In some embodiments, the one or more Nrf2-activating agents are
selected from the
group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract,
green tea extract,
turmeric extract, and combinations thereof.
[00071 In some embodiments, the one or more Nrf2-activating agents comprises
Bacopa
extract, milk thistle extract, Ashwagandha powder, green tea extract, and
turmeric extract.
[0008] In some embodiments, the veterinary supplements comprise Type II
chicken sternum
collagen.
[0009] In some embodiments, the one or more Nrf2-activating agents is present
in an amount of
from about 100 mg to about 200 mg, said omega-3 fatty acids are present in an
amount of about
100 mg to about 300 mg, and said collagen is present in an amount of from
about 75 mg to about
175 mg. In some embodiments, the veterinary supplements of embodiment 4,
wherein said one
or more Nrf2-activating agents is present in an amount of from about 125 mg to
about 175 mg,
said omega-3 fatty acids are present in an amount of about 150 mg to about 250
mg, and said
collagen is present in an amount of from about 100 mg to about 150 mg. In some
embodiments,
the one or more Nrf2-activating agents is present in an amount of about 150
mg, said omega-3
fatty acids are present in an amount of about 200 mg, and said collagen is
present in an amount
of about 125 mg.
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[0010) In some embodiments, the veterinary supplements comprise at least about
50 mg milk
thistle extract, at least about 33.33 mg Ashwagandha extract, at least about
16.67 mg green tea
extract, at least about 33.33 mg B. monniera extract, at least about 16.67 mg
Turmeric extract, at
least about 200 mg omega-3 fatty acids, and at least about 125 mg of collagen.
[0011] In some embodiments, the veterinary supplements comprise about 50 mg
milk thistle
extract, about 33.33 mg Ashwagandha extract, about 16.67 mg green tea extract,
about 33.33 mg
B. monniera extract, about 16.67 mg Turmeric extract, about 200 mg omega-3
fatty acids, and
about 125 mg of collagen.
[0012] In some embodiments, the veterinary supplements comprise inactive
ingredients
selected from the group consisting of dicalcium phosphate, hydoxypropyl
cellulose,
hydroxylpropyl methylcellulose, magnesium stearate, maltodextrin,
microcrystalline cellulose,
silicon dioxide, stearic acid, sucrose fatty acid ester, chicken flavoring,
chicken liver flavoring,
smoked bacon flavoring, and combinations thereof.
[0013] Disclosed herein are methods of administering a veterinary supplement
comprising one
or more Nrf2-activating agents to an animal. In some embodiments, the
veterinary supplements
further comprise omega-3 fatty acids. In some embodiments, the veterinary
supplements further
comprise collagen. In some embodiments, the veterinary supplements further
comprise omega-3
fatty acids and collagen.
[0014) In some embodiments, the methods disclosed herein treat, inhibit,
reduce, and/or prevent
oxidative stress. In some embodiments, the method treats, inhibits, reduces,
and/or prevents
conditions associated with oxidative stress. In some embodiments, the method
treats, inhibits,
reduces, and/or prevents conditions associated with oxidative stress are
selected from the group
consisting of inflammation, joint disorders, arthritis, cognitive dysfunction,
diabetes, pancreatitis,
respiratory diseases, cardiac disorders, vision disorders, and combinations
thereof. In some
embodiments, the method supports joint function, improves mobility and
flexibility, enhances
cognitive function, and combinations thereof.
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DETAILED DESCRIPTION OF THE INVENTION
[0001] Disclosed herein are veterinary supplements for treating, inhibiting,
reducing, and/or
preventing oxidative stress. In some embodiments, the veterinary supplements
disclosed herein
treat, inhibit, reduce, and/or prevent conditions associated with oxidative
stress, including but not
limited to inflammation, joint disorders, arthritis, cognitive dysfunction,
diabetes, pancreatitis,
respiratory diseases, and cardiac and vision disorders. In some embodiments,
veterinary
supplements disclosed herein support joint function, improve mobility and
flexibility, enhance
cognitive function, and combinations thereof.
[0002] The veterinary supplements dis losed herein may be used in any suitable
animals,
including domestic animals (e.g., dogs, cats, and the like), farm animals
(e.g., cows, sheep, pigs,
horses, and the like), and laboratory animals (e.g., rats, mice, guinea pigs,
and the like). The
veterinary supplements disclosed herein include optimal dosages for the
particular patient
animal. For example, in some embodiments, the dosage is optimal for the
specific weight or
weight range of the patient animal species.
[0003] In some embodiments, the veterinary supplements disclosed herein
comprise Nrf2-
activating agents. As used herein, a "Nr12-activating agent" is a chemical
compound, biological
molecule, composition, formulation, and/or extract that activates
transcription of antioxidative
and/or cytoprotective genes through the Nrf2 antioxidant response pathway.
[0004] In certain embodiments, the veterinary supplements disclosed herein
comprise Nrf2-
activating agents in an effective amount. An "effective amount" is a quantity
provided by a
particular route of administration and dosing regimen that is sufficient to
achieve a desired
therapeutic, inhibitory, and/or prophylactic effect. For example, an effective
amount of a Nrf2-
activating agent is a quantity provided by a particular route of
administration and dosing regimen
that is sufficient to activate transcription of antioxidative and
cytoprotective genes through the
Nre antioxidant response pathway and treat, inhibit, reduce, and/or prevent
oxidative stress in
the patient animal.
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[0005] As used herein, the term "about," when located before a dosage amount
or dosage range
of a specific ingredient, refers to an amount or range closely above and/or
closely below the
stated amount or range that does not manifestly alter the therapeutic effect
of the specific
ingredient from the stated amount or range and is meant to encompass at least
all equivalents of
that amount. In some specific embodiments, the term "about," when located
before a dosage
amount or dosage range of a specific ingredient, refers to an amount or range
that is 10% of the
stated amount or range. Numerical quantities given herein are approximate
unless stated
otherwise, meaning that the term "about" can be inferred when not expressly
stated.
[0006] In some specific embodiments, an effective amount of a Nrf-2 activating
agent is from
about 25 mg to about 1,000 mg, or from about 50 mg to about 750 mg, or from
about 75 mg to
about 60 mg, or from about 100 mg to about 500 mg, or from about 100 mg to
about 200 mg, or
from about 125 mg to about 175 mg. In certain specific embodiments, an
effective amount of a
Nrf-2 activating agent is about 25 mg, about 50 mg, about 75 mg, about 100 mg,
about 125 mg,
about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about
275 mg, about
300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 750 mg,
or about
1,000 mg. In a specific embodiment, an effective amount of a Nrf-2 activating
agent is at least
about 150 mg.
[0007] In certain embodiments, Nrf2-activating agents include plant extracts
or powders.
Suitable Nr12-activating agents for use in the veterinary supplements
disclosed herein include
Bacopa extract, milk thistle extract, Ashwagandha powder, green tea extract,
turmeric extract,
Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N-Acetyl
Cysteine, piperine,
resveratrol, pterostilbene, sulfurophane, ginger, cinnamon, wasabi, camosic
acid, lipoic acid,
licorice, lycopene, and combinations thereof.
[0008] Bacopa monniera
[0009] Bacopa monniera (common names: water hyssop and Brahmi) is a creeping
perennial
that thrives in warmer temperate climates. The genus Bacopa includes over 100
species of
aquatic herbs distributed throughout the warmer regions of the world. The
plant is a profusely
branched herb, rooting at the nodes and forming dense mats. B. monniera
extract (Bacopine) is
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a standardized extract prepared from the leaves of the B. monniera plant
(Sabinsa Corporation,
Piscataway, N.J., USA). In some embodiments, it is standardized for a minimum
of 20%
bacosides A 8c B. Other extracts of the B. monniera plant standardized for
greater minimum
levels of bacosides A & B (e.g., 30%, 40%, 50%, etc.) are useful in the
veterinary supplements
disclosed herein and can be prepared by extraction techniques known in the
art. Extract of B.
monniera is commercially available, e.g., Viable Herbal Solutions
(Morrisville, Pa., USA).
[0010] In some embodiments, the veterinary supplements disclosed herein
comprise from about
1 mg to about 1,000 mg B. monniera extract, or from about 10 mg to about 500
mg B. monniera
extract, or from about 20 mg to about 100 mg B. monniera extract. In a
specific embodiment, at
least about 33.33 mg B. monniera extract is contained in the veterinary
supplements disclosed
herein. In a specific embodiment, about 33.33 mg B. monniera extract is
contained in the
veterinary supplements disclosed herein. In certain embodiments, the B.
monniera extract of the
herb-containing composition is Bacopin .
[0011] In a specific embodiment, veterinary supplements disclosed herein
contain a B.
monniera extract standardized for at least about 20% bacosides A & B. In
another specific
embodiment, veterinary supplements disclosed herein contain a B. monniera
extract standardized
for at least about 30% bacosides A & B. In another specific embodiment,
veterinary
supplements disclosed herein contain a B. monniera extract standardized for at
least about 40%
bacosides A & B. In another specific embodiment, veterinary supplements
disclosed herein
contain a B. monniera extract standardized for at least about 50% bacosides A
& B. In another
specific embodiment, veterinary supplements disclosed herein contain a B.
monniera extract
standardized for about 50% bacosides A & B.
[0012] Milk Thistle
[0013] Milk thistle (botanical name; Silybum marianum; other common names:
Marian,
Silybum, Silymarin) is a fine, tall plant, about the size of the Cotton
Thistle, with cut into root-
leaves, waved and spiny at the margin, of a deep, glossy green, with milk
white veins, and is
found not uncommonly in hedgebanks and on waste ground. Useful parts of the
plant include,
e.g., the whole herb, root, leaves, seeds, and hull. Milk thistle seeds
contain a bioflavonoid
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complex known as silymarin. Silymarin is an extract of the seeds of the milk
thistle plant. In
some embodiments, a standardized extract should be 80% silymarin (the active
ingredient).
Silymarin is made up of three parts: silibinin, silidianin, and silicristin.
Milk thistle (80%
silymarin) extract is commercially available, e.g., Stayleaner.com (Las Vegas,
Nev., USA).
[0014] In some embodiments, the veterinary supplements disclosed herein
comprise from about
15 mg to about 2,000 mg milk thistle extract (70%-80% silymarin), or from
about 25 mg to
about 500 mg milk thistle extract (70%-80% silymarin), or from about 40 mg to
about 150 mg
milk thistle extract (70%-80% silymarin). In a specific embodiment the
veterinary supplements
disclosed herein comprise at least about 50 mg milk thistle extract (70%-80%
silymarin). In a
specific embodiment the veterinary supplements disclosed herein comprise about
50 mg milk
thistle extract (70%-80% silymarin).
[0015] In some embodiments, the veterinary supplements disclosed herein
comprise from about
15 mg to about 2,000 mg milk thistle extract, or from about 25 mg to about 500
mg milk thistle
extract, or from about 40 mg to about 150 mg milk thistle extract. In a
specific embodiment the
veterinary supplements disclosed herein comprise at least about 50 mg milk
thistle extract. In a
specific embodiment the veterinary supplements disclosed herein comprise about
50 mg milk
thistle extract.
[0016] Ashwagandha
[0017] Ashwagandha (botanical names: Withania somnifera and Physalis flexuosa;
other
common names: winter cherry, Ashgandh, Achuvagandi, Amikkira-gadday, Amkulang-
kalang,
Amukkira-kilzhangu, Amukran-kizhangu, Asagandha, Asana, Asgandh, Asundha,
Asvagandhi,
Fatarfoda, Hirimaddina-gadday, Hirre-gadday, Penneroo-gadda, Pevette, Sogade-
beru, Indian
ginseng) is an erect branched shrub native to India, Pakistan and Sri Lanka.
Ashwaganda
powder is commercially available, e.g., iHerb Inc. (Monrovia, Calif., USA).
[0018] In some embodiments, the veterinary supplements disclosed herein
comprise from about
1 mg to about 1,000 mg Ashwagandha root extract, or from about 10 mg to about
500 mg
Ashwagandha root extract, or from about 20 mg to about 100 mg Ashwagandha root
extract. In
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a specific embodiment, the veterinary supplements disclosed herein comprise at
least about 33.33
mg Ashwagandha root extract. In a specific embodiment, the veterinary
supplements disclosed
herein comprise about 33.33 mg Ashwagandha root extract.
[0019] In some embodiments, the veterinary supplements ,disclosed herein
comprise from about
1 mg to about 1,000 mg Ashwagandha powder, or from about 10 mg to about 500 mg
Ashwagandha powder, or from about 20 mg to about 100 mg Ashwagandha powder. In
a
specific embodiment, the veterinary supplements disclosed herein comprise at
least about 33.33
mg Ashwagandha powder. In a specific embodiment, the veterinary supplements
disclosed
herein comprise about 33.33 mg Ashwagandha powder.
[0020] Turmeric
[0021] Turmeric extract 95% is prepared from the root or rhizome of the
Curcuma longa plant
(common names: Curcurna, Turmeric, 1."' on, Goeratji, Kakoenji, Koenjet,
Kondin, Kunir,
Kunyit, Oendre, Rame, Renet, Temu kuning, Temu kunyit, Tius. Curcumin). C.
longa is a
perennial plant native to India. A compound called curcumin is an extract of
the root. In some
embodiments, turmeric extract that is standardized to 95% curcumin contains
turmeric (with
95% curcumin). Turmeric extract 95% is commercially available, e.g., EZ-
FITNESS
(Northborough, Mass., USA).
[0022] In some embodiments, the veterinary supplements disclosed herein
comprise from about
1 mg to about 1,000 mg Turmeric extract, or from about 10 mg to about 300 mg
Turmeric
extract, or from about 12.5 mg to about 100 mg Turmeric extract. In a specific
embodiment, the
veterinary supplements disclosed herein comprise, at least about 16.67 mg
Turmeric extract. In a
specific embodiment, the veterinary supplements disclosed herein comprise,
about 16.67 mg
Turmeric extract.
[0023] In some embodiments, the veterinary supplements disclosed herein
comprise from about
1 mg to about 1,000 mg Turmeric extract (95% curcumin), or from about 10 mg to
about 300 mg
Turmeric extract (95% curcumin), or from about 12.5 mg to about 100 mg
Turmeric extract
(95% curcumin). In a specific embodiment, the veterinary supplements disclosed
herein
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comprise, at least about 16.67 mg Turmeric extract (95% curcumin). In a
specific embodiment,
the veterinary supplements disclosed herein comprise, about 16.67 mg Turmeric
extract (95%
curcumin).
[0024] Gotu kola
[0025] Gotu kola (botanical names: Hydrocotyle asiatica, Centella asiatica;
other common
names: Centella, March Pennywort, Indian Pennywort, Hydrocotyle, Brahmi
(Sanskrit), Luei
Gong Gen (Chinese)) is a slender, creeping perennial plant that grows commonly
in swampy
areas of India, Sri Lanka, Madagascar, South Africa and the tropics. Gotu kola
is distinct from
the kola nut. Gotu kola powder is prepared from the leaves and aerial parts of
the plant and used
for medicinal purposes. Gotu kola powder is commercially available, e.g.,
@Internatural (Twin
Lakes, Wis., USA).
[0026] In some embodiments, the veterinary supplements disclosed herein
comprise, from
about 10 mg to about 4,000 mg Gotu koi', powder, or from about 25 mg to about
2,000 mg Gotu
kola powder, or from about 50 mg to about 1,000 mg Gotu kola powder. In a
specific
embodiment, the veterinary supplements disclosed herein comprise at least
about 200 mg Gotu
kola powder. In a specific embodiment, the veterinary supplements disclosed
herein comprise
about 200 mg Gotu kola powder.
[0027] Aloe vera
[0028] Aloe vera (common names: medicinal aloe, burn plant, Barbados aloe,
unguentine
cactus) is a perennial plant. The strong, fibrous root produces a rosette of
fleshy basal leaves as
in the agave but considerably smaller that grows wild in East and South Africa
and also
cultivated in the West Indies and other tropical areas. Aloe vera powder is
commercially
available, e.g., Red Lion International Trading & Brokerage Co. (Fullerton,
Calif., USA).
[0029] In some embodiments, the veterinary supplements disclosed herein
comprise from about
mg to about 4,000 mg Aloe vera powder, or from about 25 mg to about 2,000 mg
Aloe vera
powder, or from about 50 mg to about 1,000 mg Aloe vera powder. In a specific
embodiment,
the veterinary supplements disclosed herein comprise at least about 200 mg
Aloe vera powder.
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In a specific embodiment, the veterinary supplements disclosed herein comprise
about 200 mg
Aloe vera powder.
[0030] Green Tea
[0031] Green tea extracts are useful in the compositions of the present
invention. In some
embodiments of the compositions of the invention, the green tea extract is
standardized for
polyphenols. For example, green tea extract, 98% polyphenols containing 45%
polyphenols
such as polyphenol (-)-epigallocatechin gallate (EGCG) is prepared from the
leaf of the tea herb
Camellia sinensis. Green tea extracts are commercially available, e.g., Hunan
Kinglong Bio-
Resource Co., Ltd., (Xingsha, Changsha, Hunan, P. R. China).
[0032] In some embodiments, the veterinary supplements disclosed herein
comprise from about
1 mg to about 1,000 mg green tea extract, or from about 10 mg to about 300 mg
green tea
extract, or from about 12.5 mg to about 100 mg green tea extract. In a
specific embodiment, the
veterinary supplements disclosed herein comprise at least about 16.67 mg green
tea extract. In a
specific embodiment, the veterinary supplements disclosed herein comprise
about 16.67 mg
green tea extract.
[0033] In some embodiments, the veterinary supplements disclosed herein
comprise from about
1 mg to about 1,000 mg green tea extract (98% polyphenols, 45% EGCG), or from
about 10 mg
to about 300 mg green tea extract (98% polyphenols, 45% EGCG), or from about
12.5 mg to
about 100 mg green tea extract (98% polyphenols, 45% EGCG). In a specific
embodiment, the
veterinary supplements disclosed herein comprise at least about 16.67 mg green
tea extract (98%
polyphenols, 45% EGCG). In a specific embodiment, the veterinary supplements
disclosed
herein comprise about 16.67 mg green tea extract (98% polyphenols, 45% EGCG).
[0034] Gingko biloba
[0035] Ginkgo biloba (common name: Maidenhair tree) is a dioecious tree. Ginko
biloba
extract is commercially available, e.g., from iHerb Inc. (Monrovia, Calif.,
USA).
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[00361 In some embodiments, the veterinary supplements disclosed herein
comprise from about
mg to about 2,000 mg G. biloba leaf extract, or from about 10 mg to about
1,000 mg G. biloba
leaf extract, or from about 50 mg to about 500 mg G. biloba leaf extract. In a
specific
embodiment, the veterinary supplements disclosed herein comprise at least
about 200 mg G.
biloba leaf extract. In a specific embodiment, the veterinary supplements
disclosed herein
comprise about 200 mg G. biloba leaf extract.
[00371 N-Acetyl Cysteine
[0038] N-Acetyl Cysteine (NAC) is an acetylated form of the amino acid
cysteine. N-Acetyl
Cystein is commercially available, e.g., Doctor's Trust Vitamins (Orlando,
Fla., USA).
[0039] In some embodiments, the veterinary supplements disclosed herein
comprise from about
50 mg to about 5,000 mg N-Acetyl Cysteine, or from about 100 mg to about 4,000
mg N-Acetyl
Cysteine, or from about 250 mg to about 2,000 mg N-Acetyl cysteine. In a
specific embodiment,
the veterinary supplements disclosed herein comprise at least about 500 mg N-
Acetyl Cysteine.
In a specific embodiment, the veterinary supplements disclosed herein comprise
about 500 mg
N-Acetyl Cysteine.
100401 Piperine
[00411 Piperine is an alkaloid that can be isolated from black pepper, white
pepper, and long
pepper. Chavicine is an isomer of piperine. Piperine is commercially available
as an extract of
black pepper (BioPerinee) or as the isolated compound (e.g., from Sigma-
Aldrich ).
[0042] Resveratrol
[00431 Resveratrol is a stilbenoid and phytoalexin that is produced naturally
by several plants,
including grapes. Resveratrol is commercially available in various extracts or
as the isolated
compound (e.g., from Sigma-Aldrich ).
[00441 Pterostilbene
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[0045] Pterostilbene is a stilbenoid and phytoalexin that is produced
naturally by blueberries
and grapes. Pterostilbene is commercially available in various extracts or as
the isolated
compound (e.g., from Sigma-Aldrich ).
[0046] Sulforaphane
[0047] Sulforaphane is an isothiocyanate-containing molecule that is found in
cruciferous
vegetables such as broccoli, Brussels sprouts, and cabbages. Sulforaphane is
commercially
available in various extracts or as the isolated compound (e.g., from Sigma-
Aldrich ).
[0048] Ginger
[0049] Ginger is the rhizome of the plant Zingiber officinale. Various
formulations and extracts
of ginger are commercially available.
[0050] Cinnamon
[0051] Cinnamon, sometimes referred to specifically as "true cinnamon" or
"cassia," is a spice
obtained from the inner bark of trees from the genus Cinnamomum, including
Cinnamomum
verum. Various formulations and extracts of cinnamon are commercially
available.
[0052] Wasabi
[0053] Wasabi is a member of the Brassicaceae family of plants. Wasabi is
available in
powder and paste forms.
[0054] Carnosic Acid
[0055] Carnosic acid is a benzenediol abietane diterpene found in rosmarius
officinalis and
Salvia officinalis. Carnosic acid is commercially available in various plant
extracts or as the
isolated compound (e.g., from Sigma-Aldrich ).
[0056] Lipoic Acid
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[0057] Lipoic acid (also known as ct-lipoic acid) is found in many natural
food sources, but is
more prevalent in kidney, heart, liver, spinach, broccoli, and yeast extract.
The amount of lipoic
acid present is food sources is typically quite low, but the compound can be
synthesized by
methods known in the art. Purified lipoic acid is commercially available
(e.g., from Sigma-
Aldrich0).
[0058] Licorice
[0059] Licorice is the root of Glycyrrhiza glabra. Various extracts of
licorice are commercially
available.
[0060] Lycopene
[0061] Lycopene is a bright red carotenoid (carotene) pigment and
phytochemical found in
various red fruits and vegetables, including tomatoes, red carrots, red bell
peppers, watermelons,
gac, and papayas. Lycopene is available in various plant extracts (e.g., from
Sigma-Aldrich ).
[0062] In some embodiments, veterinary supplements disclosed herein further
comprise omega-
3 fatty acids, collagen, or a combination thereof.
[0063] In some embodiments, omega-3 catty acids include docosahexaenoic acid
(DHA),
eisocapentaenoic acid (EPA), a-linolenic acid (ALA), and combinations thereof.
In some
embodiments, the source for omega-3 fatty acids is a marine source, including
but not limited to
fish oils, algal oil, and squid oil. In certain embodiments, the source of
omega-3 fatty acids is
plant oils.
[0064] In certain embodiments, an effective amount of omega-3 fatty acids is
an amount from
about 25 mg to about 1,000 mg, or from about 50 mg to about 800 mg, or from
about 75 mg to
about 600 mg, from about 100 mg to about 300 mg, or from about 150 mg to about
250 mg. In
certain specific embodiments, an effective amount of omega-3 fatty acids is
about 25 mg, about
50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg,
about 300 mg,
about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 750 mg, or about
1,000 mg. In
a specific embodiment, an effective amount of omega-3 fatty acids is at least
about 200 mg
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omega-3 fatty acids. In a specific embodiment, an effective amount of omega-3
fatty acids is
about 200 mg omega-3 fatty acids.
[0065] In some embodiments, the source of collagen is an animal. In certain
embodiments, the
collagen is a source of natural glucosamine, chondroitin, and hyaluronic
acids. In a specific
embodiment, veterinary supplements disclosed herein include collagen in the
form of Type II
collagen, for example, Type II chicken sternum collagen.
[0066] In certain embodiments, an effective amount of collagen is an amount
from about 25 mg
to about 500 mg, or from about 50 mg to about 300 mg, from about 100 mg to
about 300 mg,
from about 75 mg to about 175 mg, or from about 100 mg to about 150 mg. In
certain specific
embodiments, an effective amount of collagen is about 25 mg, about 50 mg,
about 75 mg, about
100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg,
about 300
mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In a specific
embodiment, an
effective amount of collagen is at least about 125 mg of collagen. In a
specific embodiment, an
effective amount of collagen is about 125 mg of collagen.
[0067] The veterinary supplements disclosed herein may be administered in
various therapeutic
and/or prophylactic methods. For example, the veterinary supplements disclosed
herein can be
administered to an animal to treat, inhibit, reduce, and/or prevent conditions
associated with
oxidative stress, including but not limite(j to inflammation, joint disorders,
arthritis, cognitive
dysfunction, diabetes, pancreatitis, respiratory diseases, and cardiac and
vision disorders. In
some embodiments, veterinary supplements disclosed herein can be administered
to an animal to
support joint function, improve mobility and flexibility, enhance cognitive
function, and
combinations thereof.
[0068] The veterinary supplements disclosed herein may be administered in
various dosage
forms. The term "dosage form," as used herein, is the form in which the dose
is to be
administered to the animal. Dosage forms, for example, may be solid, liquid or
gaseous. Dosage
forms may include, for example, a capsule, tablet, caplet, gel caplet
(gelcap), syrup, a liquid
composition, a powder, a concentrated powder, a concentrated powder admixed
with a liquid, a
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=
chewable form, a swallowable form, a d:isolvable form, an effervescent, a
granulated form, and
an oral liquid solution. In a specific embodiment, the dosage form is a
chewable tablet.
[0069] In some embodiments, the veterinary supplements disclosed herein are
prepared with
inactive ingredients that will protect the active agents from rapid
elimination from the body, such
as a controlled release formulation, implants, or microencapsulated delivery
system. Such
systems may improve bioavailability and stability of the active agents. The
dosage forms may be
administered by any suitable means, including but not limited to orally,
sublingually, nasally,
topically, parenterally, or intravenously. The dosage forms may be
administered as frequently as
needed until the desired therapeutic or prophylactic effect is achieved, for
example, once daily,
twice daily, thrice daily, etc.
[0070] In some embodiments, the veterinary supplements disclosed herein may
include
biologically or pharmacologically active agents useful for treating,
inhibiting, reducing, and/or
preventing oxidative stress other than those specifically disclosed herein.
For example, in certain
specific embodiments, the veterinary supplements disclosed herein may include
additional Nrf2-
activating ingredients other than those specifically disclosed herein. In some
embodiments, the
veterinary supplements disclosed herein may include biologically or
pharmacologically active
agents useful for treating, inhibiting, and/or preventing conditions or
symptoms associated with
oxidative stress. For example, in certain specific embodiments, the veterinary
supplements
disclosed herein include biologically or pharmacologically active agents that
treat, inhibit, and/or
prevent inflammation, joint disorders, artnritis, cognitive dysfunction,
diabetes, pancreatitis,
respiratory diseases, and cardiac and vision disorders. In some embodiments,
the veterinary
supplements disclosed herein include biologically or pharmacologically active
agents that
support joint function, improve mobility and flexibility, enhance cognitive
function, and
combinations thereof.
[00711 In some embodiments, the veterinary supplements disclosed herein may
include other
biologically or pharmacologically inactive agents. In certain embodiments,
said inactive
ingredients include, but are not limited to, binders, diluents, lubricants,
glidants, colorants,
emulsifiers, disintegrants, starches, water, oils, alcohols, preservatives,
sugars, and flavoring
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agents. In certain specific embodiments, the inactive ingredients are selected
from the group
consisting of dicalcium phosphate, hydc õypropyl cellulose, hydroxylpropyl
methylcellulose,
magnesium stearate, maltodextrin, microcrystalline cellulose, silicon dioxide,
stearic acid,
sucrose fatty acid ester, and combinations thereof. In certain specific
embodiments, flavoring
agents are selected from the group consisting of chicken flavoring, chicken
liver flavoring,
smoked bacon flavoring, and combinations thereof.
[0072] The present disclosure will be further illustrated by the following non-
limiting
Examples. These Examples are understood to be exemplary only, and they are not
to be
construed as limiting the scope of the invention as defined by the appended
embodiments.
EXAMPLES
[0073] Example 1 ¨ A representative veterinary supplement
ACTIVE INGREDIENT AMOUNT
Nrf2-activating agent: 150 mg
Milk thistle seed extract (Silybum marianum) (50 mg)
Ashwagandha root extract (Withania somnifera) (33.33 mg)
Green tea leaf extract (Camellia sinensis) (16.67 mg)
Bacopa whole herb extract (Bacopa nommieri) (33.33 mg)
Turmeric rhizome extract (Curcuma longa) (16.67 mg)
Omega-3 fatty acids 200 mg
Type II chicken sternum collagen 125 mg
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Representative dosages for dogs being administered the representative
veterinary supplement
shown above are as follows:
Toy dogs (4-10 lbs.): 1/2 tablet daily
Small dogs (11-29 lbs.): 1 tablet daily
Medium dogs (30-69 lbs.): 2 tablets daily
Large dogs (70-109 lbs.): 3 tablets daily
Giant dogs (110+ lbs.): 4 tablet daily
[0074] Example 2¨ Clinical trial conducted with representative veterinary
supplement
General Design
[0075] A 60-day, double blinded, placebo controlled prospective study in 48
arthritic and 32
healthy client-owned neutered dogs of any breed and gender that were >5 years
of age and > 11
lbs.
[0076] Materials and Methods
[0077] Site Selection: Sites were recruited based on being multi-doctor
practices within driving
distance of the Monitor, having ultralow temperature storage capacity, and
familiar with
conducting clinical field trials. Investigators and key personnel were trained
in patient data
collection methods, sample storage, evaluation forms, and reimbursement
policies.
[0078] Enrollment Period: This was a time-sensitive study, and as such was
initiated under
rapid conditions to meet Sponsor deadlines. At Sponsor's request, a healthy
group of dogs
(n=32) were enrolled in parallel with arthritic dogs (n=48) to reduce
timelines and obtain the
primary outcomes for assessment. At Sponsor's request, the weights and ages of
arthritic dogs
were reduced in order to facilitate enrollment to meet timelines.
[0079] Patient Selection: Dogs were recruited from a client owned population
and selected
based on their ability to meet specific inclusion and exclusion criteria. Dogs
in the healthy dog
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cohort were deemed in good health and excluded if receiving any steroids in
the last month or
starting any new supplements or new diets in the last week. Dogs in the
musculoskeletal
disability cohort were included if having a musculoskeletal disability
(lameness, etc.) consistent
with arthritis for at least three months, but excluded if (a) having received
a hip or joint
replacement surgery, (b) currently receiving NSAIDs, steroids, Adequan, or
joint injections, (c)
currently on joint supplements such as glucosamine, chondroitin, (d) having
any known systemic
infection, neuropathology, neoplasia or endocrinopathy, or (e) if starting a
joint diet in the last
month. Patients were enrolled using a specific patient qualification form.
[0080] Owner Selection: Owners were required to sign an informed consent
including
commitment to the study. Owners that elected to participate received
instructions and were
scheduled with follow-up appointments by the veterinary hospital.
[0081] Cohorts: The Sponsor requested rapid enrollment to obtain TBAR and
Catalase data,
and therefore the cohorts were shifted to 32 healthy dogs and 48 arthritic
dogs to facilitate data
capture and reduce clinical phase timelines.
[0082] Groupings and Randomization: 80 dogs were randomized in blocks of 8 and
allocated
into two groups, being Group A(active; n = 40) and Group B (placebo; n = 40).
[0083] Blinding: Investigative site personnel and owners were blinded as to
being enrolled into
active or placebo groups.
[0084] Articles: Test articles (active and placebo) consisted of a chewable
flavored tablet
administered once daily by weight. The treatment tablet contained the
representative veterinary
supplement of Example 1. The placebo was an identical product without the anti-
oxidant & joint
complex. Tablets were provided in a labeled bottle with feeding instructions.
The monitor
placed a grouping designation "A" or "B" on the product's bottle and cap using
a permanent
marker. Bottles were placed into boxes labeled "A" or "B", which corresponded
with patient
pack assignments.
=
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[0085] Patient Packs: Each patient was assigned an individual folder
containing all enrollment
and evaluation forms. Folders were labeled according to cohort (healthy or
arthritic) and
grouping (A or B).
[0086] Materials: This project required substantial oversight for sample
acquisition and
maintenance. AHC acquired a large cooler and a shipping cooler for the
project. Other materials
for the dewars (liquid nitrogen, canes, etc.), folders, cash lockboxes, and
other items were also
purchased for the study.
[0087] Veterinary Evaluations: Veterinarians evaluated arthritic dogs and
could evaluate up to 4
joints per animal for lameness, pain and range of motion. The unit of
assessment was the dog,
and a non-weighted numerical value was assigned to the chosen descriptor. The
sum of dog
disability was used for assessment of each variable.
[0088] Owner Scoring: All owners were issued a questionnaire which addressed
overall
disability, cognition, energy level, social behavior, and skin and coat
assessment, and overall
response. Owner disability was scored based on a 0 to 3 scale for walking,
running, jumping,
rising, lying down, going up or down stairs, squatting, stiffness in morning
and evening,
ambulation on slippery floors and a willingness to play. The sum of scores was
used to calculate
an Owner Overall Disability Score. Owners also graded social behavior,
cognitive function,
energy level, skin condition, coat condition, and overall improvement.
[0089] Chemistry and CBC: Whole blood was obtained by venipuncture in 48 dogs
at Day 1
and 30 for chemistry and CBC. These data were used for safety evaluation.
[0090] Serum: Serum was collected at Days 1, 30 and 60 and stored at -20 C
for future
analysis.
[0091] Plasma Sample Collection and Storage: Plasma samples were collected
from 80 dogs.
Whole blood was obtained via venipuncture from clinical subjects on Days 1, 30
and 60 using
EDTA purple top tubes for consistency. Whole blood was processed rapidly and
ice of plasma
was placed in Nunc Cryotubes suitable for liquid phase liquid nitrogen
storage. The Nunc
Cryotubes tubes contained 300mM BHT (butylated hydroxytoluene) in methanol.
The
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addition of BHT to the plasma at collection prevents further oxidation of
lipids and other
substances in the plasma from storage through the assay. The target final BUT
concentration
was 3 mM. Samples were flash frozen either on dry ice or in liquid nitrogen
and then stored
under liquid nitrogen conditions until being shipped for analysis.
[0092] Assays: Thiobarbituric Acid Reactive Substances (TBARS) and Catalase
Analysis.
TBAR analysis was performed using a commercially available TBAR assay (Cayman
Chemical
Item Number 10009055). Catalase analysis was performed using a commercially
available
catalase assay (Cayman Chemical Item Number 707002). Samples were rapidly
thawed and
placed on ice, then assayed using a commercial ELISA reader. Any samples that
did not fall on
the standard curve were re-assayed at appropriate dilutions (2 dilutions per
sample). Catalase
data were corrected for volume, incubation time and sample dilution and
activity is presented
in Units, defined as nmol/min/mL plasma. Lipid peroxidation is measured by the
TBARS
assay, yielding p.M malondialdehyde.
[0093] Normalization: TBAR and catalase values were normalized to total
protein (TP) of each
sample.
[0094] Results
[0095] Population: 76 out of 80 dogs completed the study (n = 44 arthritic; n
=32 healthy; 38
female spayed, 36 male neutered, 2 male intact). Average age was 8.6 years old
(range 2.5 to 16),
average weight was 54.4 lbs (range 13 to 116).
[0096] Significant Clinical Findings: Owner Overall Disability score was
significantly lower (p
= 0.027) on average in arthritic dogs receiving active treatment (Group A) vs.
placebo. Group A
also had a significant improvement (p <0.01) in Owner Overall Improvement at
Day 30 but not in
placebo.
[0097] Noteworthy Clinical Findings: Dogs with bilateral hip disability
receiving active product
had a 27% reduction (improvement) in Owner Overall Disability Scores compared
to only a 2%
in the placebo group (Figure 1).
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Owner Overall Disability Score in Dogs with
Hip Involvement
12.0
eri
rek
0
rt 10.0
go 8.0
71:1
0
Q.
0 6.0
0
4'0
1-
2 0
do =
3
0
0.0
Active (n=13) Placebo (n=171
I Day 1 10.7 10.9
II Day 50 7.8 10.6
Figure 1: Owner Overall Disability in dogs with hip disabilities over 60 days.
[0098] Noteworthy Biochemical Findings: Dogs in the active group had a 47%
increase in
catalase activity compared to placebo at Day 60. The active group had a 36%
increase in catalase
from Day 1 to 60, whereas the placebo group had an 11% decrease at Day 60
(Figure 2).
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=
% catalase change from baseline
catalase change from baseline
36%
,
Active
-11%
Figure 2: % average changes in catalase activity (U) from baseline in active
and placebo groups.
[0099] Correlations: There were no apparent correlations between changes in
owner overall
disability or veterinary composite changes and weight or age (Day I to Day 60
changes).
[001001 Chemistry and Complete Blood Count Results: There were no clinically
significant
changes over time in Groups A or B.
[00101] Clinical Safety: Only one dog had a side effect considered to be
likely associated with
the placebo test article. This patient (5 year old healthy Golden Retriever)
developed diarrhea
before Day 30, which resolved after discontinuation of the placebo tablet. The
diarrhea returned
when the dog was placed back on the placebo tablet. The dog's diarrhea
resolved without
incidence after removal from the study.
[001021 Loss to Study: 3 patients did not complete the study, as follows:
Patient 38 (group B): Loss - renal failure ¨ unrelated to product
Patient 55 (group A): Loss - removed owing to failure to control pain
Patient 66 (group A): Loss - euthanized for reasons unrelated to study
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1001031 TBAR and Catalase Results: There were no significant changes in TBAR
or catalase,
although the treated group had a strong trend towards an increase in catalase.
[00104] Conclusions
[00105] Dogs receiving the active product had a 47% difference in catalase
activity at Day 60
compared to placebo, as measured by average of all samples. Although not
significant, these
changes in catalase activity showed a strong trend in the active group,
suggesting that the active
product may up-regulate oxidative capacity within 60 days.
[00106] Owners appeared to be more cognizant of disability changes compared to
veterinarians,
which is not surprising. One significant finding was the category Owner
Overall Disability
(Arthritic Dogs), which measured a composite of a variety of everyday
disabilities common to
arthritic patients. The active treatment showed a significant (p --= 0.027)
averaged (all time-
points) overall lower disability compared to the placebo group, as reported by
owners. AHC also
determined there may be a significant Overall Response to treatment in the
active group at Day
30 in arthritic dogs as measured by owners. Additionally, there could be
differences in dogs
=
based on which joints are affected.
[00107] The study also suggested the product is safe for use in dogs with no
evidence of toxicity.
No severe adverse events were noted in either group, and no product related
adverse events were
observed in the treatment group.
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