U.S. patent application number 11/889060 was filed with the patent office on 2008-07-24 for combination of unsaponifiable lipids combined with polyphenols and/or catechins for the protection, treatment and repair of cartilage in joints of humans and animals.
This patent application is currently assigned to Nutramax Laboratories, Inc.. Invention is credited to Charles Filburn, David Griffin, Todd R. Henderson, Louis Lippiello.
Application Number | 20080176935 11/889060 |
Document ID | / |
Family ID | 35757689 |
Filed Date | 2008-07-24 |
United States Patent
Application |
20080176935 |
Kind Code |
A1 |
Henderson; Todd R. ; et
al. |
July 24, 2008 |
Combination of unsaponifiable lipids combined with polyphenols
and/or catechins for the protection, treatment and repair of
cartilage in joints of humans and animals
Abstract
The present invention relates to a composition and a kit for the
protection, treatment and repair of cartilage in humans and animal
joints. The composition or kit contains a combination of
unsaponifiable lipids together with one or more of polyphenols
and/or catechins. Preferably, the composition or kit contains
avocado:soybean unsaponifiables (ASU) and green tea
Inventors: |
Henderson; Todd R.;
(Jarrettsville, MD) ; Lippiello; Louis; (Forest
Hill, MD) ; Filburn; Charles; (Forest Hill, MD)
; Griffin; David; (Belair, MD) |
Correspondence
Address: |
COVINGTON & BURLING, LLP;ATTN: PATENT DOCKETING
1201 PENNSYLVANIA AVENUE, N.W.
WASHINGTON
DC
20004-2401
US
|
Assignee: |
Nutramax Laboratories, Inc.
Edgewood
MD
|
Family ID: |
35757689 |
Appl. No.: |
11/889060 |
Filed: |
August 8, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11192362 |
Jul 29, 2005 |
|
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11889060 |
|
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60592322 |
Jul 30, 2004 |
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Current U.S.
Class: |
514/456 |
Current CPC
Class: |
A61K 31/685 20130101;
A61P 19/04 20180101; A61K 36/54 20130101; A61K 31/05 20130101; A61K
36/82 20130101; A61K 31/353 20130101; A61P 29/00 20180101; A61K
9/0053 20130101; A61K 36/48 20130101; A61P 19/00 20180101; A61K
31/05 20130101; A61K 2300/00 20130101; A61K 31/353 20130101; A61K
2300/00 20130101; A61K 36/48 20130101; A61K 2300/00 20130101; A61K
36/82 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/456 |
International
Class: |
A61K 31/353 20060101
A61K031/353; A61P 19/00 20060101 A61P019/00 |
Claims
1. A composition comprising unsaponifiable lipids and at least one
or more of polyphenols and catechins for the protection, treatment
and repair of cartilage in joints of humans or animals.
2. The composition of claim 1, wherein the source of polyphenols
and catechins is green tea and the source of unsaponifiable lipids
are avocado:soybean unsaponifiables (ASU).
3. The composition of claim 2, wherein the green tea is further
combined with phosphatidylcholine.
4. A kit comprising unsaponifiable lipids and at least one or more
of polyphenols and catechins for the protection, treatment and
repair of cartilage in joints of humans or animals.
5. The kit of claim 4, wherein the source of polyphenols and
catechins is green tea and the source of unsaponifiable lipids is
avocado:soybean unsaponifiables (ASU).
6. The composition of claim 5, wherein the green tea is further
combined with phosphatidylcholine.
7. A composition comprising avocado:soybean unsaponifiables (ASU)
and green tea.
8. A kit comprising avocado:soybean unsaponifiables (ASU) and green
tea.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit, pursuant to 35 U.S.C.
.sctn. 119, of U.S. Provisional Patent Application No. 60/592,322,
filed Jul. 30, 2004, the entirety of which is incorporated herein
by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a composition for the
protection, treatment and repair of cartilage in humans and animal
joints.
BACKGROUND OF THE INVENTION
[0003] Degenerative joint disease (DJD) results from the cumulative
effects of an imbalance between synthesis and degradation of
components of cartilage extracellular matrix. This imbalance is
associated with disregulated activity of inflammatory cytokines and
production of prostaglandins that mediate pain. Progression of the
disorder occurs when this imbalance persists. Agents that act to
increase synthesis of cartilage components and suppress the
activity of specific cytokines, particularly of interleukin-1-beta
(IL-1-B) and tumor necrosis factor alpha (TNF-.alpha.), have the
potential to relieve symptoms of DJD and stop its progression. Both
of these cytokines act through mechanisms that involve generation
of reactive oxygen species (ROS) and reactive nitrogen species
(RNS) that lead to suppression of synthesis of cartilage matrix
proteoglycans along with increased production of prostaglandins,
nitric oxide, and activation of metalloproteinases that degrade
cartilage proteins. A combination of agents that is capable of
interacting with these mechanisms in different ways and to
stimulate the anabolic response needed in chondrocytes for
maintenance and/or restoration of matrix components could be
effective in the-protection, treatment and repair of connective
tissue.
Polyplenols and Catechins
[0004] Various polyphenols can be sourced from berries and other
fruits. Catechins are found primarily in teas. The preferred source
of polyphenols and catechins are sourced from green tea. Green tea
contains a mixture catechins, including epicatechin (EC),
epigallocatechin (EGC), epicatechin gallate (ECG) and
epigallocatechin gallate (EGCG). These catechins have potent
antioxidant activity, acting as scavengers of the free radicals
(ROS and RNS) involved in damage to cells. They also act by
chelating metals that catalyze production of ROS (1). This
antioxidant activity may interfere with the damaging effects of
agents, e.g. fibronectin fragments (Fn-f) and cytokines, that can
cause DJD . Antioxidants block the effects of Fn-f, which include
increased expression and activity of both cytokines IL-1 and TNF-a
(2,3). In addition, recent studies have shown that green tea
polyphenols significantly reduce the incidence of collagen-induced
arthritis in mice that was associated with reduced expression of
TNF-a and cyclooxygenase 2, a TNF-a regulated enzyme that catalyzes
the production of prostaglandin E2 (4). Other studies have shown
that the EGCG in green tea inhibits IL-1 induced expression of
nitric oxide synthase and nitric oxide production and suppresses
activation of nuclear factor-kB, a key step in initiation of the
cytokine effects (5). Furthermore, the catechins in green tea were
recently shown to potently inhibit aggrecanase activities known to
be involved in the early stages of destruction of cartilage
proteoglycans (6). Thus, the components of green tea have the
potential to ameliorate the cause and the symptoms of DJD through
multiple mechanisms. The green tea may be administered as an
extract or standardized to polyphenols or catechins.
Unsaponifiable Lipids
[0005] Vegetable oils, including coconut, peanut and safflower oil
to name a few, are possible components of the human diet that
contain an important class of compounds termed unsaponifiable
lipids. One rich source of unsaponifiable lipids are avocados and
soybean oil, with avocado having approximately four times more
lipids than those found in other commonly eaten fruits. Many of the
health benefits of soy, widely used as a staple food in Asian
countries, may be due to this unsaponifiable fraction which also
includes isoflavones. Unsaponifiable lipids are defined as the
material which does not react with basic agents to form soaps.
Included in this class are phytosterols, fat soluble vitamins A, D,
E and K, bioflavinoids, phytoestrogens and small organic molecules
called terpenes. The major components by weight of the
unsaponifiable lipid fraction are a group of compounds called
phytosterols which differ slightly in structure and include beta
sitosterol, campesterol and stigmasterol. Of the many beneficial
actions attributed to phytosterols, their ability to reduce pain,
swelling, and tissue injury in joints is proposed. With aging and
stress, increased amounts of phytosterols are thought to be
necessary to maintain normal biological functions (1,2).
Biological Activity
[0006] Phytosterols have potent biological activities, some of
which reduce the joint pain and swelling characteristic of
inflammatory joint disorders as well as symptoms characteristic of
trauma or aging related joint disorders. In addition, these agents
beneficially alter the bodies immune response in a fashion which
helps to minimize joint tissue destruction attributed to an
allergic tissue reaction. Studies indicate phytosterols are active
in immune modulation (3) and have anti-inflammatory and antipyretic
activity (4). Most of these activities are a result of the effect
of phytosterols inhibiting the production by inflammatory cells of
chemical agents (cytokines) which cause tissue damage and
stimulation of anabolic activity of chondrocytes. Avocado/soybean
oil unsaponifiables (ASU) is a preferred source of unsaponifiable
lipids for the protection, treatment and repair of connective
tissue conditions.
In Vitro Tests
[0007] Prior researchers have conducted in vitro tests on ASU. The
in vitro model previously used to test ASU is based on monitoring
reduction of interleukin-1 (IL-1)-induced metalloprotease activity,
nitric oxide or prostaglandin synthesis (all agents associated with
cartilage degradation, tissue inflammation, or pain) (5-9). ASU was
shown to inhibit the action of IL-1 at doses of 1 to 10 ug/ml. A
combination of 2:1 soy:avocado was found to be even more. effective
than either agent alone (5,8). It was also noticed that this
mixture was the main combination that was effective in decreasing
production of collagenolytic activity (9). Fibroblasts also appear
to be responsive to ASU. Metalloprotease activity (MMP-2 and MMP-3)
was inhibited at low doses of ASU and at higher doses the
tissue-inhibitors of metalloproteases was increased (7). The above
mentioned assays could be related to the beneficial physiological
(symptomatic relief) effects. Other indices tested relate to a
possible increase capacity for repair and regeneration of articular
cartilage. For example, the anticatabolic activity of ASU was shown
to be paired with a direct effect of ASU on stimulating collagen
and proteoglycan production, possibly by increasing transforming
growth factor-beta 1 and 2 synthesis (6). Research in our
laboratory also has shown that ASU is effective in improving
cartilage synthesis in-vitro.
In Vivo Tests in Animals
[0008] Prior researchers have conducted in vivo animal tests on
ASU. An increase in collagen synthesis was observed in a
carrageenan induced granuloma in the "Hairless" rat following 15
days of percutaneously applied ASU (10). Mice that had subcutaneous
implantation of rat articular cartilage wrapped in cotton were
treated orally for 2 weeks with the unsaponifiable fraction of
either ASU, avocado alone or soybean alone daily for 2 weeks (13
mg/kg avocado or 26 mg/kg soya or both in a ratio of 1:2 at a dose
of 39 mg/kg). Parameters measured included proteoglycans and
hydroxyproline content of the cartilage. Results indicate that
unsaponifiables of both avocado and soybean reduced the
degeneration of proteoglycans and hydroxyproline content of the
implanted cartilage that was induced by the granuloma tissue. A
greater effect was seen using a combination of avocado and soybean,
an effect which was dose dependent(11).
[0009] A third more pertinent study involved oral administration of
ASU (900 mg/weekday) to meniscectomized sheep for 3 and 6 months
(12). In this model a "subtle but statistically significant
protective effect on articular cartilage" was noted from
computerized image analysis of histological stained cartilage.
[0010] Many plants contain similar type agents generally classified
as unsaponifiable lipids. Potent anti-inflammatory activity has
also been associated with these sources. For example, Park et al
(13) found anti-inflammatory activity in an ethanolic extract of
cactus which was identified as beta sitosterol. Using the
carrageenan paw oedema model in rats, beta sitosterol was found to
be one of the potent anti-inflammatory agents in extracts of
Verbena officinalis (14). The isolated sterols stigmasterol and
beta sitosterol were potent anti-inflammatory agents when
administered topically and in a chronic inflammation model in the
mouse (15). A sterol fraction containing 7.6% campesterol, 28.4%
stigmasterol and 61.1% beta sitosterol demonstrated
anti-inflammatory activity in the carrageenan paw oedema model in
mice after oral administration of 30 and 60 mg/kg (16).
In Vivo Tests in Humans
[0011] Prior researchers have conducted in vivo tests in humans on
ASU. Individuals with primary femorotibial or hip OA of at least
six months duration were dosed with 300 mg of a 2:1 avocado:soybean
unsaponifiable preparation for 3 months. Indices measured included
NSAID intake, Lequesne's index and physician visual analog scale
for pain and functional index. All indices showed improvement at
p<0.01 or better (17). In a double-blind study, individuals with
knee OA (femoro-tibial) were dosed with 300 or 600 mg of an
avocado:soybean unsaponifiable for three months. Indices measured
included NSAID and analgesic intake between day 30 and day 90. All
indices improved with treatment at p<0.01 or better with NSAID
intake decreasing by more than 50% in 71% of the individuals
compared to 36% in individuals receiving placebo. Lequesne's index
dropped by 3.9 and 2.9 points in ASU 300 and 600 mg respectively
against 1.6 in placebo. Similar results were observed in
individuals given 300 or 600 mg (18). Eighty-five out of 164
individuals with painful primary OA of the knee or hip were dosed
for 6 months with 300 mg unsaponifiables after a 15 day washout
period for NSAIDs. Efficacy was determined by Lequesne's functional
index, visual analog pain scale, intake of NSAIDs and overall
disability score. Pain decreased from a score of 56.1 to 35.3 in
the ASU group and from 56.1 to 45.7 in the placebo group
(p<0.003). Values for NSAID intake showed consumption lower in
ASU group (48% versus 63%). Lequesne's test score decreased from
9.7 to 6.8 in the ASU group and from 9.4 to 8.9 in the placebo
group. The overall success rate was 39% in the ASU group and 18% in
the placebo group. Improvement was more marked in individuals with
hip OA and a residual effect was observed at month eight (19).
[0012] One hundred sixty three individuals in this pilot 2 year
study evaluating structural changes in the hip joint. Individuals
with painful primary OA of hip and joint space>or=to 1 mm
(Kellgren grade 1 to 3) with at least a 6 month history of pain and
AFI index>or=to 4. Primary assessment was decrease in joint
space width performed in standing position. Results indicate a
failure to demonstrate significant reduction in progression of
joint space loss compared to placebo. ASU did reduce progression of
joint space loss (20).
Rationale
[0013] We believe that polyphenols and catechins, especially from
green tea, together with unsaponifiable lipids, especially from
ASU, can have beneficial effects on the biochemical processes that
underlie development and/or progression of DJD. In our invention,
by "green tea" we mean green tea available as a tea, as well as
green tea available as an extract, such as in a powder form. The
anti-oxidant activity of components of green tea have the capacity
to attack the free radicals known to be involved in disregulated
cytokine activity in osteoarthritis. The additional capacity to
inhibit specific proteases involved in cartilage degradation
provides an additional mechanism for combating DJD. The
anti-inflammatory activity of avocado and soybean unsaponifiables
can also attack cytokine signaling, but apparently by less
understood mechanisms. They also provide direct anabolic activity
that is needed to restore the balance between anabolic and
catabolic activity. A combination of unsaponifiable lipids with one
or more of polyphenols or catechins should work well together. Thus
the present invention consists of a combination of these agents
over a range of doses.
Dosage Ranges and Preferred Sources
[0014] Polyphenols/catechins: about 3 mg to about 10 grams, with
the preferred source of polyphenols being green tea. The green tea
may be combined with phosphatidylcholine to improve absorption.
[0015] Unsaponifiable lipids: about 5 mg to about 12 grams, with
the preferred source being ASU.
EXAMPLES
[0016] The following examples are merely illustrative of the
present invention and are not to be considered as limiting the
invention, which is properly delineated in the following claims.
Moreover, it should be noted that the use of the present or future
tense in these examples is reflective of the fact that the examples
are prophetic. MPEP 608.01(p).
Example 1
[0017] A 70 kg 60 year old man has knee joint pain and
radiologically diagnosed degenerative joint disorder. Intake on a
daily basis of a supplement that contains 100 mg green tea extract
and 300 mg avocado-soybean unsaponifiables reduces these
symptoms.
Example 2
[0018] A 20 kg 6 year old Labrador retriever has degenerative joint
disorder localized to the hip and has difficulty rising and
ascending stairs. Intake on a daily basis of a supplement
containing 20 mg green tea extract and 30 mg avocado-soybean
unsaponifiables reduces these symptoms.
Example 3
[0019] A 5 kg cat is diagnosed with spinal arthritis and cannot
jump on the windowsill. The cat is administered 3 mg of polyphenols
and catechins and 5 mg avocado soybean unsoponifiables. The cat
improves dramatically and is now capable of jumping on the
windowsill.
Example 4
[0020] A 1000 kg horse is diagnosed with bone spavin and treated
with 3 grams of epigallocatechin gallate and 4 grams of ASU. The
horse responds dramatically.
References for Green Tea
[0021] The following references regarding green tea are herein
incorporated by reference in their entirety into this
specification.
[0022] 1. Higdon J V and Frei B Tea Catechins and Polyphenols:
Health Effects, Metabolism, and Antioxidant Functions. Critical
Reviews in Food Science and Nutrition 4389-143, 2003.
[0023] 2. Homandberg G A and Wen F H Fibronectin Fragment Mediated
Cartilage Chondrolysis. I. Suppression by Anti-oxidants. Biochimica
Biophysica Acta 1317:134-142, 1996.
[0024] 3. Homandberg G A, Hui F, Wen C, Purple C, Bewsey K, Koepp
H, Huch K and Harris A. Fibronectin-Fragment-Induced Cartilage
Chondrolysis is Associated with Release of Catabolic Cytokines.
Biochemical Journal 321:751-757, 1997.
[0025] 4. Haqqi T, Anthony D D, Gupta S, Ahmad N, Lee M S, Kumar G
K and Mukhtar H. Prevention of Collagen-induced Arthritis in Mice
by a Polyphenolic Fraction From Green Tea. Proceedings National
Academy Science USA 96:4524-4529, 1999.
[0026] 5. Singh R, Ahmed S, Islam N, Goldberg V M and Haqqi T M.
Epigallocatechin-3-Gallate Inhibits Interleukin-1l-Induced
Expression of Nitric Oxide Synthase and Production of Nitric Oxide
in Human Chondrocytes. Arthritis & Rheumatism 45:2079-2086,
2002.
[0027] 6. Vankernmelbeke M N, Jones, G C, Fowles C, Ilic M Z,
Handley C J, Day A J, Knight C G, Mort J S and Buttle, D J.
Selective inhibition of ADAMTS-1,-4, and -5 by Catechin Gallate
Esters. European Journal Biochemistry 270:2394-2403, 203.
References for ASU
[0028] The following references regarding ASU are herein
incorporated by reference in their entirety into this
specification.
[0029] 1. Ling W H, Jones P J H: Minireview. Dietary Phytosterols:
A Review of Metabolism, Benefits and Side Effects. Life Sciences
57: 195-206, 1995
[0030] 2. DeJong A, Plat J, Mensink R P: Metabolic Effects of Plant
Sterols and Stanols (Review). J Nutri Biochem 14: 362-369, 2003
[0031] 3. Bouic P J: The Role of Phytosterols and Phytosterolins in
Immune Modulation: A Review of the Past 10 Years. Curr Opin Clin
Nutr Metab Care 4: 471-475, 2001
[0032] 4. Gupta M B, Nath R, Srivastava N, Shanker K, Kishor K,
Bhargava K P: Antiinflammatory and Antipyretic Activities of Beta
Sitosterol. Planta Med 39: 157-163, 1980
[0033] 5. Henrotin Y E, Labasse A H, Jaspar J M, DeGroote D D,
Zheng S X, Guillou G B, Reginster J Y: Effects of Three
Avocado/Soybean Unsaponifiable Mixtures on Metalloproteinasses,
Cytokines and PGE2 Production by Human Articular Chondrocytes. Clin
Rheumatol 17: 31-39, 1998
[0034] 6. Boumediene K, Felisaz N, Bogdanowiez P, Galera P, Guillou
G B, Pujol J P: Avocado/Soya Unsaponifiables Enhance the Expression
of Transforming Growth Factor Beta 1 and Beta 2 in Cultured
Articular Chondrocyctes. Arthritis Rheum 42: 148-156,1999
[0035] 7. Kut-Lasserre C, Miller C C, Ejeil A L, Gogly B, Dridi M,
Piccardi N, Guillou B, Pellat B, and Godeau. Effect of Avocado and
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(MMP-3) and Tissue Inhibitors of Matrix Metalloproteinase (TIMP-1
and TIMP-2) Secretion by Human Fibroblasts in Culture. J
Periodontol 72: 1685-1694, 2001
[0036] 8. Henrotin Y E, Sanchez C, Deberg M A, et al.
Avocado/Soybean Unsaponifiables Increase Aggrecan Synthesis and
Reduce Catabolic and Proinflanrmatory Mediator Production by Human
Osteoarthritic Chondrocytes. J Rheumatol 30: 1825-1834, 2003
[0037] 9. Mauviel A, Loyau G, Pujol J P: Effect of Unsaponifiable
Extracts of Avocado and Soybean (Piascledine) on the Collagenolytic
Action of Cultures of Human Rheumatoid Synoviocytes and Rabbit
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Osteoartic 58: 241-245, 1991
[0038] 10. Lamaud M E, Miskulin M, Robert A M, Wepierre J:
Biochemical Modifications of Connective Tissue Induced by the
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Percutaneously in the Hairless Rat. Pathol Biol 26: 269-274,
1978
[0039] 11. Khayyal M T, El-Ghazaly M A: The Possible
"Chondroprotective" Effect of the Unsaponifiable Constituents of
Avocado and Soya In Vivo. Drugs Exptl Clin Res 24: 41-50, 1998
[0040] 12. Cake M A, Read R A, Guillou B, Ghosh P: Modification of
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[0041] 13. Park E H, Kahng J H, Lee S H, Shin K H: An
Antiinflammatory Principle from Cactus. Fitoterapia 72: 288-290,
2001
[0042] 14. Deepak M, Handa S S: Antiinflammatory Activity and
Chemical Composition of Extracts ofverbena Officinalis. Phytother
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[0043] 15. Gomez M A, Saenz M T, Garcia M D, Fernandez M A: Study
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[0044] 16. Navarro A, DeLasHeras B, Villar A: Antiinflammatory and
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Efficacy and Safety of Avocado/Soybean Unsaponifiables in the
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Bourgeois P. Grouin J M, Rozenberg S: Symptomatic Efficacy of
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2002.
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