U.S. patent application number 12/473452 was filed with the patent office on 2009-11-26 for aminosugar, glycosaminoglycan, and s-adenosylmethionine composition for the treatment and repair of connective tissue.
This patent application is currently assigned to NUTRAMAX LABORATORIES, INC.. Invention is credited to Tarek Hammad, Robert W. HENDERSON.
Application Number | 20090291909 12/473452 |
Document ID | / |
Family ID | 25118246 |
Filed Date | 2009-11-26 |
United States Patent
Application |
20090291909 |
Kind Code |
A1 |
HENDERSON; Robert W. ; et
al. |
November 26, 2009 |
AMINOSUGAR, GLYCOSAMINOGLYCAN, AND S-ADENOSYLMETHIONINE COMPOSITION
FOR THE TREATMENT AND REPAIR OF CONNECTIVE TISSUE
Abstract
A composition for the protection, treatment and repair and for
reducing the inflammation of connective tissue in mammals and a
method for the treatment of connective tissue in mammals by the
administration of the composition. The composition includes
S-Adenosylmethionine (SAM), and a component selected from an
aminosugar or salts thereof (e.g., glucosamine) or
glycosaminoglycans (e.g., chondroitin salts) or mixtures or
fragments thereof. The composition optionally includes manganese
which promotes the production of connective tissue matrix. The
composition also optionally includes methyl donors or methyl donor
cofactors, such as vitamin B12, vitamin B6, folic acid,
dimethylglycine or trimethylglycine.
Inventors: |
HENDERSON; Robert W.;
(Baldwin, MD) ; Hammad; Tarek; (Baltimore,
MD) |
Correspondence
Address: |
ARENT FOX LLP
1050 CONNECTICUT AVENUE, N.W., SUITE 400
WASHINGTON
DC
20036
US
|
Assignee: |
NUTRAMAX LABORATORIES, INC.
Edgewood
MD
|
Family ID: |
25118246 |
Appl. No.: |
12/473452 |
Filed: |
May 28, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11785915 |
Apr 20, 2007 |
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12473452 |
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10408255 |
Apr 8, 2003 |
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11785915 |
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09834726 |
Apr 16, 2001 |
6583123 |
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10408255 |
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08797294 |
Feb 7, 1997 |
6271213 |
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09834726 |
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08779996 |
Dec 23, 1996 |
6492349 |
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08797294 |
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Current U.S.
Class: |
514/46 |
Current CPC
Class: |
A61P 25/08 20180101;
A61P 25/00 20180101; A61K 45/06 20130101; A61K 31/727 20130101;
A61P 29/00 20180101; A61K 31/726 20130101; A61K 31/7076 20130101;
A61P 19/04 20180101; A61K 31/715 20130101; A61K 31/7004 20130101;
A61K 31/7076 20130101; A61K 2300/00 20130101; A61K 31/727 20130101;
A61K 2300/00 20130101; A61K 31/726 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/46 |
International
Class: |
A61K 31/7076 20060101
A61K031/7076; A61P 25/00 20060101 A61P025/00 |
Claims
1. A composition for treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising:
S-Adenosylmethionine; a glycosaminoglycan selected from the group
consisting of chondroitin, chondroitin salts, fragments, and
mixtures thereof; and an aminosugar selected from the group
consisting of glucosamine, glucosamine salts and mixtures
thereof.
2. The composition of claim 1, wherein the salt of glucosamine is
selected from the group consisting of glucosamine hydrochloride,
glucosamine sulfate, and N-acetylglucosamine.
3. A method for the treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising
the step of administering the S-Adenosylmethionine, the
glycosaminoglycan, and the aminosugar of the composition of claim
1, to a human or an animal.
4. The composition of claim 1, wherein a dose of the
S-Adenosylmethionine ranges from about 2 mg to about 20,000 mg, a
dose of the aminosugar ranges from about 50 mg to about 40,000 mg,
and a dose of the glycosaminoglycan ranges from about 15 mg to
about 30,000 mg.
5. A method for the treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising
the step of administering the composition of claim 1 to a human or
an animal.
6. A method for the treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising
the step of administering the S-Adenosylmethionine, the
glycosaminoglycan, and the aminosugar of the composition of claim 1
to a human or an animal.
7. The method of claim 6, wherein each of the S-Adenosylmethionine,
the aminosugar, or the glycosaminoglycan are administered orally,
sublingually, nasally, gutturally, rectally, transdermally, or
parenterally.
8. A composition for treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising:
S-Adenosylmethionine and an aminosugar selected from the group
consisting of glucosamine, glucosamine salts and mixtures
thereof.
9. The composition of claim 8, wherein the salt of glucosamine is
selected from the group consisting of glucosamine hydrochloride,
glucosamine sulfate, and N-acetylglucosamine.
10. A method for the treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising
the step of administering the S-Adenosylmethionine and the
aminosugar of the composition of claim 8, to a human or an
animal.
11. The composition of claim 6, wherein a dose of the
S-Adenosylmethionine ranges from about 2 mg to about 20,000 mg, and
a dose of the aminosugar ranges from about 50 mg to about 40,000
mg.
12. A method for the treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising
the step of administering the composition of claim 8, to a human or
an animal.
13. A composition for treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising:
S-Adenosylmethionine and a glycosaminoglycan selected from the
group consisting of chondroitin, chondroitin salts, fragments, and
mixtures thereof.
14. A method for the treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising
the step of administering the S-Adenosylmethionine and the
glycosaminoglycan of the composition of claim 13, to a human or an
animal.
15. The composition of claim 13, wherein a dose of the
S-Adenosylmethionine ranges from about 2 mg to about 20,000 mg, and
a dose of the glycosaminoglycan ranges from about 15 mg to about
30,000 mg.
16. A composition for treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising:
S-Adenosylmethionine and an aminosugar selected from the group
consisting of glucosamine, glucosamine salts and mixtures
thereof.
17. The composition of claim 16, wherein the salt of glucosamine is
selected from the group consisting of glucosamine hydrochloride,
glucosamine sulfate, and N-acetylglucosamine.
18. A method for the treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising
the step of administering the S-Adenosylmethionine and the
aminosugar of the composition of claim 16, to a human or an
animal.
19. The composition of claim 16, wherein a dose of the
S-Adenosylmethionine ranges from about 2 mg to about 20,000 mg, and
a dose of the aminosugar ranges from about 50 mg to about 40,000
mg.
20. A method for the treatment and repair and for reducing the
inflammation of connective tissue in humans and animals comprising
the step of administering the composition of claim 16 to a human or
an animal.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application is a continuation of U.S. patent
application Ser. No. 11/785,915, filed on Apr. 20, 2007, which is a
continuation of U.S. patent application Ser. No. 10/408,255, filed
on Apr. 8, 2003, now abandoned, which is a continuation of U.S.
patent application Ser. No. 09/834,726, filed on Apr. 16, 2001, and
issued on Jun. 24, 2003, as U.S. Pat. No. 6,583,123, which is a
continuation of U.S. patent application Ser. No. 08/797,294, which
was filed on Feb. 7, 1997, and issued on Aug. 7, 2001, as U.S. Pat.
No. 6,271,213, which is a continuation-in-part of U.S. patent
application Ser. No. 08/779,996, filed Dec. 23, 1996, and issued on
Dec. 10, 2002, as U.S. Pat. No. 6,492,349, the disclosure of which
is incorporated by reference herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to compositions for the repair
and reduction of inflammation of connective tissue in humans and
animals and, in particular, to compositions capable of promoting
anti-inflammation, chondroprotection, chondromodulation,
chondrostabilization, chondrometabolization and the repair and
replacement of human and animal connective tissue.
[0004] 2. Background of the Invention
[0005] The connective tissues of humans and animals are constantly
subjected to stresses and strains from mechanical forces and from
diseases that can result in afflictions, such as arthritis, joint
inflammation and stiffness. Indeed, connective tissue afflictions
are quite common, presently affecting millions of Americans.
Further, such afflictions can be not only painful but, in their
extreme, debilitating.
[0006] The treatment of connective tissue afflictions can be quite
problematic. A simple decrease in the stress to which the
connective tissue is subjected is often not an option, especially
in the case of athletes and animals such as race horses.
Consequently, treatment is often directed at controlling the
symptoms of the afflictions and not their causes, regardless of the
stage of the degenerative process.
[0007] Presently, steroids, such as corticosteroids and NSAIDs, are
widely used for the treatment of these ailments. [Vidal, et al.,
Pharmocol. Res. Commun., 10:557-569 (1978)]. However, drugs such as
these, which inhibit the body's own natural healing processes, may
lead to further deterioration of the connective tissue.
[0008] Connective tissue, for example articular cartilage, is
naturally equipped to repair itself by manufacturing and remodeling
prodigious amounts of collagen (a chief component of connective
tissue such as cartilage) and proteoglycans (PGs) (the other major
component of connective tissue such as cartilage). This ongoing
process is placed under stress when an injury occurs. In such
cases, the production of connective tissue matrix (collagen and
PGs) can double or triple over normal levels, thereby increasing
the demand for the building blocks of both collagens and
proteoglycans.
[0009] The building blocks for collagen are amino acids, especially
proline, glycine and lysine. PGs are large and complex
macromolecules comprised mainly of long chains of modified sugars
called glycosaminoglycans (GAGs) or mucopolysaccharides. The terms
GAGs and mucopolysaccharides are understood in the art to be
interchangeable. PGs provide the framework for collagen formation
and also hold water to give flexibility, resiliency and resistance
to compression.
[0010] Like almost every biosynthetic pathway in the body, the
pathways by which both collagen and GAG form single molecule
precursors are quite long. As is also characteristic of other
biosynthetic pathways, the pathways by which collagen and GAGs are
produced include what is called a rate-limiting step--that is, one
highly regulated control point beyond which there is a commitment
to finish. The presence of such rate-limiting steps permits
complicated biosynthetic processes to be more easily and
efficiently controlled by permitting the organism to focus on one
point. For example, if conditions demand production and all the
requisite raw materials are in place, then stimulation of the
rate-limiting step will cause the end product to be produced. To
stop or slow production, the organism needs simply to regulate the
rate-limiting step.
[0011] In the production of PGs, the rate-limiting step is the
conversion of glucose to glucosamine for the production of GAGs.
Glucosamine, an aminosugar, is the key precursor to all the various
modified sugars found in GAGs, including glucosamine sulfate,
galactosamine, N-acetylglucosamine, etc. Glucosamine also makes up
to 500 of hyaluronic acid--the backbone of PGs--on which other
GAGs, like chondroitin sulfate are added. The GAGs are then used to
build PGs and, eventually, connective tissue. Once glucosamine is
formed, there is no turning away from the synthesis of GAG
polymers.
[0012] Glucosamine has been shown to be rapidly absorbed into
humans and animals after oral administration. A significant portion
of the ingested glucosamine localizes to cartilage and joint
tissues, where it remains for long periods. This indicates that
oral administration of glucosamine reaches connective tissues,
where glucosamine is incorporated into newly-synthesized connective
tissue.
[0013] Glycosaminoglycans and collagen are the chief structural
elements of all connective tissues. Their synthesis is essential
for proper maintenance and repair of connective tissues. In vitro,
the introduction of glucosamine has been demonstrated to increase
the synthesis of collagen and glycosaminoglycans in fibroblasts,
which is the first step in repair of connective tissues. In vivo,
topical application of glucosamine has enhanced wound healing.
Glucosamine has also exhibited reproducible improvement in symptoms
and cartilage integrity in humans with osteoarthritis. [L. Bucci,
Nutritional Supplement Advisor, (July 1992)].
[0014] The pathway for the production of proteoglycans may be
briefly described as follows. Glucosamine is the main building
block of connective tissue and may be provided either through the
enzymatic conversion of glucose or through diet or external
administration (see FIG. 1). Glucosamine may be converted into the
other main component of connective tissue, namely PGs, upon
incorporation of glucosamine into GAGs (see FIG. 2).
[0015] More specifically, GAGs are large complexes of
polysaccharide chains associated with a small amount of protein.
These compounds have the ability to bind large amounts of water,
thereby producing a gel-like matrix that forms the body's ground
substance. GAGs stabilize and support cellular and fibrous
components of tissue while maintaining the water and salt balance
of the body. The combination of insoluble protein and the ground
substance forms connective tissue. For example, cartilage is rich
in ground substance while tendon is composed primarily of
fibers.
[0016] GAGs are long chains composed of repeating disaccharide
units of monosaccharides (aminosugar-acidic sugar repeating units).
The aminosugar is typically glucosamine or galactosamine. The
aminosugar may also be sulfated. The acidic sugar may be
D-glucuronic acid or L-iduronic acid. GAGs, with the exception of
hyaluronic acid, are covalently bound to a protein, forming
proteoglycan monomers. These PGs consist of a core protein to which
linear carbohydrate chains formed of monosaccharides are attached.
In cartilage proteoglycan, the species of GAGs include chondroitin
sulfate and keratin sulfate. The proteoglycan monomers then
associate with a molecule of hyaluronic acid to form PG aggregates.
The association of the core protein to hyaluronic acid is
stabilized by link proteins.
[0017] The polysaccharide chains are elongated by the sequential
addition of acidic sugars and aminosugars, and the addition is
catalyzed by a family of transferases. Aminosugars, such as
glucosamine, are synthesized through a series of enzymatic
reactions that convert glucose to glucosamine, or alternatively may
be provided through the diet. The glucosamine is then incorporated
into the GAGs as described above. Acidic sugars may be provided
through the diet, may be obtained through degradation of GAGS by
degradative enzymes, or produced through the uronic acid
pathway.
[0018] Since repeating disaccharide units contain one aminosugar
(such as glucosamine), it is clear that the presence of an
aminosugar in the production of connective tissue is important.
Glucosamine is, by far, the more important ingredient in the
production of connective tissue since it is the essential building
block of GAGs. See FIG. 1. All GAGs contain hexosamine or uronic
acid derivative products of the glucose pathway and from exogenous
glucosamine, for example:
TABLE-US-00001 Hyaluronic acid Glucosamine + Glucuronic Acid
Keretan-Sulfate Glucosamine + Galactose Chondroitin Sulfate
Glucuronic Acid + Galactosamine Heparin Sulfate Glucosamine +
Glucuronic or Iduronic Acid Heparin Sulfate Glucosamine +
Glucuronic or Iduronic Acid Dermatin Sulfate Iduronic Acid +
Galactosamine
[0019] Chondroitin sulfate is a GAG that provides a further
substrate for the synthesis of the proteoglycans. The provision of
the chondroitin in its salt (sulfate) form facilitates its delivery
and uptake by the humans and animals in the production of
connective tissue. In addition, the sulfate portion of chondroitin
sulfate is available for use in catalyzing the conversion of
glucosamine to GAGs. Fragments of GAGS, including chondroitin
sulfate, may also be used to provide a substrate for synthesis of
proteoglycans since the assembly of PG occurs in the extracellular
space.
[0020] In addition, chondroitin sulfate has been shown to have
cardiovascular health benefits. [Morrison et al., Coronary Heart
Disease and the Mucopolysaccharides (Glycosaminocaycans), pp.
109127 (1973)]. Thus, the preferred form of glycosaminoglycan
included in the compositions of the present invention is
chondroitin sulfate or fragments thereof.
[0021] Chondroitin may be more efficacious than glucosamine for
injury rehabilitation. [Christensen, Chiropractic Products, pp.
100-102 (April 1993)]. An evaluation of glucosamine versus
chondroitin for treatment of osteoarthritis has been conducted and
concludes, contrary to Christensen, that glucosamine is preferred.
[Murray, MPI's Dynamic Chiropractic, pp. 8-10 (Sep. 12, 1993)].
Neither reference teaches or suggests combining the materials.
Bucci (Townsend Letter for Doctors, pp. 52-54, January 1994),
discloses the combination of glucosamine and chondroitin for
treatment of osteoarthritis. Bucci has acknowledged that this
combination was personally disclosed to him by one of the present
inventors.
[0022] Chondroitin sulfate also acts to inhibit the degradative
enzymes that break down connective tissue. so doing, chondroitin
sulfate promotes the maintenance of healthy connective tissues.
When combined with glucosamine, which functions primarily as a
building block for the synthesis of connective tissue, chondroitin
sulfate works in concert with the glucosamine but may work in a
different fashion. The ability of chondroitin sulfate to block
degradation is one of its important functions.
[0023] S-Adenosylmethionine (SAM) is a significant physiologic
compound which is present throughout body tissue and takes part in
a number of biologic reactions as a methyl group donor or as an
enzymatic activator during the synthesis and metabolism of
hormones, neurotransmitters, nucleic acids, phospholipids, and
proteins. SAM may be second only to adenosine triphosphate (ATP) in
the variety of reactions in which it is a cofactor. SAM is
metabolized via three metabolic pathways of transmethylation,
transsulfuration, and aminopropylation. [Stramentinoli, Am. J.
Med., 83(5A):35-42 (1987)]. In higher organisms, SAM plays a
significant role in transmethylation processes with more than 40
anabolic or catabolic reactions involving the transfer of the
methyl group of SAM to substrates such as nucleic acids, proteins,
and lipids, among others. Also, the release of the methyl group
from SAM is the start of a "transsulfuration" pathway that produces
all endogenous sulfur compounds. After donating its methyl group,
SAM is converted into S-adenosylhomocysteine, which in turn is
hydrolyzed to adenosine and homocysteine. The amino acid cysteine
may then be produced from the homocysteine. The cysteine thus
produced may exert a reducing effect by itself or as an active part
of glutathione, which is a main cell anti-oxidant. [Stramentinoli,
cited above].
[0024] SAM has been used to treat various disorders. In various
forms of liver disease, SAM acts as an anticholestatic agent.
[Adachi et al., Japan Arch. Inter. Med., 33:185-192 (1986)]. SAM
has also been administered as an antidepressant for use in the
management of psychiatric disorders [Caruso et al., Lancet, 1: 904
(1984)], and as an anti-inflammatory compound in the management of
osteoarthritis [Domljan et al., Int. J. Clin. Pharm. Toxicol.,
27(7):329-333 (1989)].
[0025] Low levels of SAM are believed to play a role in reducing
the risk of certain cancers. [Feo et al., Carcinogenesis, 6:1713-20
(1985)]. In addition, the administration of SAM has also been
associated with a fall in the amount of early reversible nodules
and the prevention of the development of late pre-neoplastic
lesions and hepatocellular carcinomas. [Garcea et al.,
Carcinogenesis, 8:653-58 (1987)].
[0026] Unfortunately, SAM per se is unstable due to its high
reactivity. The relatively recent synthesis of stable salts,
however, has made SAM available for research and therapeutic use.
[See, e.g., U.S. Pat. Nos. 4,990,606 and 5,102,791].
[0027] SAM has been used outside of the United States in a number
of clinical trials concerning the treatment of osteoarthritis.
While used in these trials primarily as an analgesic and
replacement for NSAID therapy, SAM is a precursor of polyamines. In
addition to their analgesic and anti-inflammatory properties, and
their ability to scavenge free radicals, polyamines may stabilize
the polyanionic macromolecules of proteoglycans. [Schumacher, Am.
J. Med., 83(5A):2 (1987)].
[0028] SAM may also function as a source of endogenous sulfur,
which will increase sulfation of GAGs to be incorporated in
proteoglycans. The inclusion of SAM is particularly beneficial in
instances of subclinical deficiencies of SAM, occurring especially
in elderly populations with higher risk of osteoarthritis [Frezza
et al., Gastroenterol., 99:211-215 (1990)]. The supplementation of
SAM may aid in instances of SAM deficiency where the ability of the
body to sulfate GAGs may be compromised.
[0029] In addition, a number of metabolites of SAM aid in the
repair of connective tissue, including glutathione, polyamines,
methylthioadenosine, and adenosine. Glutathione works as a
scavenger of oxygen-related products [Shumacher, Am. J. Med.,
83(Supp 5a):1-4 (1987); Matthew & Lewis, Pharmacol. (Life Sci.
Adv.), 9:145-152 (1990); Szabo et al., Science, 214:200-202 (1981)]
and thus has an anti-inflammatory effect. Polyamines, including
spermine, spermidine, and putrescine, stabilize polyanionic
macromolecules of proteoglycans [Schumacher, cited above; Conroy et
al., Biochem. J., 162:347-350 (1977)] and thus protect proteolytic
and glycolytic enzymes. These polyamines also have an
anti-inflammatory effect [Bird et al., Agents Actions, 13:342-347
(1983); Oyangui, Agents Actions, 14:228-237 (1984)], probably as a
scavenger of oxygen-related products [Kafy et al., Agents Actions,
18:555-559 (1986); Matthews & Lewis, cited above], and have an
analgesic effect [Bird et al., cited above; Oyangui, cited above].
The SAM metabolite methylthioadenosine has a pronounced
anti-inflammatory effect [Matthews & Lewis, 1990] while
adenosine has a more modest anti-inflammatory effect [Matthews
& Lewis, 1990].
[0030] Studies have shown that some forms of exogenous SAM are
stable in digestive juices when given orally. [Stramentinoli et
al., cited above; Vendemiale et al., Scand. J. Gastroenterol.,
24:407-415 (1989)]. The metabolism of exogenous SAM appears to
follow known pathways of endogenous SAM metabolism. [Kaye et al.,
Drugs, 40 (Suppl. 3):124-138 (1990)]. In humans, oral SAM was
tolerated to the same extent as placebo with very mild nonspecific
side effects. [Schumacher, cited above; Frezza et al., cited
above].
[0031] Manganese plays a role In the synthesis of GAGs, collagen
and glycoproteins which are important constituents of cartilage and
bone. Manganese is important for enzyme activity of
glycosyltransferases. This family of enzymes is responsible for
linking sugars together into glycosaminoglycans, adding sugars to
other glycoproteins, adding sulfate to aminosugars, converting
sugars into other modified sugars, and adding sugars to lipids. The
enzymatic functions of glycosyltransferases are important in
glycosaminoglycan synthesis (hyaluronic acid, chondroitin sulfate,
keratan sulfate, heparin sulfate and dermatin sulfate, etc.),
collagen synthesis, and in the functions of many other
glycoproteins and glycolipids.
[0032] Manganese also plays a role in the synthesis of
glycosaminoglycans and glycoproteins, which are important
constituents of cartilage and bone. Many reproductive problems in
horses and skeletal abnormalities in foals have been ascribed to
manganese deficiency. [Current Therapy in Equine Medicine,
2:402-403 (1987)].
[0033] Manganese deficiency leads to abnormal bone growth, swollen
and enlarged joints, and slipped tendons in humans and animals. In
humans, manganese deficiencies are also associated with bone loss
and arthritis. Levels of all glycosaminoglycans are decreased in
connective tissues during manganese deficiencies, with chondroitin
sulfates being most depleted. Manganese-deficient organisms quickly
normalize glycosaminoglycans and collagen synthesis when manganese
is replenished.
[0034] Approximately 40% of dietary manganese is absorbed by the
body tissue. Storage of manganese in the body is minimal--a mere 12
to 20 mg is present in the body at any one time. Large amounts of
calcium and phosphorus in the intestine are also known to interfere
with manganese absorption. The richest dietary sources are the
foods least consumed by the general public, such as whole grain
cereals and breads, dried peas, beans and nuts. The ascorbate form
of manganese is preferred due to the high bioavailability and the
need for vitamin C (ascorbic acid) for collagen production. Vitamin
C also enhances manganese uptake by the body.
[0035] Other optional ingredients in the compositions of the
present invention are methyl donors or methyl donor cofactors, such
as vitamins B12 and B6, folic acid, dimethylglycine, and
trimethylglycine. These ingredients augment the function of SAM in
that they are cofactors in methylation. In addition, these
compounds are likely to be lacking in patients suffering from
connective tissue disorders. For example, it is estimated that 12%
of the elderly population in the United States suffers from a
vitamin B12 deficiency, a group more likely to suffer from
connective tissue disorders.
[0036] An adequate amount of vitamin B12, for example, has an
important environmental influence on the accumulation of
homocysteine that results from the metabolism of SAM. In other
words, methyl donors or methyl donor cofactors, such as vitamin B12
and the others listed in the preceding paragraph, can reduce levels
of homocysteine when administered either alone or in
combination.
[0037] Vitamin B12 is generally known to function as a coenzyme in
biochemical reactions such as the synthesis of proprionic acid and
of methionine. Recent evidence suggests that the elevated levels of
plasma homocysteine increase the risk of occlusive vascular
disease. Adequate amounts of vitamin B12 are considered the most
important environmental influence on the accumulation of
unnecessary homocysteine. [Joosten et al., Am. J. Clin. Nutr.,
58(4): 468-76 (1993)). In addition, it is also understood that
vitamin B12 may play a role in the methylation of selenium. [Chen
and Whanger, Tox. and Appl. Pharm., 118:65-72 (1993)].
Specifically, increased levels of vitamin B12 significantly
contribute to selenium methylation and might decrease overall
selenium toxicity by preventing its accumulation in tissues. [Chen
and Whanger, cited above).
[0038] 3. Description of Background Art
[0039] Several disclosures suggest provide exogenous quantities of
glucosamine in order to bypass the rate-limiting step of the
conversion of glucose to glucosamine in those pathways that produce
PGs. For example, the intravenous administration of glucosamine (a
precursor of the GAGs) and derivatives thereof has been disclosed
in U.S. Pat. No. 3,232,836, issued to Carlozzi et al., for
assisting in the healing of wounds on the surface of the body. In
U.S. Pat. No. 3,682,076, issued to Rovati, the use of glucosamine
and salts thereof is disclosed for the treatment of arthritic
conditions. Finally, the use of glucosamine salts has also been
disclosed for the treatment of inflammatory diseases of the
gastrointestinal tract in U.S. Pat. No. 4,006,224 issued to
Prudden. In vitro, glucosamine increases synthesis of collagen and
glycosaminoglycans, the first step in repair of connective tissues,
in fibroblasts. In vivo, topical application of glucosamine has
enhanced wound healing.
[0040] Several disclosures also suggest going one step further in
bypassing the glucose-to-glucosamine rate-limiting step, by
providing exogenous quantities of various of the modified sugars
found in the GAGs for producing proteoglycans. For example, in U.S.
Pat. No. 3,6797,652 issued to Rovati et al., the use of
N-acetylglucosamine is disclosed for treating degenerative
afflictions of the joints.
[0041] In still other disclosures of which we are aware, it has
been taught to go still one step further in bypassing the
glucose-toglucosamine rate-limiting step by providing exogenous
quantities of the GAGs themselves (with and without various of the
modified sugars). For example, in U.S. Pat. No. 3,371,012 issued to
Furuhashi, a preservative is disclosed for eye graft material that
includes galactose, N-acetylglucosamine (a modified sugar found in
the GAGs) and chondroitin sulfate (a GAG). Additionally, U.S. Pat.
No. 4,486,416 issued to Soll et al., discloses a method of
protecting. corneal endothelial cells exposed to the trauma of
intraocular lens implantation surgery by administering a
prophylactically effective amount of chondroitin sulfate. Also,
U.S. Pat. No. 5,141,928 issued to Goldman discloses the prevention
and treatment of eye injuries using glycosaminoglycan
polysulfates.
[0042] U.S. Pat. No. 4,983,580 issued to Gibson, discloses methods
for enhancing the healing of corneal incisions. These methods
include the application of a corneal motor composition of
fibronectin, chondroitin sulfate and collagen to the incision.
[0043] In U.S. Pat. No. 4,801,619 issued to Lindblad, the
intraarticular administration of hyaluronic acid is disclosed for
the treatment of progressive cartilage degeneration caused by
proteoglycan degradation.
[0044] The use of a SAM and selenium composition as a nutritional
supplement is disclosed in U.S. patent application Ser. No.
08/725,194 filed by one of the present inventors and is herein
incorporated by reference. In addition, one of the inventors of the
present invention has taught, in U.S. Pat. No. 5,587,363 the
combination of an aminosugar, such as glucosamine, and a
glycosaminoglycan, such as chondroitin, for treatment of
degenerative joint diseases. One of the present inventors has
further taught the optional inclusion of manganese in a composition
of an aminosugar and a glycosaminoglycan in U.S. Pat. No.
5,364,845.
[0045] Accordingly, it can be seen that there remains a need for
compositions which include analgesic, anti-inflammatory, and
antidepressant components, as well as components that provide the
building blocks for the production of connective tissue in humans
and that also protect against the degradation of that tissue.
SUMMARY OF THE INVENTION
[0046] It is therefore an object of the present invention to
provide a composition for the protection and repair and for
reducing the inflammation of connective tissue in humans and
animals.
[0047] It is a further object of the present invention to provide
compositions which contain S-Adenosylmethionine and an aminosugar
or salts thereof, such as glucosamine, for facilitating the repair
and reducing the inflammation of connective tissue in humans and
animals.
[0048] It is another object of the present invention to provide
compositions which contain S-Adenosylmethionine and GAGs, such as
chondroitin salts and fragments thereof, for facilitating the
repair and for reducing the inflammation of connective tissue in
humans and animals.
[0049] It is yet a further object of the present invention to
provide compositions which contain S-Adenosylmethionine, an
aminosugar or salts thereof, and GAGs or fragments thereof for
facilitating the repair and for reducing the inflammation of
connective tissue in humans and animals.
[0050] It is another object to optionally provide manganese to any
these compositions for humans and animals.
[0051] It is still a further object to optionally provide methyl
donors or methyl donor cofactors, such as vitamins B12 and B6,
folic acid, dimethylglycine, and trimethylglycine, to the
compositions of the present invention for humans and animals if
desirable.
[0052] It is a further object of the present invention to provide
methods of administering these compositions.
[0053] These and other objects of the present invention will become
readily apparent from a reading of the following detailed
description and examples.
BRIEF DESCRIPTION OF THE DRAWINGS
[0054] FIG. 1 is a sequence for the biosynthesis of
hexosamines.
[0055] FIG. 2 is a schematic flowchart illustrating the biological
pathway by which the composition of the present invention aids in
protection and repair of connective tissue.
[0056] FIG. 3 is an enlarged portion of the flowchart of FIG.
2.
DETAILED DESCRIPTION OF THE INVENTION
[0057] According to the present invention, a composition selected
from the group consisting of SAM and an aminosugar or salts thereof
(e.g., glucosamine); SAM and GAGs (e.g., chondroitin salts) or
fragments thereof; and SAM, an aminosugar (or salts thereof), and
GAGs (or fragments thereof) is provided to humans and animals for
stimulating both collagen and PG synthesis and for reducing
inflammation. Manganese, preferably manganese salts, may optionally
be included to any of these compositions. In addition, other
optional ingredients include methyl donors or methyl donor
cofactors, such as vitamins B12 and B6, folic acid,
dimethylglycine, and trimethylglycine. These compositions may act
to accomplish several functions, including bypassing the glucose to
glucosamine rate-limiting step in the natural production of
proteoglycans in humans and animals, and producing additional
quantities of collagen and proteoglycans for use in the repair of
damaged connective tissue. In addition, inflammation of connective
tissue may be reduced by the compositions of the invention. The
compositions of the present invention may achieve these functions
directly or through indirect pathways--i.e., through their effect
on other components in the living system which in turn can increase
connective tissue synthesis or reduce inflammation.
[0058] In one embodiment, a composition of the present invention
include S-Adenosylmethionine (SAM) and an aminosugar, such as
glucosamine, preferably in a salt form. In another embodiment of
the present invention, the composition includes SAM and a
glycosaminoglycan, such as chondroitin (preferably in a salt form
such as chondroitin sulfate). In another embodiment, the
composition of the present invention includes SAM, an aminosugar,
such as glucosamine, preferably in a salt form, and a
glycosaminoglycan, such as chondroitin (preferably in a salt form,
such as chondroitin sulfate). Alternatively, fragments of a
glycosaminoglycan may be used in a composition of the invention in
addition to or in substitution for the glycosaminoglycan. Each of
these compositions may optionally include manganese. A preferred
form of manganese in such compositions is a manganese salt, such as
manganese ascorbate, because the ascorbate is a soluble form of
manganese which further provides ascorbic acid, a substance needed
for collagen synthesis. Other manganese salts such, as for example,
sulfate or gluconate, may be used however. Each of these
compositions may optionally contain one or more methyl donors or
methyl donor cofactors selected from the group consisting of
vitamins B12 and B6, folic acid, dimethylglycine, and
trimethylglycine.
[0059] Referring to FIGS. 2 and 3, the biosynthetic pathway for the
production of connective tissue, which is affected by the method of
the present invention by virtue of the components of the
composition of the present invention which aid in connective tissue
repair, functions as described in the above background section of
this application.
[0060] In a preferred embodiment, the aminosugar glucosamine is the
base of the composition, providing the primary substrate for both
collagen and proteoglycan synthesis. Glucosamine is the preferred
substrate for proteoglycan synthesis, including chondroitin
sulfates and hyaluronic acid. The glucosamine preferably is in a
salt form so as to facilitate its delivery-and uptake by humans and
animals. The preferred salt forms are glucosamine hydrochloride,
glucosamine sulfate and N-acetylglucosamine.
[0061] Administration of a preferred embodiment of the composition
of the present invention provides the human or animal organism with
exogenous quantities of SAM, an aminosugar or salts thereof, and a
glycosaminoglycan or fragments thereof. If desired, the composition
also provides the human or animal organism with exogenous.
quantities of manganese cofactors. Also if desired, the
compositions of the present invention may include methyl donors or
methyl donor cofactors, such as vitamins B12 and B6, folic acid,
dimethylglycine, and trimethylglycine.
[0062] The exogenous glucosamine provided by the composition of
present invention is converted to proteoglycans as is seen in FIG.
2 and as described above.
[0063] In the former case, the glucosamine may be converted with
the aid of manganese directly into GAG, including hyaluronic acid
(which is 50% glucosamine and which forms the backbone of the
proteoglycans). This core protein is then linked to the hyaluronic
acid via the link protein, as is seen in FIG. 3.
[0064] In the latter case, the free amino acids are, with the aid
of manganese and zinc cofactors (and ascorbic acid or vitamin C),
converted to procollagen. The procollagen is then converted into
collagen with the aid of copper or iron cofactors and vitamin C
(ascorbic acid) and sulfate chelates.
[0065] Thus, preferred compositions of the present invention
containing SAM and glucosamine advantageously stimulate the
synthesis of collagen and glycosaminoglycans or mucopolysaccharides
(GAGs), including hyaluronic acid, the backbone of proteoglycans
(PG's), thereby providing a natural tissue repair function. These
compositions provide the connective tissue repair function of
glucosamine, the increased sulfation of GAGs by SAM, the
stabilization by SAM metabolites of the polyanionic macromolecules
of proteoglycans, and the additional analgesic, anti-inflammatory,
and anti-depressant effects of SAM. The optional addition of
manganese provides a further benefit if a deficiency of the mineral
exists or if it is otherwise desired. The optional inclusion of
methyl donors or methyl donor cofactors, such as vitamins B12 and
B6, folic acid, dimethylglycine, and trimethylglycine, helps to
promote methylation and thereby convert homocysteine to
methionine.
[0066] Another preferred composition of the invention comprises SAM
and chondroitin salts (such as chondroitin sulfate). SAM operates
in this composition, in conjunction with endogenous glucosamine, as
described above. Chondroitin salts operate with SAM and endogenous
glucosamine by inhibiting the synovial degradative enzymes.
Chondroitin salts (such as chondroitin sulfate) also directly
contribute to the pool of GAGs of cartilaginous tissue. Manganese
salts may also be included in this composition in those cases where
a deficiency of manganese exists. Methyl donors or methyl donor
cofactors, such as vitamins B12 and B6, folic acid,
dimethylglycine, and trimethylglycine, may optionally be included
in these compositions to help promote methylation and thereby
convert homocysteine to methionine.
[0067] Another preferred embodiment of the composition of the
present invention contains SAM, glucosamine, and chondroitin salts
(such as chondroitin sulfate) and mixtures and fragments thereof,
and also advantageously stimulates the synthesis of collagen and
glycosaminoglycans or mucopolysaccharides (GAGs), including
hyaluronic acid, thereby providing a natural tissue repair
function. This composition provides the superior connective tissue
repair function of glucosamine, the above-described benefits of
SAM, and the above-described benefits from chondroitin salts
(including chondroitin sulfate) and fragments of chondroitin salts.
Chondroitin salts (including chondroitin sulfate) also operate with
SAM and glucosamine by inhibiting the synovial degradative enzymes.
Chondroitin salts (including chondroitin sulfate) also directly
contribute to the pool of GAGs of cartilaginous tissue. Manganese
provides a further benefit if a deficiency of the mineral exists.
As with the compositions described above, methyl donors or methyl
donor cofactors, such as vitamins B12 and B6, folic acid,
dimethylglycine, and trimethylglycine, may optionally be included
in these compositions to help promote methylation and thereby
convert homocysteine to methionine. Tissue repair can thus be
accomplished, in the context of the treatment and repair of
connective tissue and the treatment of arthritic conditions, in
almost all areas of the body both human and animal.
[0068] In the present method for the treatment and repair and for
reducing the inflammation of connective tissue in humans and
animals, preferred compositions comprising amounts of SAM in
combination with glucosamine including salts thereof in combination
with chondroitin salts (including chondroitin sulfate) or fragments
thereof, or amounts of SAM and chondroitin salts (including
chondroitin sulfate) or fragments thereof in combination with
glucosamine including salts thereof, may be administered to humans
and animals thereof for stimulating both collagen and proteoglycan
synthesis. An additional preferred composition comprising amounts
of SAM and chondroitin salts (including chondroitin sulfate) or
fragments thereof may be administered to humans and animals for
stimulating proteoglycan synthesis and reducing inflammation.
Manganese salts may also be optionally included in each composition
in cases where a deficiency of manganese exists. Methyl donors or
methyl donor cofactors, such as vitamins B12 and B6, folic acid,
dimethylglycine, and trimethylglycine may optionally be included to
these compositions as well.
[0069] The compositions of the present invention are administered
to promote tissue repair, including cartilage repair, and the
treatment of arthritic conditions as well as connective tissue
damage in humans and animals. The anti-depressant effect of SAM may
help to alleviate the burden of sickness for some patients, thus
enhancing their quality of life. This effect, as well as the
analgesic and anti-inflammatory effects of SAM which will help
alleviate the pain associated with arthritic conditions, may help
remove impediments to physical activity. Increased levels of
physical activity, in turn, can supply the loading and unloading
forces necessary for the regeneration of articular cartilage.
Supplementation with glucosamine, with its chondroprotective role,
thus helps to ensure that the raw materials are available to
support the increased regeneration of cartilage. The compositions
of the present invention are also understood to play a role in
chondromodulation, chondrostabilization, and
chondrometabolizaton.
[0070] The dosage of SAM in the nutritional supplements of the
present invention ranges from about 5 mg to about 5,000 mg in
humans and small animals, and from about 2 mg to about 20,000 mg in
large animals (e.g., equine). The dosage of glucosamine in the
nutritional supplements of the present invention ranges from about
50 mg to about 5,000 mg in humans and small animals, and from about
250 mg to about 40,000 mg in large animals (e.g., equine). The
dosage of chondroitin salts in the nutritional supplements of the
present invention ranges from about 15 mg to about 5,000 mg in
humans and small animals, and from about 100 mg to about 30,000 mg
in large animals. When included in the compositions of the present
invention, manganese may optionally be present in the range of
about 2 to about 75 mg in humans and small animals, and from about
10 mg to about 500 mg in large animals. The ascorbate component of
the manganese ascorbate may range from about 10 mg to about 500 mg
in humans and small animals, and from about 50 mg to about 2,500 mg
in large animals. When included in the compositions of the present
invention, the methyl donors or methyl donor cofactors, such as
vitamins B12 and 86, folic acid, dimethylglycine, and
trimethylglycine may be present in the range of about 0.1 mg to
about 10 mg in humans and small animals, and from about 1 mg to
about 100 mg in large animals.
[0071] As a preferred embodiment, a dosage of the nutritional
supplement composition of the present invention may consist of one
or more capsules or tablets for human oral consumption. In such an
embodiment, the preferred weight of the dosage is between about 5
mg to about 5,000 mg, and preferably about 2,500 mg. The dosage may
be administered in a single daily dosage form in which all
components are present, e.g., a capsule or tablet of preferably
2,500 mg. The dosage may also be administered in more than one
dosage form in which each dosage form contains at least one
component. When a single dosage is administered in more than one
dosage form, the multiple dosage forms may be co-administered as a
single dosage. Thus, for example, a single dosage may be comprised
of a SAM dosage form co-administered with a glucosamine and
chondroitin salts dosage form.
[0072] Alternatively, the nutritional supplement compositions of
the present invention may be administered more than once daily.
Hence, for example, the nutritional supplement compositions of the
present invention may be in the form of an oral dosage form of 1250
mg administered twice daily or 833 mg administered three times
daily. The number of daily administrations will depend upon the
needs of the human or animal recipient. Different connective tissue
disorders and injuries require different amounts of the
compositions of the present invention. In that regard, several
dosages may be administered depending on the particular needs of
the human or animal.
[0073] Alternatively, and of particular use in large animals, the
compositions of the present invention may for example be
administered in scoops. Such administration may take the form, for
example, of a level scoopful containing about 1,800 mg glucosamine,
about 600 mg chondroitin salts, about 16 mg of manganese (when
included in the form of manganese ascorbate), and about 104 mg of
ascorbate (when included in the form of manganese ascorbate).
[0074] These preparations may be made by conventional methods. For
example, to prepare the compositions of the invention, the
above-described ingredients are combined as the active ingredient
in intimate admixture with a suitable carrier according to
conventional compounding techniques. This carrier may take a wide
variety of forms depending upon the form of preparation desired for
administration, e.g., oral, sublingual, nasal, guttural, rectal,
transdermal or parenteral.
[0075] In preparing the compositions in oral dosage form, any usual
pharmaceutical medium may be employed. For oral liquid preparations
(e.g., suspensions, elixirs, and solutions), media containing for
example, water, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like may be used. Carriers such as
starches, sugars, diluents, granulating agents, lubricants,
binders, disintegrating agents, and the like may be used to prepare
oral solids (e.g., powders, capsules, pills, caplets, tablets,
microencapsulated granules, microtablets, coated granules and
lozenges). Capsules or tablets are a preferred oral dosage form.
Controlled release forms may also be used. Because of their ease in
administration, lozenges, tablets, pills, caplets, and capsules
represent the most advantageous oral dosage unit form, in which
case solid pharmaceutical carriers are obviously employed. If
desired, tablets may be sugar coated or enteric coated by standard
techniques. The compositions of the present invention may be in the
form of one or more of these oral dosage forms--i.e., a single
dosage may be in multiple forms.
[0076] For parenteral products, the carrier will usually comprise
sterile water, although other ingredients may be included, e.g., to
aid solubility or for preservation purposes. Injectable suspensions
may also be prepared, in which case appropriate liquid carriers,
suspending agents, and the like may be employed.
[0077] Having discussed the composition of the present invention,
it will be more clearly perceived and better understood from the
following specific examples which are intended to provide examples
of the preferred embodiments and do not limit the present
invention.
Example 1
[0078] The composition of the present invention is made in one or
more capsules for oral administration in humans and small animals.
In a preferred embodiment, each dosage contains:
TABLE-US-00002 Human & Small Animal Range/Dose SAM 5-5,000 mg
Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg
Example 2
[0079] For those situations in which manganese supplementation is
desired, a manganese salt is added to the composition of Example 1
so that each dosage contains:
TABLE-US-00003 Human & Small Animal Range/Dose SAM 5-5,000 mg
Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese
(as Ascorbate) 2-75 mg Ascorbate (as Manganese Ascorbate) 10-500
mg
Example 3
[0080] For larger animals, such as horses, the composition of
Example 1 is administered as filled scoops.
TABLE-US-00004 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg
Example 4
[0081] For those situations in which manganese supplementation is
desired, manganese salts may be added to the composition of Example
3 so that each dosage contains:
TABLE-US-00005 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg
Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese
Ascorbate) 50-2,500 mg
Example 5
[0082] For a further preferred composition, each dosage
contains:
TABLE-US-00006 Human & Small Animal Range/Dose SAM 5-5,000 mg
Glucosamine 50-5,000 mg
Example 6
[0083] For those situations in which manganese supplementation is
desired, a manganese salt is added to the composition of Example 5
so that each dosage contains
TABLE-US-00007 Human & Small Animal Range/Dose SAM 5-5,000 mg
Glucosamine 50-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate
(as Manganese Ascorbate) 10-500 mg
Example 7
[0084] For larger animals, such as horses, the composition of
Example 5 is administered as filled scoops.
TABLE-US-00008 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Glucosamine 250-40,000 mg
Example 8
[0085] For those situations in which manganese supplementation is
desired, manganese salts may be added to the composition of Example
7 so that each dosage contains:
TABLE-US-00009 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Glucosamine 250-40,000 mg Manganese (as Ascorbate) 10-500 mg
Ascorbate (as Manganese Ascorbate) 50-2,500 mg
Example 9
[0086] For a further preferred composition, each dosage
contains:
TABLE-US-00010 Human & Small Animal Range/Dose SAM 5-5,000 mg
Chondroitin Sulfate 15-5,000 mg
Example 10
[0087] For those situations in which manganese supplementation is
desired, a manganese salt is added to the composition of Example 9
so that each dosage. contains:
TABLE-US-00011 Human & Small Animal Range/Dose SAM 5-5,000 mg
Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg
Ascorbate (as Manganese Ascorbate) 10-500 mg
Example 11
[0088] For larger animals, such as horses, the composition of
Example 10 is administered as filled scoops.
TABLE-US-00012 Larqe Animal (Equine) Range/Dose SAM 2-20,000 mg
Chondroitin Sulfate 100-30,000 mg
Example 12
[0089] For those situations in which manganese supplementation is
desired, manganese salts may be added to the composition of Example
11 so that each dosage contains:
TABLE-US-00013 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500
mg Ascorbate (as Manganese Ascorbate) 50-2,500 mg
Example 13
[0090] For those situations in which methyl donors or methyl donor
cofactors are desired, such compounds may be added to the
composition of Example 1 so that each dosage contains:
TABLE-US-00014 Human & Small Animal Range/Dose SAM 5-5,000 mg
Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg vitamin B12
0.1-10 mg
Example 14
[0091] For those situations in which manganese supplementation is
desired, a manganese salt is added to the composition of Example 13
so that each dosage contains:
TABLE-US-00015 Human & Small Animal Range/Dose SAM 5-5,000 mg
Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese
(as Ascorbate) 2-75 mg Ascorbate (as Manganese Ascorbate) 10-500 mg
vitamin B12 0.1-10 mg
Example 15
[0092] For larger animals, such as horses, the composition of
Example 13 is administered as filled scoops.
TABLE-US-00016 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg vitamin
B12 1-100 mg
Example 16
[0093] For those situations in which manganese supplementation is
desired, manganese salts may be added to the composition of Example
15 so that each dosage contains:
TABLE-US-00017 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg
Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese
Ascorbate) 50-2,500 mg vitamin B12 1-100 mg
Example 17
[0094] For a further preferred composition, each dosage
contains:
TABLE-US-00018 Human & Small Animal Range/Dose SAM 5-5,000 mg
Glucosamine 50-5,000 mg vitamin B12 0.1-10 mg
Example 18
[0095] For those situations in which manganese supplementation is
desired, a manganese salt is added to the composition of Example 17
so that each dosage contains:
TABLE-US-00019 Human & Small Animal Range/Dose SAM 5-5,000 mg
Glucosamine 50-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate
(as Manganese Ascorbate) 10-500 mg vitamin B12 0.1-10 mg
Example 19
[0096] For larger animals, such as horses, the composition of
Example 17 is administered as filled scoops.
TABLE-US-00020 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Glucosamine 250-40,000 mg vitamin B12 1-100 mg
Example 20
[0097] For those situations in which manganese supplementation is
desired, manganese salts may be added to the composition of Example
19 so that each dosage contains:
TABLE-US-00021 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Glucosamine 250-40,000 mg Manganese (as Ascorbate) 10-500 mg
Ascorbate (as Manganese Ascorbate) 50-2,500 mg vitamin B12 1-100
mg
Example 21
[0098] For a further preferred composition, each dosage
contains:
TABLE-US-00022 Human & Small Animal Range/Dose SAM 5-5,000 mg
Chondroitin Sulfate 15-5,000 mg vitamin B12 0.1-10 mg
Example 22
[0099] For those situations in which manganese supplementation is
desired, a manganese salt is added to the composition of Example 21
so that each dosage contains:
TABLE-US-00023 Human & Small Animal Range e/Dose SAM 5-5,000 mg
Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg
Ascorbate (as Manganese Ascorbate) 10-500 mg vitamin B12 0.1-10
mg
Example 23
[0100] For larger animals, such as horses the composition of
Example 21 is administered as filled scoops.
TABLE-US-00024 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Chondroitin Sulfate 100-30,000 mg vitamin B12 1-100 mg
Example 24
[0101] For those situations in which manganese supplementation is
desired, manganese salts may be added to the composition of Example
23 so that each dosage contains:
TABLE-US-00025 Large Animal (Equine) Range/Dose SAM 2-20,000 mg
Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500
mg Ascorbate (as Manganese Ascorbate) 50-2,500 mg vitamin B12 1-100
mg
[0102] Many modifications may be made without departing from the
basic spirit of the present invention. Accordingly, it will be
appreciated by those skilled in the art that within the scope of
the appended claims, the invention may be practiced other than has
been specifically described herein.
* * * * *