U.S. patent application number 11/435120 was filed with the patent office on 2009-03-05 for methods for the treatment of diabetes, the reduction of body fat, improvement of insulin sensitivity, reduction of hyperglycemia, and reduction of hypercholesterolemia with chromium complexes, conjugated fatty acids, and/or conjugated fatty alcohols.
Invention is credited to Danielle Greenberg, David P. Katz, James R. Komorowski.
Application Number | 20090060941 11/435120 |
Document ID | / |
Family ID | 26927971 |
Filed Date | 2009-03-05 |
United States Patent
Application |
20090060941 |
Kind Code |
A9 |
Katz; David P. ; et
al. |
March 5, 2009 |
Methods for the treatment of diabetes, the reduction of body fat,
improvement of insulin sensitivity, reduction of hyperglycemia, and
reduction of hypercholesterolemia with chromium complexes,
conjugated fatty acids, and/or conjugated fatty alcohols
Abstract
A composition for treating insulin-dependent diabetes, reducing
body fat, improving insulin sensitivity, reducing hyperglycemia,
and reducing hypercholesterolemia with at least one chromium
complex and a conjugated fatty acid or conjugated fatty alcohol is
disclosed. A method of treating a subject suffering from
insulin-dependent diabetes by administering a composition that
includes at least one chromium complex and a conjugated fatty acid
or conjugated fatty alcohol is similarly provided. The
administration of a composition containing an effective dose of at
least one chromium complex and a conjugated fatty acid or
conjugated fatty alcohol for the treatment of obesity is likewise
provided.
Inventors: |
Katz; David P.; (Dobbs
Ferry, NY) ; Komorowski; James R.; (Trumbull, CT)
; Greenberg; Danielle; (Waccabuc, NY) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
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Prior
Publication: |
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Document Identifier |
Publication Date |
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US 20060204517 A1 |
September 14, 2006 |
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Family ID: |
26927971 |
Appl. No.: |
11/435120 |
Filed: |
May 16, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10319328 |
Dec 12, 2002 |
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11435120 |
May 16, 2006 |
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09957876 |
Sep 20, 2001 |
6809115 |
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10319328 |
Dec 12, 2002 |
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60234474 |
Sep 21, 2000 |
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60296688 |
Jun 6, 2001 |
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Current U.S.
Class: |
424/195.16 ;
424/748; 424/769; 424/771; 514/184; 514/420; 514/560; 514/570 |
Current CPC
Class: |
A61K 31/23 20130101;
A61K 31/045 20130101; A61K 31/19 20130101; A61K 31/045 20130101;
A61K 36/45 20130101; A61K 33/24 20130101; A61K 36/328 20130101;
A61P 5/50 20180101; A61K 31/20 20130101; A61K 31/455 20130101; A61K
31/555 20130101; A61K 36/324 20130101; A61K 31/20 20130101; A61K
31/165 20130101; A61K 36/76 20130101; A61K 31/455 20130101; A61K
31/555 20130101; A61K 31/045 20130101; A61K 31/20 20130101; A61K
2300/00 20130101; A61K 31/045 20130101; A61K 31/20 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 31/405 20130101; A61K
31/19 20130101; A61K 31/455 20130101; A61K 31/455 20130101; A61K
31/045 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
31/19 20130101; A61K 2300/00 20130101; A61K 31/045 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/045 20130101; A61K 31/455 20130101; A61K 2300/00 20130101;
A61K 31/455 20130101; A61K 31/20 20130101; A61K 31/20 20130101;
A61K 2300/00 20130101; A61K 31/165 20130101; A61K 2300/00 20130101;
A61K 31/165 20130101; A61K 2300/00 20130101; A61K 31/20 20130101;
A61K 31/20 20130101; A61K 31/405 20130101; A61K 31/455 20130101;
A61K 2300/00 20130101; A61K 31/20 20130101; A61K 31/045 20130101;
A61K 31/20 20130101; A61K 31/09 20130101; A61K 31/455 20130101;
A61K 31/455 20130101; A61K 31/045 20130101; A61K 31/19 20130101;
A61K 2300/00 20130101; A61K 31/455 20130101; A61K 2300/00 20130101;
A61K 31/045 20130101; A61K 36/185 20130101; A61K 45/06 20130101;
A61K 36/328 20130101; A61K 36/45 20130101; A61P 3/10 20180101; A61P
3/04 20180101; A61K 31/19 20130101; A61K 36/73 20130101; A61K
31/555 20130101; A61K 36/76 20130101; A61K 31/23 20130101; A61K
31/405 20130101; A61K 36/06 20130101; A61P 43/00 20180101; A61P
31/00 20180101; A61K 31/455 20130101; A61K 31/455 20130101; A61K
31/165 20130101; A61K 31/455 20130101; A61K 31/555 20130101; A61K
36/73 20130101; A61K 31/405 20130101; A61K 31/455 20130101; A61K
36/06 20130101; A61P 3/06 20180101; A61K 31/555 20130101; A61K
36/185 20130101; A61K 33/24 20130101; A61K 36/324 20130101; A61K
31/555 20130101 |
Class at
Publication: |
424/195.16 ;
424/748; 514/184; 424/769; 424/771; 514/560; 514/570; 514/420 |
International
Class: |
A61K 36/328 20060101
A61K036/328; A61K 31/555 20060101 A61K031/555; A61K 31/192 20060101
A61K031/192; A61K 31/405 20060101 A61K031/405; A61K 31/202 20060101
A61K031/202; A61K 36/76 20060101 A61K036/76 |
Claims
1. A method of treating obesity in a subject in need thereof
comprising: identifying a subject presenting with obesity;
administering to said subject a pharmaceutically effective dose of
a conjugated fatty acid or conjugated fatty alcohol in combination
with a pharmaceutically effective dose of at least one chromium
complex selected from the group consisting of chromium picolinate,
chromium nicotinate, chromic tripicolinate, chromic polynicotinate,
chromium chloride, chromium histidinate, and chromium yeasts.
2. The method of claim 1, wherein said conjugated fatty acid is
selected from the group consisting of a conjugated version of
linoleic acid, linolenic acid, gamma linolenic acid, arachidonic
acid, mead acid, stearidonic acid, alpha-eleostearic acid,
eleostearic acid, pinolenic acid, docosadienic acid,
docosatetraenoic acid, octadecadienoic acid, octadecatrienoic acid,
eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid,
and docosapentaenoic acid.
3. The method of claim 1, wherein said conjugated fatty acid is
conjugated linoleic acid.
4. The method of claim 1, wherein said conjugated fatty alcohol is
selected from the group consisting of a conjugated version of
linoleic alcohol, linolenic alcohol, gamma linolenic alcohol,
arachidonic alcohol, mead alcohol, stearidonic alcohol,
alpha-eleostearic alcohol, eleostearic alcohol, pinolenic alcohol,
docosadienic alcohol, docosatetraenoic alcohol, octadecadienoic
alcohol, octadecatrienoic alcohol, eicosatetraenoic alcohol,
eicosapentaenoic alcohol, docosahexaenoic alcohol, docosapentaenoic
alcohol, and all other diunsaturated and polyunsaturated fatty
alcohols.
5. The method of claim 1, wherein said composition further
comprises at least one uncomplexed chelating agent.
6. The method of claim 5, wherein said chelating agent is picolinic
acid, nicotinic acid, or both.
7. The method of claim 1, wherein said composition further
comprises at least one of a cyclooxygenase inhibitor, a mucolytic,
and a salicin-containing herb.
8. The method of claim 1, wherein said at least one cyclooxygenase
inhibitor is selected from the group consisting of indomethacin,
ibuprofen, acetaminophen, and naproxen.
9. The method of claim 7, wherein said salicin-containing herb is
selected from the group consisting of Boswellia serrata
(frankincense), Betula lenta (sweet birch), Betula pubescens (white
birch), Filipendula ulmaria (meadowsweet), Gautheria procumbens
(wintergreens), Polulus balsamifera, Populus jackii (balm of
Gilead) and Salix alba (white willow).
10. The method of claim 7, wherein said mucolytic is
guaifenesin.
11. A method of reducing body fat comprising administering to a
subject in need of body fat reduction a pharmaceutically effective
dose of a conjugated fatty acid or conjugated fatty alcohol in
conjunction with a pharmaceutically effective dose of at least one
chromium complex selected from the group consisting of chromium
picolinate, chromium nicotinate, chromic tripicolinate, chromic
polynicotinate, chromium chloride, chromium histidinate, and
chromium yeasts.
12. The method of claim 11, wherein said conjugated fatty acid is
selected from the group consisting of a conjugated version of
linoleic acid, linolenic acid, gamma linolenic acid, arachidonic
acid, mead acid, stearidonic acid, alpha-eleostearic acid,
eleostearic acid, pinolenic acid, docosadienic acid,
docosatetraenoic acid, octadecadienoic acid, octadecatrienoic acid,
eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid,
and docosapentaenoic acid.
13. The method of claim 11, wherein said conjugated fatty acid is
conjugated linoleic acid.
14. The method of claim 11, wherein said conjugated fatty alcohol
is selected from the group consisting of a conjugated version of
linoleic alcohol, linolenic alcohol, gamma linolenic alcohol,
arachidonic alcohol, mead alcohol, stearidonic alcohol,
alpha-eleostearic alcohol, eleostearic alcohol, pinolenic alcohol,
docosadienic alcohol, docosatetraenoic alcohol, octadecadienoic
alcohol, octadecatrienoic alcohol, eicosatetraenoic alcohol,
eicosapentaenoic alcohol, docosahexaenoic alcohol, docosapentaenoic
alcohol, and all other diunsaturated and polyunsaturated fatty
alcohols.
15. The method of claim 11, wherein said composition further
comprises at least one uncomplexed chelating agent.
16. The method of claim 15, wherein said chelating agent is
picolinic acid, nicotinic acid, or both.
17. The method of claim 1, wherein said composition further
comprises at least one of a cyclooxygenase inhibitor, a mucolytic,
and a salicin-containing herb.
18. The method of claim 17, wherein said at least one
cyclooxygenase inhibitor is selected from the group consisting of
indomethacin, ibuprofen, acetaminophen, and naproxen.
19. The method of claim 17, wherein said salicin-containing herb is
selected from the group consisting of Boswellia serrata
(frankincense), Betula lenta (sweet birch), Betula pubescens (white
birch), Filipendula ulmaria (meadowsweet), Gautheria procumbens
(wintergreens), Polulus balsamifera, Populus jackii (balm of
Gilead) and Salix alba (white willow).
20. The method of claim 17, wherein said mucolytic is guaifenesin.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of prior application Ser.
No. 09/957,876, filed Sep. 20, 2001, which claims priority to
provisional application filed Sep. 21, 2000 having application No.
60/234,474, and provisional application filed Jun. 6, 2001 having
application No. 60/296,688, each of which is hereby incorporated by
reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The disclosed invention related to compositions and methods
for the treatment of type 1 diabetes, reduction of body fat,
improvement of insulin sensitivity, reduction of hyperglycemia, and
reduction of hypercholesterolemia. Specifically, compositions
comprising chromium complexes in combination with conjugated
compounds such as isomers of conjugated fatty acids or conjugated
fatty alcohols.
[0004] 2. Description of the Related Art
Insulin-Dependent Diabetes
[0005] Diabetes is a chronic metabolic disorder which afflicts 16
million people in the United States, over one and one half million
of whom have its most severe form, childhood diabetes (also called
juvenile, type 1 or insulin-dependent diabetes). Insulin-dependent
diabetes appears suddenly, most often in children and young adults,
and progresses rapidly. In this form, the pancreas ceases to
manufacture insulin, a hormone necessary to convert the food we eat
into energy for the body. In the United States, diabetes is the
fourth leading cause of death, killing more than 162,000 people
each year. Notably, the mortality rate of patients with
insulin-dependent diabetes increases dramatically after 15 years of
disease duration. In addition, virtually every major organ system
in the body is damaged by diabetes. Complications can include
blindness, kidney failure, heart disease, stroke, amputation of
extremities, loss of nerve sensation, early loss of teeth,
high-risk pregnancies and babies born with birth defects.
[0006] Insulin resistance is characterized by reductions of glucose
uptake in skeletal muscle. Currently, insulin injection is the only
treatment method available for the over 1.5 million type 1
diabetics and becomes the eventual course of treatment for many of
the more than 16 million type 2 diabetics in the United States.
Nutritional therapies that positively impact glucose uptake in the
face of insulin insufficiency would have a major impact on the long
term treatment costs associated with diabetic care.
Obesity
[0007] More than half of U.S. adults are overweight and nearly
one-quarter of the U.S. adults are considered to be obese. The
increasing prevalence of overweight and obesity is a major public
health concern, since obesity is associated with several chronic
diseases. For example, overweight and obesity are known risk
factors for diabetes, heart disease, stroke, hypertension,
gallbladder disease, osteoarthritis, sleep apnea, and some forms of
cancer such as uterine, breast, colorectal, kidney, and
gallbladder. Furthermore, obesity is associated with high
cholesterol, complications of pregnancy, menstrual irregularities,
hirsutism, and increased surgical risk.
[0008] Drugs currently approved by the FDA for the treatment of
obesity produce weight losses of about 10% of initial body weight
at one year when used singly. Combination therapy with phentermine
and fenfluramine produced weight losses of about 15% of initial
body weight at one year. Phenylpropanolamine (PPA) is an
over-the-counter drug that has not been tested for long term use
and is recommended for use for only about 12 weeks. With the
exception of PPA, all of these drugs require a physician's
prescription and are generally quite expensive. Side effects occur
with all these drugs. For example, the administration of
fenfluramine and phentermine for the treatment of obesity resulted
in cardiac valve damage in some patients and ultimately led to the
withdrawal of fenfluramine from the market. Two of the newest drugs
for the treatment of obesity have side effects that limit their
use. Sibutramine increases blood pressure in a subset of patients,
and orlistat may have unpleasant gastrointestinal side effects.
The Role of Chromium Complexes in the Treatment of
Insulin-Dependent Maladies
[0009] Chromium picolinate is reported to produce modest weight
loss and changes in body composition (Kaats, 1998, Cefalu, 1999).
Chromium is a nutritionally essential trace element. The
essentiality of chromium in the diet was established in 1959 by
Schwartz, as cited in Present Knowledge in Nutrition, page 571,
fifth edition (1984, the Nutrition Foundation, Washington, D.C.).
Chromium depletion is characterized by the disturbance of glucose,
lipid and protein metabolism and by a shortened lifespan. Chromium
is essential for optimal insulin activity in all known
insulin-dependent systems (Boyle et al., Southern Med. J.
70:1449-1453, 1977). Insufficient dietary chromium has been linked
to both maturity-onset diabetes and to cardiovascular disease.
[0010] The principal energy sources for the body are glucose and
fatty acids. Chromium depletion results in biologically ineffective
insulin and compromised glucose metabolism. Under these conditions,
the body must rely primarily on lipid metabolism to meet its energy
requirements, resulting in the production of excessive amounts of
acetyl-CoA and ketone bodies. Some of the documented acetyl-CoA is
diverted to increased cholesterol biosynthesis, resulting in
hypercholesterolemia. Diabetes mellitus is characterized in large
part by glycosuria, hypercholesterolemia, and often ketoacidosis.
The accelerated atherosclerotic process seen in diabetics is
associated with hypercholesterolemia (Boyle et al., supra.).
[0011] Dietary supplementation of chromium to normal individuals
has been reported to lead to improvements in glucose tolerance,
serum lipid concentrations, including high-density lipoprotein
cholesterol, insulin and insulin binding (Anderson, Clin. Psychol.
Biochem. 4:31-41, 1986). Supplemental chromium in the trivalent
form, e.g. chromic chloride, is associated with improvements of
risk factors associated with adult-onset (type 2) diabetes and
cardiovascular disease.
[0012] Chromium functions as a cofactor for insulin. It binds to
the insulin receptor and potentiates many, and perhaps all, of its
functions (Boyle et al., supra.). These functions include, but are
not limited to, the regulation of carbohydrate and lipid
metabolism. (Present Knowledge in Nutrition, supra. at p. 573-577).
The introduction of inorganic chromium compounds per se into
individuals is not particularly beneficial. Chromium must be
converted endogenously into an organic complex or must be consumed
as a biologically active molecule. Only about 0.5% of ingested
inorganic chromium is assimilated into the body (Recommended Daily
Allowances, Ninth Revised Edition, The National Academy of
Sciences, page 160, 1980). Only 1-2% of most organic chromium
compounds are assimilated into the body.
[0013] U.S. Pat. No. Re. 33,988 discloses that when selected
essential metals, including chromium, are administered to mammals
as exogenously synthesized coordination complexes of picolinic
acid, they are directly available for absorption without
competition from other metals. This patent describes a composition
and method for selectively supplementing the essential metals in
the human diet and for facilitating absorption of these metals by
intestinal cells. These complexes are safe, inexpensive,
biocompatible and easy to produce. These exogenously synthesized
essential metal coordination complexes of picolinic acid
(pyridine-2-carboxylic acid) have the following structural formula:
##STR1## wherein M represents the metallic cation and n is equal to
the cation's valence. For example, when M is Cr and n=3, then the
compound is chromic tripicolinate. Other chromium picolinates
disclosed include chromic monopicolinate and chromic
dipicolinate.
[0014] The U.S. Recommended Daily Intake (RDI) of chromium is 120
.mu.g. U.S. Pat. No. 5,087,623, the entire contents of which are
hereby incorporated by reference, describes the administration of
chromic tripicolinate for the treatment of adult-onset diabetes in
doses ranging from 50 to 500 .mu.g. International Patent
Application No. WO96/35421 discloses the use of high doses of
chromic tripicolinate (providing 1,000-10,000 .mu.g chromium/day)
for reducing hyperglycemia and stabilizing the level of serum
glucose in humans with type 2 diabetes. U.S. Pat. No. 5,789,401
discloses achromic tripicolinate-biotin composition and its use in
lowering blood glucose levels in humans with type 2 diabetes.
[0015] U.S. Pat. Nos. 5,087,623; 5,087,624; and 5,175,156, the
entire contents of which are hereby incorporated by reference,
disclose the use of chromium tripicolinate for supplementing
dietary chromium, reducing hyperglycemia and stabilizing serum
glucose, increasing lean body mass and reducing body fat, and
controlling blood serum lipid levels, including the lowering of
undesirably high blood serum LDL-cholesterol levels and the raising
of blood serum HDL-cholesterol levels. U.S. Pat. Nos. 4,954,492 and
5,194,615, the entire contents of which are hereby incorporated by
reference, describe a related complex, chromic nicotinate, which is
also used for supplementing dietary chromium and lowering serum
lipid levels. Picolinic acid and nicotinic acid are position
isomers having the following structures: ##STR2##
[0016] Nicotinic acid and picolinic acid form coordination
complexes with monovalent, divalent and trivalent metal ions and
facilitate the absorption of these metals by transporting them
across intestinal cells and into the bloodstream. Chromium
absorption in rats following oral administration of CrCl.sub.3 was
facilitated by the non-steroidal anti-inflammatory drugs (NSAIDs)
aspirin and indomethacin (Davis et al., J. Nutrition Res.
15:202-210, 1995; Kamath et al., J. Nutrition 127:478-482, 1997).
These drugs inhibit the enzyme cyclooxygenase which converts
arachidonic acid to various prostaglandins, resulting in inhibition
of intestinal mucus formation and lowering of intestinal pH which
facilitates chromium absorption.
[0017] Additional pharmacological treatments for disorders caused
by or exacerbated by improper glucose uptake are needed.
Specifically, compositions for the treatment of diabetes and
obesity would be a great boon to subjects suffering from these
disease states. A new, more effective, less expensive treatment for
diabetes and obesity with minimal side effects would be a great
benefit to the treatment and prevention of obesity.
BRIEF DESCRIPTION OF THE FIGURES
[0018] FIG. 1 shows the effect of conjugated linoleic acid (CLA) on
glucose uptake in human skeletal muscle culture.
[0019] FIG. 2 graphs the effect of CP+CLA on glucose uptake in
human skeletal muscle culture.
[0020] FIG. 3 illustrates the effect of CP+CLA on glucose uptake in
human skeletal muscle culture.
SUMMARY OF THE INVENTION
[0021] The disclosed invention is directed to compositions and
methods for treating insulin-dependent diabetes, non-insulin
dependent diabetes, reduction of body fat, improvement of insulin
sensitivity, reduction of hyperglycemia, and reduction of
hypercholesterolemia. One embodiment of the disclosed invention is
a composition that includes at least one chromium complex and a
conjugated fatty acid or conjugated fatty alcohol. Preferably, the
chromium complex is chromium picolinate or chromium nicotinate.
Advantageously, the conjugated fatty acid is conjugated linoleic
acid.
[0022] In one aspect of the invention, the composition optionally
includes a chelating agent. The chelating agent may be picolinic
acid, nicotinic acid, or both.
[0023] The recited compositions are incorporated into a
pharmaceutically effective carrier. The pharmaceutically effective
carrier may be a tablet, capsule, microbead, emulsion, powder,
granule, suspension, syrup or elixir. Preferably, when the carrier
is a microbead, the microbead is a sugar beadlet or
microcrystalline cellulose beadlet. Advantageously, the chromium
complex and conjugated linoleic acid are coated on the beadlet.
Optionally, the tablet, capsule, or microbead is coated with an
enteric coating.
[0024] In another aspect of the invention, the chromium complex and
conjugated fatty acid or conjugated fatty alcohol are in a ratio of
between about 1:666 to about 1:200 (w/w).
[0025] Additional components may be included in the composition.
For example, the composition may include at least one of a
cyclooxygenase inhibitor, a mucolytic, or a salicin-containing
herb. The cyclooxygenase inhibitor may be indomethacin, ibuprofen,
acetaminophen, or naproxen. Advantageously, the salicin-containing
herb may include Boswellia serrata (frankincense), Betula lenta
(sweet birch), Betula pubescens (white birch), Filipendula ulmaria
(meadowsweet), Gautheria procumbens (wintergreens), Polulus
balsamifera, Populus jackii (balm of Gilead) and Salix alba (white
willow). The mucolytic may be guaifenesin.
[0026] Embodiments of the invention provide a method of treating
type 1 diabetes in a subject. The method of treatment includes
administering to a subject a pharmaceutically effective dose of a
conjugated fatty acid or conjugated fatty alcohol in conjunction
with at least one chromium complex. The chromium complex may be
chromium picolinate, chromium nicotinate, chromic tripicolinate,
chromic polynicotinate, chromium chloride, chromium histidinate, or
chromium yeasts. Optionally, the composition further includes at
least one chelating agent. The chelating agent may be picolinic
acid, nicotinic acid, or both.
[0027] A method of treating obesity in a subject is similarly
contemplated. The method of treatment includes administering to a
subject a pharmaceutically effective dose of conjugated fatty acid
or conjugated fatty alcohol in conjunction with at least one
chromium complex. The chromium complex may be chromium picolinate,
chromium nicotinate, chromic tripicolinate, chromic polynicotinate,
chromium chloride, chromium histidinate, or chromium yeasts.
Optionally, the composition further includes at least one chelating
agent. The chelating agent may be picolinic acid, nicotinic acid,
or both.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0028] The disclosed invention relates to compositions for the
treatment of type 1 diabetes. In particular, these compositions can
be administered to reduce or even eliminate the need for
administration of insulin in certain patients with type 1 diabetes.
Further, they are used in methods for facilitating glucose uptake
and utilization by cells. Certain individuals with type 2 diabetes
will require insulin. The invention also relates to the treatment
of type 2 diabetics who require insulin. Additionally, methods for
treating obesity and increasing lean body mass are likewise
contemplated. A primary basis of the present invention is the novel
and unexpected discovery that compositions comprising an effective
dose of a chromium complex in combination with a conjugated fatty
acid or conjugated fatty alcohol produce a synergistic effect on
glucose uptake in a subject in need thereof. Additionally, the
co-administration of a chromium complex with a conjugated fatty
acid or conjugated fatty alcohol, or an isomer thereof, demonstrate
a synergistic, weight loss effect.
[0029] The terminology used in the description presented herein is
not intended to be interpreted in any limited or restrictive
manner, simply because it is being utilized in conjunction with a
detailed description of certain specific embodiments of the
invention. Furthermore, embodiments of the invention may include
several novel features, no single one of which is solely
responsible for its desirable attributes or which is essential to
practicing the invention herein described.
[0030] The term "conjugated compound" refers to a compound having
at least a portion that is a hydrocarbon, with at least three
consecutive carbon-carbon bonds, such that single and double
carbon-carbon bonds are found in an alternating manner. Thus, the
compound will include the subunit C.dbd.C--C.dbd.C (hydrogens and
other substituents not shown). Two preferred categories of
conjugated compounds are fatty acids and fatty alcohols. It should
be noted that these di- or poly-unsaturated compounds are referred
to herein using the common names of the corresponding
naturally-occurring compounds having the same number of carbons and
unsaturations. Although such naturally-occurring compounds are not
necessarily conjugated, due to the arrangement of their
carbon-carbon double bonds, it will be understood in the context of
the present invention that only conjugated versions of those
compounds are contemplated; i.e., the arrangement of the double
bounds will be such that they contain the substructure
C.dbd.C--C.dbd.C. While compounds having as few as 4, 5, 6, or 7
carbon atoms are contemplated, the preferred conjugated compounds
have 8, 9, 10, 12, 14, 16 or more carbon atoms, preferably not more
than 32, 30, 28, or 26 carbon atoms. It should be noted that the
phrase "conjugated fatty acid" or "conjugated fatty alcohol," as
used herein, also includes isomers of fatty acids and fatty
alcohols, as well as any other polyunsaturated compounds which act
synergistically with chromium complexes to promote glucose uptake
in a subject in need thereof. Suitable conjugated fatty acids
include, without limitation, conjugated versions of linoleic acid,
linolenic acid, gamma linolenic acid, arachidonic acid, mead acid,
stearidonic acid, alpha-eleostearic acid, eleostearic acid,
pinolenic acid, docosatetraenoic acid, 9,12-octadecadienoic acid,
octadecatrienoic acid, eicosatetraenoic acid, eicosapentaenoic
acid, docosahexaenoic acid, docosapentaenoic acid, and all other
diunsaturated and polyunsaturated fatty acids. In a preferred
embodiment, the conjugated fatty acid is conjugated linoleic acid
(CLA). As used herein, the phrase "conjugated fatty alcohols"
includes, without limitation, conjugated versions of linoleic
alcohol, linolenic alcohol, gamma linolenic alcohol, arachidonic
alcohol, mead alcohol, stearidonic alcohol alpha-eleostearic
alcohol, eleostearic alcohol, pinolenic alcohol, docosadienic
alcohol, docosatetraenoic alcohol, octadecadienoic alcohol,
octadecatrienoic alcohol, eicosatetraenoic alcohol,
eicosapentaenoic alcohol, docosahexaenoic alcohol, docosapentaenoic
alcohol, and all other diunsaturated and polyunsaturated fatty
alcohols. The present invention further includes the use of other
conjugated compounds having at least 4, 5, 6, 7, or 8 carbon atoms,
that functions synergistically with a chromium complex to
facilitate glucose uptake and usage by cells. (Such function can be
readily assayed, as further described below.) Note that the present
invention includes alcohols and acids in which one or more of the
double bonds result in a cis isomer, as well as those in which one
or more of the double bonds result in a trans isomer. In some
cases, all the double bonds are cis, while in others they are all
trans, and in still other cases they are mixed cis and trans
compounds.
[0031] In a preferred embodiment, the conjugated fatty acid of the
composition is conjugated linoleic acid. Conjugated linoleic acid
(CLA) has been reported in numerous publications to reduce fat gain
in growing animals by 25%-70% (Park et al., 1997). Minimal studies
have been performed on human subjects. In a preliminary study by
Atkinson et al., there was no effect of CLA alone in obese subjects
when added to standard diet and exercise. However, a subgroup of
subjects who did not follow the diet and exercise program well, and
who gained lean body mass, had a reduction in fat mass in the CLA
subjects and an increase in fat mass in placebo subjects (Atkinson,
communication, 2000). These data, along with the animal data,
suggest that CLA is most effective in preventing fat accumulation
rather than producing fat loss. Two hypotheses have been advanced
to explain the role of CLA in weight loss: 1) CLA may act as a
.beta.-3 agonist; and 2) CLA alters nutrient partitioning within
muscles to promote fat oxidation rather than carbohydrate (CHO)
oxidation (Park et al., 1999).
[0032] Embodiments of the present invention include compositions
which contain a conjugated fatty acid or conjugated fatty alcohol
in combination with at least one chromium complex. Additionally,
uses of the compositions disclosed herein to treat diabetes and/or
obesity are provided. The co-administration of a conjugated fatty
acid or conjugated fatty alcohol and at least one chromium complex
provides a number of advantages over conventional pharmaceutical
regimes for the treatment of diabetes and promotion of weight loss.
One advantage of the compositions described herein over
conventional treatment regimes for diabetes (such as injection of
insulin) and weight loss is that compositions comprising a
conjugated compound such as a conjugated fatty acid or conjugated
fatty alcohol and at least one chromium complex have no known side
effects while still providing efficacy in glucose uptake and weight
loss. With reference to FIG. 1, one will observe that a conjugated
fatty acid such as CLA alone had no effect on glucose uptake in
human skeletal muscle culture under both basal (without insulin)
and stimulated (with insulin) conditions. The units referred to on
the vertical axis of FIGS. 1 and 2 are pico Moles per milligram of
glucose uptake. The unit referred to on the vertical axis of FIG. 3
is the percentage increase in the uptake of glucose in human
skeletal muscle culture. The term Basal as used in FIGS. 1 and 2
refers to human skeletal muscle culture without insulin. Whereas
the term Stimulated indicates human skeletal muscle culture with
insulin. Those bars on FIGS. 1, 2, and 3 representing Chromium
Picolinate (CP) and Conjugated Linoleic Acid (CLA) are measured in
nanograms per milliliter.
[0033] However, the administration of CLA in combination with a
chromium complex such as chromium picolinate (CP) (as depicted in
FIG. 2) significantly increases glucose uptake in human skeletal
muscle culture under both basal (without insulin) and stimulated
(with insulin) conditions. CP and CLA under basal conditions was
shown to have a greater effect than insulin alone.
[0034] Finally, turning to FIG. 3, it will be appreciated that CLA
plus a chromium complex synergistically aid in the percent increase
in the uptake of glucose in human skeletal muscle culture.
[0035] In some embodiments, compositions comprising an effective
dose of a chromium complex are provided. As used herein, the terms
"chromium complexes" or "chromium complex" include, without
limitation, chromium picolinate, chromic tripicolinate, chromium
nicotinate, chromic polynicotinate, chromium chloride, chromium
histidinate, and chromium yeasts. Chromium picolinate, for example,
has been shown to produce modest weight loss and changes in body
composition.
[0036] The compositions of the disclosed invention additionally
include an effective dose of conjugated compound such as a
conjugated fatty acid or conjugated fatty alcohol, of the type
previously described. In preferred embodiments, the conjugated
fatty acid component of the composition is linoleic acid (CLA).
Suitable forms of CLA include isomers with double bonds at carbons
9, 11; carbons 10,12; or a mixture thereof. Preferably, the
compositions include the 10,12 form of CLA to reduce body fat and
increase lean body mass. Advantageously, the composition will
include the conjugated compound at a dose of at least 50% by weight
of formulation. More preferably, the effective dose of the
conjugated compound for a 70 kg human is between about 100 mg to
about 10 grams. In a most preferred embodiment, the effective dose
of the conjugated compound is 75 mg, 100 mg, 250 mg, 500 mg, 750
mg, 1000 mg, 2 g, 5 g, 7 g, or 10 g.
[0037] While the chromium complexes aid in the absorption of
chromium by intestinal cells, in some embodiments, chelating agents
are advantageously included in the compositions to facilitate
absorption of other ingested chromium as well as other metals
including, but not limited to, copper, iron, magnesium, manganese
and zinc. Suitable chelating agents include picolinic acid,
nicotinic acid, or both picolinic acid and nicotinic acid. Thus,
the compositions of the disclosed invention are readily absorbable
forms of chromium which also facilitate absorption of other
essential metals in the human diet.
[0038] The chromium complexes of the disclosed invention have the
same uses as described for chromic tripicolinate in U.S. Pat. Nos.
5,087,623, 5,087,624 and 5,174,156, namely supplementing dietary
chromium, lowering blood glucose levels in diabetics, lowering
serum lipid levels and increasing lean body mass. Additionally, the
chromium complexes of the present invention act to treat symptoms
associated with overweight and obesity.
[0039] Advantageously, the chromium complexes are synthetic. The
synthesis and use of chromium picolinates is described in U.S. Pat.
Nos. Re. 33,988 and 5,087,623. Chromic tripicolinate is available
from health food stores, drug stores and other commercial sources.
The synthesis and use of chromic polynicotinate is described in
U.S. Pat. No. 5,194,615.
[0040] The chelating agents such as picolinic acid and nicotinic
acid are available from many commercial sources, including
Sigma-Aldrich (St. Louis, Mo.) (picolinic acid; catalog No. P5503;
nicotinic acid; catalog No. PN4126). Preferably, the ratio of the
chromium complex to the chelating agent from about 10:1 to about
1:10 (w/w), more preferably from about 5:1 to about 1:5 (w/w).
[0041] A variety of delivery systems are available to deliver the
compositions to a subject in need thereof. Preferably, the
compositions of the disclosed invention are prepared by
incorporating the components into a pharmaceutically acceptable
carrier, including but not limited to tablets, capsules and
microbeads, preferably sugar beadlets or microcrystalline
cellulose.
[0042] For oral administration, the chromium complex may be
incorporated into a tablet, aqueous or oil suspension, dispersible
powder or granule, microbead, emulsion, hard or soft capsule, syrup
or elixir. The components of the composition may also be
administered separately. Compositions may be prepared according to
any method known in the art for the manufacture of pharmaceutically
acceptable compositions and such compositions may contain one or
more of the following agents: sweeteners, flavoring agents,
coloring agents and preservatives. Tablets containing the active
ingredients in admixture with non-toxic pharmaceutically acceptable
excipients suitable for tablet manufacture are acceptable.
"Pharmaceutically acceptable" means that the agent should be
acceptable in the sense of being compatible with the other
ingredients of the formulation (as well as non-injurious to the
individual). Such excipients include inert diluents such as calcium
carbonate, sodium carbonate, lactose, calcium phosphate or sodium
phosphate; granulating and disintegrating agents, such as corn
starch and alginic acid; binding agents such as starch, gelatin or
acacia; and lubricating agents such as magnesium stearate, stearic
acid or talc. Tablets may be uncoated or may be coated with known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period of time. For example, a time delay material such as
glyceryl monostearate or glyceryl stearate alone or with a wax may
be employed.
[0043] In another preferred embodiment, tablets, capsules or
microbeads are coated with an enteric coating which prevents
dissolution in the acidic environment of the stomach. Instead, this
coating dissolves in the small intestine at a more neutral pH.
Because certain chromium complexes may be more stable at this
neutral pH than at the acidic pH of the stomach, enhanced
absorption occurs because the chromium complexes remain
substantially intact until they reach the small intestine. Such
enteric coated compositions are described by Bauer et al., Coated
Pharmaceutical Dosage Forms: Fundamentals, Manufacturing
Techniques, Biopharmaceutical Aspects, Test Methods and Raw
Materials, CRC Press, Washington, D.C., 1998, the entire contents
of which are hereby incorporated by reference.
[0044] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, such as peanut
oil, liquid paraffin or olive oil.
[0045] Aqueous suspensions may contain the chromium complexes of
the invention in admixture with excipients for the manufacture of
aqueous suspensions. Such excipients include suspending agents,
dispersing or wetting agents, one or more preservatives, one or
more coloring agents, one or more flavoring agents and one or more
sweetening agents such as sucrose or saccharin.
[0046] Oil suspensions may be formulated by suspending the active
ingredient in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oil suspension may contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agent, such
as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by an added antioxidant such as ascorbic acid.
Dispersible powders and granules of the invention suitable for
preparation of an aqueous suspension by the addition of water
provide the active ingredient in admixture with a dispersing or
wetting agent, a suspending agent, and one or more preservatives.
Additional excipients, for example sweetening, flavoring and
coloring agents, may also be present.
[0047] Syrups and elixirs may be formulated with sweetening agents,
such as glycerol, sorbitol or sucrose. Such formulations may also
contain a demulcent, a preservative, a flavoring or a coloring
agent.
[0048] The oral formulations described above may also include
aspirin (acetylsalicylic acid), other salicylates, or another NSAID
such as indomethacin, ibuprofen, acetaminophen, naproxen or any
drug capable of inhibiting the cyclooxygenase pathway leading to
prostaglandin synthesis. This results in a decrease in intestinal
mucus production and lower intestinal pH which facilitates
absorption of the chromium compositions of the present invention.
The oral compositions may further include mucolytics such as
guaifenesin and the like, to inhibit intestinal mucus production,
and/or acids such as ascorbic acid, citric acid and the like to
lower intestinal pH. Inclusion of one or both of these compounds
further enhances chromium absorption. There are two forms of
cyclooxygenase (cox), cox1 and cox2, which differ in their
sensitivity to inhibition by NSAIDs. The cox2 isozyme promotes
prostaglandin formation at sites of inflammation, but not at other
sites such as the gastrointestinal tract. In contrast, relatively
selective inhibition of cox 1 facilitates chromic tripicolinate and
chromic polynicotinate absorption. Although the selective
inhibition of cox1 is desirable, any inhibitor or cox1 or cox2 can
be formulated with the chromic tripicolinate and chromic
polynicotinate compositions of the invention. Cox inhibitors, acids
and mucolytics may also be coadministered with the chromic
tripicolinate and chromic polynicotinate compositions of the
invention. The amount of these drugs formulated with or
coadministered with the chromic tripicolinate compositions of the
invention are as follows: cox inhibitions, between about 50 mg and
500 mg; mucolytics, between about 10 mg and 250 mg; and acids,
between about 50 mg and about 1,000 mg.
[0049] The coadministration or formulation of salicylate-containing
herbs with the compositions of the invention is also contemplated.
Class I herbs, as documented in the American Herbal Products
Association's Botanical Safety Handbook (herbs that can be safely
consumed when used appropriately), such as Boswelia serrata
(frankincense), Betula lenta (sweet birch), Betula pubescens (white
birch), Filipendula ulmaria (meadowsweet), Gaultheria procumbens
(wintergreens), Populus balsamifera and Populus jackii (balm of
Gilead), and Salix alba (white willow) are all salicin-containing
plants with salicylate-like properties. These herbs suppress
prostaglandin synthesis by cox inhibition, thereby improving
absorption of the chromium complexes of the invention. These herbs
are relatively free from gastric ulcerogenic effects (Singh et al.,
Agents and Actions 18:407-412, 1986). In addition, pre-clinical
acute toxicity studies have shown that salicin-containing plants do
not cause hematological disturbances (American Herbal Products
Association, Botanical Safety Handbook, 1997).
[0050] The compounds and herbs described above all effect gut
physiology by inhibiting prostaglandin synthesis, decreasing mucus
production, and lowering gastrointestinal pH. The inclusion of
these compounds, as well as an enteric coating, into the oral
chromium picolinate or chromium nicotinate compositions of the
invention results in a multicomponent delivery system which allows
delivery of these agents to the gastrointestinal tract where they
work in concert to facilitate chromium absorption.
[0051] In a preferred embodiment, the chromium complex is coated
onto microbeads. In a particularly preferred embodiment, these
microbeads are sugar beadlets of various sizes, also known as
nonpareils, and are commercially available from, for example,
SmithKline Beecham. If the microbeads are to be used to administer
the compositions of the invention to diabetic patients, the
administration of other types of microbeads, such as
microcrystalline cellulose, is preferred. Microcrystalline
cellulose is commercially available and can be processed into
beadlets of various sizes by micronization, a technique well known
in the art. The microbeads are essentially a carrier for the
compositions of the invention. For a description of coated
beadlets, see, for example, Carstensen, I. T., Pharmaceutical
Principles of Solid Dosage Forms, Technonic Publishing Co., Inc.,
Lancaster, Pa., pp. 228-230, 1993, hereby incorporated by
reference. Aqueous solutions containing the chromium complexes with
or without the chelating agent components such as nicotinic acid
and picolinic acid are sprayed onto the microbeads by well known
methods by suspending the microbeads in an up current of air and
introducing a fine spray of the active ingredients which form a
coating on the outside of the microbeads which is then allowed to
dry. The desired chromium complex components with or without a
chelating agent may be combined into one same solution or applied
using separate solutions. Optionally, the coated microbeads can be
further coated with a substance to protect the active ingredients
coated onto the beads, such as latex. The microbeads may be placed
in a capsule prior to administration. In another preferred
embodiment, the capsule or the microbeads are coated with an
enteric coating to delay dissolution until reaching the small
intestine.
[0052] Typically, the dosage range of chromium administered to an
individual in the form of chromium picolinate, chromium nicotinate,
or other chromium complex provides between about 50 and 10,000
micrograms per day of chromium; preferably between about 100 and
1,000 micrograms per day; more preferably, between about 200 and
500 micrograms per day.
[0053] In some embodiments, methods of increasing glucose uptake by
cells or by organisms, such as mammals and humans, treating
insulin-dependent diabetes, reducing body fat, improving insulin
sensitivity, reducing hyperglycemia, and reducing
hypercholesterolemia with chromium complexes and conjugated
compounds such as conjugated fatty acids or conjugated fatty
alcohols are contemplated and isomers of fatty acids, as well as
isomers of fatty alcohols. Advantageously, a subject is
administered a pharmaceutically effective dose of a chromium
complex. In one embodiment, the conjugated compound is administered
substantially simultaneously with the chromium complex. In an
alternative embodiment, the chromium complex is administered first
and then the conjugated compound is added second. In yet another
embodiment, the conjugated compound is administered first.
Preferably, the chromium complex and conjugated compound are
administered to a subject within twenty-four hours of each other.
In a particularly preferred embodiment, the chromium complex and
conjugated compound are administered within an hour of each
other.
[0054] The following examples teach certain methods and
compositions for treating diabetes and obesity through the
administration of at least one chromium complex in concert with a
conjugated compound. The subject can advantageously be a
vertebrate, a mammal, a bird, and is preferably a human, a cat, or
a dog. It will be appreciated, however, that the at least one
chromium complex may be administered first, then the conjugated
compound. Alternatively, the conjugated compound can be
administered first, then the chromium complex. As illustrated in
the following examples, the composition may optionally include
picolinic acid, nicotinic acid, or both picolinic acid and
nicotinic acid in combination with a chromium complex and
conjugated compound. These examples are illustrative only and are
not intended to limit the scope of the invention disclosed herein.
The treatment methods described below can be optimized using
empirical techniques well known to those of ordinary skill in the
art. Moreover, artisans of skill would be able to use the teachings
described in the following examples to practice the full scope of
the invention disclosed herein.
EXAMPLE 1
[0055] An obese adult human subject is identified. The subject is
orally administered a tablet containing about 300 .mu.g chromium as
chromium picolinate and 1 gram conjugated linoleic acid twice a
day. The tablet additionally comprises ibuprofen in a
pharmaceutically effective dose of 200 mg. Over the course of
several weeks, a decrease in body mass is observed. The chromium
picolinate in combination with conjugated linoleic acid
synergistically reduce the subject's body mass.
[0056] It will be appreciated that although specific embodiments of
the invention have been described herein for the purposes of
illustration, various modifications may be made without deviating
from the spirit and scope of the invention. Accordingly, the
invention is not limited except as by the appended claims.
EXAMPLE 2
[0057] A subject suffering from insulin-dependent diabetes is
identified. The subject is orally administered a daily dose of one
tablet containing about 500 .mu.g chromium as chromium nicotinate
and 500 mg conjugated linoleic acid. Over the course of several
days, an improvement in glucose uptake in the subject is observed
and insulin dependence is reduced. The chromium nicotinate in
combination with linoleic acid act synergistically to improve the
subject's glucose tolerance and to treat the subject's
diabetes.
* * * * *