Charles BARKER, et al.
Copper-1 vs Lyme's Disease
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US9040514
CHLOROBIS
COPPER (I) COMPLEX COMPOSITIONS AND METHODS OF MANUFACTURE
AND USE
Inventor(s): KERRIGAN SEAN [US]; MENTE
NOLAN [US]; BARKER CHARLES LOUIS ALBARTUS [US] +
Applicant(s): LAB PHARMA INTERNATIONAL
A method of manufacturing an anhydrous copper complex of formula
C12H10ClCuN2O4 and methods of treating neuromuscular and other
diseases, including but not limited to fibromyalgia, multiple
sclerosis, muscular dystrophy, rheumatoid arthritis, pain,
fatigue, sleeplessness, loss of fine motor control, speech loss,
inflexibility, Alzheimer's, dementia, amyotrophic lateral
sclerosis, depression, lyme disease, lyme disease co-infection,
gastroparesis (GP), myopathy, chronic inflammation and/or
incontinence. The anhydrous copper complex preferably is
administered in a pharmaceutical and/or dietary supplement
composition of the invention.
RELATED
APPLICATION DATA
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/237,876 filed Feb. 8, 2014 (published as
U.S. Publication No. 20140243301), which is the U.S. National
Stage of International Application No. PCT/US2012/050212, filed
Aug. 9, 2012, which claims the benefit of U.S. Provisional
Application No. 61/521,698 filed Aug. 9, 2011, the contents of
each of which are hereby incorporated by reference in their
entireties.
BACKGROUND
OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is directed to pharmaceutical
and/or dietary supplement compositions and methods of treating
neuromuscular and other diseases, including but not limited to
fibromyalgia, multiple sclerosis, muscular dystrophy,
Alzheimer's, dementia, amyotrophic lateral sclerosis,
depression, and/or rheumatoid arthritis. The present invention
also encompasses pharmaceutical and/or dietary supplement
compositions and methods of treating other physical ailments and
disorders, including but not limited to pain, fatigue,
sleeplessness, loss of fine motor control, speech loss,
inflexibility, lyme disease, lyme disease co-infection,
gastroparesis (GP), myopathy, chronic inflammation and/or
incontinence. The method typically comprises administration to a
subject in need thereof an anhydrous copper complex of formula
C12H10ClCuN2O4. The invention also generally relates to
pharmaceutical treatment regimes and methods of making the
anhydrous copper complex of the present invention.
[0004] 2.
Discussion of the Background
[0005] A litany of human diseases and other ailments are
characterized by neuromuscular degeneration and muscle weakness.
The term “neuromuscular disease” refers to disorders that
adversely affect muscle function and/or the control thereof by
the central nervous system (CNS). In general, neuromuscular
diseases encompass a wide range of physical ailments
characterized by impaired muscle function. The following
(non-limiting) list of conditions is generally recognized as
neuromuscular diseases or conditions: multiple sclerosis,
muscular dystrophy, rheumatoid arthritis, fibromyalgia,
myopathy, inflammatory bowel disease (IBD), incontinence,
inflexibility, impaired fine motor skills, and amyotrophic
lateral sclerosis (“ALS” or Lou Gehrig's disease).
[0006] A stroke, formerly known as a cerebrovascular accident
(CVA), often results in severe neurological impairment.
Post-stroke, many individuals suffer one or more neurological
impairments including, but not limited to: loss of fine motor
control, paralysis, speech impairment/loss (aphasia and/or
dysarthria), altered smell, taste, hearing, or vision, ptosis,
ocular and facial muscle weakness, diminished reflexes, loss of
balance, altered heart rate, apraxia, loss of memory, and/or
confusion.
[0007] Numerous therapeutic methodologies are presently
available for the treatment of neurological conditions such as
the ones listed above. Efficacious treatments have proven
elusive, however, and existing drugs with the most promise often
exhibit the most undesirable side effects.
[0008] Two of the most prominent diseases associated with
impaired neurological function are MD, MS and RA. These diseases
and currently available treatments therefore, are discussed in
greater detail herein below.
Muscular
Dystrophy
[0009] The term Muscular Dystrophy (MD) actually refers to a
group of diseases characterized by muscle weakness and/or
impaired muscle function. The specific diseases include, but are
not limited to Becker, Duchenne, and Emery-Dreifuss. Over 100
diseases, however, display symptoms similar to MD. All are
characterized by reduced muscle function and muscle weakness.
[0010] No cure exists for MD and many of the related
pathologies. Physical and occupational therapy may help those
afflicted with MD manage life with the disease, but neither
therapy ameliorates or reverses the disease's underlying causes
or symptoms. Antisense oligonucleotides have shown promise as a
treatment, but are costly and difficult to obtain for many MD
patients. As a result, a significant need exists for a
cost-effective, widely available treatment for MD (and related
pathologies).
Multiple
Sclerosis
[0011] Multiple Sclerosis (MS) is an autoimmune disease
diagnosed in 350,000-500,000 people in the United States. The
disease is characterized by multiple areas of inflammation and
scarring of the myelin in the brain and spinal cord. Patients
inflicted with the disease exhibit varying degrees of
neurological impairment depending on the location and extent of
the myelin scarring. Typical MS symptoms include fatigue,
weakness, spasticity, balance problems, bladder and bowel
problems, numbness, loss of vision, tremors, and depression.
Available treatments of MS generally only alleviate symptoms or
delay the progression of the disability. Recently developed
treatments for MS (including stem cell implantation and gene
therapy) appear to be only conservatory. Consequently, improved
approaches for the treatment of MS are needed.
Rheumatoid
Arthritis
[0012] Rheumatoid Arthritis (RA) is another troublesome disorder
associated with inflammation. It is signified by chronic
inflammation in the membrane lining (the synovium) of the joints
and/or other internal organs. These inflammatory cells can also
damage bone and cartilage. For example, a joint inflicted with
RA may lose its shape and alignment, which can result in the
loss of range of motion. RA is characterized by pain, stiffness,
warmth, redness and swelling in the joint, and other systemic
symptoms like fever, fatigue, and anemia. RA currently affects
roughly 1% of the entire U.S. population (approximately 2.2
million people). The pathology of RA is not fully understood,
although it has been hypothesized to result from a cascade of
aberrant immunological reactions.
[0013] In many cases, conventional treatments for RA have proven
inefficient. For example, RA responds only partially to
symptomatic medications such as corticosteroids and
non-steroidal anti-inflammatory drugs (NSAIDs). These
medications have been around since the 1950's, and possess a
significant risk of contraindications. Moreover, the therapeutic
effects of anti-rheumatic drugs (DMARDs) such as Methotrexate
(MTX) are frequently inconsistent and only temporary. The latest
class of “biologic” DMARDs (including ENBREL®, REMICADE®,
HUMIRA®, and KINERET®) have shown promising treatment results,
but significant concerns exist regarding their long term safety
profile. For example, studies have shown an association between
the use of both ENBREL® or REMICADE® and the development of
lymphoma. Other reports have demonstrated that patients treated
with either drug exacerbate their congestive heart failure and
develop serious infection and sepsis, and aggravate symptoms of
MS and other central nervous system problems. As with MS, a need
exists for more effective treatments of RA.
Lyme
Disease
[0014] Lyme disease is a bacterial infection (borrelia
burgdorferi) spread by ticks. The number of reported cases of
Lyme disease, and the number of geographical areas in which it
is found, has been increasing. In addition to causing arthritis,
lyme disease can also cause heart, brain, and nerve problems.
Early symptoms include skin-rash, flu-like symptoms (.e.g.
chills, fever, swollen lymph nodes, headaches, fatigue, muscle
aches/pains, and joint pain). More advanced symptoms include
nerve problems and arthritis. Currently, there is no available
vaccine on the market in the US for lyme disease.
Lyme
Disease Co-Infection
[0015] Often, ticks can become infected with multiple
disease-causing microbes, resulting in co-infection. This may be
a potential problem for humans, due to Borrelia burgdorferi, and
other harmful pathogens carried and transmitted by some ticks.
Possible co-infections with viruses such as lyme borreliosis,
anaplasmosis, babesiosis, or encephalitis may occur. It is not
known how co-infection may affect disease transmission and
progression, but may help in diagnosing and treating lyme and
other such diseases. Currently, there is no reliable and regular
treatment for lyme disease co-infection.
Gastroparesis
[0016] Gastroparesis is a condition characterizes by the
inability of the stomach to empty its contents, when there is no
blockage (obstruction). The cause of gastroparesis is not known.
There is some evidence that it may be caused by a disruption of
nerve signals to the stomach. The condition is a complication of
diabetes and of some surgeries. Risk factors associated with
gastroparesis may include diabetes, gastrectomy (surgery to
remove part of the stomach), systemic sclerosis, use of
medication that blocks certain nerve signals (anticholinergic
medication). Symptoms may include abdominal distention,
hypoglycemia (in people with diabetes), nausea, premature
abdominal fullness after meals, weight loss, and vomiting. If
gastroparesis is caused by a condition that is reversible (e.g.
pancreatitis), when the condition is resolved, the symptoms will
subside. For some diabetics, better control of their blood sugar
can also improve the symptoms. If there is no reversible cause,
gastroparesis rarely resolves itself and the symptoms often grow
more sever with time. When accompanied by motility disorders of
the muscles of the small intestine, gastroparesis is
particularly difficult to treat.
SUMMARY OF
THE INVENTION
[0017] The objective of the present invention is to provide
pharmaceutical and/or dietary supplement compositions and
methods of making and using the same to treat and reduce many of
the symptoms of several diseases. The compositions contain an
active pharmacological ingredient comprised of a novel anhydrous
copper complex of formula C12H10ClCuN2O4. The pharmacologically
active ingredient may be administered alone or in combination
with additional active or inert agents or therapies (e.g. other
anti-inflammatory agents, diluents, and/or excipients).
[0018] The pharmacologically active ingredient of the present
invention possesses the following chemical structure, referred
to herein as Formula I:
[0019] The present invention is also directed to a method of
treating diseases and other physical ailments or disorders. In a
preferred embodiment the method comprises the step of
administering to a subject in need thereof an anhydrous copper
complex of formula
[0020] C12H10ClCuN2O4 to reduce and/or treat a disease or
physical ailment or disorder. Preferably the disease or physical
ailment being treated is a neuromuscular disease. The treated
diseases or disorders (or other physical ailments) include, but
are not limited to: fibromyalgia, spinal cord injury, multiple
sclerosis, muscular dystrophy, stroke, rheumatoid arthritis,
pain, fatigue, sleeplessness, loss of fine motor control, speech
loss, inflexibility, lyme disease, lyme disease co-infection,
gastroparesis (GP), chronic inflammation, myopathy, chronic
inflammation, and/or incontinence. It is also preferable that
the subject be diagnosed with one of the diseases and/or
disorders prior to treatment. Preferred embodiments of the
compositions of the present invention, including recommended
dosages and methods of use, are more fully described below in
the Detailed Description.
BRIEF
DESCRIPTION OF THE DRAWINGS
[0021] Illustrative and exemplary embodiments of the invention
are shown in the drawings in which:
[0022] FIG. 1 depicts imagery obtained from Scanning Electron
Microscope (SEM) analysis of a preferred embodiment of the
present invention.
[0023] FIG. 2 depicts imagery obtained from Scanning Electron
Microscope (SEM) analysis of a preferred embodiment of the
present invention.
[0024] FIG. 3 shows the quantitative results obtained by mass
spectrometry analysis of a preferred embodiment of the
composition of the invention.
[0025] FIG. 4 shows the O K results obtained by mass
spectrometry analysis of a preferred embodiment of the
composition of the invention.
[0026] FIG. 5 shows the Cl K results obtained by mass
spectrometry analysis of a preferred embodiment of the
composition of the invention.
[0027] FIG. 6 shows the Cu K results obtained by mass
spectrometry analysis of a preferred embodiment of the
composition of the invention.
[0028] FIG. 7 shows the N K results obtained by mass
spectrometry analysis of a preferred embodiment of the
composition of the invention.
[0029] FIG. 8 depicts imagery obtained from Scanning Electron
Microscope (SEM) analysis of a preferred embodiment of the
present invention.
[0030] FIG. 9 depicts imagery obtained from Scanning Electron
Microscope (SEM) analysis of a preferred embodiment of the
present invention.
[0031] Elements and facts in the figures are illustrated for
simplicity and have not necessarily been rendered according to
any particular sequence or embodiment.
DETAILED
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Chemical Structure and Properties:
[0032] The present invention is directed to pharmaceutical
and/or dietary supplement compositions for treating a
neuromuscular disease or other disorder. The diseases capable of
treatment by the compositions of the present invention include,
but are not limited to: fibromyalgia, multiple sclerosis,
muscular dystrophy, rheumatoid arthritis, Alzheimer's, dementia,
amyotrophic lateral sclerosis (“ALS” or Lou Gehrig's disease),
amyotrophic lateral sclerosis, depression, pain, fatigue,
sleeplessness, loss of fine motor control, speech loss,
inflexibility, lyme disease, lyme disease co-infection,
gastroparesis (GP), myopathy, chronic inflammation, incontinence
and/or depression. The treatment of the present invention
comprises administering to a subject in need thereof a compound
of formula C12H10ClCuN2O4, preferably the chemical structure is
of Formula I:
[0033] The present invention is further directed to
pharmaceutical and/or dietary supplement compositions for
treating a physical ailment or disorder including, but not
limited to: stroke, pain, fatigue, sleeplessness, inflexibility,
myopathy, incontinence, impaired fine motor skills, high
cholesterol, low sperm count, obesity, alopecia, burns, stretch
marks, scars, Attention Deficit Disorder (ADD), Attention
Deficit Hyperactivity Disorder (ADHD), and erectile dysfunction.
The treatment of the present invention comprises administering
to a subject in need thereof a compound of formula
C12H10ClCuN2O4 (e.g., “Formula I”):
Preferably the subject is first diagnosed with one of the
disease listed above before treatment.
[0034] In an alternate embodiment, the present invention is
further directed to pharmaceutical and/or dietary supplement
compositions for treating post-stroke symptoms, including, but
not limited to: loss of fine motor control, paralysis, speech
impairment/loss (aphasia and/or dysarthria), altered smell,
taste, hearing, or vision, ptosis, ocular and facial muscle
weakness, diminished reflexes, loss of balance, altered heart
rate, apraxia, loss of memory, and/or confusion. The treatment
of the present invention comprises administering to a subject in
need thereof a compound of formula C12H10ClCuN2O4 (e.g.,
“Formula I”):
[0035] Advantageously, the present invention is further directed
to pharmaceutical and/or dietary supplement compositions for
promoting one or more desired health benefits. In a preferred
embodiment, the compositions of the present invention promote
hair growth, skin healing, scar removal, nerve growth, muscle
growth, enhanced athletic performance, reduced post-traumatic
healing time, post-surgery healing, and/or enhanced libido.
[0036] Optionally, the compositions of the present invention are
used in combination with additional active or inert agents or
alternative therapies (e.g. other anti-inflammatory agents,
diluents, and/or excipients). In a preferred embodiment, the
alternative therapy is ozone therapy. Preferably, use of the
compositions of the present invention enhances the effectiveness
of the alternative therapy.
Preparations and Administrations:
[0037] The invention may be used to treat an animal with a
disease or physical ailment or disorder including, but not
limited to, one or more of the following: fibromyalgia, multiple
sclerosis, muscular dystrophy, rheumatoid arthritis,
Alzheimer's, dementia, ALS, depression, pain, fatigue,
sleeplessness, inflexibility, myopathy, lyme disease, lyme
disease co-infection, gastroparesis (GP), chronic inflammation,
incontinence, impaired fine motor skills, high cholesterol, low
sperm count, obesity, alopecia, burns, stretch marks, scars,
ADD, ADHD, and/or erectile dysfunction, wherein it is preferable
that the animal is a mammal and more preferable that the mammal
is a human.
[0038] Formula I is comprised of an anhydrous chlorobis copper I
complex (nicotinic acid). Preferably, the pharmaceutical
composition containing an effective amount of Formula I further
comprises copper ascorbate (esterified Vitamin C), ascorbic acid
(Vitamin C), and/or a pharmaceutically acceptable excipient
(carrier). More preferably, the pharmaceutically acceptable
carrier is an inert diluent.
[0039] Frequency of dosage may vary depending on the purity of
the compound and the particular disease or physical ailment
treated. However, for treatment of most diseases and physical
ailments, a dosage regimen of (4) 2.5 mg capsules (for a total
of 10 mg/day) containing Formula I is preferred. As will be
understood by one skilled in the art, however, the optimal
dosage level for a particular subject will vary depending on a
plurality of factors including the potency and activity of the
pharmacologically active ingredient (e.g., Formula I), as well
as the age, body weight, general health, sex, diet, time of
administration, route of administration and rate of excretion,
drug combination (if any) and the severity of the particular
disease or physical ailment undergoing therapy. Subject to the
above factors, a generally effective amount of Formula I is
between 1 mg and 20 mg per day. More preferably, the effective
amount of Formula I is between 5 mg and 10 mg per day.
Advantageously, the effective amount of Formula I is between 7.5
mg to 10 mg per day. Most preferably (subject to the factors
listed above), the effective amount of Formula I is 10 mg/per
day.
[0040] Formula I may also comprise a component of an overall
pharmaceutical treatment regime for reducing and/or treating a
disease or physical ailment or other disorder including, but not
limited to: fibromyalgia, multiple sclerosis, muscular
dystrophy, rheumatoid arthritis, Alzheimer's, dementia, ALS,
depression, pain, fatigue, sleeplessness, inflexibility,
myopathy, incontinence, impaired fine motor skills, high
cholesterol, low sperm count, obesity, alopecia, burns, stretch
marks, scars, ADD, ADHD, and/or erectile dysfunction, the
treatment regime comprising: administering to a subject at the
least the following pharmacologically active ingredient(s)
within a 24-hour period: a compound of Formula I, and optionally
a pharmaceutically acceptable carrier, wherein the
pharmacologically active ingredient(s) is in an amount
sufficient to reduce the symptoms of the ailment.
[0041] Optionally, the pharmaceutical treatment regime including
Formula I may include (or be combined with) additional
pharmacologically active ingredients or other complementary
treatments in order to provide synergistic therapeutic effects.
For example, Formula I may be administered in combination with
additional pharmacologically active agents including, but not
limited to, non-steroidal anti-inflammatory drugs (NSAIDs),
corticosteroids, disease modifying anti-rheumatic drugs
(DMARDs), biologic DMARDs, and/or cyclooxygenase-2 (COX-2)
inhibitors. In a preferred embodiment, Formula I is administered
in combination with ozone therapy.
[0042] The pharmaceutical and/or dietary supplement compositions
(containing Formula I) of the present invention may take a
variety of forms specially adapted to the chosen route of
administration. The compositions may be administered orally,
topically, parenterally, by inhalation or spray, or by any other
conventional means. Preferably, the compositions are prepared
and administered in dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles. In one preferred embodiment, the
composition is administered sublingually. It is further
understood that the preferred method of administration may be a
combination of methods. Oral administration in the form of a
capsule, pill, elixir, syrup, lozenge, troche, or the like is
particularly preferred. The pharmaceutical compositions of the
present invention (containing Formula I) are preferably in a
form suitable for oral use, for example, as tablets, troches,
lozenges, aqueous or oily suspensions, dispersible powders or
granules, emulsion, hard or softgel capsules, or syrups or
elixirs.
[0043] Compositions intended for oral use may be prepared
according to any method known in the art for manufacture of
pharmaceutical compositions, and such compositions may contain
one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant
and palatable preparations. Tablets may contain the active
ingredient in admixture with non-toxic pharmaceutically
acceptable excipients suitable for the manufacture of tablets.
Such excipients may include, for example, inert diluents, such
as calcium carbonate, sodium carbonate, lactose, calcium
phosphate or sodium phosphate; granulating and disintegrating
agents, for example, corn starch, or alginic acid; binding
agents, for example starch, gelatin or acacia; and lubricating
agents, for example magnesium stearate, stearic acid or talc.
The tablets may be uncoated or they may be coated by techniques
to delay disintegration and absorption in the gastrointestinal
tract and thereby provide a sustained action over a longer
period. For example, a time delay material such as glyceryl
monostearate or glyceryl distearate may be utilized.
[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, for
example peanut oil, liquid paraffin or olive oil.
[0045] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of
aqueous suspensions. Such excipients are suspending agents, for
example sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; and
dispersing or wetting agents, which may be a naturally-occurring
phosphatide, for example, lecithin, or condensation products of
ethylene oxide with long chain aliphatic alcohols—for example,
heptadecaethyleneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and
hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl-p-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and
one or more sweetening agents, such as sucrose or saccharin.
[0046] Oily suspensions may be formulated by suspending the
active ingredients in a vegetable oil, for example arachis oil,
olive oil, sesame oil or coconut oil, or in a mineral oil such
as liquid paraffin. The oily suspensions may contain a
thickening agent, for example beeswax, hard paraffin or cetyl
alcohol. Sweetening agents such as those set forth above, and
flavoring agents may be added to provide palatable oral
preparations. These compositions may be preserved by the
addition of an anti-oxidant such as ascorbic acid and/or copper
ascorbate.
[0047] Dispersible powders and granules suitable for preparation
of an aqueous suspension by the addition of water provide the
active ingredient (Formula I) in admixture with a dispersing or
wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are
exemplified by those already mentioned above. Additional
excipients, for example sweetening, flavoring and coloring
agents, may also be present.
[0048] Pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of these.
Suitable emulsifying agents may be naturally occurring gums, for
example gum acacia or gum tragacanth; naturally-occurring
phosphatide, for example soy bean, lecithin, and esters or
partial esters derived from fatty acids and hexitol; anhydrides,
for example sorbitan monooleate; and condensation products of
the said partial esters with ethylene oxide, for example
polyoxyethylene sorbitan monooleate. The emulsions may also
contain sweetening and flavoring agents.
[0049] Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, propylene glycol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative, and flavoring or coloring agents. The
pharmaceutical compositions may be in the form of a sterile
injectable aqueous or oleaginous suspension. This suspension may
be formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents, which have
been mentioned above. The sterile injectable preparation may
also be a sterile injectable solution or suspension in a
non-toxic parenterally acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono- and diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0050] Alternatively, the compositions can be administered
parenterally in a sterile medium. Formula I, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as
local anesthetics, preservatives and buffering agents can be
dissolved in the vehicle.
[0051] For administration to non-human animals, the composition
containing Formula I may be added to the animal's feed or
drinking water. Optionally, one skilled in the art will
recognize that animal feed and drinking products may be
formulated such that the animal takes in an effective amount of
Formula I via their diet. For example, Formula I may constitute
a component of a premix formulated for addition to the feed or
drinking water of an animal. Compositions containing Formula I
may also be formulated as food or drink supplements for humans.
[0052] Preferred embodiments of compositions containing Formula
I will have desirable pharmacological properties that include,
but are not limited to, oral bioavailability, low toxicity, and
desirable in vitro and in vivo half-lives. The half-life of
Formula I is inversely proportional to the frequency of dosage
of Formula I.
[0053] It is to be understood that the foregoing describes
preferred embodiments of the present invention and that
modifications may be made thereto without departing from the
scope or spirit of the present invention as set forth in the
claims. Such scope is limited only by the claims below as read
in connection with the above specification. Many additional
advantages of applicant's invention will be apparent to those
skilled in the art from the descriptions, drawings, and the
claims set forth herein.
Representative Elemental and SEM Analysis
[0054] The following Tables (1-2) illustrate the results of an
elemental analysis of a composition comprising Formula I. The
elemental analysis depicts only one preferred embodiment of the
invention and is no way intended to limit the scope of the
invention.
TABLE 1
Run 1
Element Theoretical Found Diff
Cu 18.41% 15.73% −2.68
TABLE 2
Run 29129 Run 29130
Element Theoretical Found Diff
Found Diff
C 41.75% 45.45% 3.7 45.3% 3.55
H 2.92% 2.8% −0.12 2.93% 0.01
N 8.11% 8.51% 0.4 8.47% 0.36
[0055] As indicated in Tables 1-2, a representative sample of
Formula I comprises 15.73% copper. Given this data, one can
calculate the amount of copper in a particular dose of Formula
I. For example, a 2.5 mg dose (i.e. one capsule) yields 0.39 mg
of copper. Similarly, a 10 mg dose (the preferred dose) yields
1.57 mg of copper. As will be readily apparent to one skilled in
the art, however, the actual percentage of copper present in any
given sample of Formula I will vary depending on a number of
factors including, but not limited to, the purity, consistency
and source of the sample, as well as the synthetic methodology
employed to obtain the sample.
[0056] FIGS. 1-9 depict data and imagery obtained from Scanning
Electron Microscope (SEM) and spectrometer analysis of a
preferred embodiment of the present invention. As shown in FIG.
9, the copper particles are approximately 1.4 micrometers (μm)
in size.
EXAMPLE
Preparation of Formula I
[0057] Those skilled in the art will recognize various
synthetic methodologies that may be employed to prepare
non-toxic pharmaceutically acceptable compositions of Formula
I. One such (representative) example is set forth below:
[0058] A 3 L 3-neck round bottomed flask equipped with a
mechanical stirrer, reflux condenser and a solid addition
funnel was charged with nicotinic acid (131.61 g, 1.07 mol),
ascorbic acid (21.4 g, 0.12 mol) and 90% aqueous ethanol (2 L)
then placed in an appropriately sized heating mantle. The
resultant white suspension was stirred and heated gently to
45° C. and cuprous chloride (35.2 g 0.36 mol) was introduced
via the addition funnel over 15 minutes while maintaining an
inert atmosphere of Nitrogen throughout the system. During
previous experiment attempts, an ethanolic suspension of
cuprous chloride was introduced to the reaction mixture as
described in Patent Application WO/2010/009739, however,
partial oxidation to Copper (II) chloride was observed during
addition. To avoid such oxidation, the cuprous chloride was
added via the aforementioned ‘screw-mechanism’ solid addition
funnel and no oxidation to Copper (II) chloride was observed.
The mixture was then placed under reflux and stirring was
continued for a further 4.5 hours. Heating under reflux
conditions was maintained for 4.5 hours rather than the
recommended 5 minutes to ensure complete complexation.
Previous experiment attempts had shown incomplete reaction
following just 5 minutes of stirring. Upon cooling to 50° C.,
the mixture was filtered under suction and the red filter cake
was washed with aqueous ascorbic acid 5% w/v solution (400
mL), ethanol 90% (400 mL) and then acetone (100 mL). The red
filter cake was then collected and dried en vacuo to afford a
red solid (123 g).
[0059] It is to be understood that the method set forth
hereinabove describes a preferred synthetic methodology and that
modifications thereto may be made without departing from the
scope or spirit of the invention. Such scope is limited only by
the claims below as read in connection with the above
specification. May additional synthetic methodologies and
additional advantages of applicant's invention will be apparent
to those skilled in the art from the above descriptions and the
claims below.
COPPER
(I) COMPLEXES WITH GLYCINE, PYRUVATE, AND SUCCINATE
US2018071336
Inventor: BARKER
CHARLES LOUIS ALBARTUS / BOULANGER WILLIAM A [US]
Applicant: C LAB PHARMA INTERNATIONAL
The present invention is directed to a pharmaceutical and/or
dietary supplement composition comprising an effective amount of
a copper (I) complex with glycine, pyruvate, or succinic acid
and methods of treating mitochondrial, neuromuscular, and other
diseases. Also provided are pharmaceutical treatment regimes and
kits comprising a copper (I) complex with glycine, pyruvate, or
succinate.
RELATED
APPLICATION DATA
[0001] This application is a continuation in-part of U.S. patent
application Ser. No. 14/773,289, filed on Sep. 4, 2015, which is
the U.S. national-stage application of International Application
No. PCT/US2014/021772, filed on Mar. 7, 2014, which claims the
benefit of U.S. Provisional Application No. 61/774,543, filed on
Mar. 7, 2013, the contents of each of which are hereby
incorporated by reference in its entirety.
TECHNICAL
FIELD
[0002] This application relates to pharmaceutical and/or dietary
supplement compositions comprising copper (I) complexes and the
methods of preparing such copper (I) complexes. The application
also encompasses methods of treating mitochondria,
neuromuscular, and other diseases, and pharmaceutical and/or
dietary supplement compositions and methods of treating other
physical ailments and disorders, including but not limited to
pain, fatigue, sleeplessness, loss of fine motor control, speech
loss, inflexibility, Lyme disease, Lyme disease co-infection,
gastroparesis (GP), myopathy, chronic inflammation and/or
incontinence.
BACKGROUND
OF THE INVENTION
[0003] Copper (as copper amino acid chelate) plays a role in
transporting oxygen throughout the body. The production of
collagen, which determines the integrity of bones, skin,
cartilage, and tendons, is copper dependent. Copper is also
crucial for making melanin, which provides color to skin and
hair. Copper helps keep blood vessels elastic, is needed for the
formation of elastin, functions as an iron oxidizer, and is
needed for the proper functioning of vitamin C.
[0004] Copper is also an important cofactor for metalloenzymes,
and is a necessary cofactor for superoxide dismutase (Beem J
BIOL CHEM 249:7298 (1974)). Copper has been shown to decrease in
individuals over 70 years of age and to be basically zero in
cataractous lenses (Swanson BIOCHEM BIPHY RES COMM 45:1488-96
(1971)). If copper is significantly decreased, superoxide
dismutase has been shown to have decreased function, thereby
hampering an important protective lens mechanism (Williams
PEDIAT RES 1:823 (1977)). For these and many other reasons,
copper is required for optimal human health.
[0005] The two principal oxidation states of copper are +1 and
+2 although some +3 complexes are known. Copper (I) compounds
are expected to be diamagnetic in nature and are usually
colorless, except where color results from charge transfer or
from the anion. The +1 ion has tetrahedral or square planar
geometry. In solid compounds, copper (I) is often the more
stable state at moderate temperatures.
[0006] The copper (II) ion is usually the more stable state in
aqueous solutions. Compounds of this ion, often called cupric
compounds, are usually colored. They are affected by Jahn Teller
distortions and exhibit a wide range of stereochemistries with
four, five, and six coordination compounds predominating. The +2
ion often shows distorted tetrahedral geometry.
[0007] Complexes of copper (I) are thought to have a unique
mechanism of action in promoting aerobic respiration via the
electron transport chain. By causing the mitochondria in the
cells to produce adenosine triphosphate (ATP) more efficiently
and avoiding the production of lactic acid and ethanol that
accompanies anaerobic respiration, pharmaceutical preparations
and dietary supplements with copper (I) may alleviate and treat
many illness and diseases. Among these diseases are those
involving neuromuscular degeneration and muscle weakness.
Accordingly, there is a need to develop novel copper (I)
compounds that may stimulate ATP production in the mitochondria.
SUMMARY OF
THE INVENTION
[0008] The objective of the present invention is to provide
pharmaceutical and/or dietary supplement compositions and
methods of making and using the same to treat and reduce many of
the symptoms of several diseases. The compositions contain an
active pharmacological ingredient comprised of a copper (I)
complex. The pharmacologically active ingredient may be
administered alone or in combination with additional active or
inert agents or therapies (e.g. other anti-inflammatory agents,
diluents, and/or excipients).
[0009] The pharmacologically active ingredient of the present
invention possesses a chemical structure selected from:
[0010] The present invention is also directed to a method of
treating diseases and other physical ailments or disorders. In a
preferred embodiment the method comprises the step of
administering to a subject in need thereof a copper (I) complex
having a formula of Formula (I), Formula (II), Formula (III) or
Formula (IV) to reduce and/or treat a disease or physical
ailment or disorder. Preferably the disease or physical ailment
being treated is a mitochondrial or neuromuscular disease. The
treated diseases or disorders (or other physical ailments)
include, but are not limited to fibromyalgia, spinal cord
injury, multiple sclerosis, muscular dystrophy, stroke,
rheumatoid arthritis, pain, fatigue, sleeplessness, loss of fine
motor control, speech loss, inflexibility, Lyme disease, Lyme
disease co-infection, gastroparesis (GP), chronic inflammation,
myopathy, chronic inflammation, and/or incontinence. It is also
preferable that the subject be diagnosed with one of the
diseases and/or disorders prior to treatment.
[0011] The present invention encompasses a method of treating a
mitochondrial disease selected from the group consisting of
Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial
Myopathy, Encephalopathy, Lactacidosis, and Stroke (MELAS);
Diabetes mellitus and deafness (DAD); Maternally Inherited
Diabetes and Deafness (MIDD), Leber's Hereditary Optic
Neuropathy (LHON); chronic progressive external ophthalmoplegia
(CPEO); Leigh Disease; Kearns-Sayre Syndrome (KSS); Friedreich's
Ataxia (FRDA); Co-Enzyme Q10 (Co-Q10) Deficiency; Neuropathy,
ataxia, retinitis pigmentosa, and ptosis (NARP); Myoneurogenic
gastrointestinal encephalopathy (MNGIE); Complex I Deficiency;
Complex II Deficiency; Complex III Deficiency; Complex IV
Deficiency; Complex V Deficiency; and other myopathies that
effect mitochondrial function.
[0012] Preferred embodiments of the compositions of the present
invention, including recommended dosages and methods of use, are
more fully described below in the Detailed Description.
BRIEF
DESCRIPTION OF THE DRAWINGS
[0013] Illustrative and exemplary embodiments of the invention
are shown in the drawings in which:
[0014] FIG. 1 depicts a proton NMR of an embodiment of a copper
(I) glycinate complex dissolved in deuterium oxide (D2O).
[0015] FIG. 2 depicts a proton NMR of sodium glycinate dissolved
in D2O.
[0016] FIG. 3 depicts a proton NMR of sodium ascorbate dissolved
in D2O.
[0017] FIG. 4 depicts an image of a copper (I) glycinate complex
captured with a scanning electron microscope (SEM). The scale
bar represents 200 μm.
[0018] FIG. 5 depicts the results of an Energy Dispersive
Spectroscopy analysis on an SEM (EDS-SEM) with a copper (I)
glycinate complex. The elements identified in the analysis are
carbon (C), oxygen (O), sodium (Na), aluminum (Al), chlorine
(CO, and copper (Cu).
[0019] FIGS. 6A and 6B depict two versions of the SEM image of a
copper (I) glycinate complex that was analyzed by EDS-SEM. The
scale bar represents 50 μm.
[0020] FIG. 7 depicts the distribution and relative proportion
(intensity) of the specified elements over the area scanned by
the EDS-SEM of a copper (I) glycinate complex.
[0021] FIG. 8 depicts an image of a copper (I) pyruvate complex
captured with an SEM. The scale bar represents 200 μm.
[0022] FIG. 9 depicts the results of an EDS-SEM analysis with a
copper (I) pyruvate complex. The elements identified in the
analysis are carbon (C), oxygen (O), sodium (Na), chlorine (Cl),
calcium (Ca), and copper (Cu).
[0023] FIGS. 10A and 10B depict two versions of an SEM image of
a copper (I) pyruvate complex that was analyzed by EDS-SEM. The
scale bar represents 500 μm.
[0024] FIG. 11 depicts the distribution and relative proportion
(intensity) of the specified elements over the area scanned by
the EDS-SEM of a copper (I) pyruvate complex.
[0025] FIG. 12 depicts an image of a copper (I) succinate
complex captured with an SEM. The scale bar represents 200 μm.
[0026] FIG. 13 depicts the results of an EDS-SEM analysis with a
copper (I) succinate complex. The elements identified in the
analysis are carbon (C), oxygen (O), sodium (Na), chlorine (Cl),
and copper (Cu).
[0027] FIGS. 14A and 14B depict two versions of an SEM image of
a copper (I) succinate complex that was analyzed by EDS-SEM. The
scale bar represents 500 μm.
[0028] FIG. 15 depicts the distribution and relative proportion
(intensity) of the specified elements over the area scanned by
the EDS-SEM of a copper (I) succinate complex.
[0029] FIG. 16 depicts the time course of the XF Cell Mito
Stress Test.
[0030] FIG. 17 depicts the compares results of the XF cell Mito
Stress Test in lymphoblasts from control individuals (C) and
autistic subjects with (A) or without mitochondrial dysfunction
(N). The figure also compares the effect of administering 100 μM
or 500 μM copper (I) glycinate complex on the oxygen consumption
rate of these cells.
[0031] Elements and facts in the figures are illustrated for
simplicity and have not necessarily been rendered according to
any particular sequence or embodiment.
DETAILED
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0032] The verb “comprise” as is used in this description and in
the claims and its conjugations are used in its non-limiting
sense to mean that items following the word are included, but
items not specifically mentioned are not excluded. In addition,
reference to an element by the indefinite article “a” or “an”
does not exclude the possibility that more than one of the
elements are present, unless the context clearly requires that
there is one and only one of the elements. The indefinite
article “a” or “an” thus usually means “at least one.”
[0033] The terms “copper (I) complex” and “copper (I) compound”
as used herein are interchangeable and refer to a chemical
compound in which copper is present in its +1 oxidation state
and interacts with at least one other element through ionic or
covalent bonding.
[0034] The term “extended release” herein refers to any
formulation or dosage form that comprises an active drug and
which is formulated to provide a longer duration of
pharmacological response after administration of the dosage form
than is ordinarily experienced after administration of a
corresponding immediate release formulation comprising the same
drug in the same amount. Controlled release formulations
include, inter alia, those formulations described elsewhere as
“controlled release”, “delayed release”, “sustained release”,
“prolonged release”, “programmed release”, “time release” and/or
“rate controlled” formulations or dosage forms. Further for the
purposes of this invention refers to release of an active
pharmaceutical agent over a prolonged period of time, such as
for example over a period of 8, 12, 16 or 24 hours.
[0035] As used herein, the term “subject” or “patient” refers to
any vertebrate including, without limitation, humans and other
primates (e.g., chimpanzees and other apes and monkey species),
farm animals (e.g., cattle, sheep, pigs, goats and horses),
domestic mammals (e.g., dogs and cats), laboratory animals
(e.g., rodents such as mice, rats, and guinea pigs), and birds
(e.g., domestic, wild and game birds such as chickens, turkeys
and other gallinaceous birds, ducks, geese, and the like). In
some embodiments, the subject is a mammal. In other embodiments,
the subject is a human.
Compositions
[0036] The compositions of the present invention may comprise an
effective amount of a copper (I) complex having a formula
selected from:
Preferably, the pharmaceutical composition further comprises
copper ascorbate (esterified Vitamin C), ascorbic acid (Vitamin
C), and/or a pharmaceutically acceptable excipient (carrier).
More preferably, the pharmaceutically acceptable carrier is an
inert diluent.
[0037] The compositions of the present invention may comprise a
delivery vehicle. Suitable delivery vehicles include a liposome,
a microsome, a nanosome, a picosome, a pellet, a granular
matrix, a bead, a microsphere, a nanoparticle formulation, or an
aqueous solution.
[0038] Liposomes can aid in the delivery of the copper (I)
compounds to a particular tissue and can also increase the blood
half-life of the compounds. Liposomes suitable for use in the
invention are formed from standard vesicle-forming lipids, which
generally include neutral, positively or negatively charged
phospholipids and, optionally, a sterol, such as cholesterol.
The selection of lipids is generally guided by consideration of
factors such as the desired liposome size and half-life of the
liposomes in the blood stream. A variety of methods are known
for preparing liposomes, for example as described in Szoka et
al. (1980), Ann. Rev. Biophys. Bioeng. 9: 467; and U.S. Pat.
Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369, the entire
disclosures of which are herein incorporated by reference.
[0039] Polyacrylates represent a further example of a suitable
delivery vehicle for use in the present invention. By way of
example, a terpolymer of styrene and hydroxyethyl methacrylate
cross-linked with a difunctional azo-compound may be employed.
The system depends on cleavage of the azo bond by intestinal
microflora resulting in degradation of polymer. Similarly, a pH
responsive poly (methacrylic-g-ethylene glycol) hydrogel may be
employed as an oral delivery vehicle. Once inside the basic and
neutral environment of the small intestine, the gels rapidly
swell and dissociate.
[0040] In another embodiment, a microcapsule formulation may be
employed for peroral delivery. In more detail, aqueous colloidal
terpolymers of ethylacrylate/methyl methacrylate/2-hydroxylethyl
methacrylate (poly (EA/MME/HEMA), for example as synthesized by
emulsion polymerization technique(s) may be employed. These
polymers exhibit delayed release profiles, which were
characterized by a long lag time and subsequent rapid release of
the entrapped moiety.
[0041] In another embodiment, orally administered nanoparticles
may serve as suitable delivery vehicles. By way of example,
loaded nanoparticles may be entrapped into pH sensitive
microspheres, which serve to deliver the incorporated
nanoparticle to the desired site of action. Nanoparticles have a
large specific surface, which is indicative of high interactive
potential with biological surfaces. Thus, bioadhesion can be
induced by binding nanoparticles with different molecules. By
way of example, nanoparticles may be prepared from gliadin
protein isolate from wheat gluten and then conjugated with
lectins (glycoproteins of non-immune origin which provide
specific bioadhesion). Accordingly, nanoparticles are provided,
which have a high capacity for non-specific interaction with
intestine.
[0042] The compositions of the present invention may take the
form of differently sized particles. In some embodiments,
particles are microparticles (aka microspheres or microsomes).
In general, a “microparticle” refers to any particle having a
diameter of less than 1000 μm. In some embodiments, particles
are nanoparticles (aka nanospheres or nanosomes). In general, a
“nanoparticle” refers to any particle having a diameter of less
than 1000 nm. In some embodiments, particles are picoparticles
(aka picospheres or picosomes). In general, a “picoparticle”
refers to any particle having a diameter of less than 1 nm. In
some embodiments, particles are micelles.
[0043] In one embodiment, a delivery vehicle based on an
albumin-chitosan mixed matrix microsphere-filled coated capsule
formulation may be employed. In this regard, a preparation of a
copper (I) compound of the invention is filled into hard gelatin
capsules and enteric coated.
[0044] In one embodiment, albumin microspheres may be employed
as the oral delivery system.
[0045] In one embodiment, squalane oil-containing multiple
emulsions may be employed.
[0046] In one embodiment, poly(lactide-co-glycolide)
microspheres may be employed as the oral delivery vehicle.
[0047] In one embodiment, a delivery coating comprising a
mixture of pH-responsive enteric polymer (Eudragit S) and
biodegradable polysaccharide (resistant starch) in a single
layer matrix film may be employed.
[0048] In one embodiment, delivery capsules such as liposomes,
micro- or nanocapsules (e.g. chitosan nanocapsules) may be
chemically modified with poly(ethylene glycol) (PEG). The
typical degree of PEGylation is in the range of 0.1% to 5%, such
as 0.5% to 2%, for example 0.5% or 1%. The presence of PEG,
whether alone or grafted to chitosan, improves the stability of
the delivery capsules in the gastrointestinal fluids.
[0049] PEGylated delivery vehicles such as liposomes, micro- or
nanocapsules have an intrinsic ability to accumulate at disease
sites and facilitate transfection of target cells. Unlike many
viral vectors, PEGylated liposomes are generally considered to
be non-immunogenic.
[0050] In one embodiment, a branched PEGylating reagent is
employed as branched PEG protecting groups are more effective
than linear PEG molecules.
[0051] In one embodiment, the copper (I) compounds of the
invention are prepared with carriers that will protect the
compound against rapid elimination from the body, such as an
extended release formulation, including implants and
microencapsulated delivery systems. Biodegradable, biocompatible
polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters,
and polylactic acid. Methods for preparation of such
formulations will be apparent to those skilled in the art. The
materials can also be obtained commercially from Alza
Corporation and Nova Pharmaceuticals, Inc.
[0052] Other embodiments of the invention are directed to a
single crystalline form of the copper (I) complexes
characterized by a combination of the characteristics of any of
the single crystalline forms discussed herein. The
characterization can be any combination of one or more of the
XRPD, TGA, DSC, moisture sorption/desorption measurements and
single crystal structure determination described for a
particular crystalline form. For example, the single crystalline
form of a copper (I) complex can be characterized by any
combination of the XRPD results regarding the 2θ position of the
major peaks in an XRPD scan; and/or any combination of one or
more of the unit cell parameters derived from data obtained from
the single crystal structure analysis. DSC determinations of the
temperature associated with the maximum heat flow during a heat
flow transition and/or the temperature at which a sample begins
to undergo a heat flow transition may also characterize the
crystalline form. Weight change in a sample and/or change in
sorption/desorption of water per molecule of a copper (I)
complex of the present invention as determined by moisture
sorption/desorption measurements over a range of relative
humidity can also characterize a single crystalline form of a
copper (I) complex.
[0053] Examples of combinations of single crystalline form
characterizations using multiple analytical techniques include
the 2θ positions of at least one of the major peaks of an XRPD
scan and the temperature associated with the maximum heat flow
during one or more heat flow transitions observed by a
corresponding DSC measurements; the 2θ positions of at least one
of the major peaks of an XRPD scan and one or more weight losses
associated with a sample over a designated temperature range in
a corresponding TGA measurement; the 2θ positions of at least
one of the major peaks of an XRPD scan, and the temperature
associated with the maximum heat flow during one or more heat
flow transitions observed by a corresponding DSC measurements,
and one or more weight losses associated with a sample over a
designated temperature range in a corresponding TGA measurement;
the 2θ positions of at least one of the major peaks of an XRPD
scan, and the temperature associated with the maximum heat flow
during one or more heat flow transitions observed by a
corresponding DSC measurements, one or more weight losses
associated with a sample over a designated temperature range in
a corresponding TGA measurement, and the change in
sorption/desorption measurements over a range of relative
humidity. As well, each of the aforementioned examples can
replace the use of 2θ positions of at least one of the major
peaks of an XRPD scan with one or more unit cell parameters of
the single crystalline form.
[0054] The combinations of characterization that are discussed
above can be used to describe any of the single crystalline
forms of a copper (I) complex of the present invention.
[0055] The D90 particle size diameter of the copper (I)
complexes of the present invention may be 1 to 500 microns;
e.g., any range within 1 and 500 microns, such as 1 to 100
microns, 50 to 250 microns, 100 to 300 microns, 250 to 500
microns, etc.
Indications
[0056] The compositions of the present invention may be used to
effectively treat numerous human diseases and other ailments
characterized by neuromuscular degeneration and muscle weakness.
These diseases are described in detail below.
[0057] The copper (I) complexes of the present invention are
particularly effective in treating mitochondrial diseases.
Mitochondrial diseases are often the result a deficiency in ATP
production, via the oxidative phosphorylation, which makes high
energy-demanding tissues or organs such as heart, brain, and
muscles, the main targets for these disorders. By restoring ATP
production to normal, the copper (I) complexes may prevent,
treat, or reverse mitochondrial disease.
[0058] Impairments in oxidative phoshporylation are often
referred to as mitochondrial dysfunction (and are associated
with mitochondrial disease). They can result from hereditary and
somatic mutations in nuclear genes or mtDNA, or functional
impairments by drugs or toxins. Mutations in over 100 genes
constituting the oxidative phosphorylation machinery are linked
with mitochondrial encephalopathies in humans, which are the
most common metabolic diseases with an incidence of over 1/5000
in live births.
[0059] Respiratory chain Complex I deficiency is a cause of
mitochondrial diseases in many cases. Twenty-five of at least
fifty known genes implicated in Complex I biogenesis are found
associated with mitochondrial diseases. Pathogenic mutations in
structural subunits (e.g., NDUFA 1, 2, 11; NDUFS 1-4, 6-8; NDUFV
1, 2) and assembly factors (e.g., NDUFAF1-6) have been
identified. Neurodegenerative diseases such as Parkinson's
disease, Alzheimer's disease, and Huntington's disease are also
associated with mitochondrial dysfunction. Further, mtDNA
mutations are found associated with almost all types of cancers.
Type 2 diabetes is also linked with declining mitochondrial
function in relevant tissues such as β-cells and muscles. Type 2
diabetes represents a major clinical challenge due to the sharp
rise in obesity-induced disease. Thus, in some embodiments,
methods are provided for treating a mitochondrial disease or a
mitochondrial dysfunction.
[0060] Symptoms of mitochondrial diseases usually include slow
growth, loss of muscle coordination, muscle weakness, visual
defect, hearing defects, learning disabilities, mental
retardation, heart disease, liver disease, kidney disease,
gastrointestinal disorders, respiratory disorders, neurological
problems, and dementia.
[0061] The copper (I) complexes of the present invention may be
used to treat mitochondrial diseases such as Myoclonic Epilepsy
with Ragged Red Fibers (MERRF); Mitochondrial Myopathy,
Encephalopathy, Lactacidosis, and Stroke (MELAS); Diabetes
mellitus and deafness (DAD); Maternally Inherited Diabetes and
Deafness (MIDD), Leber's Hereditary Optic Neuropathy (LHON);
chronic progressive external ophthalmoplegia (CPEO); Leigh
Disease; Kearns-Sayre Syndrome (KSS); Friedreich's Ataxia
(FRDA); Co-Enzyme Q10 (Co-Q10) Deficiency; Neuropathy, ataxia,
retinitis pigmentosa, and ptosis (NARP); Myoneurogenic
gastrointestinal encephalopathy (MNGIE); Complex I Deficiency;
Complex II Deficiency; Complex III Deficiency; Complex IV
Deficiency; Complex V Deficiency; and other myopathies that
effect mitochondrial function.
[0062] The copper (I) complexes of the present invention may
also be used to treat a neuromuscular disease. The term
“neuromuscular disease” refers to disorders that adversely
affect muscle function and/or the control thereof by the central
nervous system (CNS). In general, neuromuscular diseases
encompass a wide range of physical ailments characterized by
impaired muscle function. The following (non-limiting) list of
conditions is generally recognized as neuromuscular diseases or
conditions: multiple sclerosis, muscular dystrophy, rheumatoid
arthritis, fibromyalgia, myopathy, inflammatory bowel disease
(IBD), incontinence, inflexibility, impaired fine motor skills,
and amyotrophic lateral sclerosis (“ALS” or Lou Gehrig's
disease).
[0063] A stroke, formerly known as a cerebrovascular accident
(CVA), often results in severe neurological impairment.
Post-stroke, many individuals suffer one or more neurological
impairments including, but not limited to: loss of fine motor
control, paralysis, speech impairment/loss (aphasia and/or
dysarthria), altered smell, taste, hearing, or vision, ptosis,
ocular and facial muscle weakness, diminished reflexes, loss of
balance, altered heart rate, apraxia, loss of memory, and/or
confusion.
[0064] Three of the most prominent diseases associated with
impaired neurological function are muscular dystrophy (MD),
multiple sclerosis (MS), and rheumatoid arthritis (RA).
[0065] The term Muscular Dystrophy (MD) actually refers to a
group of diseases characterized by muscle weakness and/or
impaired muscle function. The specific diseases include, but are
not limited to Becker, Duchenne, and Emery-Dreifuss. Over 100
diseases, however, display symptoms similar to MD. All are
characterized by reduced muscle function and muscle weakness.
[0066] Multiple Sclerosis (MS) is an autoimmune disease
diagnosed in 350,000-500,000 people in the United States. The
disease is characterized by multiple areas of inflammation and
scarring of the myelin in the brain and spinal cord. Patients
inflicted with the disease exhibit varying degrees of
neurological impairment depending on the location and extent of
the myelin scarring. Typical MS symptoms include fatigue,
weakness, spasticity, balance problems, bladder and bowel
problems, numbness, loss of vision, tremors, and depression.
Available treatments of MS generally only alleviate symptoms or
delay the progression of the disability
[0067] Rheumatoid Arthritis (RA) is another troublesome disorder
associated with inflammation. It is signified by chronic
inflammation in the membrane lining (the synovium) of the joints
and/or other internal organs. These inflammatory cells can also
damage bone and cartilage. For example, a joint inflicted with
RA may lose its shape and alignment, which can result in the
loss of range of motion. RA is characterized by pain, stiffness,
warmth, redness and swelling in the joint, and other systemic
symptoms like fever, fatigue, and anemia. RA currently affects
roughly 1% of the entire U.S. population (approximately 2.2
million people). The pathology of RA is not fully understood,
although it has been hypothesized to result from a cascade of
aberrant immunological reactions.
[0068] The compositions of the present invention are
particularly effective in treating Lyme disease and Lyme disease
co-infections. Lyme disease is a bacterial infection (Borrelia
burgdorferi) spread by ticks. The number of reported cases of
Lyme disease, and the number of geographical areas in which it
is found, has been increasing. In addition to causing arthritis,
Lyme disease can also cause heart, brain, and nerve problems.
Early symptoms include skin-rash, flu-like symptoms (e.g.
chills, fever, swollen lymph nodes, headaches, fatigue, muscle
aches/pains, and joint pain). More advanced symptoms include
nerve problems and arthritis.
[0069] Lyme disease is often associated with muscle degeneration
and/or muscle weakness. In one aspect of the present invention,
treatment of Lyme disease in a subject with a copper (I) complex
results in improved muscle health and/or muscle tone. In some
embodiments, the Lyme disease is chronic Lyme disease that
persists in spite of treatment with standard antibiotic
treatments.
[0070] Often, ticks can become infected with multiple
disease-causing microbes, resulting in co-infection. This may be
a potential problem for humans, due to Borrelia burgdorferi, and
other harmful pathogens carried and transmitted by some ticks.
Possible co-infections with viruses such as Lyme borreliosis,
anaplasmosis, babesiosis, or encephalitis may occur. It is not
known how co-infection may affect disease transmission and
progression, but may help in diagnosing and treating Lyme and
other such diseases.
[0071] In one embodiment, the present invention is directed to a
method of treating a tickborne disease with a copper (I)
complex. Tickborne diseases include Babesiosis, Ehrlichiosis and
Anaplasmosis, Lyme Disease, Relapsing Fever, Rocky Mountain
Spotted Fever, and Tularemia.
[0072] Tickborne diseases can be found throughout the United
States. For example, Lyme disease, first discovered in
Connecticut in the early 1970s, has since spread to every state
except Hawaii. Rocky Mountain spotted fever, a bacterial disease
transmitted by the dog tick, was first identified in 1896.
[0073] One of the newest tickborne diseases to be identified in
the United States is called Southern tick-associated rash
illness (STARI). This disease has a bull's-eye rash similar to
that found in Lyme disease, which is caused by bacteria
transmitted by the deer tick. Although researchers know that the
lone star tick transmits the infectious agent that causes STARI,
they do not yet know what microbe causes it.
[0074] Ticks transmit ehrlichiosis and anaplasmosis, both
bacterial diseases. Babesiosis is caused by parasites carried by
deer ticks. These diseases are found in several states.
[0075] Tularemia, a less common tickborne bacterial disease, can
be transmitted by ticks as well as other vectors (carriers) such
as the deerfly. Public health experts are concerned that the
bacterium that causes tularemia (Francisella tularensis) could
be used as a weapon of bioterrorism.
[0076] Transmission of tickborne diseases is not limited to
ticks. In addition, tickborne diseases may be spread via other
vectors (e.g., mosquitoes, flies, or other insects), via
contaminated body fluids (e.g., blood transfusions), via sexual
transmission or any other number of ways.
[0077] The copper (I) complexes may be used to treat
gastroparesis. Gastroparesis is a condition characterizes by the
inability of the stomach to empty its contents, when there is no
blockage (obstruction). The cause of gastroparesis is not known.
There is some evidence that it may be caused by a disruption of
nerve signals to the stomach. The condition is a complication of
diabetes and of some surgeries. Risk factors associated with
gastroparesis may include diabetes, gastrectomy (surgery to
remove part of the stomach), systemic sclerosis, use of
medication that blocks certain nerve signals (anticholinergic
medication). Symptoms may include abdominal distention,
hypoglycemia (in people with diabetes), nausea, premature
abdominal fullness after meals, weight loss, and vomiting. If
gastroparesis is caused by a condition that is reversible (e.g.
pancreatitis), when the condition is resolved, the symptoms will
subside. For some diabetics, better control of their blood sugar
can also improve the symptoms. If there is no reversible cause,
gastroparesis rarely resolves itself and the symptoms often grow
more sever with time. When accompanied by motility disorders of
the muscles of the small intestine, gastroparesis is
particularly difficult to treat.
[0078] The invention may be used to treat an animal with a
disease or physical ailment or disorder including, but not
limited to, one or more of the following: fibromyalgia, multiple
sclerosis, muscular dystrophy, rheumatoid arthritis,
Alzheimer's, dementia, ALS, depression, pain, fatigue,
sleeplessness, inflexibility, myopathy, Lyme disease, Lyme
disease co-infection, gastroparesis (GP), chronic inflammation,
incontinence, impaired fine motor skills, high cholesterol, low
sperm count, obesity, alopecia, burns, stretch marks, scars,
ADD, ADHD, and/or erectile dysfunction, wherein it is preferable
that the animal is a mammal and more preferable that the mammal
is a human.
[0079] In an alternate embodiment, the present invention is
further directed to pharmaceutical and/or dietary supplement
compositions for treating post-stroke symptoms, including, but
not limited to: loss of fine motor control, paralysis, speech
impairment/loss (aphasia and/or dysarthria), altered smell,
taste, hearing, or vision, ptosis, ocular and facial muscle
weakness, diminished reflexes, loss of balance, altered heart
rate, apraxia, loss of memory, and/or confusion.
[0080] Advantageously, the present invention is further directed
to pharmaceutical and/or dietary supplement compositions for
promoting one or more desired health benefits. In a preferred
embodiment, the compositions of the present invention promote
hair growth, skin healing, scar removal, nerve growth, muscle
growth, enhanced athletic performance, reduced post-traumatic
healing time, post-surgery healing, and/or enhanced libido.
[0081] In one embodiment, the subject is first diagnosed with
one of the diseases listed above before treatment.
Modes of
Administration
[0082] Frequency of dosage may vary depending on the purity of
the compound and the particular disease or physical ailment
treated. However, for treatment of most diseases and physical
ailments, a dosage regimen of (4) 2.5 mg capsules (for a total
of 10 mg/day) containing copper (I) complexes of the present
invention is preferred. As will be understood by one skilled in
the art, however, the optimal dosage level for a particular
subject will vary depending on a plurality of factors including
the potency and activity of the pharmacologically active
ingredient, as well as the age, body weight, general health,
sex, diet, time of administration, route of administration and
rate of excretion, drug combination (if any) and the severity of
the particular disease or physical ailment undergoing therapy.
Subject to the above factors, a generally effective amount of
the copper (I) complexes of the present invention is between 1
mg and 20 mg per day. More preferably, the effective amount of
is between 5 mg and 10 mg per day. Advantageously, the effective
amount of is between 7.5 mg to 10 mg per day. Most preferably
(subject to the factors listed above), the effective amount is
about 10 mg/per day.
[0083] Copper (I) complexes of the present invention may also
comprise a component of an overall pharmaceutical treatment
regime for reducing and/or treating a disease or physical
ailment or other disorder including, but not limited to:
fibromyalgia, multiple sclerosis, muscular dystrophy, rheumatoid
arthritis, Alzheimer's, dementia, ALS, depression, pain,
fatigue, sleeplessness, inflexibility, myopathy, incontinence,
impaired fine motor skills, high cholesterol, low sperm count,
obesity, alopecia, burns, stretch marks, scars, ADD, ADHD,
and/or erectile dysfunction, the treatment regime comprising:
administering to a subject at the least the following
pharmacologically active ingredient(s) within a 24-hour period:
copper (I) complexes of the present invention, and optionally a
pharmaceutically acceptable carrier, wherein the
pharmacologically active ingredient(s) is in an amount
sufficient to reduce the symptoms of the ailment.
[0084] Optionally, the pharmaceutical treatment regime including
copper (I) complexes of the present invention may include (or be
combined with) additional pharmacologically active ingredients
or other complementary treatments in order to provide
synergistic therapeutic effects. For example, copper (I)
complexes of the present invention may be administered in
combination with additional pharmacologically active agents
including, but not limited to, non-steroidal anti-inflammatory
drugs (NSAIDs), corticosteroids, disease modifying
anti-rheumatic drugs (DMARDs), biologic DMARDs, and/or
cyclooxygenase-2 (COX-2) inhibitors. In a preferred embodiment,
copper (I) complexes of the present invention is administered in
combination with ozone therapy.
[0085] The pharmaceutical and/or dietary supplement compositions
of the present invention may take a variety of forms specially
adapted to the chosen route of administration. The compositions
may be administered orally, topically, parenterally, by
inhalation or spray, or by any other conventional means.
Preferably, the compositions are prepared and administered in
dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. In
one preferred embodiment, the composition is administered
sublingually. It is further understood that the preferred method
of administration may be a combination of methods. Oral
administration in the form of a capsule, pill, elixir, syrup,
lozenge, troche, or the like is particularly preferred. The
pharmaceutical compositions of the present invention are
preferably in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsion, hard or softgel
capsules, or syrups or elixirs.
[0086] Compositions intended for oral use may be prepared
according to any method known in the art for manufacture of
pharmaceutical compositions, and such compositions may contain
one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant
and palatable preparations. Tablets may contain the active
ingredient in admixture with non-toxic pharmaceutically
acceptable excipients suitable for the manufacture of tablets.
Such excipients may include, for example, inert diluents, such
as calcium carbonate, sodium carbonate, lactose, calcium
phosphate or sodium phosphate; granulating and disintegrating
agents, for example, corn starch, or alginic acid; binding
agents, for example starch, gelatin or acacia; and lubricating
agents, for example magnesium stearate, stearic acid or talc.
The tablets may be uncoated or they may be coated by techniques
to delay disintegration and absorption in the gastrointestinal
tract and thereby provide a sustained action over a longer
period. For example, a time delay material such as glyceryl
monostearate or glyceryl distearate may be utilized.
[0087] 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, for
example peanut oil, liquid paraffin or olive oil.
[0088] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of
aqueous suspensions. Such excipients are suspending agents, for
example sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; and
dispersing or wetting agents, which may be a naturally-occurring
phosphatide, for example, lecithin, or condensation products of
ethylene oxide with long chain aliphatic alcohols—for example,
heptadecaethyleneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and
hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl-p-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and
one or more sweetening agents, such as sucrose or saccharin.
[0089] Oily suspensions may be formulated by suspending the
active ingredients in a vegetable oil, for example arachis oil,
olive oil, sesame oil or coconut oil, or in a mineral oil such
as liquid paraffin. The oily suspensions may contain a
thickening agent, for example beeswax, hard paraffin or cetyl
alcohol. Sweetening agents such as those set forth above, and
flavoring agents may be added to provide palatable oral
preparations. These compositions may be preserved by the
addition of an anti-oxidant such as ascorbic acid and/or copper
ascorbate.
[0090] Dispersible powders and granules suitable for preparation
of an aqueous suspension by the addition of water provide the
active ingredient (i.e., copper (I) complex) in admixture with a
dispersing or wetting agent, suspending agent and one or more
preservatives. Suitable dispersing or wetting agents and
suspending agents are exemplified by those already mentioned
above. Additional excipients, for example sweetening, flavoring
and coloring agents, may also be present.
[0091] Pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of these.
Suitable emulsifying agents may be naturally occurring gums, for
example gum acacia or gum tragacanth; naturally-occurring
phosphatide, for example soy bean, lecithin, and esters or
partial esters derived from fatty acids and hexitol; anhydrides,
for example sorbitan monooleate; and condensation products of
the said partial esters with ethylene oxide, for example
polyoxyethylene sorbitan monooleate. The emulsions may also
contain sweetening and flavoring agents.
[0092] Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, propylene glycol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative, and flavoring or coloring agents. The
pharmaceutical compositions may be in the form of a sterile
injectable aqueous or oleaginous suspension. This suspension may
be formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents, which have
been mentioned above. The sterile injectable preparation may
also be a sterile injectable solution or suspension in a
non-toxic parenterally acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed including synthetic mono- and diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0093] Alternatively, the compositions can be administered
parenterally in a sterile medium. The copper (I) complexes of
the present invention, depending on the vehicle and
concentration used, can either be suspended or dissolved in the
vehicle. Advantageously, adjuvants such as local anesthetics,
preservatives and buffering agents can be dissolved in the
vehicle.
[0094] For administration to non-human animals, the composition
containing copper (I) complexes of the present invention may be
added to the animal's feed or drinking water. Optionally, one
skilled in the art will recognize that animal feed and drinking
products may be formulated such that the animal takes in an
effective amount of copper (I) complexes of the present
invention via their diet. For example, copper (I) complexes of
the present invention may constitute a component of a premix
formulated for addition to the feed or drinking water of an
animal. Compositions containing copper (I) complexes of the
present invention may also be formulated as food or drink
supplements for humans.
[0095] Preferred embodiments of compositions containing copper
(I) complexes of the present invention will have desirable
pharmacological properties that include, but are not limited to,
oral bioavailability, low toxicity, and desirable in vitro and
in vivo half-lives. The half-life of copper (I) complexes of the
present invention is inversely proportional to the frequency of
dosage of the compounds.
Synthesis
of the Copper (I) Complexes
[0096] In one embodiment, the present invention provides a
method of synthesizing a copper (I) glycinate complex. The
method comprises: a) charging a glycinate salt under a stream of
inert gas in an alcohol or water; b) heating the glycinate salt
in the alcohol or water at between 40° C. to 45° C.; c) adding a
copper (I) salt to the alcohol and allowing to reflux for at
least 12 hours; and d) evaporating the alcohol or water and
washing the copper (I) glycinate complex with alcohol and/or
water to remove impurities. In a preferred embodiment, the inert
gas is nitrogen. In some implementations, the glycinate salt is
charged under a stream of inert gas with an ascorbate salt in an
alcohol. In one aspect, the glycinate salt in alcohol is heated
for 30 minutes. In a preferred embodiment, the mixture of copper
(I) salt and glycinate salt in water is refluxed for between 12
to 16 hours. In some implementations, the mixture of the
glycinate salt and copper (I) salt in water is cooled to about
37° C., in a preferred embodiment, the mixture is further cooled
by stirring. In a preferred implementation, evaporating the
alcohol or water and washing the copper (I) glycinate complex
with alcohol and/or water takes place under nitrogen-purge. For
example, the water is dried by flushing a pressure filter with
nitrogen. Once the collected products on the filter is semi-dry,
the drying process continues in a drying plate, under vacuum
conditions, at a temperature of 41° C. The isolated crystals of
copper (I) glycinate complex prepared in the absence of the
ascorbate salt have a lavender purple color, whereas isolated
crystals of copper (II) glycinate complex have a blue color.
[0097] In an alternate embodiment, the present invention
provides a method of synthesizing a copper (I) pyruvate complex.
The method comprises: a) charging a pyruvate salt under a stream
of inert gas in an alcohol; b) heating the pyruvate salt in the
alcohol at about 45° C.; c) adding a copper (I) salt to the
alcohol and allowing to reflux for at least 12 hours; and d)
evaporating the alcohol and washing the copper (I) pyruvate
complex with water to remove impurities. In some
implementations, the pyruvate salt is charged under a stream of
inert gas with an ascorbate salt in an alcohol. In one aspect,
the pyruvate salt in alcohol is heated for 30 minutes. In a
preferred embodiment, the mixture of copper (I) salt and
pyruvate salt in water is refluxed for between 12 to 16 hours.
The isolated crystals of copper (I) pyruvate complex prepared in
the absence of the ascorbate salt have an orange-yellow color.
[0098] In another embodiment, the present invention provides a
method of synthesizing a copper (I) succinate complex. The
method comprises: a) charging a succinate salt under a stream of
inert gas in an alcohol; b) heating the succinate salt and the
ascorbate salt in the alcohol at about 45° C.; c) adding a
copper (I) salt to the alcohol and allowing to reflux for at
least 12 hours; and d) evaporating the alcohol and washing the
copper (I) succinate complex with water to remove impurities. In
some implementations, the pyruvate salt is charged under a
stream of inert gas with an ascorbate salt in an alcohol. In one
aspect, the succinate salt in alcohol is heated for 30 minutes.
In a preferred embodiment, the mixture of copper (I) salt and
succinate salt in water is refluxed for between 12 to 16 hours.
The isolated crystals of copper (I) succinate complex prepared
in the absence of the ascorbate salt have a pink color.
[0099] In preferred embodiments of the methods of synthesizing a
copper (I) glycinate complex, a copper (I) pyruvate complex, or
a copper (I) succinate complex, the copper (I) salt is copper
(I) chloride. The molar ratios of glycinate salt, pyruvate salt,
or succinate salt to the copper (I) salt may be about 3:1, about
3:1.1, about 3:1.2, about 3:1.3, about 3:1.4, about 3:1.5, about
3:1.6, about 3:1.7, or about 3:1.8. The ascorbate salt used may
be sodium ascorbate, and the alcohol may be ethanol. The molar
ratios of glycinate salt/pyruvate salt/succinate salt to
ascorbate salt to copper (I) salt may be about 3:1:1, about
3:1.1:1.1, about 3:1.2:1.2, about 3:1.3:1.3, about 3:1.4:1.4,
about 3:1.5:1.5, about 3:1.6:1.6, about 3:1.7:1.7, or about
3:1.8:1.8. In one embodiment, the alcohol is 90% ethanol.
[0100] The methods of synthesizing copper (I) complexes may
further comprise trituration with organic solvents and/or
recrystallization to further purify the copper (I) complexes.
[0101] It is to be understood that the foregoing describes
preferred embodiments of the present invention and that
modifications may be made thereto without departing from the
scope or spirit of the present invention as set forth in the
claims. Such scope is limited only by the claims below as read
in connection with the above specification. Many additional
advantages of applicant's invention will be apparent to those
skilled in the art from the descriptions, drawings, and the
claims set forth herein.
EXAMPLES
Example 1a.
Preparation of a Copper (I) Glycinate Complex
[0102] Those skilled in the art will recognize various synthetic
methodologies that may be employed to prepare non-toxic
pharmaceutically acceptable compositions of copper (I)
glycinate. One such (representative) example is set forth below.
[0103] A
100 mL, 3-necked flask was charged with 90% ethanol (EtOH),
sodium glycinate and sodium ascorbate under a stream of N2
while charging. The mixture was heated to 45° C. for 30
minutes. Cuprous chloride (aka copper (I) chloride, CuCl or
Cu2Cl2) was then added to the mixture and placed under reflux
overnight with N2. The amounts and volumes of each component
in the mixture are shown in Table 1. The molar ratio of sodium
glycinate:sodium L-ascorbate:cuprous chloride was 3:1:1.
TABLE 1
Reaction mixture for production of copper (I) glycinate
Mass Volume
Molecular Molar
Compound (g) (mL) Weight
mmol Equivalent Source
Sodium 2 97.05
20.6079 1 Sigma
glycinate
Aldrich
Sodium L- 1.34727 198.11
6.80061 0.33 Sigma
ascorbate
Aldrich
CuCl 0.67326 99
6.80061 0.33 Strem
Chemicals
90% EtOH 60
[0104] A red suspension was filtrated to furnish a small
amount of red powder ( ̃100 mg), which was washed with water.
The mother liquor was concentrated by evaporation of the
ethanol and contained most of the mass as a brown powder.
[0105] Proton NMR was performed to identify the copper (I)
glycinate product. Proton NMR (dissolved in D2O) of the red
powder ( ̃100 mg) indicated no presence of starting material or
product.
[0106] Proton NMR (dissolved in D2O) of the concentrated mother
liquor indicated a single peak at 3.677 ppm and other small
peaks between 3.7-4.7 ppm (see FIG. 1). The D2O solvent peak is
at 4.8 ppm.
[0107] Proton NMR (dissolved in D2O) of sodium glycinate
indicated a single peak at 3.157 ppm, which corresponds to the
methylene (CH2) (see FIG. 2). Proton NMR (dissolved in D2O) of
sodium ascorbate indicated the following peaks: 3.70-3.73 (CH2),
3.99 (CHOH), and 4.49 (CH) ppm that correspond to the expected
sodium L-ascorbate peaks (see FIG. 3).
[0108] In the proton NMR spectrum of the mother liquor there is
no presence of sodium glycinate (3.157 ppm) (see FIG. 1). There
is a singlet peak at 3.67 ppm believed to correspond to the
desired Cu (I) chelated methylene (CH2) product, copper (I)
glycinate.
Example 1b.
Preparation of a Copper (I) Glycinate Complex
[0109]
Component Qty F.W. Moles Equiv.
1) Glycine 6.7 g 75.07
0.0893 3
2) Water 70 ml — —
1
3) Ethanol 350 ml —
— 5
4) Cu(I)Cl 2.95 g 99
0.0298 1
[0110] The
preparation process requires assembly of a nitrogen-purged 500
ml reaction flask equipped with a mechanical stirrer,
temperature probe/controller, reflux condenser, solid addition
funnel and heating mantle and nitrogen purge. Under nitrogen
purge, the reaction flask is charged with glycine (6.7 g or
0.0893 mol) and deionized water (70 ml). The resulting mixture
is stirred to complete dissolution. The dissolved mixture is
heated to 40-45° C. while remaining under nitrogen. The
reaction flask is then charge with ethanol (350 ml) under
nitrogen and then heated back to 40-45° C. Via solid addition
funnel, charge the cuprous chloride slowly while maintaining a
temperature of 40-5° C. during the addition. Turn off the heat
and allow the mixture to exothermal (about 5-10° C. exothermal
is typical). The mixture is cooled to about 37° C. and stirred
for approximately one hour. Afterwards, the reaction is
removed from heat and sparged with nitrogen for approximately
one hour. The final product is filtered using a pressure
filter under nitrogen purge. The collected product was rinsed
with ethanol (200 ml) two times with 15 minutes between each
rinse. The collected product on the filter is then flushed
with nitrogen for at least 45 minutes until semi-dry. The
collected product on the filter is transferred to a drying
dish and dried under vacuum at 41° C. The drying dish is
placed at an angle of 30° to 45° to facilitate drying and
formation of clean crystals. Yield: ̃95% of copper (I)
glycinate, a lavender purple microcrystalline solid.
Example 2. SEM Analysis of Copper (I) Glycinate Complex
[0111] The copper (I) glycinate complex synthesized in Example 1
was analyzed with an SEM, and various images of the copper (I)
glycinate complex were captured (see FIG. 4 for a representative
image). An Energy Dispersive Spectroscopy analysis on the SEM
(EDS-SEM) was run with the energy-dispersive spectrometer set at
an acceleration voltage of 15.0 kV. The EDS-SEM analysis
revealed the presence of carbon I, oxygen (O), and copper (Cu)
in the copper (I) glycinate complex. Sodium (Na), aluminum (Al),
and chlorine (Cl) were also identified as impurities present in
the copper (I) glycinate complex. See FIGS. 5-7.
Example 3.
Preparation of a Copper (I) Pyruvate Complex
[0112] Those skilled in the art will recognize various synthetic
methodologies that may be employed to prepare non-toxic
pharmaceutically acceptable compositions of copper (I) pyruvate.
One such (representative) example is set forth below.
[0113] A
100 mL, 3-necked flask was charged with 90% ethanol (EtOH),
sodium pyruvate and sodium ascorbate under a stream of N2
while charging. The mixture was heated to 45° C. for 30
minutes. Cuprous chloride was then added to the mixture and
placed under reflux overnight with N2. The molar ratio of
sodium pyruvate:sodium L-ascorbate:cuprous chloride was 3:1:1.
The resulting product was concentrated by evaporation of the
ethanol and washed with water to remove residual sodium
chloride.
Example 4. SEM Analysis of Copper (I) Pyruvate Complex
[0114] The copper (I) pyruvate complex synthesized in Example 3
was analyzed with an SEM, and various images of the copper (I)
pyruvate complex were captured (see FIG. 8 for a representative
image). An EDS-SEM analysis was run with the energy-dispersive
spectrometer set at an acceleration voltage of 20.0 kV. The
EDS-SEM analysis revealed the presence of carbon (C), oxygen
(O), and copper (Cu) in the copper (I) pyruvate complex. Sodium
(Na), chlorine (CO, and calcium (Ca) were also identified as
impurities present in the copper (I) pyruvate complex. See FIGS.
9-11.
Example 5.
Preparation of a Copper (I) Succinate Complex
[0115] Those skilled in the art will recognize various synthetic
methodologies that may be employed to prepare non-toxic
pharmaceutically acceptable compositions of copper (I)
succinate. One such (representative) example is set forth below.
[0116] A
100 mL, 3-necked flask was charged with 90% ethanol (EtOH),
sodium succinate and sodium ascorbate under a stream of N2
while charging. The mixture was heated to 45° C. for 30
minutes. Cuprous chloride was then added and the mixture
placed under reflux overnight with N2. The molar ratio of
sodium succinate:sodium L-ascorbate:cuprous chloride was
3:1:1. The resulting product was concentrated by evaporation
of the ethanol and washed with water to remove residual sodium
chloride.
[0117] Because succinic acid possesses two acidic groups, there
are at least two different species of salt possible. The first
is the hemi form, in which only one of the carboxylic acids is
in the copper salt form, while the other is the full salt form
in which there are two coppers to one succinate, one at each
carboxylate. Therefore, the product of this synthesis reaction
may contain a mixture of the hemi salt and the full salt as
shown below.
Example 6. SEM Analysis of Copper (I) Succinate Complex
[0118] The copper (I) succinate complex synthesized in Example 5
was analyzed with an SEM, and various images of the copper (I)
pyruvate complex were captured (see FIG. 12 for a representative
image). An EDS-SEM analysis was run with the energy-dispersive
spectrometer set at an acceleration voltage of 20.0 kV. The
EDS-SEM analysis revealed the presence of carbon (C), oxygen
(O), and copper (Cu) in the copper (I) succinate complex. Sodium
(Na) and chlorine (Cl) were also identified as impurities
present in the copper (I) pyruvate complex. See FIGS. 13-15.
Example 7. In Vitro Effects of Copper (I) Glycinate Complex
[0119] The copper (I) glycinate complex synthesized in Example
1b was used in a mitochondrial stress test using the XF Cell
Mito Stress Test kit (Agilent, Wilmington, Del.). The cells
studies were lymphoblasts from normal subjects (C), lymphoblasts
from autistic donors without mitochondrial dysfunction (N), and
lymphoblasts from autistic donors with mitochondrial dysfunction
(A). ATP-linked respiration, proton leak, maximal respiratory
capacity, and reserve capacity were determined as measured by
the cells' oxygen consumption rate. FIG. 16 depicts the time
points during the course of mitochondrial stress tests that are
relevant for determining ATP-linked respiration, proton leak,
maximal respiratory capacity, and reserve capacity. FIG. 17
depicts the results of the stress test with that compares the
administration of 100 μM or 500 μM of the copper (I) glycinate
to the respiration of these cells without administration of the
copper (I) complex. Panel B of FIG. 17 shows that 500 μM of the
copper (I) glycinate significantly reduced proton leak
lymphoblasts with mitochondrial dysfunction. Mitochondrial
dynfunction in cells was determined using the methods of the
Frye lab, which was described in Rose et al., “Oxidative stress
induces mitochondrial dysfunction in a subset of autistic
lymphoblastoid cell lines,” Transl Psychiatry, 2014 4:e377.
[0120] Unless defined otherwise, all technical and scientific
terms herein have the same meaning as commonly understood by one
of ordinary skill in the art to which this invention belongs.
Although any methods and materials, similar or equivalent to
those described herein, can be used in the practice or testing
of the present invention, the preferred methods and materials
are described herein. All publications, patents, and patent
publications cited are incorporated by reference herein in their
entirety for all purposes.
[0121] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission
that the present invention is not entitled to antedate such
publication by virtue of prior invention.
[0122] It is to be understood that the methods set forth
hereinabove describe preferred synthetic methodologies and that
modifications thereto may be made without departing from the
scope or spirit of the invention. Such scope is limited only by
the claims below as read in connection with the above
specification. Many additional synthetic methodologies and
additional advantages of applicant's invention will be apparent
to those skilled in the art from the above descriptions and the
claims below.
US2016024118
COPPER (I) COMPLEXES WITH GLYCINE, PYRUVATE, AND
SUCCINATE
Inventor: BARKER CHARLES LOUIS ALBARTUS / BOULANGER
WILLIAM
Applicant: C LAB PHARMA INTERNATIONAL
New
stable, crystalline organometallic complexes of glycine with
metals, e.g. cobalt, magnesium, iron, zinc, manganese or
copper, useful as bioavailable metal sources for humans or
animals
FR2833187 (A1)
FR2843752 (A1)
Copper
Medicine
http://www.scripturalphysics.com
Copper
Aspirinate Synthesis
by
Brian Fraser
Disclaimer: The following
is a summary of the procedure I used to make copper aspirinate.
I offer it here for informational purposes to show that copper
aspirinate can be made with commonly available materials and
equipment. A similar procedure is typically done by second-year
college chemistry students as a laboratory exercise in a setting
supervised by a professional instructor. I do NOT recommend that
people do this at home. Some aspects of these procedures are
hazardous, and the typical home kitchen simply has too many
distractions and interruptions for a student to carry out these
procedures safely. Your wife ( or mom) will also be furious if
you get copper sulfate stains on her kitchen counter!
Copper Aspirinate synthesis
(kitchen method)
Equipment and Materials required
1. Saturated copper acetate solution. See procedure below.
2. Pure aspirin crystals. See procedure below.
3. Ethanol (95%; liquor store ethanol like Everclear (190
proof, UPC 088352100036) is what was used here.
4. Vacuum filtration facilities (Büchner funnel, coarse and
medium porosity filter paper, aspirator, filter flask, seals,
tubing, clamps, stand, etc. These common lab tools are not
absolutely necessary, but can speed things up considerably.)
5. Containers for liquid such as Rubbermaid 24 fl. oz. servin'
saver tm (used here as a "beaker").
Procedure
1. Add 1 fl. oz. of saturated copper acetate solution to a
beaker.
2. Dissolve 1 tsp (teaspoon) pure aspirin crystals in about 1
fl. oz. of ethanol (95%) in another beaker
3. Pour the aspirin solution into the copper acetate solution.
Stir occasionally.
4. Dark blue crystals will gradually form on the sides and
bottom of the beaker. The initial layer will form immediately if
the beaker has been freshly cleaned and scoured. The layer will
gradually thicken and become bluer and darker. This process may
take several hours. The endpoint is reached when the liquid has
turned a light blue and no more blue crystals are forming on the
walls of the beaker. (You can verify the endpoint by siphoning
the clear liquid, evaporating it in a separate container, and
checking the residue. The residue should be mostly aspirin
crystals.)
This procedure requires no heating. If you heat the liquid to
increase the reaction rate, be aware that aspirin can hydrolyze
into acetic and salicylic acids in a moist or liquid
environment. If that happens, the liquid will turn dark green,
and the yield of copper aspirinate will be greatly
reduced.
5. Cool the mixture in a refrigerator.
6. Scrape the crystals off the sides and bottom of the beaker.
Then vacuum filter the whole mixture. (Save the first filtrate
in a separate container if you do ethanol solvent recycling.)
7. Wash the blue powder on the filter with cold distilled water.
8. Dry the powder and filter paper in an oven at about 120F.
Store the dry powder in a small dark bottle with a label
identifying the contents and the date of creation.
Alternative Procedure
Substitute isopropanol (99%) for the ethanol in step #2
and use 1/2 teaspoon, instead of 1 teaspoon, of aspirin crystals
and 1/2 fl. oz. isopropanol instead of 1 fl. oz of ethanol.
After several hours of initial crystallization, add 1/2
fl. oz. of distilled water and place the beaker in the
refrigerator and wait a few more hours for more crystals. This
variation gives about the same results as the ethanol procedure.
Its advantages are that it uses less excess aspirin and a less
expensive alcohol.
Aspirin purification (kitchen
method)
Equipment and Materials required
1. One bottle of 1000 commercial aspirin tablets (preferably the
uncoated kind).
2. A pint or two of isopropyl alcohol (99%). This is usually
available from a hardware store. Sometimes it can be found in a
drugstore (UPC: 341226909730 ) Isopropanol is extremely
flammable, so be very careful not to expose vapors to hidden or
unexpected ignition sources.
3. A couple of gallons of deionized or distilled water.
4. Three, 24 fl. oz. wide-mouthed polypropylene containers
with covers, such as Rubbermaid servin' saver tm.
5. Oven thermometer (easily read dial type is best)
6. Modified turkey baster (see construction procedure below)
7. One kitchen (with sink, refrigerator, oven, etc)
Procedure:
1. Dump a few hundred aspirin tablets into a wide-mouthed
container.
2. Add distilled water to the container and stir. This will
break up the aspirin tablets and dissolve the hydroxypropyl
methycelluose coating that is usually used to coat aspirin
tablets. Let the mixture settle for an hour or so in the
refrigerator.
3. Siphon most of the water out with a modified turkey baster.
4. Repeat steps #2 and #3 a total of three to five
times. This will largely get rid of the
methycellulose coating, which tends to clog filters. You might
not need to repeat these steps if you use uncoated
aspirin.
5. Vacuum filter the mixture from #4 and dry the powder in air.
(Caution: aspirin tends to decompose when heated in a moist
environment).
6. Add the powder to a quart container. Add about a half-cup of
isopropyl alcohol (99%). Stir. This will dissolve part, but not
all, of the aspirin. Let the mixture settle.
7. Vacuum filter the above mixture using medium porosity filter
paper. Pour the filtrate into a clear glass container for
inspection. If the filtrate is not clear, re-establish vacuum on
the filter, and filter it again. (Sometimes simply letting the
mixture settle and then siphoning the clear liquid with a turkey
baster is more effective than filtration; the latter, however,
may be faster.)
8. Pour the clear filtrate containing the dissolved aspirin into
the second container, cover it, and place it in the
freezer (about 5 F or so). After an hour or so the aspirin will
crystallize out of solution. Return the powder on the filter to
its original quart container.
9. After the aspirin crystals have formed, remove
the container from the freezer. Carefully decant the liquid back
into the first container that contains the impure aspirin
powder. Then scrape out the pure aspirin crystals into a third
container.
10. Cover this first container (impure aspirin powder and
recovered isopropanol) and let it warm to room temperature.
Agitate it occasionally so that more aspirin will again
dissolve.
11. Repeat steps 7 through 10 until you have recovered all the
aspirin, and the filter paper has only a thin layer of the
excipients (typically calcium phosphate, starch, talc, etc.
These impurities are added to the tablets to help them break up
in water). Discard the filter paper. Dump the isopropanol down
the drain, and wash it down with some tap water.
12. Using new filter paper (medium porosity), filter
any remaining isopropanol from the recovered aspirin crystals
(third container). Rinse the third container with
distilled water and wipe it dry. Dump the filtered crystals back
into the third container and cover them with cold distilled
water. Re-establish vacuum on the filter and filter the crystals
again. This will rinse off any remaining isopropanol. Discard
the liquid. (Repeat the procedure if you can still smell
isopropanol on the crystals).
13. Finally, gently dry the aspirin crystals. (I dried mine in
an oven at 120 F. If you do this, BE SURE you have rinsed the
crystals well enough so that there are no isopropanol vapors
present. Isopropanol forms explosive vapors with air, and
allowing these to accumulate in a confined space is a recipe for
serious trouble. Also, aspirin tends to decompose when heated,
especially in hot water, so I use only a warm temperature
setting. )
Copper acetate synthesis (kitchen
method)
Equipment and Materials required
1. Copper sulfate pentahydrate 99%. This is usually available
from a hardware store in the form of a product used to kill tree
roots in sewers and septic tanks, such as Roebic K-77.
2. Arm and Hammer Baking soda (sodium bicarbonate).
3. A couple of quarts of distilled vinegar (5% acetic acid).
4. A Pyrex casserole dish (22 x 11 x 6 cm or similar)
5. Vacuum filtration facilities.
6. Various clean, quart containers.
Procedure
Preparation of filtered copper
sulfate solution
1. Dissolve 3/4 cupful of copper sulfate crystals in about a
quart of warm distilled water.
2. Vacuum filter the solution through coarse porosity filter
paper. This will filter out suspended solids (metal flecks,
"dirt", etc.). Pour the filtrate off into a clear inspection
container. Vacuum filter the solution again with medium porosity
paper until it is clear blue. Note that the filtrate may still
contain significant impurities (lead, arsenic, cadmium, etc.) at
this point. Remember that this product is normally used in
sewers.
3. Save the clear blue solution for later use.
(4. If you want higher purity copper sulfate, you can
re-crystallize it at this point.)
Preparation of sodium carbonate
solution
1. Pour a cup full of sodium bicarbonate into a Pyrex casserole
dish. Add distilled water sufficient to dissolve it.
2. Heat the solution in an oven to about 200F. This will cause
the bicarbonate to decompose into the carbonate with the
evolution of carbon dioxide. The end result will be a
solution of sodium carbonate.
3. Let the solution cool to room temperature. Carbonates are
somewhat less soluble than bicarbonates; add more distilled
water if necessary to keep the material in solution.
Preparation of copper carbonate
1. In a large container, gradually combine the copper sulfate
solution with the sodium carbonate solution. A blue-green
precipitate will immediately form along with the vigorous
release of carbon dioxide. Let the precipitate settle out.
2. At this point the liquid portion will have either an excess
of sodium carbonate or of copper sulfate. If you add a drop of
sodium carbonate and see some precipitate form, then the bulk
mixture needs more sodium carbonate solution added. Likewise, if
you add a drop of copper sulfate and see a precipitate, then the
bulk mixture needs more copper sulfate solution added. Make
these adjustments as necessary until there is no longer an
unambiguous formation of the blue-green precipitate.
3. Vacuum filter the mixture with a coarse porosity paper
filter. Discard the liquid. Wash with cold distilled water and
then refilter. This will wash out any excess sodium carbonate or
copper sulfate.
Preparation of copper acetate
solution
4. To a quart container, add the still moist copper carbonate
powder from the previous step. Then slowly pour vinegar into the
container. Carbon dioxide will evolve and copper acetate will
form. The solution will gradually become a deep blue color. A
blue-green precipitate may also settle to the bottom of the
container.
5. Let the solution settle out. If there is a substantial amount
of blue-green precipitate at the bottom of the container, add
more vinegar. Try to dissolve most, but not all, of this
precipitate. An excess of vinegar is harder to remove than a
little of the precipitate.
6. Using coarse paper, vacuum filter the resulting copper
acetate solution. Repeat until clear. Discard the paper. Save
the blue filtrate.
7. Slowly evaporate the blue filtrate in a Pyrex casserole dish
in an oven (150F) for several hours. Periodically scrape down
the sides of the dish to prevent a build up of crystals.
Continue the evaporation until some blue-black crystals of
copper acetate begin to form (and do not redissolve). The
mixture may also have some blue-green "pond scum" in it too.
8. Cool and filter the dark blue solution. Store it in a clear
glass container for observation (a one quart vinegar bottle
works fine). This is the saturated copper acetate solution that
will be used to make copper aspirinate.
9. If you want to make copper acetate crystals, continue the
evaporation process until blue-black crystals form. This will
require evaporating most, but not all, of the solution.
Impurities (and excess vinegar) tend to remain in solution
instead of crystallizing out. Hence, it is necessary to discard
a small portion of the original solution. Collect the crystals
on the vacuum filter and discard the leftover liquid. Wash the
blue-black crystals with a little bit of cold distilled water.
Then dry and store them in a labeled container.
Conversion of Aspirin to Salicylic
acid (kitchen method)
1. Put about 4 tsp of pure aspirin crystals (see above) and 1/2
cup distilled water into a small, clean jar (such as one
used for canning pickles or olives).
2. Place jar on a hot pad in a shallow pan in an oven set to
about 225F. Let the aspirin hydrolyze into acetic
and salicylic acids for an hour or two. (Add a little more water
if all the crystals have not dissolved in the hot liquid.)
3. Cool the liquid in the refrigerator. You should see
needle-like crystals.
4. Vacuum filter and wash the crystals with cold distilled
water. This will remove acetic acid residue.
5. Dump the crystals out of the filter and air dry them. (they
usually come out as a mat of fine needles). Store in a properly
labeled bottle.
Conversion of Salicylic acid to
Phenol
Phenol (carbolic acid) is an important disinfectant and
germicide, as well as an important organic reagent.
According to the Merck Index (10th ed.), salicylic acid sublimes
at 76 C, melts at 159 C, and will decompose into phenol
and carbon dioxide when rapidly heated at atmospheric pressure.
Copper Salicylate Synthesis
(kitchen method)
1. In a small custard dish, dissolve 1/4 tsp of sodium
bicarbonate (baking soda) in a few of teaspoons of distilled
water.
2. Add about 1/2 tsp of the salicylic acid crystals recovered
from the conversion described above. Mixture will fizz a little.
Stir until all the crystals dissolve.
3. Test the pH. Add more salicylic acid or bicarbonate to get pH
of about 6 (slightly acid). This is now a solution of sodium
salicylate.
4. Add copper sulfate solution drop by drop. An ugly green
precipitate (copper salicylate) will form.
NanoCopper Preparation
Three-step
reduction method preparation process for nanocopper
CN103817345
The invention relates to a three-step reduction method
preparation process for nanocopper. The preparation process
comprises the following steps: 1, preparing copper sulfate
solution, potassium hydroxide solution, ascorbic acid,
formaldehyde solution and potassium borohydride solution; 2,
single-step reduction: ascorbic acid solution is dropwise added
into the copper sulfate solution while stirring is carried out;
3, two-step reduction: the formaldehyde solution is added; 4,
three-step reduction: the potassium hydroxide solution is added,
the pH value of the solution is adjusted to 9-13, the potassium
borohydride solution is dropwise added and is stirred until
sediment is completely generated, and copper powder is obtained
by filtration; 5; cleaning and drying the copper powder to
obtain 300-800 nm nanocopper. By means of three reduction
reagents, and according to the reducibility difference of the
reduction reagents, the reduction reagents are added into the
dissolvable copper sulfate solution in sequence to prepare the
nanocopper, and the nanocopper is thinner in grain size, smaller
in distribution range and more uniform.
Technical
field
The invention relates to the technical field of metal copper
powder preparation, in particular to a three-step reduction
preparation process of nano copper powder.
Background
technique
There are many kinds of preparation methods for copper
powder, and there are high energy ball milling method and vapor
phase deposition method in physical methods. The ball milling
method selects a suitable ball mill and ball milling material,
and uses the rotation or vibration of the ball mill to make the
hard ball strongly impact, crush and grind the material, and
break the copper block into ultrafine particles. The advantages
of the ball milling method are simple. The yield is high, and
the disadvantage is that the obtained copper powder has a wide
particle size distribution, many impurities, and low purity.
Vapor deposition is a method of preparing copper powder by
rapidly cooling metal copper after heating and melting in an
inert gas such as argon gas or helium gas. Electrolytic
preparation of copper powder is a relatively common and
industrial method for the production of copper powder.
Generally, in a copper electrolysis cell, the copper powder
deposited on the cathode is scraped off at intervals of 20
minutes to avoid particle growth. The scraped copper powder is
subjected to ball milling, sieving and the like to obtain the
finally obtained copper powder. Ultrasonic electrolysis is an
improved electrolysis process that uses ultrasonic vibration and
cavitation to generate high pressure or jets to cause deposited
copper particles to detach from the surface of the cathode and
to suspend the particles in the electrolyte. In addition, there
are high temperature, high pressure hydrothermal method, ?-ray
irradiation method, polyol method and microwave polyol method.
Among the numerous preparation methods of copper powder, the
method of preparing copper powder by reducing soluble copper
salt is one of the common methods for preparing copper powder in
laboratory and industry. The commonly used reducing agents
include reducing agents such as glucose, ascorbic acid, hydrogen
peroxide, formaldehyde, sodium hypophosphite, hydrazine hydrate,
and potassium borohydride. In many laboratory experiments,
copper powder is mostly prepared by the application of a
reducing reagent. For example, Liao Wei prepared 40-200 nm
copper powder with formaldehyde as a reducing agent; Zhao Bin
prepared hydrazine hydrate as a reducing reagent. With ~500nm
copper powder, the prepared copper powder has a very wide
particle size.
Summary of
the invention
The object of the present invention is to provide a
three-step reduction preparation process of nano copper powder
in order to solve the above-mentioned technical problems, and
the obtained copper powder has a particle size ranging from 300
to 800 nm, and the particle size distribution range is small and
more uniform.
The invention solves the above-mentioned technical problems, and
the technical solution adopted is: a three-step reduction
preparation process of nano copper powder, comprising the
following steps:
(1) Preparing a copper sulfate solution having a concentration
of 0.1 to 1.0 mol/L, a potassium hydroxide solution of 5 to 10
mol/L, an ascorbic acid of 0.1 to 0.5 mol/L, a formaldehyde
solution of 0.1 to 0.5 mol/L, and 0.1 to 2 mol/ L potassium
borohydride solution, and the prepared solution is placed in a
constant temperature water bath, the temperature of the solution
is maintained at 30 ~ 90 ° C, standby;
(2) One-step reduction: in a constant temperature water bath,
add ascorbic acid solution to the copper sulfate solution while
stirring, and continue stirring for 1 to 10 minutes after the
completion of the dropwise addition;
(3) two-step reduction: in the constant temperature water bath,
continue to add formaldehyde solution, after the completion of
the addition, continue to stir for 1 ~ 10min;
(4) three-step reduction: in a constant temperature water bath,
continue to add potassium hydroxide solution, adjust the pH of
the solution 9 ~ 13, then add potassium borohydride solution,
stir until the precipitate is completely formed, filtered to
obtain copper powder;
(5) The copper powder obtained by the step (4) was washed three
times with deionized water and absolute ethanol, and then dried
in a drier filled with an inert gas to obtain a nano copper
powder of 300 to 800 nm.
10 to 50 ml of ascorbic acid is added per 50 to 150 ml of copper
sulfate solution.
Add 10 to 60 ml of formaldehyde solution per 50 to 150 ml of
copper sulfate solution.
10 to 60 ml of potassium hydroxide solution was added per 50 to
150 ml of copper sulfate solution.
100 to 400 ml of potassium borohydride solution is added per 50
to 150 ml of copper sulfate solution.
Beneficial
effect
The invention adopts three kinds of reducing reagents, and
sequentially adds soluble copper sulfate solution according to
different reducing properties of the reducing reagents to
prepare nano copper powder, which can make the copper powder
have finer particle size, smaller distribution range and more
uniformity. .
Detailed
ways
A three-step reduction preparation process of nano copper
powder, comprising the following steps:
(1)Preparing a copper sulfate solution having a concentration of
0.1 to 1.0 mol/L, a potassium hydroxide solution of 5 to 10
mol/L, an ascorbic acid of 0.1 to 0.5 mol/L, a formaldehyde
solution of 0.1 to 0.5 mol/L, and 0.1 to 2 mol/ L potassium
borohydride solution, and the prepared solution is placed in a
constant temperature water bath, the temperature of the solution
is maintained at 30 ~ 90 ° C, standby;
10 to 50 ml of ascorbic acid, 10 to 60 ml of formaldehyde
solution, 10 to 60 ml of potassium hydroxide solution, and 100
to 400 ml of potassium borohydride solution are prepared per 50
to 150 ml of copper sulfate solution.
(2)One-step reduction: in a constant temperature water bath, add
ascorbic acid solution to the copper sulfate solution while
stirring, and continue stirring for 1 to 10 minutes after the
completion of the dropwise addition;
(3), two-step reduction: in the constant temperature water bath,
continue to add formaldehyde solution, after the completion of
the addition, continue to stir for 1 ~ 10min;
(4), three-step reduction: in a constant temperature water bath,
continue to add potassium hydroxide solution, adjust the pH of
the solution 9 ~ 13, then add potassium borohydride solution,
stir until the precipitate is completely formed, filtered to
obtain copper powder;
(5)The copper powder obtained by the step (4) was washed three
times with deionized water and absolute ethanol, and then dried
in a drier filled with an inert gas to obtain a nano copper
powder of 300 to 800 nm.
The following are specific embodiments of the invention:
Example 1
A three-step reduction preparation process of nano copper
powder, comprising the following steps:
(1)Prepare 100ml of copper sulfate solution with a concentration
of 0.5mol/L, potassium hydroxide solution of 7mol/L, 15ml of
0.2mol/L ascorbic acid, 20ml of 0.15mol/L formaldehyde solution
and 200ml of 1.0mol/L potassium borohydride solution. And the
prepared solution is separately placed in a constant temperature
water bath, the temperature of the solution is maintained at 70
° C, and used;
(2)One-step reduction: in a constant temperature water bath, add
ascorbic acid solution to the copper sulfate solution while
stirring, and continue stirring for 3 minutes after the
completion of the dropwise addition;
(3), two-step reduction: in the constant temperature water bath,
continue to add formaldehyde solution, after the completion of
the addition, continue to stir for 5min;
(4)Three-step reduction: in a constant temperature water bath,
continue to add potassium hydroxide solution, adjust the pH of
the solution to 11, then add potassium borohydride solution,
stir until the precipitate is completely formed, and filter to
obtain copper powder;
(5)The copper powder obtained by the step (4) was washed three
times with deionized water and absolute ethanol, and then dried
in a drier filled with an inert gas to obtain a nano copper
powder of 300 to 800 nm.
Example 2
A three-step reduction preparation process of nano copper
powder, comprising the following steps:
(1)Prepare 150ml of copper sulfate solution with a concentration
of 0.1mol/L, potassium hydroxide solution of 5mol/L, 10ml of
0.5mol/L ascorbic acid, 30ml of 0.4mol/L formaldehyde solution
and 300ml of 0.5mol/L potassium borohydride solution. And the
prepared solution is separately placed in a constant temperature
water bath to keep the temperature of the solution at 60 ° C,
and set aside;
(2) One-step reduction: in a constant temperature water bath,
add ascorbic acid solution to the copper sulfate solution while
stirring, and continue stirring for 3 minutes after the
completion of the dropwise addition;
(3) two-step reduction: in the constant temperature water bath,
continue to add formaldehyde solution, after the completion of
the addition, continue to stir for 5min;
(4) Three-step reduction: in a constant temperature water bath,
continue to add potassium hydroxide solution, adjust the pH of
the solution to 10, then add potassium borohydride solution,
stir until the precipitate is completely formed, and filter to
obtain copper powder;
(5)The copper powder obtained by the step (4) was washed three
times with deionized water and absolute ethanol, and then dried
in a drier filled with an inert gas to obtain a nano copper
powder of 300 to 800 nm.
Example 3
A three-step reduction preparation process of nano copper
powder, comprising the following steps:
(1)60 ml of copper sulfate solution with a concentration of 0.9
mol/L, potassium hydroxide solution of 10 mol/L, 30 ml of 0.4
mol/L ascorbic acid, 50 ml of a 0.3 mol/L formaldehyde solution,
and 150 ml of a 1.5 mol/L potassium borohydride solution. And
the prepared solution is separately placed in a constant
temperature water bath to keep the temperature of the solution
at 90 ° C, and set aside;
(2) One-step reduction: in a constant temperature water bath,
add ascorbic acid solution to the copper sulfate solution while
stirring, and continue stirring for 6 min after the completion
of the dropwise addition;
(3) two-step reduction: in the constant temperature water bath,
continue to add formaldehyde solution, after the completion of
the addition, continue to stir for 8min;
(4)Three-step reduction: in a constant temperature water bath,
continue to add potassium hydroxide solution, adjust the pH of
the solution to 13, then add potassium borohydride solution,
stir until the precipitate is completely formed, and filter to
obtain copper powder;
(5)The copper powder obtained by the step (4) was washed three
times with deionized water and absolute ethanol, and then dried
in a drier filled with an inert gas to obtain a nano copper
powder of 300 to 800 nm.
Method
for preparing hexagonal nanocopper particles by utilizing
ionothermal synthesis
CN104399999
Summary of
the invention
It is an object of the present invention to provide a method
for preparing hexagonal nano-copper particles by ion thermal
method, which involves simple equipment and processes, and does
not require control during the reaction...
Embodiment 1
(1)4 g of ammonium bromide, 4 g of succinic acid and 3 g of
copper nitrate are weighed together and thoroughly ground to a
dark green transparent state;
(2)The above mixture was placed in a cleaned lining of
tetrafluoroethylene, and 15 ml of hydrazine hydrate was added at
a density of 1.03 g/cm < 3 >;
(3)The PTFE inner liner is placed in a stainless steel reaction
vessel and tightened, and the reaction kettle is placed in a
resistance furnace set at a temperature of 120 ° C for 8 hours;
(4)After the above reaction is completed, it is cooled to room
temperature, the reaction kettle is taken out, and the reaction
product is washed three times with each of alcohol and deionized
water;
(5)The obtained product was dried under vacuum at 60 ° C to give
dark red copper particles.
5)The obtained product was dried under vacuum at 60 ° C to give
dark red copper particles..