Note: Descriptions are shown in the official language in which they were submitted.
WO 2022/265829
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SYNTHETIC CELLULAR MEMBRANE CHEMICAL IONOPHORE DELIVERY
SYSTEM COMPRISING HEXA-AQUA LIGAND COMPOSITIONS
Field of the Invention
The present invention relates generally to synthetic ionophores for free-ion
carriage and
transportation across biological membranes in vivo and, more particularly, to
the use of coordination
complexes of molecules with polarized hexa-aqua systems and tetra-aqua systems
of free ionic metals
and ionic salts as the ionophores, useful in transporting pharmaceutical and
personal healthcare
compounds across biological membranes in vivo to target cellular metabolic
systems and thereby
produce desired pharmacologic actions useful in metabolic, immunological, and
other biological
system disorders, and infectious disease treatment. The compositions of the
invention relate to the
scientific fields and subjects of inorganic & organic medicinal chemistry,
redox values, pH, molecular
biology, pharmacokinetics, microbiology, cellular biology, especially of
mammalian cells,
physiology, and physiological chemistry.
Background of the Invention
There is a general need in pharmaceutical therapeutics for treatment regimens
that have
improved safety, efficacy, tolerability, improved side-effect profiles,
reduced duration of action,
reduced manufacturing costs, greater chemical stability, reliably repeatable
batch manufacture,
potential for scalability as the size of batch outputs increases, better
affordability, ease of
administration, accessible, lend themselves to distribution, and have extended
storage life, particularly
in remote geographies and in hotter or wetter climates.
There are, furthermore, global needs in pharmaceutical therapeutics for
nontoxic active drug
delivery systems that are designed to target biological functions with
mechanisms more closely
mimicking natural processes. Likewise, there are needs for active molecule
delivery systems that can
be applied in the fields of nutrition, and personal care, as well as in
therapeutics.
In the field of infectious disease and antibiotic therapeutics, there is a
need for methods of
disease treatment and prevention that can build on research in understanding
cellular redox reactions,
both in terms of antioxidant and pro-oxidant agents acting within cells, and
of research on complex
ionic structures that enable (1) delivery of positive bonding, which is the
action of cations, and (2)
oxidative free radical effects, which is the action of anions. Redox research
additionally investigates
the biological roles of redox switches, and redox relays, in clinical
proteomics and metabolomics to
reduce oxidative and nitrosative stress on a biological system. The compounds
of the invention enable
and support such research.
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Redox Signaling-RSS, RNS, and ROS Modes of Action. Redox balance is the
underlying
chemical mechanism for all biological processes. Biological homeostasis is
created, regulated, and
sustained by reduction-oxidation (redox) reactions that drive photosynthesis,
respiration, and most
other biological reactions necessary for biological systems to function.
Oxidative stress is thought to
account for aberrant redox homeostasis and contribute to aging and disease.
However, often,
administration of antioxidants to address oxidative stress is ineffective,
suggesting that our current
understanding of the underlying regulatory processes is incomplete. Miriam M.
Cortese-Krott, A. K.
(2017, Oct 1). The Reactive Species Interactome: Evolutionary Emergence.
Biological Significance,
and Opportunities for Redox Metabolomics and Personalized Medicine.
Antioxidants & Redox
Signaling, 27(10). https://doi.org/10.1089/ars.2017.7083
Key to the manipulation of many biological mechanisms to restore normal
biological
function, are the normal functioning of redox systems consisting of chemical
interactions of one or all
the following reactive species: Reactive Oxygen Species (ROS), Reactive
Nitrogen Species (RNS),
and Reactive Sulfur Species (RSS). Olson, K. R. (2020, Feb 26). Reactive
oxygen species or reactive
sulfur species: why we should consider the latter. Journal of Experimental
Biology 2020, p. 223.
Retrieved 2021 from https://jeb.biologists.org/content/223/4/jeb196352. These
species play a dual
role as capable of being both toxic compounds, when unbalanced, and beneficial
compounds, when
balanced. The delicate balance between their two antagonistic effects is
clearly an important aspect of
life. Lien Ai Pham-Huy, H. H.-H. (2008, June). Free Radicals, Antioxidants in
Disease and Health.
International Journal of Biomedical Sciences, 4(2), 89-96. Retrieved 2021 from
https://www.ncbi.nlm.nih.gov/pmdarticles/PMC3614697/. The present invention
disclosed herein
confirms that the presence of the elements of oxygen, nitrogen, and sulfur, in
their respective forms as
reactive species, are potentially involved in the targeting of both redox
signaling processes in
metabolic pathways, and in targeting key metabolic intermediates. These
reactive species provide
multiple cellular signaling pathways, redox systems, and electron transfers
for homeostasis.
Reactive Oxygen Species - ROS Cationic hydrogen (I-I+ (aq)) is an electron
donor
(reduction) for hydroxyl radical (H0=) or radical oxygen (02), and is also
known as a factor, when
overabundant, in oxidative stress, cell aging (truncated telomere length), and
DNA m ethyl ation.
Reactive Nitrogen Species - RNS Cationic metal amine complex (NH4 + (aq)) is
an electron
donor for nitrogen reduction, and/or acts as an ammonia (NH3) ligand in
triggering glutamate
production, used in amino acid synthesis. Oxidative stress is a well-
established phenomenon that
occurs in neurodegenerative disease. This, coupled with an increase in
apoptosis and autophagy,
contributes to the neurodegeneration and memory loss observed in Alzheimer's
disease, Parkinson's
disease, and amyotrophic lateral sclerosis. Overabundance of reactive oxygen
and nitrogen species
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are highly abundant in these disorders. New antioxidant and mitochondrial-
based therapies aimed at
such imbalance show promise to reduce neuronal cell loss and promote
ncuroprotection, which will
have a positive effect on patient outcomes. Sergio Di Meo, T. T. (2016, July
12). Role of ROS and
RNS Sources in Physiological and Pathological Conditions. Oxid Med Cell
Longev, 1245049.
https://dx.doi.org/10.1155%2F2016%2F1245049.
Reactive Sulfur Species - RSS Anionic Sulfur (H504 (aq)) triggers redox
switches and
redox relays. Sulfur is considered a part of cellular antioxidant systems, and
there is mounting
evidence that RSS imbalance has stressor-like properties similar to the ones
found in ROS imbalance,
but that they are formed under certain conditions as a separate class of
oxidative stressors. Arno
R.Bourgonje, M. F. (2020). Oxidative Stress and Redox-Modulating Therapeutics
in Inflammatory
Bowel Disease. Science Direct, 26(11), 1034-1046.
https://doi.org/10.1016/j.molmed.2020.06.006.
Metabolic Activities. More specifically, there is a need for achieving a non-
toxic delivery
system to the cell that provides preventative or therapeutic uses of metal
cations that are carried to a
site of action. The compositions of the present invention meet this need by
the utilization of aqua
ligand bonds, preferably hexa-aqua ligand or tetra-aqua ligand moieties, and
most preferably, hexa-
aqua ligand moieties, that can effectively protect such metal cations from
being immediately bonded
with the first available anions, and thus enabling polarity movement between
and within living cells.
Such aqua ligand bond-enabled moieties comprising the compositions of the
invention can exploit the
distinct differences between (1) aerobic cells, whether they are continuing a
process toward apoptosis,
or whether they are changing toward a mutated state, and (2), anaerobic cells,
whether they are in a
pathogenic or cancerous state, in their respective different aerobic versus
anaerobic behaviors in
glycolysis, the citric acid cycle, cellular respiration, or the electron
transport chain.
Anaerobic processes do not require oxygen, while aerobic processes do require
oxygen. The
use of oxygen is directly involved in the citric acid cycle because it is an
aerobic process. The
compositions of the invention sustain this process through positive hydrogen
electron donation
resulting in a proton, H+, in the form of a hydronium ion, H10+. Creating and
keeping a hydronium
ion equilibrium concentration is an essential factor when dealing with
chemical reactions that occur in
aqueous solutions of the compositions of the invention. The hydroniurn ion's
concentration relative to
hydroxide is a direct measure of the pH of a given solution. The hydronium ion
is formed when a
protonic acid is present in water. The compositions of the invention
contribute to the removal of high-
energy electrons from bioavailable carbon fuels. These high-energy electrons
reduce 02 to generate a
proton (H+) gradient which is used to synthesize adenosine triphosphate (ATP).
The reduction of 02
and the synthesis of adenosine triphosphate (ATP) constitute oxidative
phosphorylation.
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Glycolysis. Glycolysis occurs in all living cells and is believed to be one of
the first types of
respiration to have evolved in anaerobic cells (by some estimates, for
billions of years, before the
metabolic utilization of oxygen). Glycolysis occurs in the cell's cytoplasm,
and glycolysis precedes
the citric acid cycle. The process of glycolysis requires the use of two
adenosine triphosphate (ATP)
molecules. ATP, which constitutes a molecular metabolic currency, is
advantageously boosted
through the present invention's transport assistance of metal cations as a
part of nutrient uptake. When
glucose is broken down from a six-carbon sugar molecule into two three-carbon
sugar molecules of
pyruvate, then four ATP and two NADH (reduced nicotinamide adenine
dinucleotide) molecules are
created. NADH is transported to the citric acid cycle to create more ATP under
aerobic conditions. If
no oxygen is present, pyruvatc is not allowed to enter the citric acid cycle,
and it is further oxidized to
produce lactic acid. Fermentation and oxidative stress (02) are both created
by cells functioning
anaerohically and promote the continuation of an anaerobic cell environment. A
formulation
comprising the compositions of the invention reduces this stress by utilizing
available hydrogen (Hi)
cation donated by the invention's aqua-ligand ionic species or mixed
hydroxyl/aqua ligand ionic
species.
Citric Acid Cycle. The citric acid cycle constitutes the first stage in
cellular respiration,
removing high-energy electrons from carbon fuels. These electrons reduce 02 to
generate a proton
gradient (14 ) used to synthesize ATP. The reduction of 02 and the synthesis
of ATP constitute
oxidative phosphorylation. The compositions of the invention can donate H+ and
02 electrons directly
into the electron transport chain, thereby facilitating the function of the
citric acid cycle, and reducing
an anaerobic cell environment properly. The citric acid cycle takes place in
the matrix of the
mitochondria. It is a series of chemical reactions and electron transfers used
by all aerobic organisms
to generate energy. If oxygen is not present, the respiratory cycle cannot
function, which shuts down
the citric acid cycle, potentially initiating anaerobic cell metabolism. When
NAD+ is not in
production, the relative ratio of NADH to NAD+ increases, which causes
glycolysis to produce lactic
acid instead of pyruvate, a required component of the citric acid cycle. The
citric acid cycle is heavily
dependent on oxygen, deeming it an aerobic process.
Electron Transport Chain. When NADH is reduced to NAD, an electron transport
chain
accepts the electrons from the molecules. As the electrons are transferred to
each carrier within the
electron transport chain, free energy is released and is used to form ATP.
Oxygen is the final acceptor
of electrons in the electron transport chain. Without oxygen, the electron
transport chain becomes
overloaded with electrons, reducing or eliminating functionality. The
compositions of the invention
can transfer electrons through utilizing natural electron donors via redox
reactions across a cell
membrane, acting at the atomic level and positively altering a dysfunctional
electron transfer chain.
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Mitochondrial Function. Metabolic processes, and the multiple enzymes that
enable them,
occur within the mammalian mitochondrion, and include 13-oxidation of fatty
acids, the urea cycle, the
citric acid cycle, and ATP synthesis, each of which are respectively vital for
many metabolic
pathways in the cell. There is a need for the identification of new reactive
species involved in such
intracellular redox signaling and new redox pathways to address diverse
dietary and medical
interventions. The compounds of the present invention enable the
identification of such new reactive
species. The equilibrated interplay and proper balance between specific
micronutrients at the cellular
level is necessary in the reduction of illness and disease. Establishing
biological homeostasis through
corrective mitochondrial metabolism is a highly cost-effective method of
disease prevention. The
compounds of the invention can assist in the control of disease and of health
problems through their
actions in achieving balanced redox processes. Persistent physical impairment
of cellular redox
processes occurs before and after critical illness, and recent clinical data
points towards mitochondri al
dysfunction as an essential determinant of this problem. The prime targets of
redox modulators are
generally small molecule -reactive species" such as ROS, RNS, and RSS. The
biological impact and
the underlying chemistry of these reactive, often inorganic species provides a
holistic view of redox
control.
Anticancer Activities. One of the modes of action of the compositions of the
present
invention is that they target cancer cells by apoptosis. Clinical studies on
several human cancer cell
types have used the cell's natural death mechanism as an anticancer therapy.
Treating an afflicted
biological system to enhance the natural function of apoptosis to prevent or
treat cancer is an activity
of the compositions of the present invention. The activities of superoxide
dismutase (SODs) are often
lowered during early cancer development, making it a rational candidate target
for cancer therapeutic
intervention. Animal studies have now shown that the compositions of the
present invention exhibit
anticancer activity by activating an apoptotic pathway.
Exploiting the natural mechanisms for cell death is a highly effective method
of treatment.
Drugs targeting apoptosis are some of the most successful non-surgical
treatments. Some have proven
efficacy in all cancer cells as apoptosis evasion is a cancer hallmark, but
they come at the cost of
having high cytotoxicity. See Singh, C. M. (2018, Feb. 2). Apoptosis: A Target
for Anticancer
Therapy. (C. College, Ed.) International Journal of Molecular Science
(Department of Biology,
Division of Natural & Social Sciences), 2,
https://dx.doi.org/10.3390%2Fijms19020448. The
compositions of the present invention create apoptotic signals in several
forms through the actions of
cationic metal delivery, Zn/Cu SOD, redox signaling, and reduction of free
radicals. All these modes
of action contribute to change the tumor environment through cell death
induced by the extracellular
signals produced by the compositions of the invention.
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Reactive oxygen species (ROS) are increasingly recognized as critical
determinants of
cellular signaling and a strict balance of ROS levels must be maintained to
ensure proper cellular
function and survival. Brandon Griess, E. T.F. (2017, Aug 24). Extracellular
Superoxide Dismutase
and its Role in Cancer. Free Radic Blot Med, 1.
https://dx.doi.org/10.1016%2Fj.freeradbiomed.2017.08.013. Cancer cells switch
their metabolism to
glycolysis to meet their energy requirements, known as the Warburg effect. One
of the anticancer
activities of the compositions of the present invention is that they can
exploit the Warburg effect to
push the cancer cell further into the cellular respiration process, thereby
creating an apoptotic death.
Antimicrobial Modes of Action. Multiple studies support the antimicrobial
efficacy of the
compositions of the present invention, as are specifically described and
disclosed below. Anaerobic
cells may be clinically induced to experience cytosolic metal intoxication
from the overload of natural
metal cations that can be measuredly delivered by compositions of the present
invention, causing
necrotic and or apoptotic (programmed) cell death. Lee, S. Y. (2018, Jan 31).
Regulation of Tumor
Progression by Programmed Necrosis. (R. Franco, Ed.) Hindawi (Oxidative
Medicine and Cellular
Longevity). 2. https://doi.org/10.1155/2018/3537471. This method of cell death
triggers several
immune responses in biological system. Inc Jorgensen, M. R. (2017, Jan 31).
Programmed cell death
as a defense against infection. Nat Rev Immunol, 151-164.
https://dx.doi.org/10.1038%2Fnri.2016.147. A non-toxic essential metal (for
example as found in
nutrients) uptake by aerobic cells during cellular respiration, and apoptotic
cell death for anaerobic
cells, creates an environment that prevents the adverse cascading events
toward pathogen-induced
disease. Pete Chandrangsu, C. R. (2017, March 27). Metal Homeostasis and
Resistance in Bacteria.
Nat Rev Microbial. 338-350. https://doi.org/10.1038/nrmicro.2017.15. Research
has shown that
zinc and copper ions can also induce oxidative reactions, inactivation of
viral infection proton
channels, or viral membrane destabilization, all activities that can be
ascribed to the compositions of
the present invention. Vikram Gopal, B. E.-P.-s. (2021, Jan 6). Zinc-embedded
fabrics inactivate
SARS-CoV-2 and influenza A virus. (bioRxiv, Ed.) bioRxiv, 1-27.
https://dx.doi.org/10.1101%2F2020.11.02.365833.
Accordingly, a need exists for a solution to at least one of the
aforementioned challenges.
More specifically, a need exists for a chemical means for carriage and
transport of free ions across
biological membranes in vivo.
Features, Objects, and Advantages of the Compositions of the Present Invention
The concentrated ionophoretic metal ion delivery system of the present
invention as
disclosed herein, includes compositions comprised of one or more active
ionophore moieties,
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pharmaceutical formulations of such active moieties compounded with
pharmaceutically acceptable
excipients, methods of making such moieties, compositions, and formulations,
and methods of
administering such formulations in the prevention and treatment of diseases.
Multiple administration
methods and dosing levels provide a spectrum of safety profiles that target
tumor environments,
tumor areas in all age groups, and concurrent treatments. These compositions,
formulations, methods
of preparation, and methods of administration address the aforementioned
needs.
Activities of the compositions of the present invention include the following
non-limiting
exemplary list: promoting increased production of superoxide dismutase;
preventing formation of free
radicals; mitigating levels of free radicals; increasing and improving the
antioxidant capacity of a
biological system; reducing levels of oxidative stress; protecting a
biological systcm from
overproduction of, and reducing & detoxifying existing levels of, reactive
oxygen species, reactive
nitrogen species, and reactive sulfur species; reducing levels of pro-
oxidants; addressing deficiencies
of enzymatic and non-enzymatic antioxidants; antagonizing superoxide
overproduction; supporting
normal mitochondrial function and normal ATP biosynthesis; decreasing the
ratio of NADH to
NAD+; raising levels of apoptosis; and constituting anti-pathogen direct
toxins.
Acidic pH. A key feature of the compositions of the present invention in all
of its various
pharmaceutical formulations is that they register very low pH levels of from
0.2 to 4.0, and most
preferably 2.0, which not only acts to increase their delivery efficiency and
therapeutic efficacy, but
which also show, surprisingly and unexpectedly, limited or no adverse
reactions in biological systems
at such low pH levels.
It is a feature of any given preferred embodiment of the present invention
that it contains a
high level of one or more of free sulfur, amine, sulfate ions, metal hexa-aqua
structures, metal tetra-
aqua structures, metal hydroxyl/aqua mixed ligand species, and hydronium ion,
which can be
transported to the various targeted locations in a biological system through
micro or macro circulatory
transport, and respectively work to balance reactive oxygen species, reactive
nitrogen species, and
reactive sulfur species, that arc involved in cell signaling, protein actions,
and the multiple balances
of the metabolic cell cycle.
Delivery of High Levels of 14+. Compositions of the present invention deliver
high levels of
H+, having pH's at 1.0 or below 1.0, and may be characterized as carrying 1-1+
in a Zn' Cu'
superoxide dismutase (SOD) ligand. There are many unknown beneficial
potentials for the
technology of the present invention, based on the processes and relationships
of the invention's
preferred compositions with ROS, RNS, RSS, and the interactions with NO,,,
H2S, and 02, and their
derived species. The core non-metal components of preferred embodiments of the
present invention,
NH3, HSO4 , and fl+, influence and modulate levels of each of the above
reactive species by chemical
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mechanics, electron transfer, or biological processes. Gopi K. Kolluru, X. S.
(2020, Mar 5). Reactive
Sulfur Species - A New Rcdox Player in Cardiovascular Pathophysiology. (T. a.
Arteriosclerosis, Ed.)
Arteriosclerosis, Thrombosis, and Vascular Biology.
https://doi .org/10.1161/ATVBAHA .120.314084.
Superoxide Dismutase (SOD) Production. Natural forms of SOD and their prior
art
delivery methods are difficult to manufacture, hard to reproduce, and
expensive. In contrast, the
artificial SOD produced by the present invention can be produced in large
quantities and utilized in
several application technologies such as creams, injectables, transdermal
patches, inhalers, and other
administration methods currently used by health practitioners. Compositions of
the present invention
in their SOD forms can be further developed with manganese, as Mn2+ SOD and
iron, as Fe' SOD, as
ionic metals in addition to the Zn21-/Cu2+ SOD described above. Zinc is a
redox-inert metal, that is, it
functions as an antioxidant through the catalytic action of copper/zinc-
superoxide dismutase,
stabilization of membrane structure, protection of protein sulfhydryl groups,
and upregulation of the
expression of metallothionein, (which itself possesses a metal-binding
capacity and exhibits
antioxidant function. Lee, S. R. (2018, Mar 20). Critical Role of Zinc as
Either an Antioxidant or a
Prooxidant in Cellular Systems. (G. Gobe, Ed.) Hindawi.
https://www.hindawi.com/journals/omc1/2018/9156285/. Preferred embodiments of
the compositions
of the invention comprise or support the production of artificial SOD in
biological systems. Preferred
compositions containing and delivering suitable metals will support the
production of natural SOD
enzymes with the canonic role of oxygen radical enzymatic dismutation.
Multiple studies support the
need for SOD balances in biological systems in order to prevent and mitigate
free radicals. These
radicals affect the functionality of the immune system and are frequently a
precursor to mutations and
disease. Superoxide dismutase is widespread in the human body, including the
skin of the trunk and
of the appendages. Giovanna G. Altobelli, S. V. (2020, May 12). Copper/Zinc
Superoxide Dismutase
in Human Skin: Current Knowledge. (F. i. Medicine, Ed.) Frontiers in Medicine,
1.
https://doi.org/10.3389/fmcd.2020.00183.
Members of the SOD family are found in several preferred embodiments of the
invention.
SOD has been studied in different models since the discovery of its
involvement in ALS disease, a
disease in which mechanisms of prion-like protein misfolding and pathology
propagation arc known
to play roles in ROS generation, with subsequently-caused extensive damage to
SOD. A strategy in
administration of compositions of the invention is to serve as an effective
antioxidant, and to
neutralize a radicalized SOD1 with a synthetic SOD delivered via a carrier
compound of the
invention. An early-stage trial of an investigational therapy for amyotrophic
lateral sclerosis (ALS)
suggests that people could tolerate the experimental drug that is a preferred
embodiment of the
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invention, and in exploratory results, the experimental drug was linked to
possible slower progression
in people with a genetic form of the disease that was causcd by mutations in a
gene called the
superoxide dismutase gene SOD1 on chromosome 21. American Academy of
Neurology. (2019, May
1). Experimental drug shows promise for genetic form of ALS. (S. News, Ed.)
Science News, p. 1.
Retrieved 2021 from
https://www.sciencedaily.conVreleases/2019/05/190501161224.htm.
Copper/Zinc Superoxide Dismutase (Cu/Zn SOD) is an important enzyme that has
elicited
significant interest among medicinal chemists. Zinc is a redox-inert metal,
and it functions as an
antioxidant through the catalytic action of copper/zinc superoxide dismutase,
stabilization of
membrane structure, protection of protein sulfhydryl groups, and upregulation
of the expression of
metallothioncin. See Paolo Mondola, S. D. (2016). The Cu, Zn Superoxide
Dismutase: Not Only a
Dismutase Enzyme. Frontiers in Physiology, 1.
https://doi.org/10.3389/fphys.2016.00594.
Manganese Superoxide Dismutase (MnSOD) enzyme helps protect and reinforce the
mitochondria]
and biological functions. The mechanism by which MnSOD protects cells from the
harmful effects of
overproduction of reactive oxygen species (ROS) and the effects of ROS on
mitochondrial metabolic
enzymes is not yet known. A preferred composition of the invention that
contains the manganese
metal ion will beneficially mimic and/or increase the production of MnSOD
enzymes. MnSOD
converts superoxide anions to hydrogen peroxide plus oxygen, providing the
first line of defense
against oxidative stress in mitochondria. Heart mitochondria are known to
exhibit higher MnSOD
activity than liver mitochondria. In mitochondria from both tissues MnSOD
activity decreased after
incubation at low oxygen concentration (hypoxic mitochondria). The effects of
free Ca' ([Ca']f) and
free Mg' (Welt) on normoxic and hypoxic mitochondria from either organ were
tested. In
normoxic mitochondria from either tissue, both [Ca'if and [Mg24]f activated
the enzyme, although
[Me]t was less efficient as an activator and the effect was lower in heart
than in liver mitochondria.
When added simultaneously, high [Ca2+]f and [Mg21f- exhibited additive effects
which were more
pronounced in heart mitochondria and were observed regardless of whether
mitochondria had been
incubated under normal or low oxygen. The data suggest that [Ca2+]f plays a
role in regulating
MnSOD in concert with the activation of aerobic metabolism. Perez-Vazquez, V.,
Ramirez, J.,
Aguilera-Aguirre, L. et al. Effect of Ca2+ and Mg2+ on the Mn-superoxide
dismutase from rat liver
and heart mitochondria. Amino Acids 22, 405-416 (2002). Retrieved in 2021 from
https://doi.org/10.1007/s007260200024
H+ As An Antioxidant. The cationic hydronium component that is present in
preferred
embodiment compounds of the invention can donate hydrogen from the ligand
complex to an 02
radical, acting as a powerful antioxidant to reduce oxidative stress and the
related diseases caused by
such stress. Oxidative stress can be defined as excess production of reactive
oxygen/nitrogen species
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(ROS/RNS) as prooxidants and/or a deficiency of enzymatic and nonenzymatic
antioxidants, which
are involved in the detoxification of ROS/RNS.
SOD and Anaerobes. SOD can also eliminate certain anaerobic diseases present,
including
any living disease associated with protein bound beta-N-Methyl Amino-L-Alanine
(BMA A)
associated with neurodegeneration in subjects. Superoxide dismutase in the
extracellular space has
unique characteristics and functions in cellular signal transduction, showing
anti-cancer properties.
Preferred compositions of the invention create an artificial in situ SOD that
can be administered and
utilized to treat superoxide overproduction. The metallic form of such an
artificial SOD can increase
the concentration of the natural enzymatic form of SOD by re-balancing
deficiencies of metal ions
that are needed in the production of SOD enzymes, to thereby increase a
positive level of biological
function. The compositions of the invention therefore may be used in treating
deficiencies in the
production of SOD enzymes, rebalancing levels of SOD, and neutralizing radical
SOD, all to
reestablish normalcy in biological systems.
Prevention of disease. Another goal of the invention is to aid in the
prevention of disease,
through preventing metabolic disturbances in biological systems, treating
cells at the atomic level
directed towards balanced mitochondrial harmony, reducing free radicals
arising from environmental
stress, toxicities, and the eventual mutations they cause. Synergy between the
elements occurs largely
on a metabolic level. The invention can be developed into specific
formulations that aid in prevention
of disease through rebalancing of the biological system by the application of
stimulant or sedative
pharmacological substances. With a better understanding and application of
these concepts, a more
comprehensive approach to health care can be realized, thus avoiding the
necessities of a nutritional
version of roulette that is described in the literature. Specially
individualized administration of known
stimulants and sedatives to individual treatment regimens may then lead to
improved responses with
fewer undesirable side effects. Watts, David L. (1990, Jan 01). Nutrient
Interrelationships Minerals
¨ Vitamins ¨ Endocrines, Journal of Orthomolecular Medicine Vol. 5, No. 1,
1990. Retrieved 2021
from http://orthomolecular.org/library/jom/1990/pdf/1990-v05n01 -p011.pdf.
Gastrointestinal Absorption. The synthesized ionophores of the invention are
compounds
that can safely target low absorbency deficiencies and provide a soluble
mineral delivery means in all
administration methods. Biological systems must break down food firstly into
its nutritional
components, and this is typically done in the digestive system. Many types of
foods effectively reduce
nutritional absorption, create antagonistic nutritional imbalances, and
destroy critical processes in the
biology of the gut. Formulations of the invention solve this problem by
carrying and providing a
highly bioavailable soluble nutrient in water, it being bioavailable directly
to the cellular environment
where needed in the subject. This delivery system thereby circumvents the
variables of the digestive
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system process, such as gut maladies, pathologies and diseases, gut energy
requirements, patient age,
and gastrointestinal tract absorbance issucs. Any impairment of the
gastrointestinal (GI) tract can
increase the risk of developing infectious, inflammatory, and dysfunctional GI
processes, ultimately
reducing drug delivery, nutritional absorbency, and/or the uptake of one
nutrient and not another, thus
creating an imbalance in the biological system. Administration methods of the
invention provide an
alternative to oral supplementation and a targeted approach to nutritional
delivery. Appropriate
physiological function requires optimal nutrition, which needs to be in
balance in order to prevent
potential detrimental interactions, especially when administered at typical
pharmacological dosages.
Many nutrients function in harmony to complement digestive function and
assimilation. Some
nutrients may hinder these processes and compete for uptake, while others may
also be required in
tandem to assist in metabolism which may ultimately affect several biochemical
cycles.
Schoendorfer, Niikee (2012, Jan 01). Micronutrient interrelationships:
Synergism and antagonism,
JOUR, 159. Retrieved 2021 from
https ://w w w.re searchgate. net/public ation/286184266 Micronutrient
interrelationships Synergism a
nd antagonism.
Adequate nutrient levels are essential for mitochondrial function as several
specific
micronutrients play crucial roles in energy metabolism and ATP-production. E.
Wesselinka, W. K.
(2018, Aug 31). Feeding mitochondria: Potential role of nutritional components
to improve critical
illness convalescence. (Elsevier, Ed.) Elsevier, 38(3), 982-995. Retrieved
2021 from
https://www.sciencedirect.com/science/article/pii/S0261561418324269.
Nutritional disease or
nutrient-related diseases are conditions that cause illness in humans, and
they can be treated with
compositions of the invention. Such diseases may include dietary deficiencies
or excesses, obesity,
eating disorders, and chronic diseases such as cardiovascular disease,
hypertension, cancer, and
diabetes mellitus. Weininger, J. (2021, November 11). Nutritional disease.
(Britannica, Editor,
Britannica, Producer, & Britannica) Retrieved 2021 from:
haps ://www.bri tan n ca.com/sci en cc/nutri ti oral -disease.
Nutrient Supplementation. The compositions of the invention allow for
personalized
approaches in administration methods and dosing to establish a homeostatic
state in a biological
system. Oxidative stress occurs when the levels of reactive species surpass
the antioxidant capacity of
the organism. In low nutritional absorbency conditions, the role of gut health
and food sources
become magnified and relatively small deficiencies may then have a detrimental
effect on nutritional
balances. For example, magnesium Mg deficiency can go unnoticed even after a
blood test shows it
as being in an average range. Serum Mg does not reflect intracellular Mg, the
latter making up more
than 99% of total body Mg. Most cases of Mg deficiency are undiagnosed. Mg
deficiency correlates
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with the formation of many different diseases and is a common occurrence in
many diets. For
example, adipose tissue is considered an endocrine organ that promotes
excessive production of
reactive oxygen species when in excess, thus contributing to lipid
peroxidation, and magnesium
deficiency is now known to contribute to the development of oxidative stress
in obese individuals, as
this mineral plays a role as an antioxidant, participates as a cofactor of
several enzymes, maintains
cell membrane stability, and mitigates the effects of oxidative stress.
Studies show that obese subjects
have low serum concentrations of magnesium, as well as high concentrations of
oxidative stress
markers in these individuals Morais, J.B.S., Sever , J.S., Santos, L.R.d. et
al. Role of Magnesium in
Oxidative Stress in Individuals with Obesity. Biol Trace Elem Res 176,20-26
(2017). Retrieved
2021 from: https://doi.org/10.1007/s12011-016-0793-1. Furthermore, it is
evident that adequate
intake of magnesium contributes to its appropriate homeostasis in the body.
Thus, there is a need for
intervention with supplementation of this mineral for the prevention and
treatment of disorders
associated with this chronic disease. The compositions of the invention can be
developed to address
specific nutritional deficiencies, toxicities, and multi-complexes to prevent
and create nutritional
homeostasis in a biological system. As an example, with Mg' a maximal increase
in Mn-SOD
activity was obtained in the presence of 1.5mM [Mg2+]. Perez-Vazquez, V.,
Ramirez, J., Aguilera-
Aguirre, L. et al. Effect of Ca' and Mg' on the Mn-superoxide dismutase from
rat liver and heart
mitochondria. Amino Acids 22,405-416 (2002).
https://doi.org/10.1007/s007260200024. The
compositions of the invention comprise highly bioavailable nutritional
supplement carriers,
incorporating all forms and ratios of essential minerals, vitamins, and
deliver all other nutrition
benefits through the digestive tract, topical, nasal, intravenous, or
nebulized routes, and/or by oral
ingestion. The compositions of the invention increase levels of essential
transitional metals in the
skin, lymph fluids, interstitial or extracellular fluids, blood, or cells.
Nutritional balancing can be
achieved through the synergistic or antagonistic effects of essential
minerals, vitamins, and managing
deficiencies or toxicities through ratios within the invention, as has been
done with Zn and Cu as an
example. Additionally, they can be used for the reduction of Oxidative Stress
and used in ketogenesis
as a ketogenic set of reactions that aim to regain energy released in
ketolysis via oxidation of ketone
bodies, and they can furthermore he used as a hiocatalyst in clinical or
nutritional metabolomics.
Health Adjunctive Aid. Another goal of the invention is to support the
capacity to treat
metabolic imbalances and deficiencies, toxicities, pathogens, and mutations
prior to the diagnosis of a
disease, i.e. to act as a preventative measure. As an example, zinc can widely
adjust energetic
metabolism and is essential in restoring the impaired energetic metabolism of
cellular physiology.
Studies show that obese subjects have low serum concentrations of magnesium as
well as high
concentrations of oxidative stress markers. Furthermore, it is evident that an
adequate intake of
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magnesium contributes to its appropriate homeostasis in the body. Morais,
J.B.S., Severo, J.S.,
Santos, L.R.d. ct al. Role of Magnesium in Oxidative Stress in Individuals
with Obesity. Biol Trace
Elem Res 176, 20-26 (2017). https://doi.org/10.1007/s12011-016-0793-1. Zinc
enhances the cellular
energy supply to improve cell motility and restore impaired energetic
metabolism in a toxic
environment induced by OTA. (S. Reports, Ed.) Scientific Reports, 7, 14669.
https://doi.org/10.1038/s41598-017-14868-x. The high safety profile of the
compositions of the
invention allows for long-term preventive dosing in all biological systems of
all ages. The
compositions of the invention can be designed for nutritional purposes to be
delivered by all types of
administrative methods and routes. These methods can be administered locally
or delivered
systemically to circumvent poor gut health and nutritional absorbency issues.
The compositions in
topical applications protect the skin, the largest organ of the body, from the
free radicals arising out of
environmental stress.
Treatment of Cancer. The next major goal and feature of the compositions of
the invention
is directed to addressing the treatment of cancer. Cancers include Actinic
keratoses (Aks), Acute
Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenal gland
tumors, Anal
cancer, Basal cell carcinoma, Bile duct cancer, Bladder cancer, Blood cancers,
Bone cancer, Bowel
cancer, Brain tumors, Breast cancer, Cancer of Unknown Primary (CUP), Cancer
metastasis to bone,
Cancer metastasis to brain, Cancer metastasis to liver, Cancer metastasis to
lung, Carcinoid, Cervical
cancer, Children's cancers, Chronic Lymphocytic Leukemia (CLL), Chronic
Myeloid Leukemia
(CML), Colorectal cancer, Ear cancer, Endometrial cancer, Eye cancer,
Follicular dendritic cell
sarcoma, Gallbladder cancer, Gastric cancer, Gastro-esophageal junction
cancers, Germ cell tumors,
Gestational Trophoblastic Disease (GTD), Hairy cell leukemia, Head and neck
cancer, Hodgkin's
lymphoma, Kaposi's sarcoma, Kidney cancer, Large bowel and rectal
neuroendocrine tumors,
Laryngeal cancer, Leukemia, Linitis plastica of the stomach, Liver cancer,
Lung cancer, Lung
Neuroendocrine Tumors (NETs), Lymphoma, Malignant schwannoma, Mediastinal germ
cell tumors,
Melanoma skin cancer, Men's cancer, Merkel cell skin cancer, Mesothelioma,
Molar pregnancy,
Mouth and oropharyngeal cancer, Myeloma, Nasal and paranasal sinus cancer,
Nasopharyngeal
cancer, Neuroblastoma, Neuroendocrine Tumors, Neuroendocrine Tumors of the
pancreas, Non-
Hodgkin lymphoma, Non-Hodgkin lymphoma in children, Esophageal cancer, Ovarian
cancer,
Pancreatic cancer, Penile cancer, Persistent trophoblastic disease and
choriocarcinoma,
Phaeochromocytoma, Prostate cancer, Pseudomyxoma peritonei, Rare cancers,
Rectal cancer,
Retinoblastoma, Salivary gland cancer, Secondary cancer, Signet cell cancer,
Skin cancer, Small
bowel cancer, Small bowel Neuroendocrine Tumors (NETs), Soft tissue sarcoma,
Stomach cancer,
Stomach Neuroendocrine Tumors (NETs), Squamous cell carcinoma, Testicular
cancer, Thymus
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gland tumors, Thyroid cancer, Tongue cancer, Tonsil cancer, Tumors of the
adrenal gland, Unknown
primary cancer, Uterine cancer, Vaginal cancer, Vulvar cancer, Wilms' tumors,
Womb cancer, and
Women's cancers (gynecological cancer).
Anticancer Actions. The compositions of the invention attack multiple cancer
pathways. A
commonality in anticancer pathways may explain why several preclinical studies
of each composition
of the invention tested show high apoptotic anticancer kill rates over a range
of different cancer cell
types. Potentially similar pathways are shown by approved metallic anticancer
pharmaceuticals like
the physicochemical properties of cisplatin and related platinum-based drugs,
and they are supported
by the evidence collected from their long-term uses (either alone or in
combination other drugs) for
the treatment of various human cancers. Tchounwou, S. D. (2014, Oct 5).
Cisplatin in cancer
therapy: molecular mechanisms of action. (S. D. Tchounwou, Ed.) Retrieved 2021
from US National
Library of Medicine: https://dx.doi.org/10.1016%2Fj.ejphar.2014.07.025 . The
metal components of
the compositions of the invention are reported, through a significant number
of publications on
research, and in clinical reports, to have multiple therapeutically beneficial
actions on cancer cells.
(Krishant M. Deo, 2016). Krishant M. Deo, B. J.-W. (2016, Oct 31). Transition
Metal Intercalators as
Anticancer. (S. H. Hadjiliadis, Ed.) International Journal of Molecular
Sciences, 1-17. Retrieved
2021 from https://doi.org/10.3390/ijins17111818 . Mechanisms include reduction
of radicals creating
oxidative stress, changing metabolic pathways, and opening of cell signaling
mechanisms, and these
are mechanisms that are exhibited by any one of Zinc, Copper, Manganese,
Magnesium, Calcium,
Selenium, Potassium, Hydrogen (as H30+ in the invention), and SOD, all of
which may themselves be
incorporated into compositions of the invention. There is a wide range of
evidence about the
regulatory roles exerted by ion channels and transporters upon the phases of
the cell cycle, and other
aspects of cell physiology that change or shape multistep neoplastic
progression, such as resistance to
apoptosis, cell invasiveness, and angiogenesis. Andrea Becchetti, L. M.
(2013). The role of ion
channels and transporters in cell proliferation and cancer. Frontiers in
Physiology, 1.
https://doi.org/10.3389/fphys.2013.00312. The compositions of the invention
are administered for the
treatment of cancer in a variety of ways: intravenously (IV), intramuscularly
(IM) orally (PO),
subcutaneously (SC), intralesionally (IL), intrathecally (TT), and topically.
Use of the specific metal
ions carried in the compositions of the present invention lowers the toxicity
levels seen in current
cancer drug treatments. Studies have demonstrated a significant decrease in
SOD enzymatic activity
in a variety of human cancers. As a result, increased levels of oxidative
stress enhance the progression
of tumor formation and cancer incidence, but the compositions of the invention
antagonize increases
in levels of oxidative stress.
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Iontophoretic Transport. The compositions of the invention can be used
separately or
adjunctively combined with chemotherapy or used as a chemosensitizer to treat
cancers, cancer
tumors, and cancer circulating stem cells. The ionic homeostasis induced
following administration
may start a cascade of signaling events, ultimately leading to cancer cell
death. Studies have
implicated the modulation of cellular ion homeostasis by either activation or
deactivation of ion
transporters and ion channels, which is the mechanism of action of
compositions of the invention, in
sensitizing cancer cells to otherwise ineffective drugs. Kaushik, V. Y.
(2018). Ionophores: Potential
Use as Anticancer Drugs and Chemosensitizers. US National Library of Medicine,
2.
https://dx.doi.org/10.3390%2Fcancers10100360. Current research presents a body
of evidence that
suggests that an altered ion transport dynamic is present in cancer cells.
Cancer cells rewire their
cellular circuitry to establish, adopt, proliferate, and metastasize in
various challenging conditions by
manipulating their ion homeostasis and ion channels, and ion pumps play a
critical role in this
reorganization.
Treatment of Pathogenic Infections. Another major goal and feature of the
invention is the
ability to treat pathogenic disease, including compositions that may treat
pathogens known as
infectious agents, viruses, bacteria, whether gram-negative bacteria or gram-
positive bacteria,
methicillin-resistant staph aureus (MRSA), fungi, protozoa, parasites, worms,
Lyme disease, and
biofilm, among others. It is now widely known that a variety of metal ions are
toxic to bacteria.
Overall, the metals that are being increasingly considered for antimicrobial
agents are typically within
the transition metals of the d-block (V, Ti, Cr, Co, Ni, Cu, Zn, Tb, W, Ag,
Cd, Au, Hg) and a few
other metals and metalloids from groups 13-16 of the periodic table (Al, Ga,
Ge, As, Se, Sn, Sb, Pt,
Te, Pb, and Bi). Of major importance is the discovery made over ten years ago
that metals have
strong efficacy against microbes growing as a biofilm. Turner, R. J. (2017,
Jul 26). Metal-based
antimicrobial strategies. Microb Biotechnol, 1062-1065.
https://doi.org/10.1111/1751-7915.12785.
A quintessential phenotype of biofilms is their ability to confer
antimicrobial resistance, and the
metals described above actively degrade the ability to construct or maintain
such biofilms.
Furthermore, such metals have shown some efficacy on those cells that are the
dormant variants of
normal cells impervious to antibiotics. The biological properties of these
compounds can he explained
based on several factors including type of donor atom present in ligands,
metal ion type, and
coordination geometry Pahont, E. (2017, April 19). Synthesis,
Characterization, Antimicrobial and
Antiproliferative Activity Evaluation of Cu(II), Co(II), Zn(II), Ni(II) and
Pt(II) Complexes with
Ioniazid-Derived Compound. International Journal of Molecular Sciences, 4.
From
https://dx.doi.org/10.3390%2Fmolecules22040650. Pathogens are known to compete
for limited
amounts of metals that are necessary to the functionality of the pathogen's
metabolism within a host,
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while simultaneously possessing biological systems that shield themselves from
metal toxicity.
Pathogens have developed a series of metal regulatory, acquisition, and efflux
systems. The
compositions of the invention have specific metal ratios to cause disruptions
in such pathogen defense
systems.
Lower order organisms are not as complex regarding their metabolic pathways as
are the
higher-order organisms. The cycle followed by lower-order diseases caused by
organisms such as
bacteria, fungi, and viruses follow a less complicated process that allows the
disease to multiply at an
almost exponential rate based on available resources in an anaerobic cycle
that has far fewer steps.
This invention exploits that difference.
Treatment of Autoimmune Disorders. The next major feature and object of the
present
invention is to provide compositions for the treatment of autoimmune
disorders. Autoimmune
disorders include Achalasia, Addison's disease, Adult Still's disease,
Agammaglohulinemia, Alopecia
areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis,
Antiphospholipid
syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune
encephalomyelitis,
Autoimmune hepatitis, Autoimmune Inner Ear Disease (AIED), Autoimmune
myocarditis,
Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis,
Autoimmune retinopathy,
Autoimmune urticaria, Acute Motor Axonal Neuropathy(AMAN), Ballo disease,
Behcet's disease,
Benign mucosal pemphigoid, BulIons pemphigoid, Castleman Disease (CD), Celiac
disease, Chagas
disease, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic
Recurrent Multifocal
Osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS), Eosinophilic
Granulomatosis (EGPA),
Cicatricial pemphigoid, Cogan's syndrome, Cold agglutinin disease, Congenital
heart block,
Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis
herpetiformis,
Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus,
Dressler's syndrome,
Endometriosis, Eosinophilic Esophagitis (EoE), Eosinophilic fasciitis,
Erythema nodosum, Essential
mixed cryoglobulinemia, Evans syndrome, Eczema, Fibromyalgia, Fibrosing
alveolitis, Giant cell
arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis,
Goodpasture's syndrome,
Granulomatosis with Polyangiitis, Graves' disease, Guillain-Barre syndrome,
Hashimoto's
thyroiditis, Hemolytic anemia, Henoch-Schonlein Purpura (HSP), Herpes
gestations or Pemphigoid
Gcstationis (PG), Hidradenitis Suppurativa (HS), Acne Invcrsa,
Hypogammaglobulincmia, IgA
Nephropathy, IgG4-related sclerosing disease, Immune Thrombocytopenic Puipura
(ITP), Inclusion
Body Myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile
diabetes (Type 1 diabetes),
Juvenile Myositis (JM), Kawasaki disease, Lambert-Eaton syndrome,
Leukocytoclastic vasculitis,
Lichen planus, Lichen sclerosis, Ligneous conjunctivitis, Linear lgA Disease
(LAD), Lupus, Chronic
Lyme disease, Meniere's disease, Microscopic polyangiitis (MPA), Mixed
Connective Tissue Disease
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(MCTD), Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy
(MMN),
MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolcpsy, Neonatal
Lupus,
Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic
neuritis Palindromic
Rheumatism (PR) PANDAS, Paraneoplastic Cerebellar Degeneration (PCD),
Paroxysmal Nocturnal
Hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral
uveitis), Parsonage-
Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous
encephalomyelitis, Pernicious
Anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes
type I, II, III,
Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome,
Postpericardiotomy
syndrome, Primary biliary cirrhosis. Primary sclerosing cholangitis,
Progesterone dermatitis,
Psoriasis, Psoriatic arthritis, Pure Red Cell Aplasia (PRCA), Pyoderma
gangrcnosum, Raynaud's
phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing
polychondritis, Restless
Legs Syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid
arthritis, Sarcoidosis,
Schmidt syndrome, Scleritis, Scleroderma, Sjogren' s syndrome, Sperm &
testicular autoimmunity,
Stiff Person Syndrome (SPS), Subacute Bacterial Endocarditis (SBE), Susac's
syndrome,
Sympathetic Ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant
cell arteritis,
Thrombocytopenic Purpura (TIP), Thyroid Eye Disease (TED), Tolosa-Hunt
Syndrome (THS),
Transverse myelitis, Type 1 diabetes, Ulcerative Colitis (UC),
Undifferentiated Connective Tissue
Disease (UCTD), Uveitis, V asculitis, V itiligo, and Vogt-Koyanagi-Harada
Disease.
Autoimmune diseases represent the phenomenon of a body's own immune cells
attacking the
host's own cells and tissue. Five to eight percent of the world's population
are currently affected by
80-100 autoimmune diseases. The compositions of the present invention bring
several known and
several potential mechanisms of action, in combination, to address the
treatment of autoimmune
disease by changing the conditions of the radical SOD1 enzyme, by pathogenic
involvement, and by
reducing an over-simplified immune system through treating the underlying
problem. The antioxidant
properties of the compositions of the invention that have high ORAC and ORP
values provide
additional rational approaches to the reduction of immune responses, thereby
potentially relieving or
reducing Autoimmune diseases.
Zinc, in the form of the zinc cation, is a component in many of the preferred
embodiments of
the invention and is recognized as constituting a targeted approach to
autoimmunc disorders. Its
homeostasis behavior is essential against inflammatory diseases to regulate
the immune system's
different aspects, both for innate and for adaptive immune response, cell
cycle progression, and cell
maturation and differentiation. Zinc deficiency is therefore associated with
the incorrect maturation
and function of T and B cells, an unbalanced ratio between Thl cells and Th2
cells, and between
regulatory and pro-inflammatory T cells, as well as a weakening of NK cell
function. Alessandro
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Sanna, D. F. (2018, Jan 11). Zinc Status and Autoimmunity: A Systematic Review
and Meta-
Analysis. (Nutrients, Ed.) Nutrients, 10(1), 68. From
https://dx.doi.org/10.3390%2Fnu10010068.
Copper is a preferred component in the compositions of the invention. Patients
suffering
from inflammatory rheumatic diseases were found to he almost totally depleted
of the I ow-molecul ar-
weight copper protein copper thionein, which exerts pronounced superoxide
dismutase activity and
scavenges hydroxyl radicals and singlet oxygen effectively. Ralf Miesel, M. Z.
(1993, June). Copper-
dependent antioxidase defenses in inflammatory and autoimmune rheumatic
diseases. Inflammation,
283-294. From https://doi.org/10.1007/BF00918991.
Hydrogen, present as a hydroniuni ion, is a preferred component of the
compositions. It is an
object of the invention to reduce levels of reactive oxygen species (ROS),
particularly the .OH
hydroxyl radicals, which are thought to be critical drivers of the type of
tissue damage that occurs in
many autoimmune diseases, particularly Psoriasis and Rheumatoid Arthritis.
Decker, C. (2019, Nov
12). Harnessing Hydrogen's Antioxidant Power to Treat Autoimmune Disease. From
Holistic
Primary Care: https://holisticprimarycare.net/topics/chronic-
disease/harnessing-hydrogen-s-
antioxidant-power-to-treat-autoimmune-disease/.
Homeostasis in RSS, RNS, and ROS. Yet another feature and object of the
invention is to
achieve and maintain redox balance and biological homeostasis in the presence
of reactive oxidative
species, namely reactive oxygen species, ROS, reactive nitrogen species, RNS,
and reactive sulfur
species, RSS. When an overload of free radicals cannot timely be destroyed,
their accumulation in the
body generates a phenomenon called oxidative stress. Oxidative Stress has been
clinically proven to
be involved in hundreds of diseases. Compositions of the invention may reduce
and balance free
radicals such as, and not limited to, reactive oxygen species, reactive
nitrogen species, and reactive
sulfur species, each of which cause oxidative damage and cellular dysfunction.
Mitochondrial Support. The compositions of the invention transport molecular
signals
activating stress responses within the mitochondria that are beneficial to the
biological system.
Transport pathways play a significant role in the reduction of tissue
oxidative damage and
dysfunction. The compositions protect against excessive tissue dysfunction
through several
mechanisms, including stimulation of opening of permeability transition pores.
Additional goals, features, and advantages of the invention as disclosed and
claimed herein
include the following non-limiting list within certain uses and fields, these
uses made possible by the
biological properties of the compositions of the invention.
Pharmaceutical Oral and Topical Treatments. Uses of the compounds of the
invention in
topical treatment can be used to treat infections, effectuate load-reduction
of pathogens, and as an
adjunct or replacement for antibiotics; to create high kill-rates for the
treatment of all viruses, fungi,
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methicillin resistant staph aureus (MRSA), Gram-Negative or Gram-Positive
bacterial infections, and
parasitic infections; to reduce average treatment times and reduce prolonged
symptoms in the
treatment of viruses, fungi, MRSA, Gram-Negative and Gram-Positive Bacterias
and Parasites; and
infectious and systemic diseases, including, hut not limited to, Alzheimer's
disease, Lyme disease,
MRSA, or any other pathogenic-related disease.
Passage through and reduction of biological biofilm. The synthesized
ionophores of the
invention are able to pass through and reduce biofilm (extracellular polymeric
substances) to mimic
or create antipathogenic toxicity of cellular RNA replication, thereby acting
to reduce viral, fungal,
and bacterial loads on the system, or to reduce antibiotic resistance within
these pathogens.
Use as an antioxidant in inflammation reduction. Due to their antioxidant
properties, the
compositions of the invention are useful in pain management therapies, and
anti-inflammatory
therapies. The compositions are non-ototoxic, unlike many anti-inflammatories,
both steroidal and
non-steroidal.
Skin trauma. The compositions can be used on damage to the skin or other areas
exposed to
external factors, including damage caused by excess exposure to sunlight,
extreme heat, flame,
contact with hot objects, radioactive burns, or chemical burns, and used in
providing burn pain relief.
Wound healing. Increases in the rate of wound healing, as well as in pre-
traumatic, and
post-traumatic, or pre-surgery or post-surgery intervention, can be achieved
with compositions of the
invention.
Vascular Disorders. Vascular disorders, including heart disease,
arteriosclerosis,
thrombosis, and cardiovascular disorders can be addressed using compositions
of the invention.
Additional indications. The compositions of the invention may also be useful:
as a smooth
muscle relaxant, encompassing a broad spectrum of agents that relax both
vascular and nonvascular
smooth muscle disorders; as part of the treatment of all cancer cell types,
including reducing cancer
solid tumors and non-solid cancers, cancers of the circulating stem cells,
cancers in the metastasis
phase, and pre-cancerous atypical cells, treatment of all skin cancer cell
types while additionally
providing positive eschar actions, as an adjunct with pre-surgical and post-
surgical cancerous and pre-
cancerous cell removal procedures, as an adjunct in Mohs surgery, and as an
adjunct or replacement
for chemotherapy creams; in auto-immune disorders, including, but not limited
to, psoriasis and
eczema; neurological disorders, migraine headache of neurological origin,
cardiovascular stroke
recovery, Multiple Sclerosis, traumatic nerve injury to nerves of the
peripheral nervous system and
the central nervous system, Amyotrophic Lateral Sclerosis, Alzheimer's
disease, epilepsies, and
epileptic seizures, and smooth and striated muscle relaxation; arthritis and
arthritic conditions due to
their role in the reduction of oxidative stress and levels of free radicals in
a region afflicted by over-
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production of a superoxide detoxification of a biological system, especially
an avian system, a
mammalian system, or a human system, for preventative or medicinal clearing of
toxic substances
therefrom; in nasal administration as a spray or drops for sinus congestion,
sinus cleansing, or for
sinus infections; reduction of Alzheimer's and non-Alzheimer's dementia, and
for the improvement of
cognitive enhancement; for use in psychiatric disorders, including
schizophrenia, depression, and Post
Traumatic Stress Disorder (PTSD), as well as other severe mental disorders and
complicated
diagnostic stress issues in a patient; or as a formulation delivering the
compositions of the invention,
solely or in combination with other carrier formulations.
The compositions may further be used as: a pharmaceutically acceptable oral,
otic,
ophthalmic, buccal, sinus, vaginal, urethral, rectal or topical medication; an
image enhancing agent in
PET or CT scans, and as a preliminary contrast media; an antimicrobial applied
as a therapeutic mist
or spray over an infected area; agents causing the reduction of free radicals
and cells mutated by
radiation exposure or from overdosing radiotherapy treatments or radio
imaging; agents to reduce
infection from implants or prosthetic device surgeries; infection reduction
agents from Intravenous
therapy, injections, catheters, implanted access ports, or other invasive
medical devices; dentistry
applications and uses, including dental infections and treatments of a tooth's
root; cavities (caries)
prevention and treatment of the teeth; and infection prevention and treatment
of the teeth or gums,
gingivitis prevention and treatment, or improved dental hygiene outcomes, all
in a paste, gel, gum,
spray, chewable tablet, buccal tablet, or injectable formulation.
The compositions of the inventions are also useful for: fixed dose combination
or
monotherapy formulations compounded to achieve a specific drug indication and
systemic delivery
profile in fixed dose combinations with oncology drugs and their delivery
formulations, narcotic
drugs and their delivery systems, in combination with protein enhancement or
protein synthesis
blockading therapies; in combination with hormone enhancement or blocking
therapies in the
treatment of endocrinological disorders; in combination with cellular receptor-
blocking or cell
signaling modification therapies; in combination with biological or biosimilar
products that arc
relatively large, complex molecules that may be produced through biotechnology
in a living system,
including microorganisms, plant cells, or animal cells; combined biological
actions that provide
anticancer cell death through apoptosis, antipathogenic cell death through
necrosis, and change within
a diseased environment to regress or stabilize anaerobic cell growth; in
coordinated usage with redox
biology and redox medicine strategies to obtain therapeutic benefits and
treatments that affect all
outcome by modifying the levels of pro-oxidant and antioxidant agents in
cells; in personal care and
cosmetic skin care products; in cosmetic formulations for medical and non-
medical skincare products;
in skin antiaging, repair, esthetic beautification, moisturization, and skin
restoration, in tanning
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acceleration, in sunscreens, in treatment of sunburns and in reduction of free
radical generation
occurring as a result of exposure to sun; a nontoxic preservative and
antimicrobial excipient in
formulations.
Penetration and absorption of a substance into skin, membranes, tissues, and
organs is
affected by the physicochemical properties of pharmaceutical formulations
compounded for such
delivery purposes, and the compositions of the present invention enhance and
support such skin
penetration and absorption.
The compositions of the invention are characterized by a low pH, by high redox
values
(positive electrical charge), and by the inherent powers of natural metal
cations and water to
coordinate together and then to react with oxidative reactive species,
nitrogen reactive species, and
sulfur reactive species, to result in a novel cellular delivery method.
This background information is provided to present and disclose information
believed by the
applicants to be of possible relevance to the present invention. No admission
is necessarily intended,
nor should be construed, that any of the preceding information constitutes
prior art against the present
invention.
Summary of the Invention
The compounds or the invention comprise one or more of the most preferably
hexa-aqua
octahedral ligand configurations of metal ionic structures, or alternatively
preferably tetra-aqua
tetrahedral, or planar ligand configurations of metal ionic structures, or tri-
aqua trihedral ligand
configurations of metal ionic structures, in aqueous solution, of the general
formula
H20
H2O. -0H2
'=.' m2+
H20111/1111f.
H20
Where M is a p-block element, a d-block element, or an s-block element. At
equilibrium
state, there can be an alternative preferred embodiment of the invention,
namely a metal tetra-aqua
tetrahedral or planar ligand dihydroxy species present, which will be amine
concentration-dependent
and/or solution acidity-dependent. Based on anionic and cationic equilibriums,
these lower-order
ionic structures can configure to higher-order complex ionic structures.
In summary, the invention is a composition comprising one or more compounds
selected
from the group consisting of any one of RZn(1-170)6]2]w , 11Cu(1-120)612]õ ,
which is an example of a
hexa-aqua octahedral ligand configuration, Ku(1-1,0)41 , which is an
example of a tetra-aqua
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tetrahedral or planar ligand configuration, 111V1g(H20)elz ,11-1S0-4]c , 11\11-
13ld , [NHele , [H]f,
[S032 ]g [NH411SO4]11 , and [1-12S041, , and mixtures thereof, wherein w, x,
y, z, c, d, e, f, g, h, and j
are integers that are independently greater than or equal to 0; [H+] is
present as the combined
molecule EV-- H20; and the pharmaceutically or nutritionally acceptable salts,
solvates, hydrates,
structural isomers, and stereoisomers thereof, and is most preferably in an
aqueous solution. The
compositions may additionally comprise one or more compounds selected from the
group consisting
of any one of [Zn(II)(H20)6l2Thv , 1Cu(II)(H20)6l2lx ,1Cu(I)(H20)4113, ,
1Mg(II)(H20)6121z ,
[1-13P041, , and potassium hydrogen phthalate, and mixtures thereof, wherein:
w, x, y, z, and j are
integers that are independently greater than or equal to 0; [H+] is present as
the combined molecule
1-1+= WO; and likewise the pharmaceutically or nutritionally acceptable salts,
solvates, hydrates,
structural isomers, and stereoisomers thereof. In these compositions,
11\1H4HS041 may be present in a
concentration of from 0.1% to 4.0% w/w, [H2SO4] may be present in a
concentration of from 0.01%
to 3.0% w/w, Vn(II)(H20)61 may present in a concentration of from 2.0% to 8.0%
w/w,
Ku(II)(H20)6] may be present in a concentration of from 1.0% to 3.0% w/w,
[Mg(II)(H20)6] may be
present in a concentration of from 1.0% to 3.0% w/w, RI3P041 may be present in
a concentration of
from 0.1% to 15.0% w/w. The compositions may additionally comprise one or more
compounds
selected from the group consisting of hexa-aqua, tetra-aqua or tri-aqua s-
block, d-block or p-block
hydrates, or more preferably may additionally comprise a compound selected
from the group
consisting of any one of [Se0(H0)2121-, which is an example of a trihedral
ligand configuration metal
ionic structures, [Mn(H20)6P, [Ag(H20)612+, [Au(H20)6F+. [V(H20)6P, and
11\11(H20)6P and
mixtures thereof. Additionally, the compound potassium hydrogen phthalate may
be present in a
concentration of from 0.01% to 8.0%. The compositions are advantageously
delivered to a patient in
need thereof in a pharmaceutically acceptable formulation for administration
in a form selected from
the group consisting of oral, nasal, ophthalmic, otic, topical, topical
administered with thermal,
ultrasound, infrared, iontophoretic or radiation means, transdermal, urethral,
vaginal, rectal,
intravenous injection, subcutaneous injection, nebulization, and inhalation
formulations. Topical
formulations may be prepared at active composition concentrations of up to 30%
w/w. Transdermal
formulations may prepared at active composition concentrations of up to 20%
w/w. Oral formulations
may be prepared at active composition concentrations of up to 20% w/w.
Inhalational formulations
may be prepared at active composition concentrations of up to 10% w/w.
Injectable formulations may
be prepared at active composition concentrations of up to 5% w/w. The
formulations may be prepared
to have a final product pH that is in a range selected from the group of
ranges consisting of a pH of
less than 1.0, a pH in the range of 1.01 to 3.99, and a pH in the range of
4.00 to 5.00, and the
formulation may exhibit an oxidation reduction potential of greater than 200
millivolts.
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A preferred alternative embodiment of the present invention may be a
composition
comprising one or more compounds selected from the group consisting of any one
of: ,
UM(L2)a.21cly D4(1-3)a3r iz [ANi-]e , and [CAglf, , and mixtures thereof,
wherein: L1, L2, and L3 are
any ligand or mixed ligand comprising any one of OH, CO, NH3, H20, H30, NO,
NO2, NO3, SO4,
SO3, HSO4, NH, S, N, NH4, PO4, CH3, CH2, or CO2; and mixtures thereof; M is
selected from the
group consisting of p-block elements, d-block elements, and s-block elements,
more preferably any
one of Cu, Zn, Mn, Mg, Se, Au, Ag, Vn, and Ni, and mixtures thereof; x, y, z,
e, and fare
independently an integer that is the number of ions forming a complex ionic
structure and is greater
than or equal to 0; al is an integer that is greater than or equal to 0 and
less than or equal to 6 and is
the coordination number of ligands that are coordinated to metal M; a2 is an
integer that is greater
than or equal to 0 and less than or equal to 6 and is the coordination number
of ligands that are
coordinated to metal M; a3 is an integer that is greater than or equal to 0
and less than or equal to 6
and is the coordination number of ligands to metal M; b, c, and d may be
independently an integer
that is greater than or equal to 0 and less than or equal to 6 and is that
amount of charge that is
localized on metal center M or that amount of charge delocalized around
coordinate ligands; AN is an
anion that is in solution, that is selected from the group consisting of the
ionic forms of any one of
OH, CO, NH3, NO, NO2, NO3, SO4, SG1, HSO4, NH, NH4, PO4, N, Cl, I, and Br and
mixtures thereof;
and CA is a cation that is in a solution consisting of a cation that is
selected from the group consisting
of the ionic forms of any one of H, Ca, Na, Fe, K, Mg, Mn, Zn, Cu, Li, or
mixtures thereof, and a s-
block element, a p-block element, or a d-block element, and mixtures thereof,
and the
pharmaceutically or nutritionally acceptable salts, solvates, hydrates,
structural isomers, and
stereoisomers thereof.
The invention further comprises a method of administering the compositions
disclosed
herein for treating a disease, comprising the step of administering to a
mammal in need thereof an
aqueous ionic mineral complex comprising an ionic metal bonded to a plurality
of H20 ligands to
form a metal-ligand complex, the ILO ligands enabling transport of the metal-
ligand complex through
the human patient to a cellular target affected by over-production of
superoxide ion, said metal-ligand
complex selected from the group consisting of any one of [Vn(H20)612],õ, ,
Ku(1120)6l'h ,
1lCu(H20)41 ly 11-Mg(H20)612+1z rHSO 4ic INI131d [N1-14 1e , 114+1f , [S032
ig , INH411S041h , and
[1-12S041, , and mixtures thereof, wherein: w, x, y, z, c, d, e, f, g, h, and
j are integers that are
independently greater than or equal to 0; and RP] is present as the combined
molecule H' H20: and
the pharmaceutically or nutritionally acceptable salts, solvates, hydrates,
and structural or stereomeric
isomers thereof, and may further comprise a compound selected from the group
consisting of
lZn(11)(H20)61 2+liv + LCu(11)(H20)61 241. , LCu(1)(H20)41 , lMg(11)(H20)61
241z , 11-13P041j , and
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potassium hydrogen phthalate, and mixtures thereof, wherein w, x, y, z, and j
are integers that are
independently greater than or equal to 0; and [11+1 is present as the combined
molecule II .II,O; and
the pharmaceutically or nutritionally acceptable salts, solvates, hydrates,
structural isomers, and
stereoi smilers thereof, and in particular may he administered for a purpose
selected from the group
consisting of medical diagnosis, detection of anaerobic cells in a biological
system, medical
treatment, personal care, cosmetic purposes, and nutritional supplementation.
Also disclosed and claimed within the scope of the present invention are the
pharmaceutically acceptable salts, hydrates, solvates. structural isomers, and
stereoisomers thereof.
The compositions of the invention are intended to be used in human and
veterinarian
patients, in the fields of allopathic, osteopathic, homeopathic, and
naturopathic medicine.
Brief Description of the Drawings
FIGURE 1 is an 1I-I-NMR spectrum generated at Watergate 'H- NMR spectra of
red: 275K,
spectra blue: 298K, and spectra green: 320K temperatures.
FIGURE 2 is an NMR spectrum generated at ca. 100 mM NH4 + in the presence of 5
and
10% D20.
FIGURE 3 is an NMR spectrum generated at '51\I- '11 in 2D HISQC spectrum of a
solution
containing 100 mM N}14 -
FIGURE 4 is a graph of a titration curve showing the overall acid content of a
pH-
potentiometric titration.
Detailed Description of the Invention
The present invention in its varying embodiments will now be described more
fully This
invention may, however, be embodied in many different forms and should not be
construed as being
limited to the embodiments set forth herein. Rather, these embodiments are
provided so that this
disclosure will he thorough and complete, and will fully convey the scope of
the invention to those
skilled in the art.
The invention utilizes preferred compounds within a composition that is a
formulation of
aqueous ligands in a hcxa-aqua delivery system. A preferable active compound
is a synthesized
ionophore that actively transports free ions to the shells of cell membranes
or through cell membranes
to interact with internal/external cellular environments. The metal ionic
structures in the aqueous
solution are primarily in a hexa-aqua octahedral ligand configuration. The
metal ionic structures are
alternatively in a tetra-aqua tetrahedral or planar geometry. These lower-
order ionic structures may
configure to higher-order complex ionic structures based on anionic and
cationic equilibriums which
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contain a high level of free sulfur, amines, sulfate ions, metal hexa-aqua
structures, metal
hydroxyl/aqua mixed ligand species, and H+. These ionic structures utilize
amine and sulfate ions in
concert with free protons (H+) in specific ratios to enable effective bridging
of multiple metal-aqua
species nearby, creating a concentrated ionophoric metal ion delivery system
through cellular
membranes.
The equilibrium between these ionic metal structures and stabilized free
anions and cations
in solution is crucial to the stability and steric proximity of the
coordinating metal ions in order to
provide effective cell wall penetration and delivery of the metal ions to a
host of intracellular
biological processes to address the metabolic and pathological conditions
described above. By
modifying the concentrations of the ionic compounds and H+ in aqueous
solution, the system of the
present invention can be fine-tuned to penetrate and deliver metal ions into a
multitude of cell types,
to attach to cellular walls, or to provide a pathway for single metal ions or
complex metal ionic
bridged structure delivery. The composition compounds of the present invention
enter cells and
deliver one or more structures therein to impact biological processes and
mechanisms in humans or
animals.
A complex ion has a metal ion at its center with several other molecules or
ions, creating
inorganic coordination complexes or coordinate (dative covalent) bonds where
both electrons come
from the same atom. A covalent bond forms by two atoms sharing a pair of
electrons. The atoms hold
together because both nuclei attract the electron pair. The invention has
created a unique relationship
with ligand bonding, becoming the carrier or co-bonding mechanism with other
molecules to move
within biological systems. The anions or molecules attached to the metal are
the ligands. The
coordination number is the number of places on the metal ion where ligands are
bound. The bond
between the metal ion and the ligand, where the ligand supplies both
electrons, is a coordinate
covalent bond. Simple ligands include water, ammonia, phosphorus, and chloride
ions.
Every metal ion has at least one coordination sphere, which determines the
number of
coordinate bonds possible for each metal atom. The coordinate bonds attract
negatively charged ions
possessing unshared electron pairs. The cations use the unshared pair to fill
gaps in the outer electron
orbitals where those electron shells are incomplete. All the 3-level orbitals
are now empty, making
use of all six empty orbitals to accept lone pairs from six water molecules.
The moiety re-organizes
(hybridizes) the 3s, the three 3p, and two of the 3d-shell orbitals to utilize
six orbitals, all with similar
energy. Six is the maximum number of water molecules around most metal ions,
comprising the
maximum number of bonds, and is the most energetically stable. The bonds
formed between the
cations and the unshared pairs of electrons become hexa-aqua ligand bonds.
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The most preferred embodiments of the present invention will use each of six
water
molecules as a hcxa-aqua ligand attached to a central metal cation via a
coordinate bond using one of
the available lone pairs on oxygen. These metal hexa-aqua species then form
higher-order ionic
structures with the amine and sulfate ions in concert with H, which is
effectively bridging multiple
metal aqua species nearby, creating an iontophoretic metal delivery system.
The equilibrium between
these ionic metal structures and stabilizing free anions and cations in
solution is crucial to the stability
and steric proximity of the coordinating metal ions to provide effective cell
wall penetration and
delivery of the metal ions to a host of intracellular biological processes. By
modifying the
concentrations of the ionic compounds and free hydrogen in the solution, the
ionophore delivery
system of the invention can be custom synthesized and formulated to penetrate
and deliver metal ions
into cells, attach to cellular walls, and provide a pathway for single metal
ions or complex metal ionic
bridged structures. A preferred embodiment composition is illustrated in FIG.
5, to show a delivery
system formulation in which six water molecules are present, that may form
hexa-aqua ligands with
any metal cations of Zn'' Cu', or Mg', here forming hexa-aqua copper, hexa-
aqua zinc, and hexa-
aqua magnesium species, in the presence of NH4, H+, and HSO4- ions, in a
pharmaceutical
formulation soup-like milieu of cationic ligands and ionic salts.
Ionophore delivery. Ionophores are any of a number of naturally occurring
carrier of ions.
The present invention is a synthesized ionophore that can mimic natural
versions of ionophores or
create similar ionophore signaling functions to produce enzymes, protein
actions, and electron
transfers in biological systems' metabolic processes. The compounds of the
present invention that
comprise the therapeutic compositions have multiple ionophore pathways
available to them through
cellular membranes. Thus, they allow entry through all tissue, blood, organ,
and cellular barrier types.
Ion channels are membrane proteins found in all domains of cellular life. They
are present in all
intracellular membranes as well as the plasma membrane. Transport mechanisms
through these ion
channels allows for the compounds of the invention to have multifunctional
forms of permeability.
Fluid and ion transfer across the blood-brain and blood-cerebrospinal barriers
arc highly
restrictive due to tight junctions creating a fluid barrier. Hladky, S. B.
(2016). Fluid and ion transfer
across the blood¨brain and blood¨cerebrospinal fluid harriers; a comparative
account of mechanisms
and roles. (S. Nature, Ed.) Springer Nature, 1. Retrieved from
https://doi.org/10.1186/s12987-016-
0040-3. Since the compounds of the present invention are preferably an
ionophore of water, their
ligand structure, and low pH, allows for higher permeability across these
tight central nervous system
transport junctions. This provides for a higher ion delivery rate than most
current methods of drug
delivery. Filip Vlahovic, M. P. (2015, June 7). Assessment of TD-DFT and LF-
DFT for study of d -
D transitions in first row transition metal hexaaqua complexes. Researchgate,
142, 214111. Retrieved
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2021 from https://www.researchgate.net/figure/The-structure-of-investigated-
hexaaqua-transition-
metal-ion-complexes-MH-2-0-6-n fig4 277895193.
Passive Transport. As a hexa-aqua water-based carrier, a preferred compound of
the
present invention will have simple concentration gradients. Water is found in
different concentrations
over a region of cellular space or on opposite sides of a membrane; therefore,
water is highly neutral
and absorbent in biological systems and allows the compounds utilized in the
present invention to
engage in a very passive degree of transport. Large quantities of water
molecules continuously move
across cell membranes by osmosis, a simple diffusion process through membrane
proteins and
aquaporins movement. Lumen. (2020). Membrane Transport. (Pressbooks, Editor, &
Pressbooks)
From The Cellular Level of Organization: :
https://courseslumenlearning.com/nemcc-
ap/chapter/3204/ Up to one hundred times the volume of a cells water molecules
will diffuse across,
e.g., a red blood cells membrane every second; the cell does not lose or gain
water because equal
amounts go in and out through osmosis, the effect of which is to make the hexa-
aqua ligand an
extremely efficient delivery system. The hexa-aqua ligands found in the
present invention take
advantage of osmosis, tonicity, and hydrostatic pressure in a passive
transport system in which water
flows from the membrane with the lower solute concentration into the membrane
with higher solute
concentration. The hexa-aqua ligands of the invention carry a free ion with
low molecular weight,
allowing for passive entry, and potentially can deliver larger molecules that
are hidden in a biological
soup comprised of ionophore carriers and their respective bonded molecules.
Active transport. The synthetic ionophore compounds of the invention have a
highly
positive electron charge providing an electrical gradient, or difference in
charge, across a plasma
membrane, an atypical condition found in biological active transport. Living
cells typically have a
membrane potential, which is an electrical potential difference (voltage)
across their cell membrane.
Electrical potential differences exist whenever there is a net separation of
charges in that space. In the
case of a cell, positive and negative charges are separated by the cell
membrane's barrier, with the
inside of the cell having extra negative charges relative to the outside.
Sodium and Potassium Pathways. The compositions of the invention exploit the
actions of
sodium and potassium pathways. The inside of a cell has a higher concentration
of potassium and a
lower sodium concentration than the extracellular fluid around it. When sodium
ions are outside of a
cell, they will tend to move into the cell based on their concentration
gradient and the voltage across
the membrane (the more negative charge on the inside of the membrane). The
combination of the
concentration gradient and voltage that affects an ion' s movement is the
electrochemical gradient that
is a property of the compounds of the invention.
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Primary and Secondary Active Transport. The ionophore compounds of the
invention
can be designed to affect different transports in thc case of a primary
transport known to use ATP as a
source of energy. Presence of a magnesium ion is required for this energy
production. In the case of a
secondary active transport (cotransport), the ionophores of the invention use
an electrochemical
gradient cationic charge as an attractant to move molecules against their
gradient and thus does not
directly require a chemical source of energy such as ATP. Through variation of
stoichiometry ratios
of ions, the compounds of the invention can be designed to target the desired
transfer method.
Although the following detailed description contains many specifics for the
purposes of
illustration, anyone of ordinary skill in the art will appreciate that many
variations and alterations to
the following details are within the scope of the invention. Accordingly, the
following embodiments
of the invention are set forth without any loss or diminution of generality
to, and without imposing
limitations upon, the claimed invention.
As used herein, the word "exemplary" or "illustrative" means "serving as an
example,
instance, or illustration." Any implementation described herein as "exemplary"
or "illustrative" is not
necessarily to be construed as preferred or advantageous over other
implementations. All of the
implementations described below are exemplary implementations provided to
enable persons skilled
in the art on how to make or use the embodiments of the disclosure and are not
intended to limit the
scope of the disclosure of the invention, which is defined solely by the
claims.
Furthermore, in this detailed description, a person skilled in the art should
note that
quantitative qualifying terms such as "generally," "substantially," "mostly,"
and other terms are used,
in general, to mean that the referred to object, characteristic, or quality
constitutes a majority of the
subject of the reference. The meaning of any of these terms is dependent upon
the context within
which it is used, and the meaning may be expressly modified.
Minerals are naturally occurring chemical compounds comprising metal elements,
and they
are often required as essential nutrients by organisms to perform functions
necessary for life. Metals
have played an essential role in biological systems from the beginning of
time. As catalytic or
structural cofactors, metal ions are critical to the function of as many as
one-third of all enzymes by
some estimates, and they have extensive roles in biological systems.
An ionophorc is a chemical species that reversibly binds ions. Many ionophores
are lipid-
soluble entities that transport ions across the cell membrane. Ionophores
catalyze ion transport across
hydrophobic membranes, such as liquid polymeric membranes (carrier-based ion
selective electrodes)
or lipid bilayers found in the living cells or synthetic vesicles, for example
liposomes. Structurally, an
ionophore contains a hydrophilic center and a hydrophobic portion that
interacts with the membrane.
Some ionophores are synthesized by microorganisms to import ions into their
cells. The compositions
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of the invention comprise compounds that are synthetic ionophores. Ionophores
selective for cations
and anions have found many applications in analysis. These compounds have also
been shown to
have various biological effects and a synergistic effect when combined with
the ion they bind.
Biological activities of metal ion-binding compounds can be changed in
response to the
increment of the metal concentration, and based on the latter characteristic,
compounds can be
classified as "metal ionophores", "metal chelators" or "metal shuttles". If
the biological effect i.s
augmented by increasing the metal concentration, it is classified as a "metal
ionophore". If the
biological effect is decreased or reversed by increasing the metal
concentration, it is classified as a
"metal chelator", if the biological effect is not affected by increasing the
metal concentration., and the
compoun.d-rneta.1 complex enters the cell, it is classified as a "metal
shuttle",
The term p-block element means an element from the group consisting of
Phosphorus (P),
Boron (B), Nitrogen (N), Carbon (C), Sulfur (S), Oxygen (0), Aluminum (Al),
Fluorine (F), Bromine
(Br), Indium (In), Silicon (Si), Arsenic (As), Argon (Ar), Lead (Pb), Bismuth
(Bi), Chlorine (Cl), Tin
(Sn), Iodine (I), Neon (Ne), Selenium (Se), Germanium (Ge), Xenon (Xe),
Antimony (Sb), Tellurium
(T), Krypton (Kr), Polonium (Po) Nihonium (Nh), Radon (Rn), Moscovium (Mc),
Oganesson (Og),
Flerovium (F1), Livermorium (Lv), and Tennessine (Ts).
The term d-block element means an element from the group consisting of Zinc
(Zn), Copper
(Cu), Chromium (Cr), Iron (Fe), Nickel (Ni), Cobalt (Co), Mercury (Hg), Gold
(Au), Manganese
(Mn), Cadmium (Cd), Silver (Ag), Titanium (Ti), Vanadium (V), Yttrium (Y),
Ruthenium (Ru),
Palladium (Pd), Molybdenum (Mo), Tungsten (W), Hafnium (Hf), Niobium (Nb),
Zirconium (Zr),
Osmium (Os), Platinum (Pt), Rhodium (Rh), Technetium (Tc), Tantalum (Ta),
Bohrium (Bh),
Copernicium (Cu), Lutetium (Lu), Rutherfordium (RI), Roentgenium (Rg),
Lawrencium (Lr),
Meitnerium (Mt), Hassium (Hs), Darmstadtium (Ds), Dubnium (Db), and Seaborgium
(Sg).
The term s-block element means an element from the group consisting of
Potassium (K),
Hydrogen (H), Beryllium (Be), Sodium (Na), Magnesium (Mg), Lithium, (Li),
Calcium (Ca), Barium
(Ba), Caesium (Cs), Rubidium (Rh), Strontium (Sr), Francium (Fr), Radium (Ra),
and Helium (He).
Abbreviations, nomenclature, and technical & non-technical term definitions as
used in
these Examples are as follows:
The phrase "A" or "an" in the context of an entity or moiety as used herein
refers to one or
more a that entity or moiety, as in for example, "a" compound refers to one or
more compounds or at
least one compound. As such, the terms "a" (or "an"), "one or more," and "at
least one," and "and or
"can" be used interchangeably. The term "about" has its plain and ordinary
meaning of
"approximately." Regarding metal ion ratios and dosing amounts, the qualifier
"about" reflects the
standard experimental error. The terms "optional" or "optionally" as used
herein means that a
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subsequently described event or circumstance may, but need not, occur and that
the description
includes instances where the event or circumstance occurs and instances in
which it does not. The
term "subject" as used herein, means any species in need of therapy or
supplementation, both non-
mammalian and mammalian animals, and humans. Preferably the subject is a
human. The term
"preparation" and "compound" or "compounds" and "formulation" or
"formulations" is intended to
include any of solid, liquid, or gaseous formulations of the active compounds,
and one skilled in the
art will appreciate that an active pharmaceutical ingredient ("API") can exist
in different preparations
depending on the desired dose and pharmacokinetic design parameters. The terms
"compositions" and
"excipient" and "pharmaceutical excipient" as used herein refer to a compound
used to prepare a
pharmaceutical composition and is generally safe, non-toxic, and neither
biologically nor otherwise
undesirable, and includes excipients that are acceptable for veterinary use as
well as human
pharmaceutical use. The term "dosage" intends to include either or both solid
and liquid formulations
of the active compound, and one skilled in the art will appreciate that an
active ingredient can exist in
different preparations of administration methods, percent of the API,
prescribed dose, length of use,
time of use, type of indication, desired outcome, and pharmacokinetic design
parameters. The term
"mixing" or "efficient mixing" as used herein is not limited to the same
compounding process; it
involves all mixing methods in a manufacturing process. The term "biological
system", as used
herein, refers to the interactions of the key elements such as DNA, RNA,
proteins, and cells
concerning one another in a subject. The term "Iontophoresis," as used herein,
is a process of
transdermal drug delivery by use of a voltage gradient for electromotive drug
administration (EMDA)
on the skin. Molecules are transported across the stratum corneum by
electrophoresis and
electroosmosis, and the electric field can also increase the permeability
through tissue membranes for
diagnostic or therapeutic use. As used herein, "treatment" or "treating" or
"therapy" or "therapeutic"
or "medicaments" or -prevention" is an approach for obtaining beneficial or
desired clinical results.
Beneficial or desired clinical results include, but are not limited to,
prevention, alleviation of
symptoms, diminishment of the extent of disease, stabilized state of disease,
delay or slowing of
disease progression, amelioration or palliation of the disease state, and
remission, whether detectable
or undetectable in part or total. "Treatment" can also mean prolonging
survival as compared to
expected survival if not receiving treatment. "Treatment" is an intervention
performed to eliminate or
prevent a disease or develop to eliminate or prevent a disease or alter a
medical disorder's pathology
in a biological system. The term "Ion Biotechnology Hex.a-aqua Delivery
System", describes the
invention as being a combination of Ion Biotechnology Aqueous Ligands, which
will be
abbreviated as "IBAL".
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"API" = Active Pharmaceutical Ingredient.
"Acid Mix" = A preparatory mixture of acids for use in the production of
compositions of the
invention, to receive metal salts or combinations thereof, as disclosed below.
API = Active Pharmaceutical Ingredient
BP = British Pharmacopoeia
CAS = Chemical Abstract Service Registry Number
EP = European Pharmacopoeia
FEUM = Farmacopea de los Estados Unidos Mexicanos
Ionophore = A substance which may reversibly bind ions and to transport
reversibly bound
ions across a lipid membrane in a cell.
NF = National Formulary
ORAC = Oxygen Radical Absorbance Capacity
ORP = Oxidation Reduction Potential
USP = United States Pharmacopoeia
Exogenous nutrient elements modulate the energetic metabolism responses that
are
prerequisites for cellular homeostasis and metabolic physiology. Specifically,
the delivery of
micronutrients in the form of metals is critical in oxidative stress and
cytoprotecting processes.
Commonly administered minerals and drugs are not in a highly bioavailable form
nor can they target
the immediate area of therapeutic or nutritional need. They are commonly
unable to effectively or
efficiently cross through a hydrophobic lipid bilayer membrane, whether by
active transport, or by
passive transport, and often for this reason fail to activate a natural
therapeutic response. With
nutrients, a key factor in membrane transport is the solubility of nutrients
as determined by their
molecular polarity properties (Dewey Holten, 1999).
Small molecule drugs widely disburse, and the more pharmacologically
promiscuous they
are, the more cell types are targeted, exacerbating the appearance of multiple
side effects, while many
may not be able to travel to the cell adequately or at all to exert their
pharmacologic action or
correctly or adequately influence extracellular pathways. The present
invention, or Ion
Biotechnology Aqua Ligand (IBAL), provides an effective carrier of polarized
molecules via active
transport across cell membranes. Natural active transport also occurs, as the
osmotic pressure of water
created by the presence of hexa-aqua ligands creates a dispersion of free ions
facilitated by polarity
and size (small molecular weight) throughout the interstitial fluids,
increasing direct uptake through
the lipid bilayer of the cellular membrane and into the cytoplasm of the cell.
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Reactions of the preferred embodiment hexa-aqua complexes of the invention in
an ammonia
solution arc complex because ammonia can act with two significantly different
functions. Firstly,
ammonia can act as a Bronsted-Lowry base, a ligand, or as a Lewis Base (Clark,
J., Reactions of the
Hexa-aqua Metal Ions With an Ammonia Solution. (2017, April 1), (Chemguide,
Editor) Retrieved
2021 from Chemguide:
https://www.chemguide.co.uk/inorganic/complexions/aquanh3.html#top.
Secondly, ammonia is also a possible ligand that can bond with water molecules
around a central
metal ion. This ligand appears when small amounts of a dilute ammonia solution
is added to metals,
creating a hexa-aqua ligand solution or a mixed aqua amine ligand system. At
equilibrium, amines are
acting as acids by donating hydrogen ions to water molecules in the solution.
According to Le
Chatelicr's Principle (When any system at equilibrium for a long period of
time is subjected to a
change in concentration, temperature, volume, or pressure, the system changes
to a new equilibrium,
and this change partly counteracts the applied change), if the ligand solution
is increasing in pH, the
equilibrium position will move to production of more of the new ammonia
complex ions replacing
hydronium ions A unique property of the present invention is the coordinated
complex ionic structure
that maintains the solution's equilibrium by two reactive processes. An
ammonia molecule is more
likely to cause the replacement of a water ion on the metal, instead of the
reverse exchange reaction
that occurs when the pH is low (under 1.0). If that low pH reaction is allowed
to go too far, it will
create a "neutral complex" consisting of one or more hydroxyl groups or mixed
hydroxyl (OH-),
water, and or amine groups, which can be insoluble in water, and so a
precipitate is formed. When
ammonia is acting in a ligand exchange reaction, ammonia replaces water around
the metal ion to
give a soluble complex. There is thus an interaction between the two
equilibria. To obtain a dissolved
precipitate, the invention needs the ligand exchange equilibrium to be correct
to maintain ionic
stability, but the invention also needs for the acid-base equilibrium to be
easily manipulated in reverse
as well. The present invention solves the difficulty in obtaining this
required balance in the reaction
process. The present invention, including its most preferred embodiment, an
Ion Biotechnology
Aqueous Ligand (IB AL) has been manufactured and researched in these completed
complexes
including obtaining the pH levels, Redox Potential values (ORP), and metal
cation ratios described
herein for the invention. Multiple in-vitro, in-vivo, and preclini cal animal
and human trials have been
performed, supporting the invention's safety, components, efficacy, and modes
of action in biological
systems.
The number of ammonia molecules is double the metallic ion valence, and the
valence charge
does not change at a low pH. The unshared pair of electrons from the ligand
bond is the ligand system
supplying both the unshared electrons to a free hydrated metal ion. The use of
transition metals is
critical to obtain the proper ligand bond. Transition Metal Ions may act as
Bronsted Acids while
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others like Cu2+ cannot by themselves, due to the delocalization of charge to
one or more of the aqua
ligands becoming acidic. The hydration reaction is defined as the transfer of
an ion or a neutral
chemical species from the gaseous phase into water; for metal ions Mn(g)
Mn+(aq) (Persson,
2010). These ligand reactions give rise to a net increase in the fl+ ion
concentration in these solutions,
thereby making the solutions acidic and a stable ligand exchange equilibrium.
To obtain the ligand
bond, at least one or more of the elements of the 3d block (scandium to zinc)
as a transition metal are
preferably and advantageously used in the IBAL coordinated ionic bond complex.
See Brown, D. P.
(2015). Introduction to 3d-block Transition Metal chemistry concepts
definition data table
characteristics variable ions oxidation states colored compounds complexes
catalysts high melting
points high density. Retrieved 2021 from Doc Brown's Chemistry:
http://www.docbrown.info/page07/transitionl.htm.
The addition of metals singly or in combinations of ratios in the
manufacturing process
include but are not limited to any one of Calcium, Chromium, Cobalt, Copper,
Iodine, Iron,
Magnesium, Manganese, Molybdenum, Nickel, Potassium, Selenium, Silver,
Vanadium, and Zinc
and any combination thereof, in any stable oxidation state. Additional
compounds are organic or
inorganic, such as, but not limited to, chemicals, molecules, proteins, urea,
and combinations with
other known pharmaceuticals, carriers, and personal care formulations
described in the specification
and in the claims for method of use.
The compounds of the present invention can be prepared readily according to
the following
Examples or modifications thereof using readily available starting materials,
reagents and
conventional synthesis procedures. In these reactions, it is also possible to
make use of variants which
are themselves known to those of ordinary skill in this art, but these are not
mentioned in greater
detail.
The most preferred compounds of the invention are any or all of those
specifically set forth in
these Examples. These compounds are not, however, to be construed as forming
the only genus that is
considered as the invention, and any combination of the compounds or their
moieties may itself form
a genus. The following examples further illustrate details for the preparation
and the quantitative and
qualitative analysis of the compounds of the present invention. Those skilled
in the art will readily
understand that known variations of the conditions and processes of the
following preparative
procedures can be used to prepare these compounds. All temperatures are
degrees Celsius unless
noted otherwise.
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EXAMPLE 1
A Zinc Hexa-aqua, Copper-Hexa-aqua, Magnesium Hcxa-aqua Composition 0.5 Kg
Batch:
ZCM-5/2/2
Target Metal
Ingredient Batch mass (Kg) Mass
Percentage
ion mass %
Sulfuric Acid 0.0170 3.40%
Ammonium Sulfate 0.0022 0.44%
Dcionizcd Water 0.2301 46.03%
Zinc Sulfate Heptahydrate 5% 0.1100 21.99%
Cupric Sulfate Pentahydrate 2% 0.0393 7.86%
Magnesium Sulfate Heptahydrate 2% 0.1014 20.28%
Total 0.5000 100.00%
In Step 1, Sulfuric acid was placed into a glass or glass lined reactor and
stirred at room
temperature. Ammonium sulfate was added while stirring and completely
dissolved. Deionized water
was then added, drop wise, slowly under constant stirring to minimize the
exothermic reaction
increasing temperature of the solution above 50 degrees Celsius and maintain a
temperature of less
than or equal to 45 degrees Celsius. The mixture was mixed to homogeneity and
allowed to cool back
to room temperature (-25 degrees Celsius).
in Step 2, the zinc sulfate heptahydrate was combined into the solution
prepared in Step 1
and mixed until completely dissolved and the solution was homogeneous. Then
the cupric sulfate
pentahydrate was added and mixed until completely dissolved and the solution
was homogeneous.
Finally, the magnesium sulfate heptahydrate was then added and mixed until
completely dissolved
and the solution was homogeneous. Mixing was continued for 12 hours until an
even consistency was
obtained at room temperature.
Starting material considerations and alternatives: Starting materials to
produce NH3 or NH4+
in an aqueous solution are advantageously ammonium water (0.5 - 28%), ammonium
sulfate or
ammonium hydrogen sulfate and sulfamic acid by any method of manufacture known
to those of
ordinary skill in the art. Starting materials to produce HSO4+ in an aqueous
solution are sulfuric acid
(1.0 - 98% concentration) or sulfamic acid, prepared by any method known to
those of ordinary skill
in the art. Starting materials to produce any or all of the starting materials
to produce metal hexa-aqua
ions in an aqueous solution are any metal sulfate, metal nitrate, metal
hydroxide, metal
hydroxide/amine species, metal amine, metal chloride, metal iodide, metal
bromide, metal carbonate,
or metal carbonyl including, but not limited to, any combination of ligands
stated.
Zinc Hexa-aqua, Copper-Hexa-aqua, Magnesium Hexa-aqua Compositions
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Using the procedure of Example 1, the following ingredients in the following
w/w% ranges
of component ions are combined, depending on administration and application:
Material w/w% Minimum w/w% Maximum
Sulfuric Acid 1.00% 4.50%
Ammonium Sulfate 0.01% 5.00%
Deionized Water 35.00% 75.00%
Zinc Sulfate Heptahydrate 10.00% 30.00%
Cupric Sulfate Pentahydrate 5.00% 10.00%
Magnesium Sulfate Heptahydrate 10.00% 30.00%
EXAMPLE 2
Zinc Hexa-aqua, Copper-Hexa-aqua, Magnesium Hexa-aqua and Selenous acid
Composition:
ZCMS-5/2/1/1 in a 0.5Kg batch
Target metal ion
Ingredient mass Mass percentage
Ingredient mass
(Kg) (w/w%)
percentage:
Sulfuric Acid 0.01997 3.99%
Ammonium Sulfate 0.00259 0.52%
Deionized Water Type 1 0.27049 54.10%
Zinc Sulfate Heptahydrate 5.0% 0.10992 21.98%
Cupric Sulfate Pentahydrate 2.0% 0.03929 7.86%
Magnesium Sulfate Heptahydrate 1.0% 0.05070 10.14%
Selenium Dioxide 1.0% 0.00704 1.41%
Total 0.5 100%
In Step 1, Sulfuric acid was placed into a glass or glass lined reactor and
stirred at room
temperature_ Ammo-nium sulfate was added while stirring until completely
dissolved_ Deionized
water was then added, drop wise, slowly under constant stirring to minimize
the exothermic reaction
increasing temperature of the solution above 50 degrees Celsius and maintain a
temperature of less
than or equal to 45 degrees Celsius. The mixture was mixed to homogeneity and
allowed to cool back
to room temperature (-25 degrees Celsius).
In Step 2, the zinc sulfate heptahydrate was combined into the solution
prepared in Step 1
and mixed until completely dissolved and the solution was homogeneous. The
cupric sulfate
pentahydrate was then added and mixed until completely dissolved and the
solution was
homogeneous. Finally, the magnesium sulfate heptahydrate was then added and
mixed until
completely dissolved and the solution was homogeneous. Mixing was continued
for 12 hours until an
even consistency was obtained at room temperature.
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Starting material considerations and alternatives: Starting materials to
produce NH3 or NH4+
in an aqueous solution are advantageously ammonium water (0.5 - 28%), ammonium
sulfate or
ammonium hydrogen sulfate and sulfamic acid by any method of manufacture known
to those of
ordinary skill in the art. Starting materials to produce HSO4+ in an aqueous
solution are sulfuric acid
(1.0 - 98% concentration) or sulfamic acid by any method known to those of
ordinary skill in the art.
Starting materials to produce any or all of the starting materials to produce
metal hexa-aqua ions in an
aqueous solution are any metal sulfate, metal nitrate, metal hydroxide, metal
hydroxide/amine
species, metal amine, metal chloride, metal iodide, metal bromide, metal
carbonate, or metal carbonyl
including, but not limited to, any combination of ligands stated.
Zinc Hexa-aqua, Copper-Hexa-aqua, Magnesium Hexa-aqua and Selenous acid
Compositions:
Using the procedure of Example 1, the following ingredients are combined in
the following
w/w% ranges of component ions, depending on desired route of administration
and application:
Material w/w% Minimum w/w% Maximum
Sulfuric Acid 1.00% 4.50%
Ammonium Sulfate 0.01% 5.00%
Deionized Water 35.00% 75.00%
Zinc Sulfate Heptahydrate 10.00% 30.00%
Cupric Sulfate Pentahydrate 5.00% 10.00%
Magnesium Sulfate Heptahydrate 10.00% 30.00%
Selenium Oxide 0.25% 5.00%
EXAMPLE 3
Zinc Hexa-aqua, Copper-Hexa-aqua, Magnesium Hexa-aqua and Sclenous Acid
Composition:
ZCMS-AHS-5/2/1/1 in a 0.5Kg batch
Following the procedure of Example 1, the ammonium sulfate is substituted with
ammonium hydrogen sulfate to compensate for the non-reacted sulfuric acid in
the reaction in
Example 1. In Step 2 from Example 1, selenium dioxide is added first, in the
same method as the
other metal salts are added. This formulation is a more efficient one-batch
synthesis using the method
of Example 1, to produce the preferred composition shown below:
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Target metal Mass
Ingredient
Ingredient ion mass
percentage
mass (Kg)
percentage: (w/w%)
Sulfuric Acid 0.01739
3.48%
Ammonium Hydrogen Sulfate 0.00576
1.15%
Deionized Water Type 1 0.26991
53.98%
Zinc Sulfate Heptahydrate 5.0% 0.10992
21.98%
Cupric Sulfate Pentahydrate 2.0% 0.03929
7.86%
Magnesium Sulfate Heptahydrate 1.0% 0.05070
10.14%
Selenium Dioxide 1.0% 0.00704
1.41%
Total 0.5000 100%
Using the procedure of Example 1 and the modifications noted above, there is
combined the
following ingredients in the following w/w% ranges of component ions,
depending on the preferred
route of administration and application:
Material w/w% Minimum w/w% Maximum
Sulfuric Acid 0.50% 4.50%
Ammonium Hydrogen Sulfate 0.05% 10.00%
Deionized Water 35.00% 80.00%
Zinc Sulfate Heptahydrate 10.00% 30.00%
Cupric Sulfate Pentahydrate 5.00% 10.00%
Magnesium Sulfate Heptahydrate 10.00% 30.00%
Selenium Oxide 0.05% 2.50%
EXAMPLE 4
Zinc Hexa-aqua, Copper-Hexa-aqua, Magnesium Hexa-aqua, Manganese Hexa-aqua,
and Selenous
Acid Composition:
ZCMMS-AHS-5/2/1/1/1 in a 0.5Kg batch
Using the procedure of Example 1, the ammonium sulfate is instead substituted
with
ammonium hydrogen sulfate and thereby will compensate for the non-reacted
sulfuric acid reaction
product of Example 1 when ammonium sulfate is used. In Step 2 of Example 1,
the selenium dioxide
is instead added in the same method as the other metal salts and is added
first, and manganese sulfate
is added second, after the selenous acid product is formed. This formulation
is a more efficient one-
batch synthesis of Example 1, to produce the preferred composition shown
below:
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Target mass Batch mass Mass
percentage
Ingredient
percentage inputs: (Kg) (w/w%)
Sulfuric Acid 0.01657 3.31%
Ammonium Hydrogen Sulfate 0.00549 1.10%
Deionized Water Type 1 0.25726 51.45%
Zinc Sulfate Heptahydrate 5.0% 0.10992 21.98%
Cupric Sulfate Pentahydrate 2.0% 0.03929 7.86%
Magnesium Sulfate Heptahydrate 1.0% 0.05070 10.14%
Selenium Dioxide 1.0% 0.00703 1.41%
Manganese Sulfate anhydrous 1.0% 0.01374 2.75%
Total 0.5000 100%
Using the procedure of Example 1 and modifications described above, there is
combined the
following ingredients in the following w/w% ranges of component ions,
depending on the desired
route of administration and application:
Material w/w% Minimum w/w% Maximum
Sulfuric Acid 0.50% 4.50%
Ammonium Hydrogen Sulfate 0.05% 10.00%
Deionized Water 35.00% 80.00%
Zinc Sulfate Heptahydrate 8.00% 25.00%
Cupric Sulfate Pentahydrate 3.00% 10.00%
Magnesium Sulfate Heptahydrate 8.00% 25.00%
Selenium Oxide 0.05% 5.00%
Manganese Sulfate anhydrous 0.05% 5.00%
EXAMPLE 5
Zinc Hexa-aqua, Copper-Hexa-aqua, Magnesium Hexa-aqua Compositions
Using the procedure of Example 1, there is combined the following ingredients
in the
following w/w% ranges of component ions:
Material w/w% Minimum w/w% Maximum
Deionized Water 50.00% 95.00%
Hydrogen Sulfate 5.00% 20.00%
Ammonium ion 0.01% 3.00%
Hexa-aqua zinc 2.00% 8.00%
Hexa-aqua copper 1.00% 3.00%
Hexa-aqua magnesium 1.00% 3.00%
Hydrogen cation 0.01% 0.50%
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The pharmaceutically acceptable salts of the compounds used in the
compositions of the
invention include the conventional non-toxic salts or the quarternary ammonium
salts of said
compounds formed, e.g., from non-toxic inorganic or organic acids, and for
example, such
conventional non-toxic salts include those derived from inorganic acids such
as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the
salts prepared from organic
acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic,
pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-
acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isethionic, and
the like. Generally, the salts are prepared by reacting the free base or acid
with stoichiometric
amounts or with an excess of the desired salt-forming inorganic or organic
acid or bases in a suitable
solvent or various combinations of solvents. The pharmaceutically acceptable
salts are also readily
prepared by conventional procedures such as treating an acid with an
appropriate amount of a base,
such as an alkaline or alkaline earth metal hydroxide e.g. sodium, potassium,
lithium, calcium, or
magnesium, or an organic base such as an amine, e.g., dibenzyl
ethylenediamine, trimethylamine,
piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium
hydroxide such as
tetramethylammonium hydroxide and the like.
The compounds of Formula I, may be administered to animals, preferably to
mammals, and
most especially to a human subject either alone or, preferably, in combination
with pharmaceutically-
acceptable carriers or diluents, optionally with known adjuvants, such as
alum, in a pharmaceutical
composition, according to standard pharmaceutical practice. The compounds can
be administered
orally or parenterally, including by intravenous, intramuscular,
intraperitoneal, subcutaneous, or
topical administration. For oral use of a composition according to this
invention, it may be
administered, for example, in the form of tablets or capsules, or as an
aqueous solution or suspension.
In the case of tablets for oral use, carriers which are commonly used include
lactose and corn starch,
and lubricating agents, such as magnesium stearate, are commonly added. For
oral administration in
capsule form, useful diluents include lactose and dried corn starch. When
aqueous suspensions are
required for oral use, the active ingredient is combined with emulsifying and
suspending agents. If
desired, certain sweetening and/or flavoring agents may be added. For
intramuscular, intraperitoneal,
subcutaneous and intravenous use, sterile solutions of the active ingredient
are usually prepared, and
the pH of the solutions should be suitably adjusted and buffered. For
intravenous use, the total
concentration of solutes should be controlled, to render the preparation
isotonic. When a composition
of the invention is used in a human subject, the daily dosage will normally be
determined by the
prescribing physician with the dosage generally varying according to the age,
weight, and response of
the individual patient, as well as the severity of the patient's symptoms.
However, in most instances.
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an effective daily dosage will be in the range of from about 0.005 mg/kg to
about 50 mg/kg of body
wcight, and preferably, of from about 0.05 mg/kg to about 50 mg/kg of body
weight, and most
preferably, of from about 0.5 mg/kg to about 20 mg/kg of body weight,
administered in single or
divided doses.
An ordinarily skilled formulation scientist may modify the formulations within
the
specifications' teachings to provide numerous formulations for a particular
administration route
without rendering compositions containing IBAL unstable or compromising their
therapeutic activity.
EXAMPLE 6
A Zinc Hexa-aqua, Copper-Hcxa-aqua, Magnesium Hcxa-aqua Composition Formulated
into a
Topical Gel Medicament
The composition product of Example 1, Ion ZCM 1, as the active ingredient, was
prepared in
a dermatological gel formulation for topical administration at a concentration
of 25% w/w, comprising:
Ingredient Amount
Purified Water 0.6625 gm
Ion ZCM 1 0.250 gm
SEPTNE0 DERM 0.043 gm
Sodium Hyaluronate PC 0.020 gm
Glycerin 0.020 gm
Sodium Hydroxide 0.005 gm
Ingredient Amount
Purified Water 0.665 gm
Ion ZCM 1 0.250 gm
SEPINIO D.E.R.M. 0.040 gm
Sodium Hyaluronate PC 0.020 gm
Glycerin 0.020 gm
Sodium Hydroxide 0.05
SEPINIOTM D.E.R.M. is a multi-functional powder polymer manufactured by
SEPPIC, CAS
number 111286-86-3, used for thickening, stabilizing/emulsifying, co-
stabilizing and texturizing all
dosage forms. This polymer needs no neutralization, works at all pH and
enables room-temperature
manufacturing. It is composed of hydroxyethyl acrylate, sodium acryloyl
dimethyl taurate copolymer,
and may function as a co-stabilizer, emulsifier-stabilizer, texturizing agent,
thickener, topical
excipient, and viscosity agent.
Example of the formulation of a 1 kg batch of Ion Gel ZCM-25
To 0.5625 kg of deionized water was slowly added the Sepineo Derm, then
stirred with a
teflon-coated marine propeller at 500 rpm until the Sepineo Derm had hydrated
completely, as
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demonstrated when no lumps were observed. The sodium hyaluronate PC was added
and stirred at
500 rpm until a homogeneous mixture was obtained. The glycerin was added and
mixed at 500
rpm until a homogeneous mixture was obtained. In a glass beaker, the sodium
hydroxide was
dissolved in 10% purified water (0.1 kg of purified water for 1 kg of Ion Gel
ZCM-25. The sodium
hydroxide solution was added to the mixture and stirred at 500 rpm until
homogenized, pausing
and stirring between each successive addition. The Ion ZCM-1 was added and
stirred at 750 rpm
until the mixture appeared homogeneous and no lumps or discolorations were
observed. The pH
of the product was measured, and sodium hydroxide solution was added until the
observed pH was
2Ø Ion Gel ZCM-25 - Production Process (Laboratorios Manuell, 2020).
Product analysis:
Determination Specifications Result Reference
Color Sky blue
Odor Odorless
pH 1.0 to 2.5 2.26 PLUM 12
Ed. MGA
0701 pages 493-494
Zinc ion Presence of a white precipitate Compliant FLUM
12 Ed. MGA
identification 0701 page
441
Copper ion Formation of a blue precipitate Compliant PLUM
12 Ed. MGA
identification 0511 page
438
Magnesium ion Formation of a white crystalline Compliant FEUM 12
Ed. MGA
identification precipitate 0511 page
439
Ion evaluation Copper ion: >0.025 to 0.063 gm Cu Compliant
USP 29-NF 24 Page
602
Viscosity To be in a range of 7,960 to 8,040 cP 8.030.67
cP PLUM 12 Ed. MGA
0951pages 520-523
EXAMPLE 7
A Copper hexa-aqua, Zinc hexa-aqua Composition (ZC-1)
Mass
Molar
Material/
Name Formula CAS Number Concentration
Concentration
Reagent
range w/w%
Hexa-aqua
433 mM
1 Copper (Ii) Cu(H20) 62 (aq) none 2.33%
Ion
Hexa-aqua
1300 mM
Zinc 01) Ion
2 Zn(H20)62' (aq) none 7.2%
Hydrogen
1120mM
3 H+ (aq) none 0.1%
Cation
4 Ammonium NH4+ (aq) 14798-03-9 1.43%
933 mM
Hydrogen
2350 mM
5 H504( aq) 14996-02-2 19.31%
Sulfate
6 Water H20 7732-18-5 69.64%
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EXAMPLE 8
A Hexa-aqua Delivery System of Zinc, Magnesium, and Copper Coordinated
Complexes
Material/ CAS Mass
Concentration
Name Formula
Reagent Number range
w/w%
1 Hexa-aquaCopper (I1) Ion Cu(H20) 62+ (aq) none
1.00-3.00%
2 Hexa-aquaZinc (I1) Ion Zn(H20)62+ (aq) none
2.00-8.00%
3 Hexa-aquaMagnesium (I1) Ion Mg(H20)62+ (aq)
none 1.00-3.00%
4 Hydrogen Cation 14+ (aq) none
0.01-0.5%
Ammonium NI-14+ (aq) 9 0.10-3.00%
03-14798-
14996-
6 Hydrogen Sulfate HSO4 (aq) 02-2
5.00-28.00%
7 Water H20 7732-18-
50-95%
5
EXAMPLE 9
5 A Copper hexa-aqua, Zinc hexa-aqua. Magnesium hexa-aqua Composition
Mass
Molar
Material/
Name Formula CAS Number Concentration
Concentration
Reagent
range w/w%
Hex a-
444 mM
1 aquaCopper Cu(H20) 62+ (aq) none 2.39%
(I1) Ion
Hexa-
1300 mIVI
2 aquaZinc (I1) Zn(H20)62+ (aq) none 7.2%
Ion
Hydrogen
1120mM
3 H+ (aq) none 0.1%
Cation
4 Ammonium NH4' (aq) 14798-03-9 1.43%
933 inM
H ydro en
2350 mM
g
5 HSO4- (aq) 14996-02-2 19.31%
Sulfate
6 Water H20 7732-18-5 69.64%
NMR Analysis of the Composition of Example 8, ZC-1. NMR studies verified the
presence of dominant NH4 ammonium ions. The NMR studies were conducted as
follows. An
original stock solution was diluted 100 times using a H20/D20 95/5% w/w
solvent and 1H NMR
spectra, with watergate water suppression technique, were collected first at
275 K temperature, to
slow down anticipated chemical exchange effects. The first spectra showed well
resolved triplets with
equal intensity of lines of 52 Hz splittings at 6.82 ppm chemical shift, with
an assumed water
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reference at 4.7 ppm. At the same time, there were observed low intensity
satellites to the left from
the main lines, well separated from the main triplet, that exhibited triplet-
like structure with small,
1.3-1.4 Hz splittings. Raising the temperature in two steps to 298 K and 320 K
proved the exchange
hypothesis. Referring to FIG. 1, the slow exchange between NH4+ protons and
solvent water were
increased by temperature, that caused first line broadening and then
coalescence of the two "species"
into a single broad line. The explanation of the triplet is that in a slowly
exchanging system, the four
equivalent protons show spin-spin coupling to the 14N nucleus. Since the
nuclear spin of 14N is I=1,
the proton lines were split to a triplet. The small satellites at the foot of
the signals were explained
take into account the presence of ca. 5% D20 in the solution. Then, 14NH3D+
groups were formed due
to an exchange with water that resulted in the pop-up of the three extra
signal, with the isotope shifted
from main signals. Their small triplets were due to the coupling of three
equivalent protons to one
deuterium of spin 1. To double check the deuterium isotope shift effect, a
solution was prepared,
containing 1M NH+4 ammonium ion. 50 p.1 of this solution was extended by 425
1 H20 and 25
1320 for NMR. Then an additional 25 1 1)20 was added. The two resulting
spectra are shown in
Figure 2, where it is seen that the amount of 14NH3D+ satellites has doubled.
In the presence of 10%
D20 there are also visible the new deuterium satellite signals of 14NH2D2+ ,
due to further deuteration.
There, multiplicity is five, due to two deuterons: m = 2n1+1 =2*2*1+1 = 5. The
concentration of this
solution allowed the observation of the low natural abundance 15N signals in
2D HISQC experiment
(16 hrs. acquisition at 273 K). This spectrum is shown in Figure 3. The ''.1\1
chemical shift is 32.4
ppm, which accorded with the predicted expected values for 15NH4+ (for charged
Lysine NH3 + groups
this is also around 32 ppm in proteins).
Acid Content of the Stock Solution. Using direct potentiometry: a 100-fold
serial dilution
was performed, and the pH was measured finding a pH= 2.3, indicating that even
the diluted sample
was also highly acidic. To measure the overall acid content, a pH-
potentiometric titration was carried
out. A 600 uL of stock acid solution was diluted to 6 mL, and the sample was
titrated by 0.2115
mol/dm3 NaOH solution. The resulting titration curve shown at FIG. 4 showed
three inflection
points. The first one, 11+ + NaOH = Na + + H70, at 0.3127 nil was attributed
to the base-consumption
of a strong acid (HSO4) in the sample, yielding a 1.12 mol/dm3 concentration
in the stock acid
solution. The second (less characteristic) pH-change, with an inflection point
at about 0.509 nil was
related to the formation of barely soluble metal-hydroxides, which is
characteristic for Cu(II) and
Zn(II) in a pH range near neutral. The sample is not homogenous in the pH = 6 -
8 range. This
phenomenon is well known for Cu' and Zn' and the reaction can be exemplified
by the reaction as:
2CuSO4 + 2Na0H = Cu2(OH)2(SO4) + Na2SO4, where the underlining indicated the
formation of a
solid precipitate. The third pH jump is related to the deprotonation of the
NH4 + ions: NH4 + + NaOH =
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NH3 + Na + + 1-120 The free ammonia (NH3) is a good ligand for both Cu' and
Zn2+ cations. The
reaction of the complex formation is as follows:
Cu' + 4N113 0 [Cu (NH3)412+ The formation of the tetra-amine complex results
in the
dissolution of the precipitates and a clear, bluish (azure) solution. The
analogous tetra-amine zinc
complex 1Zn (NH3)41' is colorless. The difference between the first and the
third inflection point
(1.06 -0.31 = 0.76 ml) gives CuNH4+= 2.69 mol/dm3 in the stock solution.
EXAMPLE 10
A Copper hexa-aqua, Zinc hexa-aqua, Magnesium hexa-aqua, Selenous acid, and
Manganese hexa-
aqua Composition
Mass Concentration
No. Name Formula CAS Number
range w/w%
1 Hexa-aqua Copper (I1) Ion Cu(H20) 62+ (aq) none
1.00-3.00%
2 Hexa-aqua Zinc (I1) Ion Zn(H20)6' (aq) none
2.00-8.00%
Hexa-aqua Magnesium (I1)
3 Mg(H20)62+ (aq) none 1.00-3.00%
Ion
Selenium Oxide
3 Se0(H0)24+ (aq) 7783-00-8 0.10-2.00%
dihydroxidc (IV) Ion
Hexa-aqua Manganese (II)
3 Mn(H20)6' (aq) none 0.10-3.00%
Ion
4 Hydrogen Cation H (aq) none 0.01-0.5%
5 Ammonium NH4+ (aq) 14798-03-9 0.01-
3.00%
6 Hydrogen Sulfate H504( aq) 14996-02-2 5.00-
28.00%
7 Water H20 7732-18-5 50-95%
Metal ratios are 5 Zn:2 Cu:! Mg:0.5 Se:0.5 M
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EXAMPLE 11
A Copper (II) hexa-aqua, Zinc (II) hexa-aqua, Magnesium (II) hexa-aqua
Composition
Mass
Material/
Name Formula CAS Number
Concentration
Reagent
range w/w%
1 Hexa-aqua Copper (I1) Ion Cu(H20) 62+ (aq)
none 1.00-2.50%
2 Hexa-aqua Zinc (I1) Ion Zn(H20)62+ (aq)
none 3.50-5.00%
3 Hexa-aqua Magnesium (I1)
Mg(H20)62+ (aq) none
1.00-2.50%
Ion
4 Hydrogen Cation 1-1+ (aq) none
0.01-3.00%
Ammonium NH4 + (aq) 14798-03-9 0.05-3.00%
6 Hydrogen Sulfate HSO4- (aq) 14996-02-2 18.00-
20.00%
7 Water H20 7732-18-5 70.0%-
71.5%
EXAMPLE 12
5 A Copper (II) hexa-aqua, Zinc (II) hexa-aqua Composition
Material/Reagent Name Formula CAS
Number
1 Hexa-aqua copper (II) Ion
Cu(H20)62+ None
2 Hexa-aqua zinc (II) Ion Zn(H20)62+ None
3 Hydrogen Cation 1-1+ None
4 Ammonium NH4 + 14798-03-
9
5 Hydrogen Sulfate HS01- 14996-02-
2
6 Water H20 7732-18-5
EXAMPLE 13
Rcdox Potential Assay
A Redox Potential Assay of ZCM-1 was measured at 453.2 mV using method SM2580B
EXAMPLE 14
Oxygen Radical Absorbance Capacity (ORAC) Activity Assay ION ZCM-1 yielded
ORAC values of:
= Total ORAC = H-ORAC value of 1138 tiM TE /100 g
= Total ORAC value for 1ION-ZCM11 is 1025 0/1 TE/ml when measured at a
dilution of 12.5%
= Total ORAC value for [ION-ZCM1] is 740 uM TE/ml when measured at a dilution
of 6.25%
= Comparators:
= Total ORAC value for Vitamin E is 580 to 585 timol TE/g at 1:1
= Total ORAC value for Vitamin C is 128 to 133 funol TE/g at 1:1
= Total ORAC value for Pepper Leaf Extract is 64.47 ttmol TE/g at 1:50 or
approximately a 2%
solution.
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Materials and methods disclosed at INDEVION Biotechnology Research and
Development.
(2018). ORAC Study of Antioxidant Capabilities. University of Debrecen, Dept.
Microbial
Biotechnology and Cell Biology, Faculty of Natural Sciences and Technology.
Debrecen, Hungary:
Dr. Zsolt Keresztessy, PhD, MBA. Retrieved 2021 from
https://drive.google.com/file/d/1HDhtRcW9D-F-dKDuA-
YxnQWukne3UnCO/view?usp=sharing, the
entire disclosure of which is incorporated herein by reference.
EXAMPLE 15
Anti-Tumor Efficacy Studies in Mouse Melanoma
The compositions of the invention attack a multitude of cancer pathways. Three
specific in-
vitro and in-vivo preclinical studies have shown anti-cancer activities of ZC-
1.
A first study concluded the following: (Anti-Tumor Efficacy Study by
Intravenous Injection
¨ B16 Mouse Melanoma ¨30 Mice. Completed in 2016 by the University of
Debrecen, Hungary) that
safety abnormalities compared to control tumor mice were not noted for any of
the animals when
necropsied at the conclusion of the 14-day observation period.
Histopathology: tumors isolated from mice treated with various concentrations
of the
invention by IV injections show massive necrosis, which is not pronounced as
much in tumors
isolated from control tumor mice; blood vessels were much less frequent, and
less developed in the
invention-treated mice compared to control tumor mice; and invention
composition by injection
resulted in spleen enlargement, which is remarkably (2-3 times) bigger in
extent than that of the
spleen of control (untreated) tumor mice and was consistent with the invention
inducing a strong anti-
tumor immune response.
A second study concluded the following: (Topical Cream Anti-Tumor Efficacy
Study ¨
Syngeneic Mouse Melanoma ¨ 30 Mice. Completed in 2017 by the University of
Debrecen,
Hungary); the invention composition formulated in a topical cream (17%) was
significantly
efficacious against metastatic mouse melanoma as tested in a subcutaneous
syngeneic mouse model
(B16-F0 in C57BL/6J mice); was more efficacious than Imiquimod Topical Cream
(5%); showed that
tumor volumes recorded over the treatment period in the three animal model
groups supported the
observation that tumor growth was slower, having been inhibited by the
invention composition
topical cream (17%), and its effect was more pronounced when compared to the
inhibitory effect of
ALDARA (5% Imiquimod), the positive control substance, on tumor growth; and
that the invention
composition topical cream (17%) treatment extended survival time.
A third study concluded the following: that the invention composition
formulated in a
solution was a responsive cytotoxic agent against renal carcinoma cell line
Caki-1 (1050 36.12 1.00
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LM), in triple negative breast cancer (MDA-MB-231), and melanoma cancer cell
line A375 (IC50
95.20 1.01 uM) while also highly selective whcn comparcd to the cytotoxicity
of the invcntion
composition on control cells IMR-90 (IC50 142.6 6.65 ilM): and that the
invention composition in
solution form induced apoptotic death in 92% of renal carcinoma cell line Caki-
1 at dose IC50 36.12
1.00 ittM.
EXAMPLE 16
Antimicrobial Activity of ZC-1
ZC-1 Product Type of Study Pathogen Pathogen Pathogen Name
Test Method
Concentratio Type Code
II
1.063 % v/v Broth Gram N - ATCC
ESCHERICHIA COLT CLSI-BMD
Microdilution Bacteria 25922
0.354 % v/v Broth Gram P - ATCC
STAPHYLOCOCCUS CLSI-BMD
Microdilution Bacteria 29213 AUREUS
2.125 % v/v Broth Gram N - ATCC
PSEUDOMONAS CLSI-BMD
Microdilution Bacteria 27583 AERUGINOSA
1.063 % v/v Broth Gram N - ATCC
KLEBSIELLA CLSI-BMD
Microdilution Bacteria 70603 PNEUMONIAE
0.531 % v/v Broth Gram N - ATCC
ENTEROCOCC US CLSI-BMD
Microdilution Bacteria 29212 FAECALIS
E063 % v/v Broth Gram N - ATCC PR
OTEUS MIR ABILIS CLSI-BMD
Microdilution Bacteria 61370
0.133 % v/v Broth Fungus ATCC
CANDIDA CLSI-BMD
Microdilution 10231 ALBICANS
<0.008 % v/v Broth Fungus ATCC
CANDIDA CLSI-BMD
Microdilution 90030 GLABRATA
0.0170 % v/v Broth Fungus ATCC
CANDIDA CLSI-BMD
Microdilution 22019
PARAPSILOSIS
0.1773 % v/v Broth Fungus ATCC CANDIDA
CLSI-BMD
Microdilution 750 TROPICALIS
0.0330 % v/v Broth Fungus ATCC
SACCHAROMYCES CLSI-BMD
Microdilution 20446 CEREVISIAE
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ZC-1 Pathogen Name Test Time Test Count Kill
Rate
ESCHERICHIA COLT 24 Hours 1x10^3 CFU/mL 50%
Turbidity
Reduced
STAPHYLOCOCCUS 24 Hours lx10^3 CFU/mL 50%
Turbidity
AUREUS
Reduced
PSEUDOMONAS 24 Hours 1x10^ 3 CFU/mL 50%
Turbidity
AERUGINOSA
Reduced
KLEBSIELLA 24 Hours 1x10^3 CFU/mL 50%
Turbidity
PNEUMONIAE
Reduced
ENTEROCOCCUS 24 Hours 1x10^3 CFU/mL 50%
Turbidity
FAECALIS
Reduced
PROTEUS MIRABILIS 24 Hours 1x10^3 CFU/mL 50%
Turbidity
Reduced
CANDIDA ALBICANS 24 Hours lx10^3.5 CFU/mL 50%
Turbidity
Reduced
CANDIDA GLABRATA 24 Hours lx10^3.5 CFU/mL 50%
Turbidity
Reduced
CANDIDA PARAPSILOSIS 24 Hours 1x10^3.5 CFU/mL 50%
Turbidity
Reduced
CANDIDA TROPICALIS 24 Hours lx10^3.5 CFU/mL 50%
Turbidity
Reduced
SACCHAROMYCES 24 Hours 1x10^3.5 CFU/mL 50%
Turbidity
CEREVISIAE
Reduced
EXAMPLE 17
MRSA Antimicrobial Activity of ZC-1
ZC-1 Product Type of Study Pathogen Pathogen Pathogen Name
Test Method
Concentration Type Code
0.425 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 43032 aureus
(MRSA)
0.212 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 43088 aureus
(MRSA)
0.212 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 43072 aureus
(MRSA)
0.212 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 42631 aureus (MRSA)
0.212 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 42762 aureus
(MRSA)
0.212 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 43167 aureus
(MRSA)
0.212 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 43100 aureus
(MRSA)
0.425 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 43221 aureus (MRSA)
0.212 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 42472 aureus
(MRSA)
0.425 % v/v Broth Gram P - ATCC
Staphylococcus CLSI-BMD
Microdilution Bacteria 12890 aureus
(MRSA)
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ZC-1 Pathogen Name Test Time Test Count Kill Rate
Staphylococcus 24 Hours lx10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
Staphylococcus 24 Hours lx10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
Staphylococcus 24 Hours 1x10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
Staphylococcus 24 Hours lx10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
Staphylococcus 24 Hours 1x10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
Staphylococcus 24 Hours 1x10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
Staphylococcus 24 Hours lx10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
Staphylococcus 24 Hours lx10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
Staphylococcus 24 Hours lx10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
Staphylococcus 24 Hours 1x10^3 CFU/mL 50%
Turbidity Reduced
aureus (MRSA)
EXAMPLE 18
Antimicrobial Activity of ION ZCM-1
ION- Product Type of Pathogen Pathogen Pathogen Name
Test Method
ZCM-1 Concentration Study Type Code
100% Microbial Gram N. ATCC Pseudomonas
AOAC 17th Ed.
challenge Bacteria 15442 aeruginosa
Cap.6 page 10
100% Microbial Gram P. ATCC Staphyloccoccus
NMX-BB-040-
challenge Bacteria 6538 aureus
SCFI-1999
100% Microbial Gram N. ATCC Escherichia coli
NMX-BB-040-
challenge Bacteria 11229
SCFI-1999
ION Pathogen Name Test Time Test Count Kill Rate
ZCM-1
Gram N. Bacteria 30 seconds 0 UFC/M1 >120 000 000
UFC/mL; 100%
Gram P. Bacteria 30 seconds 0 UFC/M1 >87 000 000
UFC/mL; 100%
Gram N. Bacteria 30 seconds 0 UFC/M1 >110 000 000
UFC/mL; 100%
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EXAMPLE 19
Antimicrobial Activity of the Product of ION GEL ZCM-25
ION Product Type of Study Pathogen Pathogen Pathogen
Name Test Method
GEL Concentration Type Code
ZCM-
25% Microbiological Gram+ Not
Staphyloccoccus FEUM 12a.
analysis bacteria avail able
aureus Ed. Page
Gram- Pseudomonas
464
bacteria aeruginosa
!,
25% Microbiological Gram+ Not
Staphyloccoccus FEUM 12a.
analysis bacteria available aureus
Ed. Page
Gram - Pseudomonas
464
bacteria aeruginosa
!,
25% Microbiological Gram+ Not
Staphyloccoccus FEUM 12a.
analysis bacteria available aureus
Ed. Page
Gram - Pseudomonas
464
bacteria aeruginosa
.,
25% Microbiological Gram+ Not
Staphyloccoccus FEUM 12a.
analysis bacteria available aureus
Ed. Page
Gram - Pseudomonas
464
bacteria aeruginosa
!,
25% Microbial Gram N. ATCC Pseudomonas
AOAC 17th
challenge Bacteria 15442 aeruginosa
Ed. Cap.6
page 10
!, 25% Microbial Gram P. ATCC
Staphyloccoccus NMX-BB-
challenge Bacteria 6538 aureus
040-
25% Microbial Gram N. ATCC Escherichia
coli NMX-BB-
challenge Bacteria 11229
040-SCEI-
1999
!,
25% Microbiological Mesofflicos Not Mesofflicos
FEUM 12a.
analysis aerObios available aerobios
Ed. Page
464
.,
25% Microbiological Hongos y Not Hongos
y FEUM 12a.
analysis levaduras available levaduras
Ed. Page
464
!,
25% Microbiological Gram+ Not
Staphyloccoccus FEUM 12a.
analysis bacteria available aureus
Ed. Page
464
!,
25% Virucidal Virus ATCC SARS CoV-2
E 1053-97
activity test VR-796
(Equine
arteritis)
!,
25% Microbial Bacterium ATCC MRSA
E 1053-97
activity test 33591
(MRSA)
!,
25% Fungicidal Fungus ATCC Aspergillus
E 1053-97
activity test 16404 brasiliensis
(A spergillus)
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ION GEL Pathogen Name Test Time Test Count Kill
Rate
ZCM-25
Staphyloccoccus aureus NA 0 UFC/M1
100.00%
Pseudomonas aeruginosa 0 UFC/M1
100.00%
Staphyloccoccus aureus NA 0 UFC/M1
100.00%
Pseudomonas aeruginosa 0 UFC/M1
100.00%
Staphyloccoccus aureus NA 0 UFC/M1
100.00%
Pseudomonas aeruginosa 0 UFC/M1
100.00%
Staphyloccoccus aureus NA 0 UFC/M1
100.00%
Pseudomonas aeruginosa 0 UFC/M1
100.00%
Pseudomonas aeruginosa 30 seconds 0 UFC/M1 >120
000 000
UFC/mL; 100%
Staphyloccoccus aureus 30 seconds 0 UFC/M1 >87
000 000
UFC/mL; 100%
Escherichia coli 30 seconds 0 UFC/M1 >110
000 000
UFC/mL; 100%
Microbiological analysis NA <10 UFC/g
100.00%
Microbiological analysis NA <10 UFC/g
100.00%
Microbiological analysis NA 0 UFC/M1
100.00%
Virucidal activity test 10 minutes <20 Remaining
99.9999%
(Equine arteritis) Viral Titre
Microbial activity test 30 seconds 1'200,000
99.990%
(MRSA)
Fungicidal activity test 30 seconds 25,000
99.9561%
(Aspergillus
brasiliensis)
EXAMPLE 20
Biofilm Reduction Activity of the Product of ZC-1
ZC-1 Product Type of Study Pathogen Pathogen
Pathogen Test
Concentration Type Code Name
Method
6.25% Broth Biofilm ATCC22953 Bioflim CLSI-
Microdilution
BMD
ZC-1 Pathogen Name Test Time Test Count Kill Rate
Biofilm 24 hours lx10^3 CFU/mL 50%
Turbidity Reduced
EXAMPLE 21
Anti-MRSA Activity of ZC-1
A non-biofilm antimicrobial assay using the broth microdilution-based
sensitivity method was
completed at thc University of Debrecen. Hungary. The results showed that
minimum inhibitory
concentration (MIC) values for ZC-1 against the 10-methicillin-resistant
Staphylococcus aureus isolate
tested were in the range of 0.212 ¨ 0.85% (v/v). The Control for Vancomycin
MIC values was in the
range of 4-16 mg/L. The study compares the average MIC value of Example 6 of
0.531% (v / v) with
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the average MIC value of 10 mg / L for vancomycin. A percentage solution
calculation established
that twice the amount of vancomycin was needed to crcatc the same 50%
turbidity reduction in MRSA
when tested in comparison to ZC-1.
EXAMPLE 22
Safety Studies
Study Composition Title Result
A ZC-1 Acute Intravenous Non-toxic at
test dosage of 667
Toxicity in Mice mg/kg mouse body
weight
ION ZCM-1 Cell-based in Vitro By a HACAT
human cell line-
Cytotoxi ci ty based, the MTT
Cytotoxicity
test method established a
safety profile for topical use at
up to 25% concentration.
ION GEL ZCM-25 Dermic Irritation of At up to
five times greater than
the Product on the proposed
human dosing
Rabbits - Multiple over three 24-
hour
3-day Dose. applications,
there was no
irritability on the test rabbit.
ION GEL ZCM-25 Dermic Irritation of On a topical
administration
the Product on over one day at
the proposed
Rabbits - Single human dosing
there was no
Dose. irritability or
adverse reactions
on the test rabbits
ION GEL ZCM-25 Dermic Irritation of No
irritability or adverse
the Product on reactions on the
20 clinical trial
Humans. Chronic subjects
following 14 days of
dosing over 14 administration
at the proposed
Days with 20 trial human dosing.
subjects.
Completed as a
fully registered
Clinical Phase 1
Trial
While the above description contains much specificity, these should not be
construed as
limitations on the scope of any embodiment, but as exemplifications of the
presented embodiments
thereof. Many other alternative embodiments and variations are possible within
the teachings of the
various embodiments. While the invention has been described with reference to
exemplary
embodiments, it will be understood by those skilled in the art that various
changes may be made, and
equivalents may be substituted for elements thereof without departing from the
scope of the
invention. In addition, many modifications may be made to adapt a particular
situation or material to
the teachings of the invention without departing from the essential scope
thereof. Therefore, it is
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intended that the invention will not be limited to the particular embodiment
disclosed as the best or
only mode contemplated for carrying out this invention, but that the invention
will include all
embodiments falling within the scope of the appended claims. Also, in the
drawings and the
description, there have been disclosed exemplary embodiments of the invention
and, although
specific terms may have been employed, they are, unless otherwise stated, used
in a generic and
descriptive sense only and not for purposes of limitation, the scope of the
invention therefore not
being so limited. Moreover, the use of the terms first, second, etc. do not
denote any order or
hierarchy of importance, but rather the terms first, second, etc. are used to
distinguish one element
from another. Furthermore, the use of the terms a, an, etc. do not denote a
limitation of quantity, but
rather denote the presence of at least one of the referenced items.
While the invention has been described, exemplified, and illustrated in
reference to certain
preferred embodiments thereof, those skilled in the art will appreciate that
various changes,
modifications, and substitutions can be made therein without departing from
the spirit and scope of
the invention.
It is intended, therefore that the invention be limited only by the scope of
the claims which
follow, and that such claims be interpreted as broadly as is reasonable.
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