Synthetic cell membrane chemical ionophore delivery systems containing hexa-aqua ligand compositions

Abstract

Synthetic ionophores for the active delivery and transport of free ions across biological membranes in vivo include coordination complexes of molecules with polarized hexa-aqua and / or tetra-aqua systems of free ionic metals and ionic salts as ionophores, and are useful for the delivery of pharmaceutical, nutritional, and personal health care compounds. Methods for their administration, methods for their synthesis and preparation, and ionophore products of such synthesis and preparation methods are also described.

Description

[Technical field]

[0001] The present invention relates generally to synthetic ionophores for carrying and transporting free ions across biological membranes in vivo, and more particularly to the use of coordination complexes of molecules with polarized hexaaqua and tetraaqua systems of free ionic metals and ionic salts as ionophores, useful in transporting pharmaceutical and personal health care compounds across biological membranes in vivo to target cellular metabolic systems and thereby produce desired pharmacological effects useful in metabolic, immune, and other biological disorders and infectious disease treatment. The compositions of the present invention relate to the scientific fields and subjects of inorganic and organic medicinal chemistry, redox values, pH, molecular biology, pharmacokinetics, microbiology, cell biology, particularly mammalian cell biology, physiology, and physiological chemistry. [Background technology]

[0002] There is a general need for pharmaceutical therapeutics for treatment regimens that have improved safety, efficacy, tolerability, improved side effect profile, reduced duration of action, reduced production costs, greater chemical stability, reliably repeatable batch production, potential for scalability with increasing size of batch output, better affordability, ease of administration, availability, suitable for distribution, and have an extended shelf life, especially in remote areas and hot or humid climates.

[0003] Furthermore, there is a global need in pharmaceutical therapeutics for non-toxic active drug delivery systems designed to target biological functions with mechanisms that more closely mimic natural processes. Similarly, there is a need for active molecule delivery systems that can be applied in the fields of nutrition and personal care as well as therapeutics.

[0004] In the field of infectious diseases and antibiotics therapeutics, there is a need for methods of disease treatment and prevention based on research into understanding cellular redox reactions, both for antioxidants and pro-oxidants acting within cells, and on complex ionic structures that allow (1) the delivery of positive bonds, which is the action of cations, and (2) the oxidizing free radical effect, which is the action of anions. Redox research further explores the biological role of redox switches and redox relays in clinical proteomics and metabolomics to reduce oxidative and nitrosative stress on biological systems. The compounds of the present invention enable and support such research.

[0005] Redox signaling - RSS, RNS, and ROS modes of action. Redox balance is the chemical mechanism underlying all biological processes. Biological homeostasis is generated, regulated, and sustained by oxidation-reduction (redox) reactions that drive photosynthesis, respiration, and most other biological reactions necessary for living systems to function. Oxidative stress is thought to cause abnormal 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. Non-Patent Document 1.

[0006] The key to the operation of many biological mechanisms to restore normal biological function is the normal function of the redox system, which consists of the chemical interaction of one or all of the following reactive species: reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS). Non-Patent Document 2. These species play a dual role as both toxic compounds when unbalanced and beneficial compounds when balanced. The delicate balance between their two antagonistic effects is clearly a critical aspect of life. Non-Patent Document 3. The invention disclosed herein identifies the presence of the elements oxygen, nitrogen, and sulfur, in their respective forms as reactive species, potentially involved in the targeting of redox signaling processes in metabolic pathways, and in the targeting of key metabolic intermediates. These reactive species provide electron transport for multiple cell signaling pathways, redox systems, and homeostasis.

[0007] Reactive oxygen species - ROS. Cationic hydrogen (H + (aq)) is converted to either the hydroxyl radical (HO·) or the radical oxygen (O2 - ), and in excess is also known to be a factor in oxidative stress, cellular senescence (broken telomere length), and DNA methylation.

[0008] Reactive nitrogen species-RNS. Cationic metal amine complexes (NHT(aq)) are electron donors for nitrogen reduction and / or act as ammonia (NH3) ligands to trigger glutamate production used in amino acid synthesis. Oxidative stress is a well-established phenomenon occurring in neurodegenerative diseases. This, coupled with increased apoptosis and autophagy, contributes to the neurodegeneration and memory loss observed in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Excessive reactive oxygen and nitrogen species are highly abundant in these diseases. Novel antioxidant and mitochondrial-based therapies targeting such imbalances are expected to reduce neuronal cell loss and promote neuroprotection, which will have a positive effect on patient outcomes. Non-Patent Document 4.

[0009] Reactive Sulfur Species-RSS. Anionic sulfur (HSO4(aq)) induces redox switches and redox relays. Sulfur is considered part of the antioxidant system of cells, and there is growing evidence that RSS imbalance has similar stressor-like properties as those seen in ROS imbalance, but forms under certain conditions as a distinct class of oxidative stressor. Non-Patent Document 5.

[0010] Metabolic activity. More specifically, there is a need to realize a non-toxic delivery system to cells that provides prophylactic or therapeutic use of metal cations delivered to the site of action. The compositions of the present invention fulfill this need by utilizing aqua ligand binding, preferably hexa-aqua ligand or tetra-aqua ligand sites, most preferably hexa-aqua ligand sites, which can effectively protect such metal cations from being immediately combined with the first available anion, thus allowing polar movement between and within living cells. Such aqua ligand binding sites, including the compositions of the present invention, can exploit the distinct differences between (1) aerobic cells (whether they are continuing the process toward apoptosis or they are changing toward a mutational state) and (2) anaerobic cells (whether they are in a pathogenic or cancerous state) in their respective different aerobic versus anaerobic behavior in glycolysis, the citric acid cycle, cellular respiration, or the electron transport chain.

[0011] Anaerobic processes do not require oxygen, whereas aerobic processes do. The citric acid cycle is an aerobic process and therefore directly involves the use of oxygen. The compositions of the present invention support this process by donating positive hydrogen electrons, producing hydronium ions, HO. + Protons in the form of H +The generation and maintenance of hydronium ion equilibrium concentration is an essential element in managing chemical reactions occurring in aqueous solutions of the compositions of the present invention. The concentration of hydronium ions relative to hydroxide is a direct measure of the pH of a given solution. Hydronium ions are formed when protonic acids are present in water. The compositions of the present invention contribute to the removal of high energy electrons from bioavailable carbon fuels. These high energy electrons are used to reduce O2 to produce protons (H + ) gradient. The reduction of O2 and the synthesis of adenosine triphosphate (ATP) constitute oxidative phosphorylation.

[0012] Glycolysis. Glycolysis occurs in all living cells and is thought to be one of the first types of respiration to have evolved in anaerobic cells (estimated to have occurred billions of years before the metabolic use of oxygen). Glycolysis occurs in the cytoplasm of the cell, and glycolysis precedes the citric acid cycle. The process of glycolysis requires the use of two adenosine triphosphate (ATP) molecules. ATP, which constitutes the molecular metabolic currency, is advantageously enhanced by the transport assistance of the metal cations of the present invention as part of nutrient intake. When glucose is broken down from a six-carbon sugar molecule to two three-carbon sugar molecules, pyruvate, four ATP and two NADH (reduced nicotinamide adenine dinucleotide) molecules are produced. NADH is transported to the citric acid cycle to generate more ATP under aerobic conditions. In the absence of oxygen, pyruvate cannot enter the citric acid cycle and is further oxidized to generate lactic acid. Both fermentation and oxidative stress (O2) are produced by anaerobically functioning cells and promote the continuation of the anaerobic cellular environment. Formulations containing the compositions of the present invention utilize the available hydrogen (H) donated by the aqua ligand ionic species or mixed hydroxyl / aqua ligand ionic species of the present invention. + ) cations are used to reduce this stress.

[0013] The citric acid cycle. The citric acid cycle constitutes the first step of cellular respiration and removes high-energy electrons from carbon fuels. These electrons provide the proton gradient (H + The reduction of O2 and the synthesis of ATP constitute oxidative phosphorylation. The compositions of the present invention produce H + and O2 electrons directly to the electron transport chain, thereby facilitating the functioning of the citric acid cycle and allowing the anaerobic cellular environment to be appropriately reduced. The citric acid cycle occurs in the matrix of mitochondria. It is a series of chemical reactions and electron transfers used by all aerobic organisms to generate energy. In the absence of oxygen, the respiratory cycle cannot function, shutting down the citric acid cycle and potentially initiating anaerobic cellular metabolism. In the absence of NAD+ production, the relative ratio of NADH to NAD+ increases, triggering glycolysis and producing lactate instead of pyruvate, a necessary component of the citric acid cycle. The citric acid cycle is highly dependent on oxygen and is considered to be an aerobic process.

[0014] Electron transport chain. When NADH is reduced to NAD, the electron transport chain receives electrons from molecules. As electrons are transferred to each carrier in the electron transport chain, free energy is released and 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 present invention can act at the atomic level to transfer electrons by utilizing natural electron donors through redox reactions across cell membranes, positively altering dysfunctional electron transport chains.

[0015] Mitochondrial function. Metabolic processes, and multiple enzymes that enable metabolic processes, occur within mammalian mitochondria and include β-oxidation of fatty acids, the urea cycle, the citric acid cycle, and ATP synthesis, each of which is critical to many metabolic pathways in cells. There is a need for the identification of novel reactive species involved in such intracellular redox signaling and novel redox pathways to address diverse dietary and medical interventions. The compounds of the present invention enable the identification of such novel reactive species. Equilibrium interactions and proper balance between specific micronutrients at the cellular level are necessary for the alleviation of illness and disease. The establishment of biological homeostasis through corrective mitochondrial metabolism is a highly cost-effective method of disease prevention. The compounds of the present invention can assist in the control of diseases and health problems through their action in achieving balanced redox processes. Persistent physical impairment of cellular redox processes occurs before and after severe illness, and recent clinical data points to mitochondrial dysfunction as an essential determinant of this problem. The primary targets of redox modulators are generally small molecule "reactive species" such as ROS, RNS, and RSS. The biological effects and underlying chemical properties of these reactive species, often inorganic, provide a complete picture of redox regulation.

[0016] Anti-cancer activity. One of the modes of action of the compositions of the present invention is that they target cancer cells through apoptosis. Clinical studies on several human cancer cell types have used the natural cell death mechanism as an anti-cancer treatment. It is the activity of the compositions of the present invention to treat diseased biological systems to enhance the natural function of apoptosis in order to prevent or treat cancer. The activity of superoxide dismutase (SOD) is often decreased 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 anti-cancer activity by activating the apoptosis pathway.

[0017] Harnessing the natural mechanisms of cell death is a highly effective therapeutic approach. Drugs targeting apoptosis are some of the most successful non-surgical treatments. As apoptosis evasion is a hallmark of cancer, some have proven effective in all cancer cells, but at the cost of being highly cytotoxic. See Non-Patent Document 6. The compositions of the present invention generate apoptotic signals in several forms through the action of cationic metal delivery, Zn / Cu SOD, redox signaling, and reduction of free radicals. These modes of action contribute to altering the tumor environment through cell death induced by extracellular signals produced by the compositions of the present invention.

[0018] Reactive oxygen species (ROS) are increasingly recognized as important determinants of cell signaling, and a strict balance of ROS levels must be maintained to ensure proper cell function and survival. Non-Patent Document 7. Cancer cells switch metabolism to glycolysis to meet their energy requirements, known as the Warburg effect. One of the anti-cancer activities of the composition of the present invention is that it can exploit the Warburg effect to drive cancer cells further into the cellular respiration process, thereby causing apoptotic death.

[0019] Antimicrobial Mode of Action. As specifically described and disclosed below, multiple studies support the antimicrobial efficacy of the compositions of the present invention. Anaerobic cells can be clinically induced to experience cytoplasmic metal intoxication from an overload of natural metal cations that can be discreetly delivered by the compositions of the present invention, causing necrosis and / or apoptotic (programmed) cell death. Non-Patent Document 8. This method of cell death induces several immune responses in living systems. Non-Patent Document 9. The uptake of non-toxic essential metals (e.g., as found in nutrients) by aerobic cells during cellular respiration, and apoptotic cell death for anaerobic cells, creates an environment that prevents a deleterious cascade of events for pathogen-induced disease. Non-Patent Document 10. Studies have shown that zinc and copper ions can induce oxidative reactions, inactivation of viral infection proton channels, or viral membrane destabilization, all of which activities can be attributed to the compositions of the present invention. Non-Patent Document 11. [Prior art documents] [Non-patent literature]

[0020] [Non-Patent Document 1] Miriam M. Cortese-Krott, AK (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 [Non-Patent Document 2] Olson, KR (2020, Feb 26). Reactive oxygen species or reactive sulfur species: why we should consider the latter. Journal of Experimental Biology 2020, p. 223. https: / / jeb.biologists.org / content / 223 / 4 / jeb196352 [Non-Patent Document 3] Lien Ai Pham-Huy, HH-H. (2008, June). Free Radicals, Antioxidants in Disease and Health. International Journal of Biomedical Sciences, 4(2), 89-96. https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3614697 / [Non-Patent Document 4] Sergio Di Meo, TT (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 [Non-Patent Document 5] Arno R. Bourgonje, MF (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 [Non-Patent Document 6] Singh, CM (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 [Non-Patent Document 7] Brandon Griess, ETF (2017, Aug 24). Extracellular Superoxide Dismutase and its Role in Cancer. Free Radic Biol Med, 1. https: / / dx.doi.org / 10.1016%2Fj.freeradbiomed.2017.08.013 [Non-Patent Document 8] Lee, SY (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 [Non-Patent Document 9] Ine Jorgensen, MR (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 [Non-Patent Document 10] Pete Chandrangsu, CR (2017, March 27). Metal Homeostasis and Resistance in Bacteria. Nat Rev Microbiol, 338-350. https: / / doi.org / 10.1038 / nrmicro.2017.15 [Non-Patent Document 11] Vikram Gopal, BE-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 Summary of the Invention [Problem to be solved by the invention]

[0021] Thus, there is a need for a solution to at least one of the aforementioned problems. More specifically, there is a need for a chemical means for the delivery and transport of free ions across biological membranes in vivo. [Means for solving the problem]

[0022] The concentrated ionophore metal ion delivery system of the present invention disclosed herein includes compositions containing one or more active ionophore moieties, pharmaceutical formulations of such active moieties combined with pharma-ceutically acceptable excipients, methods of making such moieties, compositions, and formulations, and methods of administering such formulations in the prevention and treatment of disease. Multiple administration methods and levels provide a range of safety profiles targeting the tumor environment, tumor regions in all age groups, and co-treatment. These compositions, formulations, preparation methods, and administration methods address the aforementioned needs.

[0023] The activities of the compositions of the present invention include the following non-limiting exemplary list: promoting increased production of superoxide dismutase; preventing the formation of free radicals; reducing the levels of free radicals; increasing and improving the antioxidant capacity of biological systems; reducing oxidative stress levels; protecting biological systems from overproduction of reactive oxygen species, reactive nitrogen species, and reactive sulfur species, and reducing and detoxifying existing levels thereof; reducing the levels of pro-oxidants; addressing deficiencies in enzymatic and non-enzymatic antioxidants; antagonizing superoxide overproduction; supporting normal mitochondrial function and normal ATP biosynthesis; decreasing the ratio of NADH to NAD+; increasing the levels of apoptosis; and constituting an anti-pathogenic direct toxin.

[0024] Acidic pH: An important feature of the compositions of the present invention in all its various pharmaceutical formulations is that they register very low pH levels of 0.2 to 4.0, most preferably 2.0, which not only acts to increase their delivery efficiency and therapeutic effectiveness, but also, surprisingly and unexpectedly, shows limited or no adverse reactions in biological systems at such low pH levels.

[0025] A feature of any given preferred embodiment of the present invention is that it contains high levels of one or more of free sulfur, amines, sulfate ions, metal hexa-aqua structures, metal tetra-aqua structures, metal hydroxyl / aqua mixed ligand species, and hydronium ions, which can be transported to various target locations within biological systems by micro- or macrocirculatory transport and serve to balance reactive oxygen species, reactive nitrogen species, and reactive sulfur species, respectively, which are involved in the multiple balances of cell signaling, protein action, and metabolic cell cycle.

[0026] High level of H + The compositions of the present invention deliver high levels of H+ with a pH of 1.0 or less than 1.0 and Zn 2+ Cu 2+ H in superoxide dismutase (SOD) ligands +The process and relationship of the preferred compositions of the present invention to ROS, RNS, RSS, and NO x Based on the interactions of NH3, HSO4, and O2 with NH4 and their derivatives, the core non-metallic components of the preferred embodiment of the present invention, NH3, HSO4, - and H + Reactive Sulfur Species - A New Redox Player in Cardiovascular Pathophysiology. (T. a. Arteriosclerosis, Ed.) Arteriosclerosis, Thrombosis, and Vascular Biology. https: / / doi.org / 10.1161 / ATVBAHA.120.314084.

[0027] Superoxide dismutase (SOD) production. Natural forms of SOD and their prior art delivery methods are difficult to manufacture, difficult 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, injections, transdermal patches, inhalers, and other administration methods currently used by medical practitioners. The SOD form of the composition of the present invention is a Zn 2+ / Cu 2+ In addition to SOD, manganese is also used as an ionic metal. 2+ As SOD, iron is added to Fe 2+It can be further developed as SOD. Zinc is a redox-inactive metal, i.e., it functions as an antioxidant through the catalysis of copper / zinc-superoxide dismutase, stabilization of membrane structure, protection of protein sulfhydryl groups, and upregulation of the expression of metallothionein (which itself has metal binding ability and shows antioxidant function). Lee, SR (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 / omcl / 2018 / 9156285 / . A preferred embodiment of the composition of the present invention includes or supports the production of artificial SOD in biological systems. A preferred composition containing and delivering a suitable metal supports the production of natural SOD enzymes with the standard role of oxygen radical enzymatic dismutation. Multiple studies support the need for SOD balance in biological systems to prevent and mitigate free radicals. These radicals affect the functionality of the immune system and are often a precursor to mutations and diseases. Superoxide dismutase is widespread in the human body, including the skin of the trunk and appendages. Giovanna G. Altobelli, SV (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 / fmed.2020.00183.

[0028] Members of the SOD family are found in some preferred embodiments of the present invention. SOD has been studied in various models since its involvement in ALS disease, a disease in which the mechanism of prion-like protein misfolding and pathological growth is known to play a role in ROS generation, followed by widespread damage to SOD. The strategy in administering the compositions of the present invention is to neutralize radicalized SOD1 with synthetic SOD, which acts as an effective antioxidant and is delivered via the carrier compound of the present invention. Early-stage trials of investigational treatments for amyotrophic lateral sclerosis (ALS) suggest that people can tolerate the experimental drug, which is a preferred embodiment of the present invention, and in exploratory results, the experimental drug has been associated with the possibility of slowing progression in people with a genetic form of the disease caused by a mutation 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.com / releases / 2019 / 05 / 190501161224.htm.

[0029] Copper / zinc superoxide dismutase (Cu / Zn SOD) is an important enzyme that has generated great interest among medicinal chemists. Zinc is a redox-inactive metal and functions as an antioxidant through catalysis of copper / zinc superoxide dismutase, stabilization of membrane structure, protection of protein sulfhydryl groups, and upregulation of metallothionein expression. Paolo Mondola, SD (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 enhance mitochondrial 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 still unknown. Preferred compositions of the invention containing manganese metal ions beneficially mimic and / or increase the production of the MnSOD enzyme. MnSOD converts superoxide anions to hydrogen peroxide and oxygen, providing a 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 was decreased after incubation in low oxygen concentrations (hypoxic mitochondria). Free Ca for normoxic and hypoxic mitochondria from either organ 2+ ([Ca 2+ ] f ) and free Mg 2+ ([Mg 2+ ] f ) was examined in normoxic mitochondria from either tissue. 2+ ] f ] f and [Mg 2+ ] f Both activated the enzyme, but [Mg 2+ ] fwas less efficient as an activator, with its effect being lower in heart mitochondria than in liver mitochondria. 2+ ] f and [Mg 2+ ] f showed an additive effect, which was more pronounced in cardiac mitochondria and was observed whether the mitochondria were incubated under normal or hypoxia. The data showed that [Ca 2+ ] f This suggests that MnSOD plays a role in regulating MnSOD in cooperation 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.

[0030] H+ as an antioxidant. The cationic hydronium moiety present in the compounds of the preferred embodiments of the present invention can donate hydrogen from the ligand complex to O2 radicals, acting as a powerful antioxidant to reduce oxidative stress and related diseases caused by such stress. Oxidative stress can be defined as the overproduction of reactive oxygen / nitrogen species (ROS / RNS) as pro-oxidants and / or the deficiency of enzymatic and non-enzymatic antioxidants involved in the detoxification of ROS / RNS.

[0031] SOD and anaerobic bacteria. SOD can also eliminate certain anaerobic diseases present, including any survival disease associated with protein-bound β-N-methylamino-L-alanine (BMAA) associated with neurodegeneration in subjects. Superoxide dismutase in the extracellular space has unique characteristics and functions in cell signaling and exhibits anti-cancer properties. The preferred compositions of the present invention generate artificial in situ SOD that can be administered and utilized to treat superoxide overproduction. Such artificial metallic forms of SOD can increase the concentration of the native enzyme form of SOD by rebalancing the deficiency of metal ions required in the production of SOD enzyme, thereby increasing the positive level of biological function. Thus, the compositions of the present invention can be used to treat deficiencies in the production of SOD enzyme, rebalance the levels of SOD, and neutralize radical SOD, all to re-establish normalcy in biological systems.

[0032] Prevention of disease. Another object of the present invention is to aid in the prevention of disease by preventing metabolic disorders in biological systems, treating cells at the atomic level towards balanced mitochondrial harmony, and reducing free radicals resulting from environmental stress, toxicity, and the eventual mutations they cause. The synergy between the elements occurs mainly at the metabolic level. The present invention can be developed into specific formulations that aid in the prevention of disease by rebalancing biological systems through 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 need for the nutritional version of roulette described in the literature. Specially individualized administration of known stimulants and sedatives for individual treatment regimens can then result in improved responses with fewer unwanted 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.

[0033] Gastrointestinal absorption. The synthetic ionophores of the present invention are compounds that can safely target low absorption deficiencies and provide a means of soluble mineral delivery in all administration methods. The biological system must first break down food into its nutritional components, which typically occurs in the digestive system. Many types of food effectively reduce nutrient absorption, creating antagonistic nutritional imbalances and disrupting important processes in gut biology. The formulations of the present invention solve this problem by carrying and providing soluble nutrients that are highly bioavailable in water and are directly bioavailable to the cellular environment when needed in the subject. This delivery system thereby avoids the variables of the digestive process, such as intestinal disease, pathology and illness, gut energy requirements, patient age, and digestive absorbance issues. Any disturbance of the gastrointestinal (GI) tract increases the risk of developing infectious, inflammatory, and dysfunctional GI processes, which can ultimately lead to drug delivery, nutrient absorbency, and / or reduced uptake of one nutrient and not another, thus causing imbalances in the biological system. The administration method of the present invention provides an alternative to oral supplementation and a targeted approach to nutrient delivery. Proper physiological function requires optimal nutrition, which must be kept in balance to prevent potential adverse interactions, especially when administered at typical pharmacological doses. Many nutrients work in harmony to complement digestive function and assimilation. Some nutrients may interfere with these processes and compete for uptake, while others may also be needed in parallel to assist metabolism, which may ultimately affect several biochemical cycles. Schoendorfer, Niikee (2012, Jan 01). Micronutrient interrelationships: Synergism and antagonism, JOUR, 159. Retrieved 2021 from https: / / www.researchgate.net / publication / 286184266_Micronutrient_interrelationships_Synergism_and_antagonism.

[0034] Sufficient nutrient levels are essential for mitochondrial function, as some specific micronutrients play a key role in energy metabolism and ATP production. E. Wesselinka, WK (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 diseases or nutrition-related diseases are conditions that cause illness in humans, and they can be treated with the compositions of the present invention. Such diseases can include dietary deficiencies or excesses, obesity, eating disorders, and chronic diseases such as cardiovascular disease, hypertension, cancer, and diabetes. Weininger, J. (2021, November 11). Nutritional disease. (Britannica, Editor, Britannica, Producer, & Britannica) Retrieved 2021 from Encyclopedia Britannica: https: / / www.britannica.com / science / nutritional-disease.

[0035] Nutritional supplementation. The compositions of the present invention allow for an individualized approach in administration methods and dosing to establish a homeostatic state in biological systems. Oxidative stress occurs when the levels of reactive species exceed the antioxidant capacity of the organism. In conditions of low nutrient absorption, the role of gut health and food sources expands, and relatively small amounts of deficiency can have a detrimental effect on nutritional balance. For example, magnesium Mg deficiency may go unnoticed even after blood tests show it to be within the average range. Serum Mg does not reflect intracellular Mg, the latter constituting more than 99% of total body Mg. Mg deficiency is most often undiagnosed. Mg deficiency correlates with the formation of many different diseases and is common with many diets. For example, adipose tissue is considered an endocrine organ that, when in excess, promotes the excessive production of reactive oxygen species and thus contributes to lipid peroxidation, and it is now known that magnesium deficiency contributes to the development of oxidative stress in obese individuals, since this mineral plays a role as an antioxidant and participates as a cofactor for several enzymes, maintaining cell membrane stability and mitigating the effects of oxidative stress. Studies show that obese subjects have lower serum concentrations of magnesium and higher concentrations of oxidative stress markers in these individuals. Morais, JBS, Severo, JS, Santos, LRd 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 / sl2011-016-0793-l. Furthermore, it is clear that sufficient intake of magnesium contributes to proper homeostasis in the body. Therefore, intervention with supplementation of this mineral is necessary for the prevention and treatment of disorders related to this chronic disease. The compositions of the present invention can be developed to address specific nutritional deficiencies, toxicities, and multicomplexes to prevent and generate nutritional homeostasis in biological systems. As an example, Mg 2+ The maximum increase in Mn-SOD activity was observed at 1.5 mM [Mg 2+Perez-Vazquez, V., Ramirez, J., Aguilera-Aguirre, L. et al. Effect of Ca 2+ and Mg 2+ 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 present invention include highly bioavailable nutraceutical carriers, incorporating essential minerals, vitamins in any form and ratio, and providing any other nutritional benefits through the gastrointestinal, topical, nasal, intravenous, or aerosol route, and / or by oral ingestion. The compositions of the present invention increase the levels of essential transition metals in the skin, lymph, interstitial or extracellular fluid, blood, or cells. Nutritional balancing can be achieved by the synergistic or antagonistic effects of essential minerals, vitamins, as was done with Zn and Cu as an example, and by managing deficiencies or toxicities with ratios within the scope of the present invention. Furthermore, they can be used for the reduction of oxidative stress, they can be used in ketogenesis as a set of ketogenic reactions aimed at recapturing the energy released in ketone breakdown through the oxidation of ketone bodies, and furthermore, they can be used as biocatalysts in clinical or nutritional metabolomics.

[0036] Health supplement. Another object of the present invention is to support the ability to treat metabolic imbalances and deficiencies, toxicity, pathogens, and mutations before disease diagnosis, i.e., to act as a preventive measure.As an example, zinc can broadly regulate energy metabolism and is essential to restore energy metabolism disorders of cell physiology.Research shows that obese subjects have low serum magnesium concentrations and high concentrations of oxidative stress markers. Moreover, it is clear that adequate intake of magnesium contributes to proper homeostasis in the body. Morais, JBS, Severo, JS, Santos, LRd et 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 cellular energy supply, improves cell motility, and restores energy metabolism disorders in the 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 composition of the present invention allows for long-term preventive dosing in all biological systems at all ages. The composition of the present invention can be designed for nutritional purposes to be delivered by any type of administration method and route.These methods can be administered locally or delivered systemically to avoid poor intestinal health and nutrition absorption problems.The composition in topical application protects the skin, the largest organ of the body, from free radicals resulting from environmental stress.

[0037] Treatment of Cancer The next major goal and feature of the compositions of the present invention relates to addressing the treatment of cancer. Cancers include actinic keratosis (AKs), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, basal cell carcinoma, bile duct cancer, bladder cancer, blood cancer, bone cancer, intestinal cancer, brain cancer, 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, childhood cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye tumors, follicular dendritic cell sarcoma, gallbladder cancer, stomach cancer, gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GTD), hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, colon and rectal neuroendocrine tumors, laryngeal cancer, leukemia, Linitis Plastica type gastric cancer, liver cancer, lung cancer, pulmonary neuroendocrine tumor (NET), lymphoma, malignant neurilemmoma, primary mediastinal germ cell tumor, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral and oropharyngeal cancer, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor, pancreatic neuroendocrine tumor, non-Hodgkin's lymphoma, childhood non-Hodgkin's lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic cell These include: cystic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rare cancers, rectal cancer, retinoblastoma, salivary gland cancer, secondary cancers, signet ring cell carcinoma, skin cancer, small intestine cancer, small intestinal neuroendocrine tumors (NETs), soft tissue sarcoma, gastric cancer, gastric neuroendocrine tumors (NETs), squamous cell carcinoma, testicular cancer, thymic tumors, thyroid cancer, tongue cancer, tonsillar cancer, adrenal tumors, cancer of unknown primary, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer, and female (gynecologic) cancers.

[0038] Anti-cancer activity. The compositions of the present invention attack multiple cancer pathways. Commonalities in anti-cancer pathways may explain why several preclinical studies of each of the compositions of the present invention tested show high apoptotic anti-cancer killing rates across a range of different cancer cell types. Potentially similar pathways are demonstrated by approved metal anti-cancer drugs such as physicochemical properties of cisplatin and related platinum-based drugs, which are supported by evidence gathered from their long-term use (alone or in combination with other drugs) for the treatment of various human cancers. Tchounwou, SD (2014, Oct 5). Cisplatin in cancer therapy: molecular mechanisms of action. (SD Tchounwou, Ed.) Retrieved 2021 from US National Library of Medicine: https: / / dx.doi.org / 10.1016%2Fj.eiphar.2014.07.025. The metal components of the compositions of the present invention have been reported to have multiple therapeutically beneficial effects on cancer cells through a significant number of published studies and in clinical reports. (Krishant M. Deo, 2016). Krishant M. Deo, BJ-W. (2016, Oct 31). Transition Metal Intercalators as Anticancer. (SH Hadjiliadis, Ed.) International Journal of Molecular Sciences, 1-17. Retrieved 2021 from https: / / doi.org / 10.3390 / ijmsl7111818. The mechanisms include the reduction of radicals that cause oxidative stress, changes in metabolic pathways, and opening of cell signaling mechanisms, which are involved in the reduction of oxidative stress-producing radicals ... +The mechanism exhibited by any one of the following: ion channels and transporters (as ion channels, ion channels, ion transporters ... Research has demonstrated a significant decrease in SOD enzyme activity in various human cancers.As a result, the increased level of oxidative stress enhances the progression of tumor formation and the incidence of cancer, but the composition of the present invention antagonizes the increased level of oxidative stress.

[0039] Iontophoretic transport. The compositions of the present invention can be used alone or in adjunctive combination with chemotherapy or used as chemosensitizers to treat cancer, cancer tumors, and cancer circulating stem cells. The ion homeostasis induced after administration can initiate a cascade of signaling events, ultimately resulting in cancer cell death. Research suggests the regulation of cellular ion homeostasis by either activating or inactivating ion transporters and ion channels, which is the mechanism of action of the compositions of the present invention in sensitizing cancer cells to otherwise ineffective drugs. Kaushik, VY (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 evidence suggesting that altered ion transport dynamics exist in cancer cells. Cancer cells colonize, recruit, grow, and metastasize in a variety of challenging conditions by rewiring cellular circuits to manipulate ion homeostasis and ion channels, and ion pumps play a key role in this reorganization.

[0040] Treatment of pathogenic infections. Another major goal and feature of the present invention is the ability to treat pathogenic diseases, including compositions that may treat pathogens known as bacteria, viruses, gram-negative or gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA), fungi, protozoa, parasites, worms, Lyme disease, and biofilms. It is now widely known that various metal ions are toxic to bacteria. Overall, metals that are increasingly being considered for antimicrobial agents are typically within the range of d-block transition metals (V, Ti, Cr, Co, Ni, Cu, Zn, Tb, W, Ag, Cd, Au, Hg), with a few other metals and metalloids in groups 13-16 of the periodic table (Al, Ga, Ge, As, Se, Sn, Sb, Pt, Te, Pb, Bi). Of great importance is the discovery made over a decade ago that metals have strong potency against microorganisms that grow as biofilms. Turner, RJ (2017, Jul 26). Metal-based antimicrobial strategies. Microb Biotechnol, 1062-1065. https: / / doi.org / 10.1111 / 1751-7915.12785. A crucial phenotype of biofilms is their ability to confer antimicrobial resistance, and the above metals actively reduce the ability to build or maintain such biofilms. Furthermore, such metals have shown some efficacy against cells that are dormant variants of normal cells that are impermeable to antibiotics. The biological properties of these compounds can be explained based on several factors, including the type of donor atom present in the ligand, the type of metal ion, and the 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 have biological systems that compete for limited amounts of metals required for the pathogen's metabolic functions in the host while simultaneously protecting themselves from metal toxicity. Pathogens have developed a series of metal regulation, acquisition, and excretion systems. The compositions of the present invention have specific metal ratios that cause disruption in such pathogen defense systems.

[0041] Lower organisms are less complex than higher organisms in terms of their metabolic pathways. The cycles that lower diseases caused by organisms such as bacteria, fungi, and viruses go through follow less complex processes, which allow the diseases to grow at near exponential rates based on available resources in the anaerobic cycle, which has many fewer steps. The present invention takes advantage of that difference.

[0042] Treatment of Autoimmune Diseases. The next major feature and object of the present invention is to provide a composition for the treatment of autoimmune diseases. Autoimmune diseases include achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, 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 thyroiditis ... Autoimmune urticaria, acute motor axonal neuropathy (AMAN), Baro's disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing 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 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-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigus gestationis (PG), hidradenitis suppurativa (HS), acne inversa, hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosis, immune thrombocytopenic purpura (ITP), obliterative myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytopoietic vasculitis, lichen planus, lichen sclerosis, lichen conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed obstructive tissue disease (MCTD), Muhlen's ulcer, Mucha-Habermann disease,Multifocal motor neuropathy (MMN), MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, cerebrospinal fluid inflammation, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polymyalgia syndrome type I, II, III, polymyalgia syndrome Polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure erythrocytosis (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, These include rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm-testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmopathy (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Tolosa-Hunt syndrome (THS), rhabdomyositis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease.

[0043] Autoimmune diseases describe the phenomenon of immune cells in the body attacking the host's own cells and tissues. Currently, 5-8 percent of the world's population suffers from 80-100 autoimmune diseases. The compositions of the present invention combine several known and several potential mechanisms of action to address the treatment of autoimmune diseases by reducing the oversimplified immune system by pathogenic involvement and by treating the underlying problem by altering the status of the radical SOD1 enzyme. The antioxidant properties of the compositions of the present invention with high ORAC and ORP values ​​provide a further rational approach to the reduction of immune responses, thereby potentially alleviating or reducing autoimmune diseases.

[0044] Zinc in the form of zinc cation is an ingredient in many of the preferred embodiments of the present invention and is recognized to constitute a targeted approach to autoimmune diseases. Its homeostatic behavior is essential for inflammatory diseases to regulate various aspects of the immune system, both innate and adaptive immune responses, cell cycle progression, and cell maturation and differentiation. Thus, zinc deficiency is associated with incorrect maturation and function of T and B cells, an unbalanced ratio between Th1 and Th2 cells, and between regulatory and inflammatory T cells, and reduced function of NK cells. Alessandro Sanna, DF (2018, Jan 11). Zinc Status and Autoimmunity: A Systematic Review and Meta-Analysis. (Nutrients, Ed.) Nutrients, 10(1), 68. https: / / dx.doi.org / 10.3390%2Fnu10010068.

[0045] Copper is a preferred component in the compositions of the present invention. It has been found that patients suffering from inflammatory rheumatic diseases have an almost complete depletion of the low molecular weight copper protein copper thionein, which exerts significant superoxide dismutase activity and effectively scavenges hydroxyl radicals and singlet oxygen. Ralf Miesel, MZ (1993, June). Copper-dependent antioxidase defenses in inflammatory and autoimmune rheumatic diseases. Inflammation, 283-294. https: / / doi.org / 10.1007 / BF00918991.

[0046] Hydrogen present as a hydronium ion is a preferred component of the compositions of the present invention. The objective of the present invention is to reduce the levels of reactive oxygen species (ROS), particularly the hydroxyl radical ·OH, which is believed to be an important driver of tissue damage of the type 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 / .

[0047] Homeostasis of RSS, RNS, ROS. Yet another feature and object of the present invention is to achieve and maintain redox balance and biological homeostasis in the presence of reactive oxidative species, i.e., reactive oxygen species, ROS, reactive nitrogen species, RNS, and reactive sulfur species, RSS. If the overload of free radicals cannot be destroyed in a timely manner, their accumulation in the body results in a phenomenon called oxidative stress. Oxidative stress has been clinically proven to be involved in numerous diseases. The composition of the present invention can reduce and balance free radicals, such as but not limited to reactive oxygen species, reactive nitrogen species, and reactive sulfur species, which respectively cause oxidative damage and cellular dysfunction.

[0048] Mitochondrial support. The composition of the present invention transports molecular signals that activate stress responses in mitochondria that are beneficial to biological systems. Transport pathways play an important role in reducing oxidative damage and dysfunction of tissues. The composition of the present invention protects against excessive tissue dysfunction through several mechanisms, including stimulating the opening of the permeability transition pore.

[0049] Additional objects, features, and advantages of the present invention as disclosed and claimed herein include the following non-limiting list of specific uses and fields within which these uses are enabled by the biological properties of the compositions of the present invention.

[0050] Medicinal oral and topical treatment. The use of the compound of the present invention in topical treatment can: treat infection, achieve pathogen load reduction, and as an adjunct or replacement of antibiotics; create high mortality rates for the treatment of all viruses, fungi, methicillin-resistant Staphylococcus aureus (MRSA), gram-negative or gram-positive bacterial infections, and parasitic infections; shorten the mean treatment time and reduce long-term symptoms in the treatment of viruses, fungi, MRSA, gram-negative and gram-positive bacteria, and parasites; and infectious and systemic diseases, including but not limited to Alzheimer's disease, Lyme disease, MRSA, or any other pathogenicity-related disease.

[0051] Penetration and Reduction of Biological Biofilms: The synthetic ionophores of the present invention can penetrate and reduce biofilms (extracellular polymeric material) and mimic or generate anti-pathogenic 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.

[0052] Use as an antioxidant in suppressing inflammation. Due to their antioxidant properties, the compositions of the present invention are useful in pain management therapy and anti-inflammatory therapy. Unlike many anti-inflammatory agents, the compositions of the present invention are non-toxic and are both steroidal and non-steroidal.

[0053] Skin Trauma: The compositions of the present invention can be used for injuries to the skin or other areas exposed to external agents, including injuries caused by excessive exposure to sunlight, extreme heat, flames, contact with hot objects, radiation burns, or chemical burns, and can be used in providing relief from burns.

[0054] Wound healing: Increased rate of wound healing, as well as pre- and post-traumatic or pre- or post-operative intervention, can be achieved using the compositions of the present invention.

[0055] Vascular Disorders Vascular disorders, including heart disease, arteriosclerosis, thrombosis, and cardiovascular disorders, can be addressed using the compositions of the present invention.

[0056] Additional Indications. The compositions of the present invention may also be useful: as smooth muscle relaxants, encompassing a broad range of agents that relax both vascular and non-vascular smooth muscle disorders; as part of the treatment of all cancer cell types, including cancer solid tumors and non-solid cancers, cancers of circulating stem cells, cancers in metastatic stages, and reduction of pre-cancerous atypical cells; as part of the treatment of all skin cancer cell types while also providing a positive eschar effect; as an adjunct to pre- and post-surgical cancer and pre-cancerous cell removal procedures; as an adjunct in Mohs surgery, and as an adjunct or alternative to chemotherapy creams in autoimmune diseases, including but not limited to psoriasis and eczema; in neurological diseases, migraines of neurological origin, cardiovascular stroke recovery, multiple sclerosis, traumatic nerve damage to nerves of the peripheral and central nervous systems, amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy. , and epileptic seizures, as well as smooth and striated muscle relaxation; arthritic and arthritic conditions due to their role in reducing oxidative stress and free radical levels in areas of living systems, particularly avian, mammalian, or human systems, afflicted by overproduction of superoxide detoxification, for prophylactic or pharmaceutical removal of toxic substances; nasal administration as a spray or drops for sinus congestion, sinus irrigation, or sinus infections; relief of Alzheimer's and non-Alzheimer's dementia, and improvement of cognitive function; for use in psychiatric disorders including schizophrenia, depression, and post-traumatic stress disorder (PTSD), as well as other severe psychiatric disorders and complex diagnostic stress problems in patients; or as formulations to deliver the compositions of the invention alone or in combination with other carrier formulations.

[0057] The compositions may further be used as: Pharmaceutically acceptable oral, otic, ophthalmic, oral, sinus, vaginal, urethral, ​​rectal or topical medications; as image enhancing agents and pre-contrast agents in PET or CT scans; antimicrobial agents applied as therapeutic mist or spray onto infected areas; agents that cause the reduction of mutated free radicals and cells due to radiation exposure or from overdosing of radiotherapy treatment or radioimaging; agents that reduce infection from implant or prosthetic device surgery; infection reducers from intravenous therapy, injections, catheters, implanted access ports, or other invasive medical devices; dental applications and uses, including dental infection and root canal treatment; dental cavity (cavity) prevention and treatment; and tooth or gum infection prevention and treatment, gingivitis prevention and treatment, or improved dental health outcomes, all in paste, gel, gum, spray, chewable tablet, buccal tablet, or injectable formulations.

[0058] The compositions of the invention are also useful for: fixed dose combination or monotherapy formulations formulated to achieve a specific drug indication and systemic delivery profile; in fixed dose combination with oncology drugs and their delivery systems, narcotics and their delivery systems; in combination with protein augmentation or protein synthesis blockade therapies; in combination with hormone augmentation or blockade therapies in the treatment of endocrine disorders; in combination with cell receptor blockade or cell signaling modification therapies; in combination with biological or biosimilar products, which are relatively large complex molecules that can be produced by biotechnology in living systems including microorganisms, plant cells, or animal cells; anti-cancer cell death through apoptosis, necrosis, and the like. in combination with biological actions that provide changes within the disease environment to regress or stabilize anaerobic cell growth, and anti-pathogenic cell death through cell death; coordinated use with redox biology and redox pharmaceutical strategies to obtain therapeutic benefits and treatments that affect outcomes by altering the levels of pro-oxidants and antioxidants in cells; personal care and cosmetic skin care products; cosmetic formulations for medical and non-medical skin care products; in anti-aging, repair, aesthetic beauty, moisturizing, and skin repair of the skin, in tanning promotion, in sun protection, in the treatment of sunburn, and in the reduction of free radical production resulting from exposure to sunlight; non-toxic preservatives and antimicrobial excipients in formulations.

[0059] The penetration and absorption of substances into the skin, membranes, tissues, and organs is influenced by the physicochemical properties of the pharmaceutical preparations formulated for such delivery purposes, and the compositions of the present invention enhance and support such skin penetration and absorption.

[0060] The compositions of the present invention are characterized by their low pH, by their high redox values ​​(positive charge), and by the inherent ability of natural metal cations and water to coordinate together and then react with oxidation-, nitrogen-, and sulfur-reactive species, resulting in a novel method of cellular delivery.

[0061] This background information is provided to present and disclose information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention.

[0062] Summary of the Invention The compounds of the invention, in aqueous solution, comprise one or more of the following general formulae, most preferably a hexa-aquaoctahedral ligand arrangement, or preferably a tetra-aquatetrahedral ligand arrangement, or a planar ligand arrangement, or a tri-aquatrihedral ligand arrangement, of the metal ion structure: [ka]

[0063] where M is a p-block element, a d-block element, or an s-block element. At equilibrium, alternative preferred embodiments of the present invention, namely metal tetra-aqua tetrahedral or planar ligand dihydroxy species, may exist, which are amine concentration dependent and / or solution acidity dependent. Based on anion and cation equilibrium, these lower ionic structures can constitute higher complex ionic structures.

[0064] In summary, the present invention is a composition comprising one or more compounds selected from the group consisting of any one of the following: [[Zn(HO)] 2+ ] w , an example of a hexa-aquaoctahedral ligand arrangement, [[Cu(H2O)6] 2+ ] x , an example of a tetra-aquatetrahedral or planar ligand arrangement, [[Cu(H2O)4] + ] y , [[Mg(H2O)6] 2+ ] z , [HSO - 4] c , [NH3] d , [NH4 + ] e , [H+ ] f , [SO3 2- ] g , [NH4HSO4] h , and [H2SO4] j and combinations thereof: wherein w, x, y, z, c, d, e, f, g, h, and j are independently integers of 0 or greater; [H + ] is the bond molecule H + Zn(II)(H2O)6; its pharma- ceutically or nutritionally acceptable salts, solvates, hydrates, structural isomers, and stereoisomers, most preferably in aqueous solution. The composition may further comprise one or more compounds selected from the group consisting of any one of the following: [Zn(II)(H2O)6] 2+ ] w , [Cu(II)(H2O)6] 2+ ] x , [Cu(I)(H2O)6] 2+ ] y , [Mg(II)(H2O)6] 2+ ] z , [H3PO4] j and potassium hydrogen phthalate, and mixtures thereof; wherein w, x, y, z and j are independently integers equal to or greater than 0; [H + ] is the bond molecule H +and likewise pharma- ceutically or nutritionally acceptable salts, solvates, hydrates, structural isomers, and stereoisomers thereof. In these compositions, [NH4HSO4] may be present at a concentration of 0.1%-4.0% w / w, [H2SO4] may be present at a concentration of 0.01%-3.0% w / w, [Zn(II)(H2O)6] may be present at a concentration of 2.0%-8.0% w / w, [Cu(II)(H2O)6] may be present at a concentration of 1.0%-3.0% w / w, [Mg(II)(H2O)6] may be present at a concentration of 1.0%-3.0% w / w, and [H3PO4] may be present at a concentration of 0.1%-15.0% w / w. The composition may further 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, and more preferably, may further comprise a compound selected from the group consisting of any one of the following: [Se(H2O)3], which is an example of a trihedral ligand arrangement metal ion structure. 2+ , [Mn(HO)] 2+ , [Ag(HO)] 2+ , [Au(HO)] 2+ , [V(H2O)6] 2+ , and [Ni(H2O)6] 2+, as well as mixtures thereof. Additionally, the compound potassium hydrogen phthalate may be present in a concentration of 0.01% to 8.0%. The composition is advantageously delivered to a patient in need thereof in a pharma- ceutically acceptable formulation for administration in a form selected from the group consisting of oral, nasal, ophthalmic, otic, topical, local administration by thermal, ultrasonic, infrared, iontophoretic or radiological means, transdermal, urethral, ​​vaginal, rectal, intravenous injection, subcutaneous injection, nebulization, and inhalation formulations. Topical formulations may be prepared in active composition concentrations of up to 30% w / w. Transdermal formulations may be prepared in active composition concentrations of up to 20% w / w. Oral formulations may be prepared in active composition concentrations of up to 20% w / w. Inhalation formulations may be prepared in active composition concentrations of up to 10% w / w. Injectable formulations may be prepared in active composition concentrations of up to 5% w / w. The formulation may be prepared to have a final product pH within 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.

[0065] An alternative preferred embodiment of the present invention may be a composition comprising one or more compounds selected from the group consisting of any one of the following: [[M(L1) a1 ] b+ ] x , [[M(L2) a2 ] c+ ] y , [[M(L3) a3 ] d+ ] z , [AN i- ] e , and [CA g+ ] fand mixtures thereof: in which L1, L2, and L3 are any ligand or mixed ligand including any one of OH, CO, NH3, H2O, H3O, 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 f are independently the number of ions forming a complex ion structure and are integers of 0 or more; a1 is an integer of 0 to 6 and is the coordination number of the ligand coordinated to the metal M; a2 is an integer of 0 to 6 and is the coordination number of the ligand coordinated to the metal M; a3 is an integer of 0 to 6 and is the coordination number of the ligand coordinated to the metal M; is the coordination number of the ligand to the genus M; b, c and d may independently be integers between 0 and 6, inclusive, and are the amount of charge localized at the metal center M or the amount of charge delocalized around the coordinating ligand; AN is an anion present in solution, selected from the group consisting of OH, CO, NH3, NO, NO2, NO3, SO4, SO3, HSO4, NH, NH4, PO4, N, Cl, I, and Br, and mixtures thereof; CA is a cation present in solution, selected from the group consisting of H, Ca, Na, Fe, K, Mg, Mn, Zn, Cu, Li, and mixtures thereof, and cations present in solution consisting of s-block elements, p-block elements, or d-block elements, and mixtures thereof; and pharma- ceutically or nutritionally acceptable salts, solvates, hydrates, structural isomers, and stereoisomers thereof.

[0066] The invention further includes a method of administering the compositions disclosed herein to treat a disease comprising administering to a mammal in need thereof an aqueous ionic mineral complex comprising an ionic metal bound to a plurality of HO ligands to form a metal-ligand complex: the HO ligands enable transport of the metal-ligand complex through the human patient to a cellular target affected by the overproduction of superoxide ions; the metal-ligand complex is [[Zn(HO)] 2+ ] w , [[Cu(H2O)6] 2+ ] x , [[Cu(H2O)4] + ] y , [[Mg(H2O)6] 2+ ] z , [HSO - 4] c , [NH3] d , [NH4 + ] e , [H + ] f , [SO3 2- ] g , [NH4HSO4] h , and [H2SO4] j and any one of mixtures thereof; wherein w, x, y, z, c, d, e, f, g, h and j are independently an integer equal to or greater than 0; [H + ] is the bond molecule H + ·H2O; and its pharma- ceutically or nutritionally acceptable salts, solvates, hydrates, and structural or stereoisomers, further comprising [Zn(II)(H2O)6] 2+ ] w , [Cu(II)(H2O)6] 2+ ] x , [Cu(I)(H2O)4] 2+ ] y , [Mg(II)(H2O)6] 2+ ] z , [H3PO4] j and potassium hydrogen phthalate, and mixtures thereof; wherein w, x, y, z, and j are independently integers equal to or greater than 0; [H +] is the bond molecule H + HO; and pharma- ceutically or nutritionally acceptable salts, solvates, hydrates, structural isomers, and stereoisomers thereof; may be administered for a purpose selected from the group consisting of medical diagnosis, detection of anaerobic cells in biological systems, medical treatment, personal care, cosmetic purposes, and nutritional supplementation.

[0067] Also disclosed and claimed within the scope of the present invention are the pharma- ceutically acceptable salts, hydrates, solvates, structural isomers, and stereoisomers thereof.

[0068] The compositions of the present invention are intended for use in the allopathic, osteopathic, homeopathic, and naturopathic fields in human and veterinary patients. [Brief description of the drawings]

[0069] [Figure 1] Red: 1H-NMR spectrum generated by Watergate 1H-NMR spectrum at 275K, blue: 298K, and green: 320K temperatures. [Diagram 2] NMR spectra generated at approximately 100 mM NH4 + in the presence of 5 and 10% D20 [Diagram 3] 15N-1H generated NMR spectrum in 2D HISQC spectrum of a solution containing approximately 100 mM NH4+ [Figure 4] Graph of titration curve showing overall acid content for pH-potentiometric titration DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] The present invention is described in more detail below in various embodiments. However, the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0071] The present invention utilizes preferred compounds within compositions that are formulations of aqueous ligands in hexaaqua delivery systems. Preferred active compounds are synthetic ionophores that actively transport free ions into or through the cell membrane shell and interact with the internal / external cellular environment. The metal ion structures in aqueous solution are primarily in hexaaquaoctahedral ligand configurations. Alternatively, the metal ion structures are tetraaquatetrahedral or planar. These lower order ionic structures may comprise higher order complex ionic structures based on anionic and cationic equilibria containing high levels of free sulfur, amines, sulfate ions, metal hexaaqua structures, metal hydroxyl / aqua mixed ligand species, and H+. These ionic structures utilize amines and sulfate ions in concert with a specific ratio of free protons (H+) to allow for effective cross-linking of multiple metal-aqua species in close proximity to generate a concentrated ionophore metal ion delivery system through cell membranes.

[0072] The equilibrium between these ionic metal structures and the stabilized free anions and cations in solution is crucial for the stability and steric proximity of the coordinated metal ions to provide effective cell wall penetration and delivery of metal ions to many intracellular biological processes to address the above metabolic and pathological conditions. By modifying the concentration of ionic compounds and H+ in the aqueous solution, the system of the present invention can be fine-tuned to penetrate and deliver metal ions to multiple cell types, attach to cell walls, or provide a pathway for single metal ion or complex metal ion bridged structure delivery. The composition compounds of the present invention enter cells and deliver one or more structures therein to affect biological processes and mechanisms in humans or animals.

[0073] Complex ions have a metal ion at the center with some other molecule or ion, creating an inorganic coordination complex or a coordinate (coordinate covalent) bond where both electrons come from the same atom. A covalent bond is formed by two atoms sharing an electron pair. The atoms are held together because both nuclei attract electron pairs. This invention creates a unique relationship with ligand bonds, which become carriers or co-binding mechanisms with other molecules that move within biological systems. The anion or molecule that is bound to the metal is the ligand. The coordination number is the number of positions on the metal ion to which the ligand is attached. The bond between the metal ion and the ligand where the ligand donates both electrons is a coordinate covalent bond. Simple ligands include water, ammonia, phosphorus, and chloride ions.

[0074] All metal ions have at least one coordination sphere, which determines the number of possible coordination bonds for each metal atom. Coordination bonds attract negatively charged ions with unshared electron pairs. The cation uses the unshared pairs to fill gaps in the outer electron orbitals where these electron shells are incomplete. All three-level orbitals become empty, and it utilizes all six empty orbitals to accept lone pairs from six water molecules. This part utilizes six orbitals, all of which have similar energy, by rearranging (hybridizing) the 3s, three 3p, and two of the 3d-shell orbitals. Six is ​​the maximum number of water molecules around most metal ions, including the maximum number of bonds, and is the most energetically stable. The bond that forms between the cation and the unshared electron pairs becomes a hexa-aqua coordination bond.

[0075] The most preferred embodiment of the present invention uses each of the six water molecules as a hexa-aqua ligand bound to a central metal cation via a coordinate bond using one of the available lone pairs on the oxygen. These metal hexaaqua species then form higher order ionic structures with amine and sulfate ions in coordination with H, which effectively bridge multiple metal aqua species in close proximity, creating an iontophoretic metal delivery system. The equilibrium between these ionic metal structures and the stabilizing free anions and cations in solution is critical to the stability and steric proximity of the coordinated metal ions, providing effective cell wall penetration and delivery of metal ions to a host of intracellular biological processes. By modifying the concentration of ionic compounds and free hydrogen in the solution, the ionophore delivery system of the present invention can be custom synthesized and formulated to penetrate and deliver metal ions into cells, attach to cell walls, and provide a pathway for single metal ions or multiple metal ion bridged structures. The composition of the preferred embodiment is shown in Figure 5, where six water molecules are present, Zn 2+ , Cu 2+ , or Mg 2+ can form hexa-aqua ligands with any metal cation of NH4 + , H + , and HSO4 - Delivery system formulations are presented that are capable of forming hexa-aqua copper, hexa-aqua zinc, and hexa-aqua magnesium species in the presence of ions.

[0076] Ionophore delivery. An ionophore is any of a number of naturally occurring carriers of ions. The present invention is a synthetic ionophore that can mimic natural ionophores or create similar ionophore signaling functions to produce enzymes, protein action, and electron transfer in metabolic processes of biological systems. The compounds of the present invention, including therapeutic compositions, have multiple ionophore pathways available to them through cell membranes. Thus, entry through all tissue, blood, organ, and cellular barrier types is possible. Ion channels are membrane proteins found in all domains of cellular life. They are present in all intracellular membranes as well as plasma membranes. The transport mechanism through these ion channels allows the compounds of the present invention to have multifunctional types of permeability.

[0077] Fluid and ion transfer across the blood-brain and blood-cerebrospinal barriers is highly restrictive due to tight junctions that create a fluid barrier. Hladky, SB (2016). Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles. (S. Nature, Ed.) Springer Nature, 1. Retrieved from https: / / doi.org / 10.1186 / s12987-016-0040-3. Because the compounds of the present invention are preferably ionophores for water, their ligand structure and low pH allow for higher permeability across these tight central nervous system transport junctions. This provides higher ion delivery rates than most current drug delivery methods. Filip Vlahovic, MP (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 2021 from https: / / www.researchgate.net / figure / The-structure-of-investigated-hexaaqua-transition-metal-ion-complexes-MH-2-O-6-n_fig4_277895193.

[0078] Passive transport. As hexaaqua aqueous carriers, the preferred compounds of the present invention have a simple concentration gradient. Water is found in different concentrations on both sides of the membrane or on the region of the cellular space; therefore, water is highly neutral and absorbent in biological systems, allowing the compounds utilized in the present invention to participate in a very passive degree of transport. Large amounts of water molecules move continuously across the cell membrane by osmosis, a simple diffusion process by the movement of membrane proteins and aquaporins. Lumen. (2020). Membrane Transport. (Pressbooks, Editor, & Pressbooks) From The Cellular Level of Organization: : https: / / courses.lumenlearning.com / nemcc-ap / chapter / 3204 / . Up to 100 times the volume of water molecules of a cell diffuses across, for example, a red blood cell membrane every second; an equal amount comes in and out by osmosis, so the cell does not lose or gain water, the effect of which is to make hexa-aqua ligands an extremely efficient delivery system. The hexa-aqua ligands found in the present invention utilize osmotic, isotonic, and hydrostatic pressures in a passive transport system where water flows from a membrane with a lower solute concentration to a membrane with a higher solute concentration. The hexa-aqua ligands of the present invention carry low molecular weight free ions, allowing passive entry and potentially delivery of larger molecules hidden in the biological soup of ionophore carriers and their respective binding molecules.

[0079] Active transport. The synthetic ionophore compounds of the present invention have a highly positive electronic charge, providing an electrical gradient or charge difference across the plasma membrane, an atypical condition found in biological active transport. Living cells typically have a membrane potential, which is the potential difference (voltage) across their cell membrane. Potential difference exists whenever there is a net separation of charges in that space. In the case of cells, positive and negative charges are separated by the barrier of the cell membrane, and the inside of the cell has an extra negative charge relative to the outside.

[0080] Sodium and potassium pathway. The composition of the present invention utilizes the action of sodium and potassium pathway. The inside of a cell has a higher potassium concentration and a lower sodium concentration than the extracellular fluid surrounding it. When sodium ions are outside the cell, they tend to move into the cell based on their concentration gradient and the voltage across the membrane (more negative charge inside the membrane). The combination of concentration gradient and voltage that affect the movement of ions is the electrochemical gradient that is the property of the compound of the present invention.

[0081] Primary and secondary active transport. The ionophore compounds of the present invention can be designed to affect different transport in the case of primary transport, which is known to use ATP as an energy source. This energy production requires the presence of magnesium ions. In the case of secondary active transport (symport), the ionophores of the present invention use the electrochemical gradient cationic charge as an attractant, moving molecules against their gradient, and therefore do not directly require a chemical energy source such as ATP. By changing the stoichiometric ratio of ions, the compounds of the present invention can be designed to target the desired translocation method.

[0082] Although the following detailed description contains many details for purposes of illustration, those skilled in the art will appreciate that many variations and modifications to the following details are within the scope of the invention. Accordingly, the following embodiments of the invention are described without any loss of generality or reduction in generality to, and without imposing limitations on, the claimed invention.

[0083] As used herein, the term "exemplary" or "illustrative" means "serving as an example, illustration, or description." Any implementation described herein as "exemplary" or "illustrative" should not necessarily be construed as preferred or advantageous over other implementations. All implementations described below are exemplary implementations provided to enable those skilled in the art how to make or use embodiments of the present disclosure, and are not intended to limit the scope of the present disclosure, which is defined solely by the claims.

[0084] Moreover, those skilled in the art should note that in this detailed description, quantitative modifiers such as "generally," "substantially," "largely," and other terms are generally used to mean that a referenced object, characteristic, or quality constitutes the majority of the referenced subject matter. The meaning of any of these terms depends on the context in which it is used, and the meaning may be expressly modified.

[0085] Minerals are naturally occurring chemical compounds that contain metallic elements and are often required by living organisms as essential nutrients to perform functions necessary for life. Metals have played essential roles in living systems since ancient times. As catalysts or structural cofactors, metal ions are estimated to be important for the function of as many as one-third of all enzymes, and they have widespread roles in living systems.

[0086] Ionophores are chemical species that reversibly bind ions. Many ionophores are lipid-soluble entities that transport ions across cell membranes. Ionophores catalyze ion transport across hydrophobic membranes, such as liquid polymer membranes (carrier-based ion-selective electrodes) or lipid bilayers found in living cells or synthetic vesicles, such as liposomes. Structurally, ionophores contain 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 of the invention include 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 synergistic effects when combined with the ions they bind.

[0087] The biological activity of metal ion-binding compounds can change in response to increasing metal concentrations, and based on the latter feature, compounds can be classified as "metal ionophores", "metal chelators" or "metal shuttles". If the biological effect is enhanced by increasing metal concentrations, it is classified as a "metal ionophore". If the biological effect is decreased or reversed by increasing metal concentrations, it is classified as a "metal chelator". If the biological effect is not affected by increasing metal concentrations and the compound-metal complex enters the cell, it is classified as a "metal shuttle".

[0088] The term p-block elements refers to elements from the group consisting of phosphorus (P), boron (B), nitrogen (N), carbon (C), sulfur (S), oxygen (O), 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 (Me), oganesson (Og), flerovium (FI), livermorium (Lv), and tennessine (Ts).

[0089] The term d-block elements refers to 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 (Cn), and tungsten (W). It refers to the elements from the group consisting of lutetium (Lu), rutherfordium (Rf), roentgenium (Rg), lawrencium (Lr), meitnerium (Mt), hassium (Hs), darmstadtium (Ds), dubnium (Db), and seaborgium (Sg).

[0090] The term s-block elements means elements from the group consisting of potassium (K), hydrogen (H), beryllium (Be), sodium (Na), magnesium (Mg), lithium (Li), calcium (Ca), barium (Ba), cesium (Cs), rubidium (Rb), strontium (Sr), francium (Fr), radium (Ra), and helium (He).

[0091] Definitions of abbreviations, nomenclature, and technical and non-technical terms used in these examples are as follows:

[0092] As used herein, the phrase "A" or "an" in the context of an entity or moiety refers to one or more of that entity or moiety, e.g., "a" compound refers to one or more compounds or at least one compound. Thus, 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." With respect to metal ion ratios and dosages, the modifier "about" reflects standard experimental error. As used herein, the term "optional" or "optionally" means that the event or circumstance described below may, but need not, occur, and that the description includes instances when the event or circumstance does or does not occur. As used herein, the term "subject" refers to any species, both non-mammals and mammals, as well as humans, that require treatment or supplementation. Preferably, the subject is a human. The terms "preparation" and "compound" or "compounds" and "formulation" or "formulations" are intended to include either solid, liquid or gas formulations of an active compound, and one skilled in the art will understand that an active pharmaceutical ingredient ("API") may be present in different formulations depending on the desired dose and pharmacokinetic design parameters. As used herein, the terms "composition" and "excipient" and "pharmaceutical excipient" refer to compounds used to prepare pharmaceutical compositions and include excipients that are generally safe, non-toxic, biologically or otherwise undesirable, and acceptable for veterinary use as well as human pharmaceutical use. The term "dosage" is intended to include either or both solid and liquid formulations of an active compound, and one skilled in the art will understand that an active ingredient may be present in different formulations of different administration methods, APT rates, prescribed doses, duration of use, time of use, type of indication, desired outcome, and pharmacokinetic design parameters. The terms "mixing" or "efficient mixing" as used herein are not limited to the same blending process; it includes all mixing methods in the manufacturing process.As used herein, the term "biological system" refers to the interaction of key elements such as DNA, RNA, proteins, and cells in relation to one another in a subject. As used herein, the term "iontophoresis" is the process of transdermal drug delivery by using a voltage gradient for electrophoretic drug administration (EMDA) to the skin. Molecules are transported across the stratum corneum by electrophoresis and electroosmosis, and electric fields can also increase the permeability through tissue membranes for diagnostic or therapeutic applications. As used herein, "treatment" or "treating" or "therapy" or "therapeutic" or "pharmaceutical" or "prevention" is an approach to obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, prevention, alleviation of symptoms, reduction in the extent of disease, stabilization of disease, delay or slowing of disease progression, improvement or alleviation of disease state, and remission, whether partially detectable or not, or entirely detectable. "Treatment" can also mean an extension of survival compared to the expected survival time without treatment. "Treatment" is an intervention performed to eliminate or prevent a disease, or to develop to eliminate or prevent a disease, or to alter the pathology of a medical disorder in a biological system. The term "Ion Biotechnology® Hexa-aqua Delivery System" describes the present invention as a combination of Ion Biotechnology® Aqueous Ligands, abbreviated as "IBAL".

[0093] “APT” = active pharmaceutical ingredient. "Acid Mix" = a premix of acids for use in making the compositions of the present invention to receive a metal salt or combinations thereof, as disclosed below. API = Active Pharmaceutical Ingredient BP=British Pharmacopoeia CAS = Chemical Abstracts Service Registry Number EP=European Pharmacopoeia FEUM = Mexican Pharmacopoeia Ionophore = a substance that reversibly binds ions and transports the reversibly bound ions across lipid membranes within cells. NF=National Formulary ORAC=Oxygen Radical Absorbance Capacity ORP = Oxidation-Reduction Potential USP=United States Pharmacopoeia.

[0094] Exogenous nutritional elements regulate the energy metabolism response, which is a prerequisite for cellular homeostasis and metabolic physiology. Specifically, the delivery of micronutrients in the form of metals is important in oxidative stress and cytoprotective processes. Minerals and drugs that are usually administered are not in a highly bioavailable form and can also target intermediate areas of therapeutic or nutritional need. They usually cannot cross hydrophobic lipid bilayer membranes effectively or efficiently, whether by active or passive transport, and therefore often cannot activate natural therapeutic responses. For nutrients, a key factor in membrane transport is the solubility of the nutrients, which is determined by their molecular polarity properties (Dewey Holten, 1999).

[0095] Small molecule drugs are widely distributed and pharmacologically promiscuous, targeting many cell types and exacerbating the appearance of multiple side effects, but many may not be able to travel sufficiently or at all to cells to exert their pharmacological action or to correctly or appropriately affect extracellular pathways. The present invention, or Ion Biotechnology® Aqua Ligand (IBAL), provides an effective carrier of polar molecules via active transport across cell membranes. Natural active transport also occurs, as the osmotic pressure of water created by the presence of the hexa-aqua ligand creates a polar and size (low molecular weight) driven dispersion of free ions throughout the interstitial fluid, increasing their uptake directly into the cytoplasm of cells through the lipid bilayer of the cell membrane.

[0096] The reactions of the hexa-aqua complexes of the preferred embodiment of the present invention in ammonia solutions are complex because ammonia can act in two significantly different functions. First, ammonia can act as a Brønsted-Lowry base, a ligand, or 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). Second, ammonia is also a possible ligand that can bind with the water molecules around the central metal ion. This ligand appears when a small amount of dilute ammonia solution is added to the metal, generating a hexa-aqua ligand solution or a mixed aqua amine ligand system. At equilibrium, the amine is acting as an acid by donating a hydrogen ion to the water molecules in the solution. According to Le Châtelier's principle (when any system in equilibrium for a long period of time is exposed to a change in concentration, temperature, volume or pressure, the system will change to a new equilibrium, and this change will partially counteract the applied change), if the pH of the ligand solution is increasing, the equilibrium position will move to the production of more new ammonia complex ions, replacing hydronium ions. The unique property of the present invention is the coordination complex ion structure that maintains the equilibrium of the solution by two reaction processes. The ammonia molecule is more likely to cause the replacement of water ions on the metal, instead of the back exchange reaction that occurs when the pH is low (below 1.0). If that low pH reaction goes too far, a "neutral complex" consisting of one or more hydroxyl groups or mixed hydroxyl (OH), water, and / or amine groups is produced, which is insoluble in water, and thus a precipitate is formed. When ammonia acts in a ligand exchange reaction, it replaces the water around the metal ion, producing a soluble complex. Thus, there is an interaction between the two equilibria.To obtain a dissolved precipitate, the present invention requires the correct ligand exchange equilibrium to maintain ionic stability, but also requires that the acid-base equilibrium 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, Ion Biotechnology® Aqueous Ligand (IBAL) has been manufactured and studied in these completed complexes, including obtaining the pH levels, redox potential values ​​(ORP), and metal cation ratios described herein for the present invention. Multiple in vitro, in vivo, and preclinical animal and human studies have been conducted to support the safety, composition, efficacy, and mode of action of the present invention in biological systems.

[0097] The number of ammonia molecules is twice the number of metal ion valences, and the valence charge does not change at low pH. The unshared electron pair from the ligand bond is a ligand system that donates both of the unshared electrons to the free hydrated metal ion. The use of transition metals is important to obtain proper ligand bonding. Transition metal ions can act as Bronsted acids, but Cu 2+ Others, such as Mn, do not act by themselves because they become acidic due to charge delocalization to one or more aqua ligands. Hydration is defined as the transfer of an ion or neutral species from the gas phase to water; for metal ions, Mn + (g) → Mn + (aq) (Person, 2010). These ligand reactions are +This results in a net increase in ion concentration, thereby acidifying the solution and resulting in 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 transition metals are preferably and advantageously used in the IBAL coordinated ion bonded complexes. See Brown, DP (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 / transition1.htm.

[0098] The addition of metals in the manufacturing process, alone or in combination in ratio, includes, but is not limited to, any one of calcium, chromium, cobalt, copper, iodine, iron, magnesium, manganese, molybdenum, nickel, potassium, selenium, silver, vanadium, and zinc in any stable oxidation state and any combination thereof. The additional compounds are organic or inorganic, including, but not limited to, chemicals, molecules, proteins, urea, and combinations with other known pharmaceuticals, carriers, and personal care formulations as described herein and in the claims regarding the method of use.

[0099] The compounds of the present invention can be easily prepared 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 use variants which are themselves known to those skilled in the art, but which will not be mentioned in more detail.

[0100] The most preferred compounds of the present invention are any or all of those specifically shown in these examples.However, these compounds should not be construed as forming the only genus considered as the present invention, and any combination of compounds or their moieties may form a genus by itself.The following examples further describe the preparation of the compounds of the present invention and the details of quantitative and qualitative analysis.Those skilled in the art will easily understand that known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds.Unless otherwise stated, all temperatures are in degrees Celsius.

[0101] Example 1 Hexaaqua Zinc, Hexaaqua Copper, Hexaaqua Magnesium Composition 0.5Kg Batch: [Table 1]

[0102] In step 1, sulfuric acid was placed in a glass or glass-lined reactor and stirred at room temperature. Ammonium sulfate was added with stirring until completely dissolved. Deionized water was then added slowly dropwise with constant stirring to minimize an exothermic reaction that would raise the temperature of the solution above 50 degrees Celsius, and to maintain a temperature below 45 degrees Celsius. The mixture was mixed until homogenous and then cooled to room temperature (~25°C).

[0103] In step 2, zinc sulfate heptahydrate was combined with the solution prepared in step 1 and mixed until completely dissolved and the solution was homogenous. Copper(II) sulfate pentahydrate was then added and mixed until completely dissolved and the solution was homogenous. Finally, magnesium sulfate heptahydrate was added and mixed until completely dissolved and the solution was homogenous. Mixing was continued for 12 hours at room temperature until a uniform consistency was obtained.

[0104] Starting material considerations and alternatives: NH3 or NH4 in aqueous solution +The starting materials for the production of HSO4 in aqueous solution are advantageously aqueous ammonia (0.5-28%), ammonium sulfate or ammonium hydrogen sulfate and sulfamic acid, by any method of preparation known to the skilled artisan. + The starting materials for producing are sulfuric acid (1.0-98% concentration) or sulfamic acid, prepared by any method known to one of skill in the art. The starting materials for producing any or all of the starting materials for producing the metal hexaaqua ions in 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 the ligands described.

[0105] Hexaaqua Zinc, Hexaaqua Copper, Hexaaqua Magnesium Composition Using the procedure of Example 1, combine the following ingredients in the following w / w% ranges of ingredient ions depending on dosage and use: [Table 2]

[0106] Example 2 Hexaaqua Zinc, Hexaaqua Copper, Hexaaqua Magnesium and Selenate Composition: ZCMS-5 / 2 / 1 / 1 in 0.5Kg batches [Table 3]

[0107] In step 1, sulfuric acid was placed in a glass or glass-lined reactor and stirred at room temperature. Ammonium sulfate was added with stirring until completely dissolved. Deionized water was then added slowly dropwise with constant stirring to minimize an exothermic reaction that would raise the temperature of the solution above 50 degrees Celsius, and to maintain a temperature below 45 degrees Celsius. The mixture was mixed until homogenous and cooled to room temperature (~25°C).

[0108] In step 2, zinc sulfate heptahydrate was combined with the solution prepared in step 1 and mixed until completely dissolved and the solution was homogenous. Copper(II) sulfate pentahydrate was then added and mixed until completely dissolved and the solution was homogenous. Finally, magnesium sulfate heptahydrate was added and mixed until completely dissolved and the solution was homogenous. Mixing was continued for 12 hours at room temperature until a uniform consistency was obtained.

[0109] Starting material considerations and alternatives: NH3 or NH4 in aqueous solution + The starting materials for the production of HSO4 in aqueous solution are advantageously aqueous ammonia (0.5-28%), ammonium sulfate or ammonium hydrogen sulfate and sulfamic acid, by any method of preparation known to the skilled artisan. + The starting materials for producing are sulfuric acid (1.0-98% concentration) or sulfamic acid by any method known to one of skill in the art. The starting materials for producing any or all of the starting materials for producing the metal hexaaqua ions in 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 the ligands described.

[0110] Hexaaqua Zinc, Hexaaqua Copper, Hexaaqua Magnesium and Selenate Composition: Using the procedure of Example 1, combine the following ingredients in the following w / w% ranges of ingredient ions depending on the desired route of administration and application: [Table 4]

[0111] Example 3 Hexaaqua Zinc, Hexaaqua Copper, Hexaaqua Magnesium and Selenate Composition: ZCMS-AHS-5 / 2 / 1 / 1 in 0.5Kg batches Following the procedure of Example 1, ammonium sulfate is replaced with ammonium hydrogen sulfate to make up for the unreacted sulfuric acid in the reaction of Example 1. In step 2 of Example 1, selenium dioxide is added first in a manner similar to other metal salts. This formulation is a more efficient one-batch synthesis using the method of Example 1 and produces the preferred composition shown below: [Table 5]

[0112] Using the procedure of Example 1 and the modifications described above, combine the following ingredients in the following w / w% ranges of ingredient ions depending on the preferred route of administration and use: [Table 6]

[0113] Example 4 Hexaaqua Zinc, Hexaaqua Copper, Hexaaqua Magnesium, Hexaaqua Manganese and Selenate Composition: ZCMMS-AHS-5 / 2 / 1 / 1 / 1 in 0.5Kg batches The procedure of Example 1 is used, substituting ammonium hydrogen sulfate for ammonium sulfate, thereby compensating for the unreacted sulfuric acid reaction product of Example 1 when ammonium sulfate is used. In step 2 of Example 1, selenium dioxide is instead added first, added in the same manner as the other metal salts, and manganese sulfate is added second, after the selenate product has been formed. This formulation is a more efficient one-batch synthesis of Example 1, and produces the preferred composition shown below: [Table 7]

[0114] Using the procedure of Example 1 and the modifications described above, combine the following ingredients in the following w / w% ranges of ingredient ions depending on the desired route of administration and use: [Table 8]

[0115] Example 5 Hexaaqua Zinc, Hexaaqua Copper, Hexaaqua Magnesium Composition: Using the procedure of Example 1, combine the following ingredients in the following w / w% ranges of ingredient ions: [Table 9]

[0116] Pharmaceutically acceptable salts of the compounds used in the compositions of the present invention include, for example, the conventional non-toxic salts or quaternary ammonium salts of the compounds formed from non-toxic inorganic or organic acids, such as, for example, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; as well as the salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. Generally, salts are prepared by reacting the free base or free acid with a stoichiometric amount or excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or a combination of various solvents. Pharmaceutically acceptable salts are also readily prepared by conventional procedures, for example, by treating the acid with an appropriate amount of base, such as an alkali or alkaline earth metal hydroxide, for example, sodium, potassium, lithium, calcium or magnesium, or an organic base, for example, an amine, for example, dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine, etc., or a quaternary ammonium hydroxide, for example, tetramethylammonium hydroxide, etc.

[0117] The compound of formula I can be administered to animals, preferably mammals, most particularly human subjects, alone or in pharmaceutical compositions, preferably in combination with pharma- ceutically acceptable carriers or diluents, optionally in combination with known adjuvants such as alum, according to standard pharmaceutical practice. The compound can be administered orally or parenterally, including intravenously, intramuscularly, intraperitoneally, subcutaneously, or topically. When the composition according to the invention is used orally, it can be administered, for example, in the form of a tablet or capsule, or as an aqueous solution or suspension. When tablets are used for oral use, commonly used carriers include lactose and cornstarch, and lubricants, such as magnesium stearate, are usually added. When administered orally in capsule form, useful diluents include lactose and dried cornstarch. 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 solution should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the formulation isotonic. When the compositions of the present invention are used in human subjects, the daily dose is usually determined by the prescribing physician, and the dose generally varies according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. In most cases, however, the effective daily dose will range from about 0.005 mg / kg to about 50 mg / kg body weight, preferably from about 0.05 mg / kg to about 50 mg / kg body weight, and most preferably from about 0.5 mg / kg to about 20 mg / kg body weight, administered in single or divided doses.

[0118] A formulation scientist of ordinary skill can modify the formulation within the teachings of this specification to provide a number of formulations for specific routes of administration without destabilizing the IBAL-containing composition or compromising its therapeutic activity.

[0119] Example 6 Hexaaqua zinc, hexaaqua copper, and hexaaqua magnesium compositions formulated in topical gel medicines The composition product of Example 1 was formulated into a skin gel formulation for topical administration at a concentration of 25% w / w, with Ion ZCM1 as the active ingredient, containing: [Table 10]

[0120] [Table 11]

[0121] SEPINIO™ DERM is a multifunctional powdered polymer with CAS number 111286-86-3, manufactured by SEPPIC, used to thicken, stabilize / emulsify, co-stabilize, and texturize all dosage forms. The polymer does not require neutralization, works at all pHs, and can be manufactured at room temperature. It is composed of hydroxyethyl acrylate, sodium acryloyldimethyltaurate copolymer, and can function as a co-stabilizer, emulsifier-stabilizer, texturizer, thickener, topical excipient, and viscosity agent.

[0122] Example of formulation for 1 kg batch of Ion Gel ZCM-25 Sepino Derm was slowly added to 0.5625 kg of deionized water and then stirred at 500 rpm with a Teflon coated marine propeller until Sepino Derm was fully hydrated, as evidenced when no lumps were observed. Sodium hyaluronate PC was added and stirred at 500 rpm until a homogenous mixture was obtained. Glycerin was added and mixed at 500 rpm until a homogenous mixture was obtained. In a glass beaker, sodium hydroxide was dissolved in 10% purified water (0.1 kg purified water for 1 kg of Ion Gel ZCM-25). Sodium hydroxide solution was added to the mixture and stirred at 500 rpm until homogenized, pausing and stirring between each successive addition. Ion ZCM-1 was stirred at 750 rpm until the mixture was homogenous and no lumps or coloring was observed. The pH of the product was measured and sodium hydroxide solution was added until the observed pH was 2.0. Ion gel ZCM-25 - Preparation method (Laboratorios Manuell, 2020). Product analysis: [Table 12]

[0123] Example 7 Hexaaqua Copper, Hexaaqua Zinc Composition (ZC-1) [Table 13]

[0124] Example 8 Hexaaqua delivery system of zinc, magnesium, and copper coordination complexes [Table 14]

[0125] Example 9 Hexaaqua Copper, Hexaaqua Zinc, Hexaaqua Magnesium Composition [Table 15]

[0126] NMR analysis of composition ZC-1 of Example 8. NMR studies show predominantly NH + The presence of ammonium ion was verified. NMR studies were performed as follows: the original stock solution was diluted 100-fold with H2O / D2O 95 / 5% w / w solvent; 1 H NMR spectra were collected initially at a temperature of 275 K using the Watergate water suppression technique to slow down the expected chemical exchange effects. The first spectrum showed a well resolved triplet with equal intensity of 52 Hz splitting at a chemical shift of 6.82 ppm, with the water reference at 4.7 ppm assumed. At the same time, to the left of the main line, a low intensity satellite well separated from the main triplet was observed, which indicated a triplet-like structure with a small splitting of 1.3-1.4 Hz. By increasing the temperature in two steps to 298 K and 320 K, the exchange hypothesis was proven. Referring to Figure 1, the NH 4 + The slow exchange between the protons and the solvent water increases with temperature, causing first the broadening of the lines and then the merging of the two "species" into a single broadened line. The triplet explanation is that in a slowly exchanging system, four equivalent protons 14 The aim is to show spin-spin coupling to the N nucleus. 14 Since the nuclear spin of N is I=1, the proton line was split into a triplet. The small satellites in the tail of the signal were explained by taking into account the presence of about 5% DO in the solution. Then, by exchange with water, 14 The NH3D+ group was formed, and three extra signals popped up and were isotopically shifted from the main signal. Those small triplets were due to the binding of three equivalent protons to one deuterium with spin 1. To double check the deuterium isotope shift effect, 1M NH+ 4 A solution containing ammonium ions was prepared. 50 μL of this solution was expanded with 425 μL of H2O and 25 μL of D2O for NMR. An additional 25 μL of D2O was then added. The two spectra obtained are shown in Figure 2. 14 NH3D+ It can be seen that the amount of satellites doubles. In the presence of 10% DO, further deuteration leads to 14 NH2D2 + A new deuterium satellite signal of 10 ... 15 This allowed the observation of the N signal, and the spectrum is shown in Figure 3. 15 The N chemical shift is 32.4 ppm, which is 15 NH4 + This is consistent with the predicted expected value of + For the group, this is also about 32 ppm in proteins).

[0127] Acid content of the stock solution. Using direct potentiometry: 100-fold serial dilutions were made and the pH was measured to be pH=2.3, indicating that the diluted samples were also strongly acidic. To measure the overall acid content, a pH-potentiometric titration was performed. 600 μL of the stock acid solution was diluted to 6 mL and the sample was titrated with 0.2115 mol / dm3 NaOH solution. The resulting titration curve, shown in Figure 4, showed three inflection points. At 0.3127 ml, the first inflection point, H + +NaOH=Na + +H2O is due to the base consumption of the strong acid (HSO4-) in the sample, and is 1.12 mol / dm 3 The second (less specific) pH change, with an inflection point at about 0.509 ml, was associated with the formation of almost insoluble metal hydroxides, characteristic of Cu(II) and Zn(II) in the near-neutral pH range. The samples are not homogeneous in the pH range 6-8. This phenomenon is consistent with the formation of Cu(II) and Zn(II) in the near-neutral pH range. 2+ and Zn 2+ is well known and the reaction can be illustrated by the following reaction: 2CuSO4 + 2NaOH = Cu 2 (OH) 2 (SO 4 )+Na2SO4, where the underline indicates the formation of a solid precipitate. The third pH jump is NH4 + Related to the deprotonation of ions: NH4 + +NaOH=NH3+Na + +H2O. Free ammonia (NH3) is 2+ and Zn 2+ The complex formation reaction is as follows: Cu 2+ +4NH3D⇔[Cu(NH3)4] 2+ Upon formation of the tetraamine complex, the precipitate dissolves and a clear bluish (light blue) solution is obtained. The similar tetraamine zinc complex [Zn(NH3)4] 2+ is colorless. The difference between the first and third inflection points (1.06-0.31=0.76 ml) indicates that the amount of CuNH4 in the stock solution is + =2.69mol / dm 3 is obtained.

[0128] Example 10 Hexaaqua Copper, Hexaaqua Zinc, Hexaaqua Magnesium, Selenate and Hexaaqua Manganese Compositions [Table 16] The metal ratio is 5 Zn:2 Cu:1 Mg:0.5 Se:0.5 M.

[0129] Example 11 Hexaaqua Copper(II), Hexaaqua Zinc(II), Hexaaqua Magnesium(II) Compositions [Table 17]

[0130] Example 12 Hexaaqua copper(II) and hexaaqua zinc(II) compositions [Table 18]

[0131] Example 13 Redox potential assay The redox potential assay of ZCM-1 was measured at 453.2 mV using the SM2580B method.

[0132] Example 14 Oxygen Radical Absorbance Capacity (ORAC) Activity Assay ION ZCM-1 produced the following ORAC values: Total ORAC = 1138μM TE / 100g H-ORAC value The total ORAC value of [ION-ZCM1] is 1025μM TE / ml when measured at 12.5% ​​dilution. The total ORAC value of [ION-ZCM1] is 740μM TE / ml when measured at a dilution of 6.25%. ·targets for comparison: Total ORAC value of Vitamin E is 580-585 μmol TE / g at 1:1 Total ORAC value of Vitamin C is 128-133 μmol TE / g at 1:1 · The total ORAC value of pepper leaf extract is 64.47 μmol TE / g in a 1:50 or approximately 2% solution.

[0133] The materials and methods are disclosed in 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-YxnQWukne3UnC0 / view?usp=sharing, the disclosure of which is incorporated herein by reference in its entirety.

[0134] Example 15 Antitumor efficacy test in mouse melanoma The compositions of the present invention attack multiple cancer pathways. Three specific in vitro and in vivo preclinical studies demonstrate the anti-cancer activity of ZC-1.

[0135] The first study concluded: (Anti-Tumor Efficacy Study by Intravenous Injection - B16 Mouse Melanoma - 30 Mice. Completed in 2016 by the University of Debrecen, Hungary) No safety abnormalities compared to control tumor-bearing mice were noted in any of the animals when necropsied at the end of the 14-day observation period.

[0136] Histopathology: Tumors isolated from mice treated with various concentrations of the present invention by IV injection showed extensive necrosis, although not as pronounced as tumors isolated from control tumor mice; blood vessels were much less frequent and less developed in mice treated with the present invention compared to control tumor mice; and the composition of the present invention by injection resulted in splenomegaly to an extent significantly (2-3 fold) greater than that of the spleens of control (untreated) tumor mice, consistent with inducing a strong anti-tumor immune response.

[0137] The second study concluded: (Topical Cream Anti-Tumor Efficacy Study - Syngeneic Mouse Melanoma - 30 Mice. Completed in 2017 by the University of Debrecen, Hungary); the composition of the present invention formulated in a topical cream (17%) was significantly more effective against metastatic mouse melanoma when tested in a subcutaneous syngeneic mouse model (B16-F0 in C57BL / 6J mice); more effective than imiquimod topical cream (5%); tumor volumes recorded over the treatment period in the three animal model groups showed that tumor growth was inhibited slower by the composition of the present invention topical cream (17%), supporting the observation that the effect was more pronounced compared to the inhibitory effect of the positive control substance, ALDARA® (5% imiquimod) on tumor growth; and showed that the composition of the present invention topical cream (17%) treatment extended survival time.

[0138] The third study concluded that the composition of the present invention formulated in solution was a responsive cytotoxic agent against the renal cancer cell line Caki-1 (IC50 36.12±1.00 μM), and melanoma cancer cell line A375 (IC50 95.20±1.01 μM) in triple negative breast cancer (MDA-MB-231), and was highly selective when compared to the cytotoxicity of the composition of the present invention against control cells IMR-90 (IC50 142.6±6.65 μM); and the composition of the present invention in solution form induced apoptotic death in 92% of the renal cancer cell line Caki-1 at a dose IC50 of 36.12±1.00 μM.

[0139] Example 16 Antibacterial activity of ZC-1 [Table 19]

[0140] [Table 20]

[0141] Example 17 Antibacterial activity of MRSZC-1 [Table 21]

[0142] [Table 22]

[0143] Example 18 Antibacterial activity of ION ZCM-1 [Table 23]

[0144] [Table 24]

[0145] Example 19 Antibacterial activity of ION GEL ZCM-25 products [Table 25-1] [Table 25-2]

[0146] [Table 26]

[0147] Example 20 Biofilm-reducing activity of ZC-1 products [Table 27]

[0148] [Table 28]

[0149] Example 21 Anti-MRSA activity of ZC-1 A non-biofilm antimicrobial assay using a broth microdilution-based sensitivity method was completed at the University of Debrecen, Hungary. Results showed that the minimum inhibitory concentration (MIC) values ​​of ZC-1 against the 10-methicillin-resistant Staphylococcus aureus isolates tested ranged from 0.212 to 0.85% (v / v). Control vancomycin MIC values ​​ranged from 4 to 16 mg / L. This study compares the average MIC value of Example 6, 0.531% (v / v), with an average MIC value of 10 mg / L for vancomycin. Percentage solution calculations established that twice the amount of vancomycin was required to produce the same 50% turbidity reduction in MRSA when tested compared to ZC-1.

[0150] Example 22 Safety Testing [Table 29]

[0151] While the above description contains many specificities, these should not be construed as limitations on the scope of any embodiment, but as illustrations of the presented embodiments. Many other alternatives and variations are possible within the scope of the teachings of the various embodiments. Although the present invention has been described with reference to exemplary embodiments, those skilled in the art will recognize that various changes can be made and elements thereof can be substituted with equivalents without departing from the scope of the present invention. In addition, many modifications can be made to adapt a particular situation or material to the teachings of the present invention without departing from the essential scope of the invention. Therefore, the invention is not limited to the particular embodiment disclosed as the best or only mode contemplated for carrying out the invention, but the invention is intended to include all embodiments that fall within the scope of the appended claims. Also, in the drawings and specification, exemplary embodiments of the present invention are disclosed, and although certain terms may be used, they are used in a generic and descriptive sense only and not for purposes of limitation, unless otherwise indicated, and therefore the scope of the present invention is not so limited. Furthermore, the use of terms such as first, second, etc. does not imply any order or hierarchy of importance, but rather terms such as 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.

[0152] While the invention has been described, illustrated and shown with reference to certain preferred embodiments thereof, those skilled in the art will understand that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. It is therefore intended 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.

Claims

1. An aqueous solution comprising: (i) ammonium ions [NH ４ ＋ ]; Sulfuric acid [H ２ SO ４ ]; a copper ion concentration of 3% w / w or less; a zinc ion concentration of 8% w / w or less; wherein the pH of the aqueous formulation base solution is 1.0 or less; or (ii) An aqueous solution comprising a dilution of the aqueous solution of (i), the aqueous solution having a pH of less than 6.

2. The aqueous solution contains the following ionic essential elements: Boron (B), calcium (Ca), chloride (Cl), cobalt (Co), copper (Cu), fluoride (F), iodine (I), iron (Fe), magnesium (Mg), manganese (Mn), molybdenum (Mo), nickel (Ni), phosphorus (P), potassium (K), selenium (Se), sodium (Na), sulfur (S), zinc (Zn) 2. The aqueous solution of claim 1, comprising at least one of:

3. An aqueous solution as described in claim 1, further containing a magnesium ion concentration of 3% w / w or less.

4. An aqueous solution as described in claim 1, further containing a manganese ion concentration of 3% w / w or less.

5. An aqueous solution as described in claim 1, further containing a selenium concentration of 2% w / w or less.

6. 10. The aqueous solution of claim 1, wherein the solution comprises an inert carrier and at least one excipient.

7. 10. The aqueous solution of claim 1, wherein the aqueous solution is diluted prior to administration.

8. The aqueous solution of claim 7, wherein the pH of the diluted aqueous solution is about 1.5 to 5.

9.

9. The aqueous solution of claim 1, wherein the aqueous solution is formulated for oral, nasal, intravenous, aerosol, or topical administration.

10. 10. The aqueous solution of claim 1 for treating cancer, wherein the aqueous solution is administered to a subject having cancer.

11. The aqueous solution of claim 10, further comprising an anticancer agent.

12. An aqueous solution according to claim 1 for inducing an immune response, characterized in that the aqueous solution or a dilution thereof is administered to a subject having a microbial infection.

13. 10. The aqueous solution of claim 1 for reducing inflammation, wherein the aqueous solution or a dilution thereof is administered to a subject having inflammation.

14. An aqueous solution as described in claim 1 for activating mitochondrial function, characterized in that the aqueous solution or a dilution thereof is administered to a subject having dysfunctional mitochondria.

15. 10. The aqueous solution of claim 1 for treating a microbial infection, wherein the aqueous solution is administered to a subject in need of antimicrobial treatment.

16. An aqueous solution or dilution thereof as described in claim 1 for use in a method for disrupting a biofilm or biofilm formation, the method comprising administering the aqueous solution or dilution thereof to the biofilm or to a subject having or at risk of having biofilm formation.

17. An aqueous solution or dilution thereof according to claim 1 for use in a method for treating cancer, the method comprising administering to a subject in need thereof an agent having antibacterial and antioxidant properties, the agent disrupting microbial contributions to cancer pathology, modulating oxidative stress, and promoting tumor inhibition and apoptosis.

18. An aqueous solution or dilution thereof according to claim 1 for use in facilitating medical diagnosis, detecting abnormal cells in biological systems, assisting medical procedures, personal care, cosmetic enhancement, and nutritional supplementation.

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