FIELD OF THE INVENTION

The present invention inter alia relates to a water-soluble gold (III) complex according to the following formula: [Au(CN) _m ]n< ^m - ^p > ⁿ (CI0 ₂ )rn, with the definitions as set out herein for m, n, p and r, or a pharmaceutically acceptable salt thereof, for use in a method of treating an inflammatory disease or for use in a method of treating a disease caused by a viral infection. An inflammatory bowel disease is a particular inflammatory disease to be treated, and COVID-19 is a particular disease caused by a viral infection to be treated.

BACKGROUND OF THE INVENTION

Gold has been used in health care since the ancient times, especially in the ancient Persia, Egypt, Arabia, India, and China. Colloidal gold, introduced in the 20 ^th century, is used in the treatment of leukaemia and some other neoplasms. Colloidal gold solution, in other words a suspension of microscopic particulates of gold in distilled water, regenerates, rebuilds and balances vital forces in the body. Colloidal gold is well bioassimilable, non-toxic, and has no taste or odour. It ensures well-being, stimulates physiological functions, improves natural immunity and viability, has a beneficial effect on balancing the cardiac rhythm and improving blood circulation. If appropriately formulated and dosed, gold preparations cause no irritations or addiction and are non-invasive.

Preparations containing gold, which became widely recognised by modern medicine and pharmacology at the end of the second half of the 20 ^th century, are the preparations used in the treatment of rheumatoid arthritis (RA). One of the preparations, containing sodium aurothiomalate (Na2AuSC ₄ H ₃ 04) as the active substance, is a medicinal product called TAUREDON®. This medicine, administered in the form of intramuscular injections or applied directly into the joints, is intended to reduce the effects of rheumatoid arthritis. Note that this medicine is administered in large doses once or twice a week, in single doses of 5 to 50 milligrams (mg) (2.53 to 25.3 mg of gold per dose), until 1 gram (g) of sodium aurothiomalate is administered in the entire treatment (which is more than 505.2 mg of gold). Maintenance treatment assumes dosing 20 to 50 mg of the active substance, which makes up for a total of 10.12 to 25.3 mg of gold. The treatment can be repeated twice per year. It should be mentioned that the single doses of gold used in this treatment are very high. Gold is a component of several dozen hormones and enzymes and, most importantly, it is a catalyst in many biochemical syntheses, mainly oxygenation of the body. In particular, it is an agent in the oxygenation of toxic carbon (II) oxide to carbon (IV) dioxide, which is easily exhaled.

The information collected above suggest the feasibility of gold and its compounds in treatment of many disorders, including neoplasms, inflammatory conditions, and various infections. Note that neoplasms, inflammatory conditions and infections, which include those of viral origin, are often related to performance deficiencies of the immune system.

The immune system is an internal, distributed, and multi-organ protection system of the body designed to counter external threats as appropriate. The correct response of the immune system to a threat is an adequate immunological response. An immunological response are all actions of the body to defend itself against antigens - pathogenic bacteria, viruses, fungi, parasites, protozoa, as well as their fragments, toxins, and all other chemicals which are hazardous to health and life. For the safety of the body, the immune system parts are distributed and located in various parts - the thymus, the spleen, the lymphatic nodes, the tonsils, the intestines, and the bone marrow. A properly functioning immune system acts gradually and depending on the case-by-case assessment of the threat. An underperforming immune system can act incorrectly, which is manifested by failure of response, insufficient response, response with incorrect defense mechanisms, or over-response to the actual conditions, and often, a response is triggered by a nondescript cause and aimed at the body’s own, healthy cells or organs. One of immunological responses is the risk of triggering inflammatory conditions by the very body. Inflammatory conditions, inflammation, inflammatory response, inflammatory reaction, or an inflammatory process (from the Latin word inflammation) is an inherent, prompt, and coordinated defense mechanism; a structured process which is developed in vascularized tissues due to a damaging agent, which may be chemical and/or physical and/or biological. An inflammatory process is multi-stage. When a proinflammatory agent overcomes the external barriers of the body, an inflammation begins. It stimulates mastocytes, dendritic cells, and macrophages, which undergo phagocytosis and secrete mediators of inflammatory conditions. A localized dilation of blood vessels ensues with migration of leukocytes. The triggering of an inflammatory condition is a defense response of the body which should end with removal of the proinflammatory agent and a prompt recovery of normal physiological condition of the affected tissue. What is crucial to a correct course of the inflammatory process is the capacity of the body to develop an immunological response which not only fast, but adequate to the actual threat. The inflammatory reaction must minimize the side effects to the whole body. An inflammatory condition is most often a short response of the body which lasts several days. The manifestation of an inflammatory condition is usually concomitant to fever, reddening, pain, swelling, purulent secretion, NK (natural killer) cells, phagocytes, interferon, and cytokines (10, 1 L- 1 a , and IL-6 interleukin).

The nature of an immunological response can be: (i) an acute inflammation - a correct immunological reaction which lasts up to several days and results with removal of the proinflammatory agent; (ii) a subacute inflammation lasting up to ten-odd days; (iii) a subchronic inflammation; (iv) a chronic inflammation, which lasts for weeks, months, or years. The triggering of an inflammatory condition by the body, the correct and controlled course of the condition, and its termination requires correct progression of many biochemical processes in the body. Note that the course of an inflammatory process features three stages: onset, effector, and termination. A delayed or incomplete onset stage may result in irreversible tissue lesions. The selection of incorrect effectors may result in fixation of defective immunological defense mechanism or defective functioning of the immune system, which is often outright harmful to the body, resulting in the inability to remove the proinflammatory agents by the body, leading to a number of complications and the emergence of chronic inflammatory conditions. Chronic inflammations, especially if untreated, are extremely hazardous to health and life. Chronic inflammatory conditions, which had been attributed as a trait of the seniors until recently, is now becoming an epidemic common to females and males in all groups of age, society background, and ethnicity. Its direct effect is the reduced quality and span of human life. Intestinal inflammatory conditions are very often. If their course is chronic, they can be very harmful to health and cause a number of other disorders, including immunological auto aggression and civilization-related diseases, like cancer. One of the root causes leading to the development of inflammatory conditions, including those of the intestines, can be insufficient activity of anti inflammatory genes, including haem oxygenase.

The immune system features functions which protect the body against pathogenic viruses. The blood courses in the blood system and the lymph runs through similar vessels, which expand into nodes at many locations, including the tonsils, the appendix, and Peyer’s patches (aggregated lymphoid nodules). The white blood cells navigate the body with the blood and lymph streams. The lymphocytes produced by the body attack antigens, including viruses, in many ways - by killing, devouring, poisoning, or hibernating.

The state of the art allows application of many treatment methods against inflammatory conditions, including those of the intestines and those chronic. Pharmacological treatment is used to alleviate or inhibit inflammatory conditions with three groups of medicines:

(i) nonsteroidal anti-inflammatory drugs (NSAIDs) - their action inhibits the prostaglandin cyclooxygenase (COX). Subsequently, it was proven that at least two forms of cyclooxygenase exist: COX-1, which is present constantly in the human body, and COX-2, released in inflammatory processes. The inhibition of COX-2 is clinically relevant, while the inhibition of COX-1 may result in side effects in the digestive system if NSAID treatment is administered. NSAIDs usually provide quick alleviation of uncomfortable inflammatory symptoms; however, administration of NSAIDs entails a risk of side effects, first with damage of the digestive tract mucosa. An active anti-inflammatory substance used against intestinal disorders is mesalazine (being the medicinal product Pentasa);

(ii) steroidal anti-inflammatory drugs (SAIDs) - corticosteroids, which are a group of anti inflammatory, anti-allergenic, and immunosuppressing medicines with a strong impact on the metabolism of carbohydrates, proteins, lipids, and water and electrolytes in the body. Over- excretion of corticosteroids, or excessive intake of medicines of the same action, results in hypercortisolemia, or Cushing’s disease. Corticosteroid insufficiency causes Addison’s disease. Corticosteroids alter the function of many organs and affect the course of immunological reactions. These substances reduce the consumption of glucose in the tissues, while aggravating gluconeogenesis, an overall result of which is elevation of blood glucose levels (or hyperglycaemia). In this respect, corticosteroids amplify the action of adrenalin. The substances inhibit the synthesis of body proteins while intensifying their decomposition. An effect of glucocorticosteroids is the breakdown of immunological protein complexes, by which the immunosuppressive effect ensues. Glucocorticosteroids may cause decomposition of muscle proteins, reducing the muscular force. Glucocorticosteroids restructurise the fatty tissue, resulting in a characteristic displacement of its deposits in the body. They reduce the uptake of calcium in the intestinal tract and amplify the excretion of the element in urine, which may result in osseous disorders (osteoporosis). In higher concentrations, corticosteroids trigger a mineralocorticoid effect: the retention of sodium in the body, resulting in swelling. In physiological conditions, corticosteroids modulate the immunological reactions by preventing overstimulation of the immune system and development of auto aggressive disorders. It is the therapeutic effect which corticosteroids are administered for. Glucocorticosteroids inhibit early and delayed immunological response. They stimulate the synthesis of lipocortin, which inhibits phospholipase A, an enzyme indispensable in the production of proinflam matory substances (eikosanoids) from arachidonic acid. This inhibition, for example, compromises the production of leukotrienes, which trigger dangerous delayed lesions in bronchial asthma. Glucocorticosteroids reduce the generation and release of cytokines and other cellular adhesion mediators. Glucocorticosteroids reduce the mobility and activity of most cells partial to immunity reactions, like neutrophiles, macrophages, basophiles, and lymphocytes T and B. They inhibit the activity of fibroblasts and the production of collagen and glycosaminoglycans. All these effects alleviate inflammatory symptoms. It is why glucocorticoids are used to reduce oversensitivity. With long term administration, these effects may cause the atrophy of lymphatic tissue, weaken the action of lymphatic nodes, and reduce the count of lymphocytes, leading to a significant reduction of immunity of the body. An active substance of the discussed type is prednisone (being the medicinal product Encorton) or dexamethason (being the medicinal product Pabi- Dexamethason);

(iii)biological anti-inflammatory drugs - a group of medicines strictly related to biologically active molecules which are naturally present in the human body and act by the effect of the mechanisms the molecules mediate. The biological drugs can: (a) mimic the function of correct human proteins; (b) affect the interactions between various biologically active molecules; (c) affect cell receptors. Some of these molecules occur naturally (like insulin, erythropoietin, or growth factors), some others are designer substances intended to affect various underlying mechanisms of diseases (like interleukin antagonists). These drugs are manufactured with biotechnological methods and by application of genetic engineering. The main groups of biological drugs include: (a) monoclonal antibodies (name suffix -mab); (b) fusion proteins (name suffix -cept); and (c) recombined human proteins (name prefix rh- or rhu-). An important group of biological drugs are medicines which affect immunological reactions and act selectively on the molecular level at various stages of pathogenesis (largely in inflammatory and neoplastic diseases, against which selective immunosuppressants and immunomodulators are used). Examples of monoclonal antibodies with anti-inflammatory properties include infliximab (the medicinal product Remicade) or vedolizumab (the medicinal product Entyvio).

The state of the art includes the knowledge about the application of gold in treatment of inflammatory conditions, viral infections, and neoplasms. One of the medicines based on gold is TAUDERON, as already mentioned. It is used against RA (rheumatoid arthritis); however, its applications in the treatment of other inflammatory conditions, including intestinal inflammations, are not known. Later research proved that gold has a therapeutic potential in the treatment of intestinal inflammation. Amira M. Abdelmegid, Fadia K. Abdo, Fayza E. Ahmed & Asmaa A. A. Kattaia published in Scientific Reports on 23 October 2018 described the effect of a gold nanoparticle (AuNP) on an ulcerative inflammation of the large intestine, triggered by DSS (dextran sulphate sodium salt) in mice. The mice tested in this experiment were assigned at random into control, DSS, and DSS + AuNP groups. The severity of the large intestine ulcerative inflammation was evaluated by measuring the disease activity index (DAI). At the end of the experiment, the final body mass values were recorded. The experimental results demonstrated that AuNP (gold nanoparticles) were effectively absorbed into the tissue of the colon and reduced the DSS-induced lesions. The report of the experiment notes the novel therapy for the large intestine ulcerative inflammation. The potential of gold nanoparticles (AuNP) was described in the work by Suqin Zhu, Xiumei Jiang, Mary D. Boudreau, Guangxin Feng, Yu Miao, Shiyuan Dong, Haohao Wu, Mingyong Zeng and Jun-Jie Yin published in 2018 in the Journal of Nanobiotechnology. The authors noted that while AuNP enjoyed interest as potential therapeutic agents in the treatment of inflammatory conditions, their mechanism of anti-inflammatory action remained undetermined. In a study on a large intestine inflammation and RAW264.7 macrophages with the application of a solution containing 5-, 10-, 15-, 30- and 60- nm AuNP stabilized, inter alia, with polyvinylpyrrolidone (PVP) and tannin acid, a promising therapeutic and anti-inflammatory potential of AuNP was demonstrated against the studied disease. The authors also noted that the therapy might have a negative impact on the intestinal microflora.

The patent literature currently does not feature any publications known to the authors of this patent that would confirm the use of gold compounds in the treatment of inflammatory conditions, including intestinal inflammations, and specifically, there are no known publications concerning the use of gold (III) compounds.

Anti-viral drugs are primarily used in anti-viral therapy. These substances can prevent the spread of viral infections. They can act by disabling or inhibiting the penetration and release of a virus, or inhibiting viral replication. It is a consensus that for a virus to infect a cell, it must joint and enter it. The next stages of infection are shedding, genome replication, reproduction of viral proteins by synthesis, and formation of the viral progeny. The entire replication cycle ends with the killing of the host cell. This mechanism of action of a virus implies there are several uptake points for anti-viral drugs, as demonstrated by G. Virell, Piotr B. Heczko (2000). Mikrobiologia i choroby zakazne, Urban & Partner. The medicines used in anti-viral therapy can be divided into several groups:

(i) Natural compounds: the human body produces natural anti-viral compounds, called interferons. Interferons provide an anti-viral action in the non-infected cells adjacent to an infected cell; they do not work in infected cells. Three types of interferon exists: Interferon a (INF-a) - demonstrates the highest anti-viral efficacy; Interferon b (INF-b) - somewhat weaker anti-viral efficacy; Interferon y (INF-y) - demonstrates a higher activity as cytokines produced by lymphocytes than as an anti-viral agent. The anti-viral action occurs by inhibiting the intra cellular synthesis of the virus RNA and DNA, thus inhibiting the proliferation of the virus. Interferons are currently used for treatment of type B and C hepatitis infections. In clinical practice, the following subtypes are used: (a) organic (natural) IFN-a; (b) recombined IFN-a (different from the natural subtype by the composition of amino acids); (c) pegylated IFN-a (containing recombined IFN-a molecules bound to large, neutral molecules of polyethylene glycol (PEG), for a longer life in the serum).

(ii) Synthetic compounds: The compounds which inhibit absorption and/or shedding of the viruses. These compounds prevent penetration of the cells by a virus. Medicine examples: amantadine and rimantadine

(iii) DNA polymerase inhibitors: These medications inhibit viral genome transcription.

(iv) Neuraminidase inhibitors: These substances are used against infections from a flu virus. Neuraminidase (an enzyme) of the flu virus cleave sialic acid. Neuraminidase enables viral hemagglutinins to identify the receptors on cell surfaces, in progeny viruses, and in the respiratory secretion. Medicine examples: oseltamivir - a potent, selective inhibitor of influenza A and B neurotransmidases; zanamivir- a sialic acid analogue, with a specific inhibitive action against influenza A and B neuraminidase

(v) Reverse transcriptase inhibitors (retroviruses): A group of polymerase inhibitors which interfere with the reverse transcriptase in retroviruses. Medicine examples: zidovudine, abakavir, adefovir, entecavir, other Non-nucleoside reverse transcriptase inhibitors (NNRTI) (retroviruses) These factors inhibit the action of reverse transcriptase. Medicine examples: nevirapin, efavirenz

(vi)Protease inhibitors: Synthetic peptides which resist hydrolysis. These compounds act by inhibiting aspartyl protease in viruses, whereas human proteases are insensitive to this effect. The compounds bind H IV-1 and H IV-2 proteases. Medicine examples: sakvinavir, ritonavir (rytonavir), indinavir, nelfinavir, atazanavir, other

(vii) Biological medicines: Biological (or biotechnological) medicines are a group of drugs closely related to natural molecules produced by the human body, yet they are produced by biotechnological engineering. These compounds are immunity response modifiers. They can, among other things, mimic the functions of natural human proteins and affect the interactions between different biologically active molecules. Medicine examples: palivizumab

Compounds of gold have been known to be used in treatment of viral infections. In recent years, studies began on the application of compounds of gold in the therapy of HIV hosts by the reason that the intra-cellular concentration of gold may inhibit replication of the virus. Studies with auranofin provided positive results by proving the compound reduced the latent viral count, as reported by Fonteh P, Meyer D., Novel gold (I) phosphine compounds inhibit HIV-1 enzymes. Metallomics 2009, 1 (5):427-433.

Several dozen patents and patent applications are currently known to describe different compounds of gold (I), which according to their descriptions can be used to fight neoplastic diseases, as well as other diseases. US Patent 5,603,963 describes cyanide, dithiocyanide, diselenocyanide, and phosphonic complexes of gold (I), which if administered in the therapeutically effective amounts, treat HIV. In the efficacy analysis of these compounds, the factors taken into account should not only include the size of particulates, but also the stability of gold (I) compounds in the blood. Undoubtedly and contrary to colloidal gold, many gold (I) compounds are water-soluble, which theoretically guarantees their unlimited solubility in the blood and lymph and therefore unlimited delivery with the blood to tumour cells. However, cases are known in which after an injection of a gold (I) salt only 1-10% of the injected dose reached the target location, meaning tumours, with a simultaneous increase in accumulation of the compound in other locations. The reason for this state of things is a relatively poor stability of these compounds in a specific environment that is blood, lymph and other body fluids. Under the influence of many factors, the compounds were quickly reduced to metallic gold.

Presented below are the patents and patent applications describing the applications and production of many compounds, or complexes of gold (III).

Patent No. PL235135 discloses water-soluble complexes of gold (III) with the generic formula [Au(CN)m]n(m-p)n x (CI02)rn, with m equal to a number from 3 to 6, and r equal to a number from 0.1 to 2. The subject of the patented solution is also a method of receiving water-soluble gold (III) complexes, distinctive in that the clusters of gold are chemically solubilized multiple times in hydrochloric acid (HCI) in the presence of a minimum of 10-mole excess of univalent chlorides of alkaline metals, and each time evaporated to a dry mass, until clusters with a size of less than 1 nanometer are obtained, preferably in the form of mono-diions of gold (III), and subsequently, in an aqueous or a water-alcohol solution, it reacts with a cyanide of a univalent alkaline metal with a mole ratio ranging from 1 :3 to 1 :6, in the presence of a mild oxidizing agent, chlorine (IV) dioxide or its precursor, sodium dioxo chlorate (III), used in a mole ratio of 0.1 to 2 in relation to gold (III). This solution also applies to the use of water-soluble, intelligent gold (111) complexes represented by formula (1 ), as a single medication or a component of a pharmaceutical agent with a complex pharmaceutical composition, in reasonable quantities and with any method of administration in neoplastic diseases. Patent application CN 111658758 discloses an anti-bacterial nanocluster of gold and its method of manufacturing and use; the method of preparation of the cluster follows these steps: suspension of HAuCI4 with a suspension of glutathione, followed by mixing with an anti bacterial polypeptide solution, adjustment of the Au <+> concentration in the solution, and heating until the anti-bacterial nanocluster of gold is obtained.

U.S. Patent 4,921,847 discloses gold (III) complexes with the formula AuLX3, where Au signifies gold, L signifies the ligand containing nitrogen selected from a group of aliphatic, aromatic, heterocyclic compounds, and X is a chloride. These compounds are useful in the treatment of tumours. It has also been revealed that gold (III) complexes can be useful as anti viral, anti-inflammatory, anti-bacterial, and anti-parasitic preparations.

The next patent description in U.S. Patent 6,413,495, presents complexes of gold (III) with mono L-aspartyl chlorites e6 monoglutamyl chlorites e6 or their pharmacologically acceptable salts. Gold (III) complexes are used to treat neoplastic diseases and in the methods of detecting and treating atherosclerosis. A method of producing gold (III) complexes is also presented.

U.S. Patent 7,632,827 discloses organic organophosphane gold (III) complexes, which if administered to a patient in a therapeutically efficient amount, treat neoplastic diseases and viral diseases, both in in vitro and in vivo studies.

U.S. Patent Application 2004036381 discloses pharmaceutical compositions containing gold (III) in complexes of porphyrin, such as Schiff bases, bis(pyridine) carboxamides and bis(pyridine) sulphonamides, or their pharmaceutically acceptable salts. It also discloses methods of using pharmaceutical compositions containing gold (III) as anti-neoplasm and anti-HIV agents.

All the presented examples describe the reduction of gold (III) ions, mainly with the use of sugars, to colloidal gold (AuO) characterised by the presence of large particulates, sized 50-100 nanometers, stored in dark glass bottles for protection against sunlight.

U.S. Patent Application 2011262500 lists organic complexes containing heterocyclic O, N and S atoms with nanoparticles of gold, silver or platinum, which are administered in the form of intravenous, subcutaneous or intramuscular injection to mammals, including humans, in an effective amount.

Patent Application WO 2010062846 discloses new aromatic gold III complexes with methods of their synthesis and applications. It presents that the new complexes are highly stable, which facilitates their use in the methods of treatment of neoplastic cells. The description contains examples of using these compounds to inhibit growth of neoplastic cells, and their therapeutically effective amounts.

Another patent application, U.S. 2013090472, discloses organic gold (III) complexes used to treat cancer. It describes the methods of producing aliphatic diamine with heterocyclic aldehydes and the formation of a Schiff base, followed by condensation with quaternary salts of chloroauric (III) acid. Organic gold III complexes are synthesized in multiple stages in a medium of toxic and flammable solvents. The organic gold (III) complexes presented above are, in most cases, poorly soluble in water. It is commonly known that all cells, including neoplastic cells, are nourished by ingredients in the blood, and the blood contains about 90% water, while the lungs - 83%, the kidneys - 79%, the brain and the heart - 73%, and the liver - 71 %. Therefore, a good active substance used in a systemic therapy should be characterised by very good solubility and stability in water, especially in the blood and lymph.

Fragmentation of the structure of an active substance containing gold is extremely important for the optimization of its efficacy of reaching the neoplasm. Therefore, it is preferable to break the structure of the cluster that the particulates of gold tend to form and reduce the size of the gold particulates to less than 1 nanometer, and more preferably, to gold (III) monoions or diions.

The patent description in DE 3,920,144 includes detailed information about the method of producing stable, orbitally transformed, monoatomic elements selected from a group consisting of cobalt, nickel, copper, silver, palladium, platinum, ruthenium, rhodium, iridium, and osmium. According to the patent description, transformed monoatomic metals are fit for use as catalysts for ceramics, fireproof materials, and corrosion-resistant materials. In addition, they have certain unique properties, such as superconductivity at high temperatures and the ability to produce energy. This extensive patent description includes chemical and electrochemical methods of producing large clusters of gold, from Au Cl to AU CI - monatomic gold with transformed orbits.

According to the authors of this solution, an action involving the transformation of elements into monoions, in particular the monoions of gold, is extremely important due to the medical-use efficacy of particulate gold. The diameter of colloidal gold particulates is very large and can be anywhere between several to several hundred nanometers, compared to the diameter of sodium-potassium channels and/or the diameter of apertures in the cell membranes, the clear size of which can be approx. 0.7 nm in extreme cases. A disparity this large impedes the free access of gold particulates (AuO) to cells with lesions via the bloodstream, thereby significantly limiting the efficacy of therapy. The size of particles formed by colloidal gold results from its tendency to form ‘clusters’, or multiparticulate formations of combined atoms. Gold clusters comprise from several to dozens of atoms of the metal, and the metal-to-metal (Au-Au) distance is identical to the original metallic form of gold, i.e. they have a crystallographic net and free electrons as in the native gold, wherein the clusters are so large that they do not pass through the cell membranes in microorganisms or mammals.

OBJECTS AND SUMMARY OF THE INVENTION

A subject of the present invention is inter alia the application of water-soluble complexes of gold (III) as an autonomous medicine, medical product, dietary supplement, cosmetic product, or pharmaceutical ingredient applied in therapeutically reasonable quantities and with any method of administration in the therapy of inflammatory conditions and viral diseases, including coronavirus infection.

The present inventors have surprisingly found that the water-soluble gold (III) complex as described herein can be used to treat an inflammatory disease, in particular an inflammatory bowel disease, or a disease caused by a viral infection, in particular COVID-19.

In a first aspect, the present application relates to a water-soluble gold (III) complex according to formula (I)

[Au(CN) _m ]n< ^m -P> ⁿ (CI0 ₂ )rn,

[formula (I)] wherein m has a value of from 3 to 6, n has a value of from 1 to 10, p has a value of from 1 to 3, and r has a value of from 0.1 to 2 or a pharmaceutically acceptable salt thereof, for use in a method of treating an inflammatory disease.

In an embodiment thereof, the water-soluble gold (III) complex according to formula (I) with the above definitions for m, n, p and r is for use in a method of treating an inflammatory disease.

In a preferred embodiment thereof, the inflammatory disease is an inflammatory bowel disease. The inflammatory bowel disease may be selected from the group consisting of Crohn’s disease, ulcerative colitis, microscopic colitis, diversion colitis, Behcet’s disease and indeterminate colitis. Crohn’s disease or ulcerative colitis is particularly preferred herein as the inflammatory bowel disease.

Thus, in a particularly preferred embodiment of the first aspect, the present application relates to a water-soluble gold (III) complex according to formula (I)

[Au(CN) _m ]n< ^m -P> ⁿ (CI0 ₂ )rn,

[formula (I)] wherein m has a value of from 3 to 6, n has a value of from 1 to 10, p has a value of from 1 to 3, and r has a value of from 0.1 to 2 for use in a method of treating Crohn’s disease or ulcerative colitis.

In yet another preferred embodiment of the first aspect, the present application relates to a water-soluble gold (III) complex of the formula [Au(CN) ₄ ] ₂ (CI0 ₂ )Na for use in a method of treating an inflammatory disease. Also in this preferred embodiment, the inflammatory disease is preferably an inflammatory bowel disease. The inflammatory bowel disease may be selected from the group consisting of Crohn’s disease, ulcerative colitis, microscopic colitis, diversion colitis, Behcet’s disease and indeterminate colitis. Crohn’s disease or ulcerative colitis is particularly preferred herein as the inflammatory bowel disease.

Thus, in a particularly preferred embodiment of the first aspect, the present application relates to a water-soluble gold (III) complex of the formula [Au(CN) ₄ ] ₂ (CI0 ₂ )Na for use in a method of treating Crohn’s disease or ulcerative colitis.

In yet another embodiment of the first aspect, the water-soluble gold (III) complex or a pharmaceutically acceptable salt thereof is comprised in a pharmaceutical formulation comprising at least one pharmaceutically acceptable excipient.

In yet another preferred embodiment, the water-soluble gold (III) complex, optionally comprised in a pharmaceutical formulation comprising at least one pharmaceutically acceptable excipient, is administered orally.

The first aspect may alternatively formulated as follows:

A method of treating a subject suffering from an inflammatory disease, comprising administering a water-soluble gold (III) complex according to formula (I)

[Au(CN) _m ]n< ^m -P> ⁿ (CI0 ₂ )rn,

[formula (I)] wherein m has a value of from 3 to 6, n has a value of from 1 to 10, p has a value of from 1 to 3, and r has a value of from 0.1 to 2 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to the subject suffering from an inflammatory disease.

All embodiments as set out above for the first aspect of course also apply for this alternative formulation.

In a second aspect, the present application relates to a water-soluble gold (III) complex according to formula (I)

[Au(CN) _m ]n< ^m -P> ⁿ (CI0 ₂ )rn,

[formula (I)] wherein m has a value of from 3 to 6, n has a value of from 1 to 10, p has a value of from 1 to 3, and r has a value of from 0.1 to 2 or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease caused by a viral infection.

In an embodiment thereof, the water-soluble gold (III) complex according to formula (I) with the above definitions for m, n, p and r is for use in a method of treating a disease caused by a viral infection.

In a preferred embodiment thereof, the viral infection is a corona-virus infection. In particular, the corona-virus is SARS-CoV2. Accordingly, a particularly preferred disease to be treated is COVID-19.

Thus, in a particularly preferred embodiment of the second aspect, the present application relates to a water-soluble gold (III) complex according to formula (I)

[Au(CN) _m ]n< ^m -P> ⁿ (CI0 ₂ )rn,

[formula (I)] wherein m has a value of from 3 to 6, n has a value of from 1 to 10, p has a value of from 1 to 3, and r has a value of from 0.1 to 2 for use in a method of treating COVID-19.

In yet another preferred embodiment of the first aspect, the present application relates to a water-soluble gold (III) complex of the formula [Au(CN) ₄ ] ₂ (CI0 ₂ )Na for use in a method of treating a disease caused by a viral infection.

Also in this preferred embodiment, the viral infection is preferably a corona-virus infection. In particular, the corona-virus is SARS-CoV2. Accordingly, a particularly preferred disease to be treated is COVID-19.

Thus, in a particularly preferred embodiment of the first aspect, the present application relates to a water-soluble gold (III) complex of the formula [Au(CN) ₄ ] ₂ (CI0 ₂ )Na for use in a method of treating COVID-19.

In yet another embodiment of the second aspect, the water-soluble gold (III) complex or a pharmaceutically acceptable salt thereof is comprised in a pharmaceutical formulation comprising at least one pharmaceutically acceptable excipient.

In yet another preferred embodiment, the water-soluble gold (III) complex, optionally comprised in a pharmaceutical formulation comprising at least one pharmaceutically acceptable excipient, is administered orally and/or nasally and/or into the oral cavity and/or pulmonary.

The second aspect may alternatively formulated as follows: A method of treating a subject suffering from a disease caused by a viral infection, comprising administering a water-soluble gold (III) complex according to formula (I)

[Au(CN) _m ]n< ^m -P> ⁿ (CI0 ₂ )m,

[formula (I)] wherein m has a value of from 3 to 6, n has a value of from 1 to 10, p has a value of from 1 to 3, and r has a value of from 0.1 to 2 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to the subject suffering from a disease caused by a viral infection.

All embodiments as set out above for the second aspect of course also apply for this alternative formulation.

DESCRIPTION OF THE FIGURES

Figure 1A. Changes in the inflammatory condition of the DSS-induced mouse colon inflammation model: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group;

(iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 1B. Stool rating in the DSS-induced mouse colon inflammation model: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 1C. Myeloperoxidase activity in the-induced mouse colon inflammation model: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 1D. Microscopic evaluation of lesions in the-induced mouse colon inflammation model: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1 .68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 2. Griess test results for LPS-stimulated RAW264.7, showing a reduction of NO concentration levels for the respective TGS 121 concentration levels: (i) 2.5x10 ^-6 ; (ii) 1x10 ^-6 ; (iii) 7.5x10 ^-7 ; (iv) 5x10 ^-7 ; (v) 2.5x10 ^-7 ; (vi) 1x10 ^-7 ; (vii) 7.5x10 ^-8 ; (viii) 5x10 ^-8 . 100% is the value for the cells untreated and stimulated with LPS (lipopolysaccharides). Figure 3. Change in the heme oxygenase (HMOX) activity: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 4. Change in the catalase activity: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 5A. Change in the reduced glutathione (GSH) concentration: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 5B. Change in the oxidized glutathione (GSSG) concentration: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 5C. Change in the glutathione peroxidase (GPX) concentration: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 6A. Change in the prostaglandin COX-1 concentration: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 6B. Change in the prostaglandin COX-2 concentration: (i) Control: the control group; (ii) DSS: DSS-only treatment group (DSS - dextran sulphate sodium salt); (iii) 121 0.1 A: DSS + TGS 121 @ 1.68 pg/kg treatment group; (iv): 121 1A: DSS + TGS 121 @ 16.8 pg/kg treatment group.

Figure 7. TGS 250 activity at a concentration of (i) 80%, (ii) 50%, and (iii) 0.1 % (purity conditions) against coronavirus 229E.

DETAILED DESCRIPTION OF THE INVENTION

1 . Main objects

The main objects have been outlined above, wherein the following definitions and additional subject matter apply.

As used in the specification and the claims, the singular forms of “a” and “an” also include the corresponding plurals unless the context clearly dictates otherwise. The same applies for plural forms used herein, which also include the singular forms unless the context clearly dictates otherwise.

The terms “about” and “approximately” in the context of the present invention denotes an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10% and preferably ±5%.

It needs to be understood that the term “comprising” is not limiting. For the purposes of the present invention, the term “consisting of is considered to be a preferred embodiment of the term “comprising of. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these embodiments only.

Furthermore, if herein a mixture is defined to comprise at least one compound, this is also meant to encompass a mixture which preferably consists of this at least one compound. For example, if a mixture B comprises an alkali halide, this is also meant to encompass a mixture B consisting of an alkali halide, i.e. a mixture B being an alkali halide. A skilled person will thus appreciate that a mixture consisting of a single compound refers to the compound itself.

Unless specified otherwise, the term “evaporating” refers to a process according to which at least a portion of water is removed from a mixture such that a constant weight of the obtained mixture is reached. Moreover, a mixture after evaporation may be defined by its total moisture content which, unless specified otherwise, is less than or equal to 10.0 wt.-%, preferably less than or equal to 5 wt.-%, and most preferably less than or equal to 4 wt.-%, based on the total weight of the mixture after evaporation.

“Reduced pressure” in the meaning of the present invention refers to a pressure of less than 1013 mbar.

A “molar ratio” of a first and a second compound according to the present invention is to be understood as the ratio of the molar mass of a first compound to the molar mass of a second compound.

The term “pharmaceutically acceptable excipient” as used herein refers to compounds commonly comprised in pharmaceutical compositions, which are known to the skilled person. Examples of suitable excipients are exemplary listed below. Typically, a pharmaceutically acceptable excipient can be defined as being pharmaceutically inactive.

The term “salt” is also meant to encompass hydrated versions of the salt. For example, the term “ alkali tetrachloroaurate salt” is also meant to encompass a hydrated version of an alkali tetrachloroaurate salt. Description of pharmaceutical compositions comprising the gold(lll) compound according to the present invention

A pharmaceutical composition according to the present invention may be formulated for oral, buccal (i.e into the oral cavity), nasal, rectal, topical, transdermal, pulmonal or parenteral application. Oral, nasal and buccal application is preferred. If applicable, a parenteral application may be carried out by an intravenous administration, but may also be carried out by intraarterial, intratumoral, intrathecal, intravesical, intramuscular or subcutaneous administration.

A pharmaceutical composition of the present invention may also be designated as formulation or dosage form.

The dosage form of the present invention can comprise various pharmaceutically acceptable excipients, which will be selected depending on which functionality is to be achieved for the dosage form. A “pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, release-modifying materials, carrier materials, diluents, binding agents and other adjuvants. Typical pharmaceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents.

The term “carrier” denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application. Suitable pharmaceutically acceptable carriers include, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, polyethylene-polypropylene block co-polymers such as poloxamer 188 or poloxamer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, polyoxyethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid esters, hydroxymethyl celluloses such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl acetate succinate, polyvinylpyrrolidone, crosspovidone and the like. The pharmaceutical compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.

If liquid dosage forms are considered, these can include pharmaceutically acceptable emulsions, solutions, suspensions and syrups containing inert diluents commonly used in the art such as water. These dosage forms may contain e.g. microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavouring agents.

For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Pharmaceutical formulations for parenteral administration are particularly preferred and include aqueous solutions of the gold(lll) compound in water-soluble form. Additionally, suspensions of the compounds of the compounds of formula (I) may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, soybean oil, or tocopherols, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.

Administration may be via injectable preparations. Thus, sterile injectable aqueous or oleaginous suspensions can for example be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents. A sterile injectable preparation can also be a sterile injectable solution or suspension or an emulsion in a non-toxic parenterally acceptable diluant or solvent. Among the acceptable vehicles and solvents that can be used are water and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvent or suspending medium.

Suppositories for rectal administration can be prepared by e.g. mixing the gold(lll) compound with a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the composition from said suppositories.

For administration by inhalation, the gold(lll) compound according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, effervescent formulations, dragees and granules. Pharmaceutical preparations for oral use can be obtained in the form of solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone (crosspovidone), agar, or alginic acid or a salt thereof such as sodium alginate. The oral dosage forms may be formulated to ensure an immediate release or a sustained release of the composition.

A solid dosage form may comprise a film coating. For example, the inventive dosage form may be in the form of a so-called film tablet. A capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hydroxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose or a two-piece capsule made of polysaccharide.

The dosage form according to the invention may be formulated for topical application. Suitable pharmaceutical application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and/or sustained release skin patches. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

As regards human patients, the gold(lll) compound may be administered to a patient in an amount of about 0.001 mg to about 1000 mg per day, preferably of about 0.01 mg to about 100 mg per day, more preferably of about 0.1 mg to about 50 mg per day. It is particularly preferred to administered the gold(lll) compound in an amount of about 0.002 / kg to about 0.2 mg / kg body weight, preferably in an amount of about 0.01 / kg to about 0.2 mg / kg body weight, more preferably of about 0.02 mg / kg to about 0.04 mg / kg bodyweight.

2. Further objects

Gold clusters form specific ‘cages’, similar in structure to fullerenes. Flowever, most of them take the form of a pyramid, prism, cone or other three-dimensional bodies. Regardless of their structure, their size is so large it prevents them from passing through the cell membranes in microorganisms or mammals. For example, an atom of gold which has the atomic radius of 0.144 nm, forming a cluster of twenty atoms, can reach a size of about 6 nanometers in extreme cases (assuming that a linear structure is formed).

The studies so far have shown that more than 50% of metallic gold (AuO ) in the form of large clusters is excreted from the body unmodified and within a day from administration, 25-30% is excreted during the next day, and the remaining part accumulates in the liver, the kidneys and the spleen, without producing the expected therapeutic effect. Studies have also demonstrated that the injection of hollow nanoshells made of gold (as carriers of the active substance) sized 20-40 nm results in only 1-10% of the injected dose reaching the target, i.e. neoplasms, while increasing the accumulation of gold particulates in other, non-target locations (the liver or the spleen). In order to improve the distribution of gold nanoparticles to the neoplasms, numerous methods of modification have been tried, including combination of the nanoparticles with antibodies, analogues of hormones, macrophages, or silicon compounds. Gold nanoparticles exist combined with biologically active peptides and ribonucleic acids (RNA). Flowever, these modifications only slightly improved the efficacy of neoplasm penetration, as they had no significant effect on the particle size and did not restrict the ability to form clusters.

From the data above, it can be concluded that the efficacy of anti-tumour therapy is closely related to the size of the gold particulates and their ability to penetrate neoplastic cells.

Referring again to the patent description in DE 3,920,144 quoted above, the gold clusters, in order to have their size reduces, are dissolved iteratively in hydrochloric acid with a 20-mole excess of sodium chloride in order to break the metal-metal bond.

In Example 1 , Operation 8, a solution of monoatomic gold (I) salt, NaAuCI ₂ H ₂ 0 is obtained, with a pH approximately at 1.0. This monatomic gold (I) form is unstable in time, and in particular, it is not resistant to sunlight, which decomposes it quickly.

3Au+1 2AuO + Au+3

The present inventors have conducted intensive studies for many years on obtaining gold (III) complexes which are water-soluble, stable in time, resistant to reduction and sunlight, as well as easily assimilable by the human body. Wishing to meet these requirements, it was necessary to create a chemical structure that was completely different from those currently used and described in patent literature. The fundamental property of the substance had to be its stability in different pH media. This is a necessary parameter if a substance is to exist that is functional in treatment of humans. It is common knowledge that in the human body, different pH values are present and range from 0.5 to 2 (in digestive juices), to 6.3 (saliva), 7.3-7.45 (blood), and 7.58- 8 (bile, pancreatic enzymes). The solubility of a complex compound in all these media is highly important if the compound is to be administered orally, intravenously or intramuscularly. It is also very important if the organ being the target of treatment is characterised by a specific pH value and it is addressed by the systemic application. Another important property is stability in time and resistance to sunlight. It is known that medicinal products should preferably have a twenty-four month period until the use-by date. When achieved, these objectives will facilitate creating a preparation that can be stored safely, to build its strategic stocks, and to use it in different climatic conditions. It is also important to make the preparation resistant to reducing agents which can appear in the body. The lack of this stability caused that many preparations performed very well in laboratory conditions, yet lost their performance in body fluids after intravenous injection or oral application. The above-mentioned TAUREDON® used in the treatment of rheumatoid arthritis also loses its properties in the case of an increase of body iron concentration or in contact with thioaminoacids, which are a component of a protein present in mammal cells.

The present inventors also decided to introduce cyanide groups (-CN) to improve the solubility of the complex. The cyanide groups are present in the structure of the compound which constitutes the subject of the invention. The presence of these groups is a significant property of the chemical compound that is the subject of the invention. As the use of this functional group - often associated with a strong poison that is potassium cyanide (KCN) - can be surprising, the common presence of this group in food and medicinal products should be clarified in detail and the scope of its harmfulness to living organisms should be unequivocally specified.

Clearly a great reference which provides the necessary knowledge on the subject of permissible concentrations of the (-CN) group in food products is the documents of the European Food Safety Authority (EFSA). While it is true that these materials, contained in the Commission Regulation of 2 March 2010, and signed in Brussels on behalf of the Commission by John Dallil (Official Journal L 052, 03/03/2010 P. 0053 - 0057) concern the legal regulations on the content of ethyl carbamate and its precursors, including hydrocyanic acid (HCN), in stone fruit spirits and stone fruit marc spirits, but they constitute a perfect ideal source material for the determination of the safety limits for the compound being the subject of this patent application in the human body and for the determination of the safety of daily use. The European Commission, considering the Treaty on the Functioning of the European Union, in particular its Article 292, as well as with regard to the arguments presented below, adopted a Regulation (produced in Brussels on 2 March 2010). On 20 September 2007, the Scientific Panel on Contaminants in the Food Chain of the European Food Safety Authority (EFSA) adopted a scientific opinion on ethyl carbamate and hydrocyanic acid in food and beverages. As the Panel acknowledged that the presence of ethyl carbamate in beverages poses a significant threat to health, it recommended introduction of measures to reduce the risk resulting from consumption of the substance. The Panel also recognised that hydrocyanic acid is an important precursor in the process of creating ethyl carbamate in stone fruit spirits and stone fruit marc spirits, therefore the Panel also decided that measures regulating and reducing consumption of the substance are necessary. Regulation (EC) No. 110/2008 of the European Parliament and the Council of 15 January 2008 on the definition, description, labelling and protection of geographical indications of spirit drinks provides that the maximum content of hydrocyanic acid in stone fruit spirits and stone fruit marc spirits shall be 7 grams per hectoliter of alcohol with 100% of volume (70mg/l), which is equal to 2.8 mg/100ml in 40% alcohol. Practice indicates that even exceeding the this limit (2.8 mg/100ml of 40% alcohol) by several times does not cause the side effects characteristic of the cyanide group.

Another example of common use of the cyanide group (-CN) in food products is kitchen salt (NaCI). According to many publications, its consumption is necessary for correct functioning of the human body. The edible kitchen salt sold to the public contains an anti-caking additive. It is usually one of the following food additives: (i) E 535 - sodium ferrocyanide; (ii) E 536 - potassium ferrocyanide; (iii) E 538 - calcium ferrocyanide. European and Polish standards specify the content of E 536 - potassium ferrocyanide at 20 mg/kg in kitchen salt and 57 mg/kg in sea salt. The maximum daily intake of edible salt is 75 grams and the average is 15 grams. The intake of 15 grams of edible salt automatically results in the intake of 0.3 mg of potassium ferrocyanide, i.e. approximately 0.13 mg of cyanide. Converted to hydrocyanide (HCN), this is exactly what the maximum daily dose of the gold (III) complex compound produced according to the present invention will be, administered in advanced neoplastic diseases, and in many cases, it will be several times lower. The high solubility of anionic gold (III) complexes produced according to the present invention is the greatest advantage. They can be administered orally, intravenously, intramuscularly, and subcutaneously, and many of them reach the target sites intact and unchanged, i.e. neoplastic cells or other pathogens having a higher affinity for gold than healthy human cells. In addition to neoplastic cells, pathogens causing tropical diseases, as well as the bacteria of Lyme disease and tuberculosis, and many others, show this activity.

A detailed analysis of data concerning the amounts of gold used for therapeutic purposes acceptable for the human body and the toxicity of the cyanide group (- CN) stabilized with chlorine dioxide (CI0 ₂ ) inspired the present inventors to create water-soluble intelligent gold (III) complex compounds, the medicinal properties of which were confirmed experimentally.

As a result of long-term tests and research, it was unexpectedly revealed that highly fragmented, preferably monoionic gold (I) can easily be oxidized with dioxochlorate (III) to gold (III) ions, which in turn can be effectively stabilized with chlorine (IV) dioxide, in presence of which the stabilisation product can react in an appropriate mole ratio an alkaline metal cyanide.

Chlorine (IV) dioxide (CI0 ₂ ) was discovered and isolated in 1811 by Sir Humphrey Davy as a result of the reaction of concentrated tetraoxosulphuric(VI) acid and potassium trioxochlorate (V). This method was very dangerous and its inventor himself modified it in 1814 by substituting potassium trioxochlorate (V) with sodium trioxochlorate (V) and the tetraoxosulphuric (VI) acid with hydrochloric acid (HCI). Reaction scheme:

2NaCI0 ₃ + 4HCI 2CI0 ₂ + Cl ₂ + NaCI + 2H ₂ 0

Chlorine (IV) dioxide, CAS 10049-04-4, is a green-yellow gas with an odour similar to chlorine, a molecular weight of 67.45g/mol, a melting point of -59°C, and a boiling point of 10-11 °C. Chlorine (IV) dioxide is poorly soluble in water, with approximately 3g/m3 solved at 25°C, and the solubility decreases as the temperature increases. Chlorine (IV) dioxide is the weakest, totally harmless oxidizing agent in contact with the human body and it is not able to oxidize anything in the blood, cells or tissues.

CI0 ₂ + e = CI0 ₂ - E°= 0.954V

In comparison to other chemical compounds used in contact with the human body, ozone (0 ₃ ) is the strongest oxidizing agent, with E° = 2.070V, and respectively, hydrogen peroxide (H ₂ 0 ₂ ) with E° = 1 800V, and oxygen (0 ₂ ) with E° = 1 300V. Chlorine (IV) dioxide is commonly used for disinfection and bleaching of pulp in paper industry. It is also used in textile, food, and petrochemical industries, sewage treatment plants, and recently, it has found use in disinfection of drinking water, as contrary to chlorine (Cl), it does not create strongly toxic halogen derivatives with aromatic compounds. Chlorine (IV) dioxide is used in Poland in the water supply systems of Warsaw, Krakow, Radom, Oswi^cim, B^dzin, and Nysa. Due to its very low stability, chlorine (IV) dioxide is produced in special generators at the application sites of the compound. Chlorine (IV) dioxide is a highly unstable gas; it decomposes with explosive force to toxic chlorine (Cl ₂ ) and oxygen (0 ₂ ), releasing large amounts of heat. It is very quickly decomposed by the sunlight and all kinds of chemical substances, where the final product of decompositions are chlorides, hypochlorites, and toxic chlorine (Cl ₂ ). The methods most often used for obtaining chlorine dioxide in special, very expensive generators, is a reaction of sodium dioxochlorate (III) with gaseous chlorine (CI2), hypochlorous acid (HOCI), or concentrated hydrochloric acid (HCI). The methods of receiving gaseous chlorine (IV) dioxide used to so far are hazardous, as gaseous chlorine, hypochlorous acid, and concentrated hydrochloric acid are the reagents with high toxicity. The gaseous chlorine (IV) dioxide is as such produced in dedicated generators, by trained operators in special protective clothing, with special precautions and highly efficient supply and exhaust ventilation systems. Patent application PL 401203 discloses a very simple and safe method of receiving chlorine (IV) dioxide by a reaction (in a water solution, even at room temperature) of chloroauric (III) acid with sodium dioxochlorate (III) in the presence of a minimum of 20 moles of sodium chloride. In this reaction of chemical change (disproportionation), one atom of trivalent chlorine is reduced to hydrochloric acid (Cl ^-1 ); at the same time, four atoms of trivalent chlorine are oxidized to chlorine (IV) dioxide. The reaction of receiving water-soluble, stable gold (III) complexes with chlorine (IV) dioxide is presented in the network scheme:

4HAUCI ₄ + 5NaCI0 ₂ + 4NaCI> 4NaAuCI ₄ ^* CI0 ₂ + (n+1)NaCI+2H ₂ 0

This disclosed complex of gold (III), chlorine dioxide in a solution of sodium (I) chloride unexpectedly turned out to be very stable over a long time of storage, even if kept in translucent containers and exposed to sunlight; it is also resistant to freezing and defrosting. This fact gave the inventors the idea to use cyanide groups, in a mole ratio of 3 to 6, to modify fragmented gold

(III) stabilized with chlorine dioxide. Unexpectedly, it turned out that inorganic, anionic, cyanide gold (III) complexes created in the presence of chlorine dioxide or its precursor, sodium dioxochlorate (III), are highly soluble in water, blood, plasma, and lymph. They efficiently and selectively destroy neoplastic cells, and cells of all kinds of pathogens within a short time (a few to ten-odd days). The ionic radius of fragmented, preferably monoionic gold (III), is the lowest of all the platinum metals, including silver and copper, which is why it can enter every cell even via sodium/potassium channels to combine with DNA (deoxyribonucleic acid) and — where necessary — correct (repair) it. The DNA modification occurs at the cellular level, restoring the “record” of the state of a healthy organism from the DNA ‘memory’. The newly developed, water-soluble gold (III) complexes never fail to target and destroy neoplastic cells. As a result of decomposition of an anionic gold (III) complex in a neoplastic cell, active hydrocyanide is produced that is deadly to the cell, and this efficiently destroys cancer cells. The released gold, to the extent necessary, corrects the DNA and catalyzes the oxygenation of lactic acid and other organic acids, carbon (II) oxide, and glucose to harmless substrates, which are carbon

(IV) dioxide and water. The newly developed, water-soluble, intelligent gold (III) complexes are very persistent, and resistant to reduction and sunlight, even if stored in translucent containers made of plastic. Due to extensive fragmentation, they are very effective and cost-efficient in use as pharmaceuticals and cosmetics administered to mammals in therapeutically reasonable quantities and in any form. The water-soluble complexes of gold (III) known from the patent description in PL 235135 are represented by a generic formula: [Au (CN) m]n< ^m -P> ⁿ (CL0 ₂ )rn where m has a value from 3 to 6, n has a value from 1 to 10, p has a value from 1 to 3, and r has a value from 0.1 to 2.

The method of obtaining water-soluble gold (III) complexes, according to the same patent description is distinctive in that the clusters of gold are chemically solubilized multiple times, preferably in hydrochloric acid (HCI) in the presence of a minimum of 10-mole excess of univalent chlorides of alkaline metals, and each time evaporated to a dry mass, until clusters with a size of less than 1 nanometer are obtained, preferably in the form of mono-diions of gold (III), and subsequently, in an aqueous or a water-alcohol solution, it reacts with a cyanide of a univalent alkaline metal with a mole ratio ranging from 1 :3 to 1 :6, in the presence of a mild oxidizing agent, chlorine (IV) dioxide or its precursor, sodium dioxochlorate (III), used in a mole ratio of 0.1 to 2 in relation to gold (III). Water-soluble gold (III) complexes have been developed with the intent of application as a component of pharmaceutical agents for treatment of neoplastic diseases.

Unexpectedly, it became evident that the compound with the formula disclosed in Patent PL 235135 finds uses as an autonomous medicinal product, medical product, dietary supplement, or another pharmaceutical product in therapeutically reasonable quantities and with any method of administration in inflammatory conditions.

Another application of water-soluble complexes of gold (III) as an autonomous medicinal product, medical product, dietary supplement, or another pharmaceutical product in therapeutically reasonable quantities and with any method of administration is the reduction of oxidation and nitrosative stress.

The application of water-soluble complexes of gold (III) as an autonomous medicinal product, medical product, dietary supplement, or another pharmaceutical product in therapeutically reasonable quantities and with any method of administration in viral infections of animals and humans and another anti-viral action, mainly in the treatment of infections caused by a coronavirus.

In pharmaceuticals, water-soluble, intelligent gold (III) complexes, can be used as the active substance, used alone in the form of an aqueous solution or as an active substance enhancing the activity of other drugs useful in the treatment of diseases associated with at least one factor from the group which includes bones, cartilage, joints, veins and arteries, hair, the skin, nails, osteoporosis, rheumatic diseases, arterial and venous sclerosis, skin diseases, cardiovascular diseases, allergic diseases, degenerative diseases, eye diseases and various neoplastic diseases, and the treatment of the alimentary system, respiratory system, circulatory system, endocrine system, excretory system, nervous system, integumentary system, reproductive system, locomotor system, and lymphatic system. These inorganic complexes are used beneficially in conjunction with physiologically acceptable additives, drugs and chemotherapeutic agents. The invention can be used, for example, alone, as an additive to potable water or various drinks, or as a dietary supplement, to supplement gold to the human organism, whose presence stimulates the mechanisms of reinforcing one or more organs, including bones, cartilage, joints, veins and arteries, hair, nails and the skin.

It is worth highlighting that for individuals with an average body mass of 70 kg, the maximum daily medicinal dose will be 10 cm ³ , i.e. several dozen times less than in one dm ³ of the preparation. Indeed, the preliminary research indicates that it is most effective to use medicinal doses of anionic gold (III) complexes of less than 0.1 mg/person/day, which is equivalent to approximately 0.06 mg of hydrogen cyanide. Such low doses of anionic gold (III) complexes, characterised by a water solubility this good in body fluids, pose absolutely no threat to human health. As a reminder, it is worth noting that the dose of potassium cyanide which is lethal to humans with a body mass of approx. 70 kg is 150-250 mg, and cyanides do not accumulate in the body. Cyanides are relatively easily oxidized to cyanates or transformed into thiocyanates, which are several hundred times less toxic. To sum up, these small, nearly homoeopathic doses of cyanide gold (III) complexes selectively destroy neoplastic cells and pathogens harmful to the human body. Using this innovative method of treating neoplastic diseases is so safe that it can be applied for treatment in pregnant women without any risk of fetal complications. The invention, as a cosmetic, can be used alone, as an aqueous solution, or as an ingredient of other cosmetics, such as creams, ointments, shampoos, gels, tonics, various skin hair and nail conditioners, and other care and regenerative products for bad skin, damaged hair and weak nails.

Embodiments of the present invention relate to:

1. Water-soluble gold (III) complexes, represented by the following generic formula:

[Au(CN) _m ]n< ^m -P> ⁿ (CI0 ₂ )rn where m has a value from 3 to 6, n has a value from 1 to 10, p has a value from 1 to 3, and r has a value from 0.1 to 2, for application as an autonomous medicine, medical product, dietary supplement, cosmetic product, or pharmaceutical ingredient applied in therapeutically reasonable quantities and with any method of administration in the therapy of inflammatory conditions.

2. Water-soluble gold (III) complexes, represented by the generic formula shown in embodiment 1 , for application as an autonomous medicine, medical product, dietary supplement, cosmetic product, or pharmaceutical ingredient applied in therapeutically reasonable quantities and with any method of administration in the reduction of oxidation and nitrosative stress. 3. Water-soluble gold (III) complexes, represented by the generic formula shown in embodiment 1 , for application as an autonomous medicine, medical product, dietary supplement, or another pharmaceutical product in therapeutically reasonable quantities and with any method of administration in viral infections of animals and humans and another anti-viral action, mainly in the treatment of infections caused by a coronavirus.

In the following section, particular examples illustrating various embodiments and aspects of the invention are presented. The present invention, however, is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only, and methods which are functionally equivalent are within the scope of the invention.

Indeed, various modifications of the invention in addition to those described herein will become readily apparent to those skilled in the art from the foregoing description, accompanying figures and the examples below. All such modifications fall within the scope of the claims as disclosed herein.

3. Examples

Example 1 : Production of cyanide-chlorite complexes of monoionic gold (III)

The complexes were produced according to the following steps: a) 100 mg of 99.99% pure metallic gold was placed into a 1 dm ³ flask with a stirrer and a trickle cooler, and the contents were dissolved with aqua regia/nitrohydrochloric acid (a mixture of concentrated hydrochloric and nitric acids at 3:1 molar ratio). After the dissolution, gold (III) formed very large clusters with (Au-Au)>11 metallic bonds. b) The water-soluble gold clusters (III) obtained as described were acidified with 120 cm ³ of concentrated (36%) hydrochloric acid (analytical reagent grade); next, the mixture was brought to boil and held this way until the volume was reduced to 20-30 cm ³ . 120 cm ³ of concentrated hydrochloric acid was added for replenishment and the mixture was brought to boil and release NOCI (nitrosyl chloride). This operation was repeated iteratively until the effect was achieved by which brown fumes and the smell of nitrogen oxides were no longer evident. This means that nitric acid and its oxides evaporated completely and gold (III) chlorides remained in the flask. c) To evaporate liquids (acids) from the gold (III) salts, a specific thermostatic polyglycol bath was used. Polyethylene glycol with a molecular weight of 400 and added antioxidants was used as a heating medium for the bath. The flask with gold (III) chlorides was placed in the bath and left to evaporate until dry salt was obtained. It is important to evaporate all the liquid and not to sinter the salt, meaning that it does not change its colour, and not to reduce gold (III) chloride to metallic gold. d) The dry salts obtained as described were dissolved again in aqua regia, with steps (b) and (c) repeated. The foregoing chemical treatment facilitated obtaining clusters of gold (III) chloride, each with less than 11 atoms. e) 300 ml of 6 M hydrochloric acid was added to the dry salt and then the contents were heated again to the boiling point of the liquid and vaporized until dry salts remained. This operation was repeated four times to produce the smallest gold (III) clusters. Once these time-consuming activities were concluded, an orange-red salt of gold (III) chloride was obtained and the chemical composition analysis of which demonstrates it was virtually pure AmCk. f) Next, 9 grams of sodium chloride (NaCI) (analytical reagent grade) was added to the obtained AmCk (the molar ratio between sodium chloride and gold was more than 300 to 1). Next, the contents were made up with distilled water to obtain approx. 500 cm3 of total volume. The whole contents were held boiling for ten-odd hours to produce a compound with the formula of Na ₂ AmCI ₈ in the presence of sodium chloride. The molar surplus of sodium chloride this high was necessary, as it facilitated the breakdown of large gold clusters with metallic (Au-Au) bonds and the production of sodium monochloroaurate (NaAuCI4). The specifically qualified amount of 9 grams of sodium chloride facilitated the ultimate production of a concentration approximate to physiological saline solution. g) The aqueous solution of sodium chloride and the salt was heated until water evaporates to leave a dry deposit of the salts. Next, the salt was treated alternately with 400 cm ³ of distilled water and 600 cm ³ of 6 M hydrochloric acid until no further change in colour was observed. 6 M hydrochloric acid was used to treat the salt. h) After the last treatment with 6 M hydrochloric acid and its final evaporation, dry salts were obtained and diluted next in 800 ml of distilled water, which produced a solution of the monoatomic gold salt, HAuCI2 H20. The pH of the solution was approx. 1.0. i) The flask with the monoioning gold (I) obtained as above was carefully filled with M (molar) sodium hydroxide to neutralize the solution to a pH level of 4-5. Next, 380 mg of 25% sodium chlorite (NaCI02), CAS 775819-2 was added. The molar ratio of gold to chlorite was 1 :2. The molar surplus of sodium chlorite was necessary to oxidize gold (I) to gold (III) and form a complex. After ten-odd hours, a water-soluble, stable gold (III) complex was obtained with chlorine dioxide and sodium chloride with the following formula: NaAuCI ₄ -CI0 ₂ -(NaCI) _z , with z equal to more than 300. j) The monoionic NaAuCI ₄ -CI0 ₂ -(NaCI) ₂ complex was neutralized with 2% sodium bicarbonate (NaHC0 ₃ ), CAS 497-19-8 up to a pH of approx. 7.8; next, 30g of 0.1 M aqueous alcoholic solution of sodium cyanide, CAS 143-33-9 was added. The molar ratio of monoionic gold (III) to cyanide was 1 :6. The whole contents were stirred for 2 hours at a temperature of 30 °C, followed by acidification with 0.1 M hydrochloric acid (HCI) under a high-capacity fume hood. Next, the synthesis was stirred for 4 hours under reduced pressure to remove free hydrogen cyanide (HCN). The highly water-soluble complexes of monoionic gold (III) were neutralized to a pH of 7.4 (the pH of blood and lymph) using 0.1 M sodium hydroxide (NaOH). Next, distilled water was added to produce a volume of 1 dm ³ containing 100 mg of monoionic gold (III), which was approx. 0.5 mM (millimole), bound in a highly soluble complex.

The synthesis was diluted ten times using physiological saline (9 g/dm ³ of sodium chloride) and given a working name “TGS I”. Example 2: Production of cyanide-chlorite complexes of di-ionic gold (III)

The complexes were produced according to the following steps: a) 200 mg of 99.99% pure metallic gold was placed into a 1 dm ³ flask with a stirrer and a trickle cooler, and the contents were dissolved with aqua regia/nitrohydrochloric acid (a mixture of concentrated hydrochloric and nitric acids at 3:1 molar ratio). After the dissolution, gold (III) formed very large clusters with (Au-Au)>11 metallic bonds. b) The water-soluble gold clusters (III) obtained as described were acidified with 200 cm ³ of concentrated (36%) hydrochloric acid (of analytical reagent grade); next, the mixture was brought to boil and held this way until the volume was reduced to 20-30 cm ³ . 200 cm ³ of concentrated hydrochloric acid was added for replenishment and the mixture was brought to boil and release NOCI (nitrosyl chloride). This operation was repeated iteratively until the effect was achieved by which brown fumes and the smell of nitrogen oxides were no longer evident. This means that nitric acid and its oxides evaporated completely and gold (III) chlorides remained in the flask. c) To evaporate liquids (acids) from the gold (III) salts, a specific thermostatic polyglycol bath was used. Polyethylene glycol with a molecular weight of 600 and added antioxidants was used as a heating medium for the bath. The flask with gold (III) chlorides was placed in the bath and left to evaporate until dry salt was obtained. All the liquid was to be evaporated and the salt was not to be sintered, meaning that it must not change its colour, and gold (III) chloride was not to be reduced to metallic gold. d) The dry salts obtained as described were dissolved again in aqua regia, with steps (b) and (c) repeated. The foregoing chemical treatment facilitated obtaining clusters of gold (III) chloride, each with less than 11 atoms. e) 300 ml of 6 M hydrochloric acid was added to the dry salt and then the contents were heated again to the boiling point of the liquid and vaporized until dry salts remained. This operation was repeated four times to produce the smallest gold (III) clusters. Once these time-consuming activities were concluded, an orange-red salt of gold (III) chloride was obtained and the chemical composition analysis of which demonstrated it was virtually pure AU ₂ CI ₆ . f) Next, 18 grams of sodium chloride (NaCI) (analytical reagent grade) was added (the molar ratio between sodium chloride and gold was more than 300 to 1). Next, distilled water was added to obtain approx. 500 cm ³ of the total volume. The whole contents were held boiling for ten-odd hours to produce a compound with the formula of Na ₂ Au ₂ Cl ₈ in the presence of sodium chloride. The molar surplus of sodium chloride this high was necessary to facilitate easy breakdown of large gold clusters with metallic (Au- Au) bonds and to produce sodium monochloroaurate (NaAuCI ₄ ). The specifically qualified amount of 18 grams of sodium chloride facilitated the ultimate production of a concentration approximate to physiological saline solution. g) The di-ionic complex of Na ₂ AmCI ₈ was neutralized with 2% sodium bicarbonate to reach a pH of 8; next, 1g of 2.5% (0.28 mM) sodium chlorite was added with 50 g of 0.1 M aqueous solution of potassium cyanide, CAS:151-50-8. The molar ratio of gold (III) to cyanide was 1 :5. The whole volume was heated to 35°C and stirred for 3 hours under a high-capacity fume hood. The whole volume was then acidified with 0.1 M phosphoric acid and stirred for 6 hours to remove free hydrogen cyanide (HCN). The highly water- soluble complexes of di-ionic gold (III) obtained this way were neutralized to a pH of 7.2 with 0.1M potassium hydroxide (KOH). Next, distilled water was added to produce a volume of 1 dm ³ containing 200 mg of di-ionic gold (III), approx. 1 mM, bound in a stable complex.

The synthesis was diluted twenty times using physiological saline and given a working name

“TGS II”.

Example 3: Production of cyanide-chlorite complexes of polyionic gold (III)

The complexes were produced according to the following steps: a) 50 mg of 99.99% pure metallic gold was added to a 1 dm ³ capacity flask with a stirrer and a condenser, and the contents were dissolved with aqua regia/nitrohydrochloric acid (a mixture of concentrated hydrochloric and nitric acids at 3:1 molar ratio). After the dissolution, gold (III) formed very large clusters with (Au-Au)>11 metallic bonds. b) The water-soluble gold clusters (III) obtained were acidified with 60 cm ³ of concentrated (36%) hydrochloric acid (of analytical reagent grade); next, the mixture was brought to boil and held this way until the volume was reduced to 20-30 cm ³ , 60 cm ³ of concentrated hydrochloric acid was added one more time and the synthesis was brought to boil and release NOCI (nitrosyl chloride). This operation was repeated iteratively until the effect was achieved by which brown fumes and the smell of nitrogen oxides were no longer evident. This means that nitric acid and its oxides evaporated completely and gold (III) chlorides remained in the flask. c) To evaporate liquids (acids) from the gold (III) salts, a specific thermostatic polyglycol bath was used. Polyethylene glycol with a molecular weight of 300 and added antioxidants was used as a heating medium for the bath. The flask with gold (III) chlorides was placed in the bath and left to evaporate until dry salt was obtained. All the liquid was to be evaporated and the salt was not to be sintered, meaning that it must not change its colour, and gold (III) chloride was not to be reduced to metallic gold. d) The dry salts obtained as described were dissolved again in aqua regia, with steps (b) and (c) repeated. The foregoing chemical treatment facilitated obtaining clusters of gold (III) chloride, each with less than 11 atoms. e) 200 cm ³ of distilled water was added to the dry salt obtained and the entire volume was heated to approximately 40°C, and stirred until complete dissolution of polychloroauric (III) acids; following this, the entire volume was neutralized with 5% sodium bicarbonate (NaHC0 ₃ ) to obtain a pH of approximately 8.0; next, 5 g of 0.5% (0.28 mM) sodium chlorate (III) was added. Next, under a fume hood, 20 g of 0.05 M aqueous alcoholic solution of potassium cyanide, CAS 151-50-8 was added. The molar ratio of polyionic gold (III) to cyanides was 1 :4. The entire volume was stirred 2 hours at a temperature of 25°C, followed by acidification with 2-aminoethanesulfonic acid 5%. Next, the entire volume was vigorously stirred in vacuum for 2 hours to extract free cyanides. The water- soluble cyanide-chlorite complexes of polyionic gold (III) were neutralized with 5% sodium bicarbonate until a pH of approx. 7.7. This synthesis was made up with distilled water to produce a volume of 1 dm ³ containing 50 mg of polyionic gold (III) (approx. 0.25 mM) bound in highly water-soluble anionic complexes.

The synthesis was diluted five times using physiological saline and given a working name “TGS

III”.

Example 4: Production of cyanide-chlorite complexes of monoionic gold (III)

The complexes were produced according to the following steps: a) 1000 mg of 99.99% pure metallic gold was added to a 1 dm ³ capacity flask with a stirrer and a condenser, and the contents were dissolved with aqua regia/nitrohydrochloric acid (a mixture of concentrated hydrochloric and nitric acids at 3:1 molar ratio). After the dissolution, gold (III) formed very large clusters with (Au-Au)>11 metallic bonds. b) The water-soluble gold clusters (III) obtained as described were acidified with 350 cm ³ of concentrated (36%) hydrochloric acid (analytical reagent grade); next, the mixture was brought to boil and held this way until the volume was reduced to 20-30 cm ³ . 350 cm ³ of concentrated hydrochloric acid was added for replenishment and the mixture was brought to boil and release NOCI (nitrosyl chloride). This operation was repeated iteratively until the effect was achieved by which brown fumes and the smell of nitrogen oxides were no longer evident. This means that nitric acid and its oxides evaporated completely and gold (III) chlorides remained in the flask. c) To evaporate liquids (acids) from the gold (III) salts, a specific thermostatic polyglycol bath was used. Polyethylene glycol with a molecular weight of 400 and added antioxidants was used as a heating medium for the bath. The flask with gold (III) chlorides was placed in the bath and left to evaporate until dry salt was obtained. It was important to evaporate all the liquid and not to sinter the salt, meaning that it did not change its colour, and not to reduce gold (III) chloride to metallic gold. d) The dry salts obtained as described were dissolved again in aqua regia, with steps (b) and (c) repeated. The foregoing chemical treatment facilitated obtaining clusters of gold (III) chloride, each with less than 11 atoms. e) 450 ml of 6 M hydrochloric acid was added to the dry salt and then the contents were heated again to the boiling point of the liquid and vaporized until dry salts remained. This operation was repeated six times to produce the smallest gold (III) clusters. Once these time-consuming activities were concluded, an orange-red salt of gold (III) chloride was obtained and the chemical composition analysis of which demonstrates it was virtually pure AmCk. f) Next, 9 grams of sodium chloride (NaCI) (analytical reagent grade) was added to the obtained AmCk (the molar ratio between sodium chloride and gold was more than 30 to 1). Next, the contents were made up with distilled water to obtain approx. 500 cm ³ of total volume. The whole contents were held boiling for ten-odd hours to produce a compound with the formula of Na ₂ AmCI ₈ in the presence of sodium chloride. The molar surplus of sodium chloride this high was necessary, as it facilitated the breakdown of large gold clusters with metallic (Au-Au) bonds and the production of sodium monochloroaurate (NaAuCI ₄ ). The specifically qualified amount of 9 grams of sodium chloride facilitated the ultimate production of a concentration approximate to physiological saline solution. g) The aqueous solution of sodium chloride and the salt was heated until water evaporated to leave a dry deposit of the salts. Next, the salt was treated alternately with 200 cm ³ of distilled water and 600 cm ³ of 6 M hydrochloric acid until no further change in colour was observed. 6 M hydrochloric acid was used to treat the salt. h) After the last treatment with 6 M hydrochloric acid and its final evaporation, dry salts were obtained and diluted next in 800 ml of distilled water, which produced a solution of the monoatomic gold salt, HAuCI ₂ H ₂ 0. The pH of the solution was approx. 1.0. i) The flask with the monoioning gold (I) obtained as above was carefully filled with M (molar) sodium hydroxide to neutralize the solution to a pH level of 4-5. Next, 3 g of 25% sodium chlorite (NaCI0 ₂ ), CAS 775819-2, was added. The molar ratio of gold to chlorite was 1:1.6. The molar surplus of sodium chlorite was necessary to oxidize gold (I) to gold (III) and form a complex. After ten-odd hours, a water-soluble, stable gold (III) complex was obtained with chlorine dioxide and sodium chloride with the following formula: NaAuCi ₄ -CI0 ₂ -(NaCI)z, with zequal to more than 30. j) The monoionic NaAuCi ₄ -CI0 ₂ -(NaCI)z complex was neutralized with 5% sodium bicarbonate (NaHC0 ₃ ), CAS 497-19-8 up to a pH of approx. 7.6; next, 60 g of 0.5M aqueous alcoholic solution of sodium cyanide, CAS 143-33-9, was added. The molar ratio of monoionic gold (III) to cyanide was 1 :6. The whole contents were stirred for 2 hours at a temperature of 35°C, followed by acidification with 0.2M hydrochloric acid (HCI) under a high-capacity fume hood. Next, the synthesis was stirred for 4 hours under reduced pressure to remove free hydrogen cyanide (HCN). k) The highly water-soluble complexes of monoionic gold (III) were neutralized to a pH of 7.4 (the pH of blood and lymph) using 0.1 M sodium hydroxide (NaOH). Next, distilled water was added to produce a volume of 1 dm ³ containing 1000mg of monoionic gold (III), which was approx. 5 mM (millimole), bound in a highly soluble complex.

The synthesis was given a working name of TGS 121.

Example 5: Production of TGS 250

A mixture was produced by diluting the complex gold (III) compound produced in Example 4 with physiological saline at a weight ratio of 1 : 1. The mixture is given a working name of TGS 250.

Example 6: Effect on inflammatory conditions

The experiments completed in a model of colon inflammation in mice induced by DSS (dextran sulphate sodium salt) showed that the gold (III) complex designated as TGS 121 (produced in Example 4) significantly reduced the inflammatory condition of the intestines caused by DSS. In vivo tests were performed with two doses of TGS 121, 1.68 pg/kg orally and 16.8 pg/kg orally, each administered once a day. TGS 121 significantly reduced the macroscopic result (Figure 1A) to, respectively: 10.98 +/- 0.49 for 1.68 pg/kg and 9.75 +/- 0.61 for 16,8 pg/kg as compared to 13.85 +/- 0.42 in mice treated with DSS only (Figure 1A).

The anti-inflammatory activity of the TGS 121 gold (III) complex (produced in Example 4) was confirmed by a change of the stool rating in the experiment. The stool rating in mice in the DSS- only treatment control group was only 0.55 +/- 0.28 in comparison to 3.15 +/- 0.25 in the mice treated with DSS. This effect was reversed, respectively, by treatment with 1.68 pg/kg of TGS 121 (2.86 +/- 0.15) and 16.8 pg/kg of TGS 121 (2.23 +/- 0.26) (Figure 1 B).

The activity of myeloperoxydase, an enzyme released in the course of the inflammatory reactions, was the highest in the DSS-only treated mice, namely 9.11 +/- 1.30 and significantly lower in the mice treated with TGS 121 (produced in Example 4, achieving the following values, respectively: (6.33 +/- 0.61) at 1.68 pg/kg of TGS 121 and (7.64 +/- 1.06) at 16.8 pg/kg of TGS 121 (Figure 1C), which also confirmed the gold (III) complex TGS 121 (produced in Example 4) to have anti-inflammatory action.

The parameters considered during the microscopic evaluation included muscle thickness, cellular infiltration, structure of the mucosa, morphology of the crypts, and the presence of caliciform cells. TGS 121 (produced in Example 4) in both concentrations tested significantly reduced the inflammatory condition parameters (6.55 +/- 0.62) at 1.68 pg/kg of TGS 121 and (6.40 +/- 0.52) at 16.8 pg/kg of TGS 121 in comparison to 9.25 +/- 0.68 in the DSS-only treated mice (Figure 1D).

Example 7: Effect on NO generation and heme oxygenase

The experiments completed in a model of colon inflammation in mice induced by DSS (dextran sulphate sodium salt) showed that the gold (III) complex designated TGS 121 (produced in Example 4), had a significant effect on the anti-oxidation profile in the course of the inflammatory condition, including a reduction of nitrogen oxide (NO) levels and an increase in the activity of heme oxygenase and catalase. TGS 121 significantly reduced the nitrosative stress caused by nitrogen oxides (NO), which belong to the reactive nitrogen species (RNS). The in vitro experiments completed included a NRU (neutral red uptake) test to verify the cytotoxicity of the compound and the Griess test to evaluate the NO generation. The NRU test did not prove a viability loss to 1 x 10 ^-6 M.

In the next stage of the experiments, the effect of TGS 121 on the production of nitrogen oxides in RAW264.7 was evaluated. The Griess test evaluates the nitrogen oxide production by the concentration of nitrites in the supernatants of cellular cultures. The efficacy of the tested compound was evaluated at concentration levels which do not reduce viability.

In the Griess test, the NO production was significantly reduced at a concentration of 2.5 x 10 ^-7 (to 75.80 ± 5.89%), with 100% being the value for the cells untreated and stimulated with lipopolysaccharides (LPS), and the inhibition was higher with higher concentration levels (52.07 ± 6.67% at 5 x 10% 36.70 ± 6.40 at 7.5 x 10 ⁷ and 24.53 ± 3.91% at 1 x 10 ⁶ M) (Figure 2).

The use of the gold (III) complex produced in Example 4 and applied as TGS 121 significantly increased the activity of heme oxygenase. It is commonly believed that heme oxygenase, specifically one of its isoforms, HO-1 , acts as a protective enzyme which reduces the expression of proinflammatory genes and protects non-lymphoid cells against apoptosis.

In the mice treated with DSS only, the activity of heme oxygenase was reduced relative to the controls (p < 0.05). While the therapy with the TGS 121 dose of 1.68 pg/kg marginally increased the activity of heme oxygenase in the DSS-treated mice, the 16.8 pg/kg dose treatment displayed a significant difference (p <0.05) (Figure 3).

Moreover, the application of DSS reduced the activity of catalase, while the administration of the gold (III) complex produced in Example 10 and used as TGS 121 in the experiment significantly increased the activity of catalase. Flere, the difference was significant already with the dose of 1.68 pg/kg (p <0.05) (Figure 4).

During the experiment it was found that administration of DSS slightly increased the levels of reduced glutathione (GSFI) and oxidized glutathione (GSSG) in the colon tissue, which provided additional confirmation that the inflammatory condition was present. This effect was reversed by administering TGS 121 produced in Example 4 (Figures 5A and 5B). The activity of glutathione peroxidase (GPX) was significantly increased (p <0.05) with the DSS treatment, but its concentration was reduced after the administration of 16.8 pg/kg of TGS 121 (Figure 5C).

Another important fact is that the DSS treatment did not affect the activity of prostaglandin COX- 1 (COX-1); however, after administering TGS 121 produced in Example 4, the activity of COX-1 increased (Figure 6A). This showed that the gold (III) complex did not result in a reduction of COX-1 concentration, which is otherwise typically observed as a side effect of many NSAIDs. The activity of prostaglandin COX-2 was slightly reduced in the DSS-treated group, but the administration of TGS 121 reversed this effect (Figure 6B).

Example 8: Effect on coronavirus

Studies carried out by the present inventors investigating anti-viral activity according to the model described in NF EN 144476:2013+A22019, “ Chemical disinfectants and antiseptics — Quantitative suspension test for the evaluation of virucidal activity in the medical a red' (which is applicable to humans) demonstrated that the gold (III) complex produced in Example 5 with the working name “TGS 250” has virucidal efficacy, especially against the human coronavirus.

Thus, the tests confirmed a virucidal efficacy of TGS 250 at 80% concentration against the human coronavirus 229E during 120 seconds at 35°C (+/- 0.1 °C). The same test demonstrated no virucidal efficacy for concentration levels of 0.1 % and 50% in TGS 250 (Figure 7). The intent of the inventors was to perform a preliminary test for a therapeutic model in which a high concentration of gold (III) complex is administered, preferably by inhalation or otherwise, over a relatively short period. Given the above results shown in Figure 7, it appears that an administration would reduce the virus population in the body, especially in the body’s respiratory system, and reduce the destructive action of ROS (reactive oxygen species) and RNS (reactive nitrogen species).