Gold-containing drugs for the treatment of pulmonary infections

Abstract

The present invention relates to inhalable medicaments comprising gold thioglucose, and to inhalers, preferably powder inhalers, medicated inhalers or atomizers, containing said medicaments. The present invention provides these medicaments for use in the prevention and treatment of lung diseases, particularly infectious and inflammatory-infectious lung diseases.

Description

[Technical Field]

[0001] The present invention relates to the field of medicine for the treatment of pulmonary diseases, preferably infectious pulmonary diseases and mixed inflammatory and infectious pulmonary diseases. DETAILED DESCRIPTION OF THE INVENTION

[0002] Infectious lung diseases are widespread and have become a major social problem. On the one hand, as seasonal infections such as influenza, they are one of the most common diseases, and on the other hand, they are often the direct cause of death in affected individuals. Until now, treatment options for viral and / or bacterial infections of the respiratory tract have been insufficient.

[0003] Among infectious lung diseases, diseases caused by members of the Coronaviridae family have become increasingly important in recent years. SARS (Severe Acute Respiratory Syndrome) was first observed in Guangdong Province, southern China, in November 2002. The pathogen of SARS was a previously unknown coronavirus, since then referred to as "SARS-coronavirus (SARS-CoV-1)." In 2019, the SARS-CoV-2 virus was first discovered; it caused the disease Covid-19, leading to the 2020 global pandemic. MERS (Middle East Respiratory Syndrome) is also a lung disease caused by a coronavirus (MERS-CoV) that can sometimes lead to severe infection. The unique feature of SARS-CoV-2 infection compared to other viral infections is that cell entry is mediated by the viral spike protein. The target of the spike protein is the membrane protein ACE2 (angiotensin-2 converting enzyme), which plays a key role in the renin-angiotensin system by enzymatically cleaving angiotensin-2, which increases blood pressure, thereby becoming its direct antagonist in physiological events. ACE inhibitors and ACE2 antagonists are a particularly important life-prolonging class of drugs for the treatment of hypertension and the prevention of stroke and myocardial infarction. They act in the same direction as physiological ACE2. Thus, every SARS-CoV-2 infection also implies a dysfunction in the function of one of the most important physiological systems.

[0004] In severe COVID infections (or SARS-CoV-2 infections), the immune system overreacts, which is the actual cause of death. Therefore, in such infections, it is not helpful to limit treatment to the viral infection alone, but rather to simultaneously treat the dysfunction of physiological systems, especially the immune system.

[0005] Until now, there has been no sufficiently effective treatment to combat coronavirus infections, particularly SARS-CoV-1, SARS-CoV-2, and MERS. The nucleoside analogue remdesivir is sometimes used against SARS-CoV-2 as an antiviral treatment. Other therapeutic approaches are directed at the immune system's overreaction, for example with the steroid dexamethasone.

[0006] Therefore, there is a great need for new treatments for pulmonary diseases, particularly infectious and mixed inflammatory and infectious pulmonary diseases. It is an object of the present invention to provide such treatments.

[0007] Thus, the present invention provides a medicament for inhalation comprising gold, preferably gold thioglucose.

[0008] Gold-containing medicines have traditionally been used in basic antirheumatic therapy. In recent years, the use of the most frequently used medicines, auranofin, gold thiomalate, and gold thioglucose, despite their effectiveness, has increasingly been postponed due to the development of biological agents and the frequent occurrence of undesirable side effects during long-term treatment. Gold compounds are known to have potent anti-inflammatory properties, which are due to the inhibition of nuclear factor NFκB. This factor also plays a central role in cystic fibrosis and, among other things, interstitial pneumonia, a devastating consequence of viral lung infections.

[0009] At the same time, auranofin is known to have significant antibacterial and antibiofilm properties (Abdel Khaleka et al., 2019). Also, gold thioglucose has antibacterial activity (Elkashif and Seleem, 2020). Antiviral activity of gold nanoparticles has been reported (Rodriguez-Isqierdo et al., 2020). However, antibacterial effects have not yet been the subject of approved pharmaceuticals.

[0010] WO2017 / 093544A1 describes alkynylphosphine-gold complexes for the treatment of bacterial infections. WO2017 / 058012A1 discloses gold(III) compounds for the treatment of COPD and asthma. WO2012 / 142615A2 describes auranofin and auranofin analogs for the treatment of proliferative diseases. WO2021 / 011466A1 describes metal nanoparticle compounds for the treatment of respiratory infections associated with cystic fibrosis. KR2015 / 0144679A discloses a composition for the prevention and treatment of immune diseases, comprising mesenchymal stem cells treated with a STAT3 inhibitor. WO2016 / 201524A1 discloses a method for producing a metal ion complex by contacting a particulate metal with a chelating agent and forming a metal complex using an oxidizing agent.

[0011] The antibacterial activity of gold and gold compounds can be directly attributed to the effect of gold ions on microorganisms. Both the noble metal gold and gold ions are highly unreactive. Apart from the ionic effect of gold ions, an exception to this is their high affinity for sulfur atoms. Cysteine ​​is a particularly important amino acid from a structure-function perspective, as it contributes substantially to the tertiary structure of proteins due to its potential to form disulfide bridges. Therefore, cysteine-rich domains are frequently located in the reactive centers of proteins.

[0012] The importance of pharmacokinetics, especially in pulmonary diseases, has long been recognized, yet the fact that direct local application of drugs to the disease site offers a wide range of important advantages, including low doses, low physiological load, and fewer potential side effects, remains largely overlooked. Thus, systemically administered gold-containing drugs can attach to sulfur atoms in amino acids and proteins en route to the site of action. Parenteral or oral administration can lead to accumulation in the body. Unfavorable pharmacokinetics with conventional oral and parenteral administration is a particularly significant drawback of gold medications, due to side effects resulting from the strong interaction between gold ions and sulfur compounds. Therefore, the standard oral and parenteral administration forms are not well suited for treating pulmonary infections with gold compounds. Injectable or oral gold compounds must be administered over a long period of time until the gold reaches the pulmonary site of action in adequate concentrations. Local application offers the most direct possible route from drug entry to the site of action. Furthermore, lung tissue is highly adept at absorbing drugs.

[0013] Our research has shown that gold thioglucose has a high affinity for the spike protein of the SARS-CoV-2 virus. This protein also contains a cysteine-rich domain to which the virus binds tightly enough to effectively displace ACE2, the virus's natural attack point. Because the spike protein-ACE2 interaction is crucial for the virus's attack on the body's cells, this finding indicates that the antiviral activity of gold compounds also lies in the specific inhibition of infection before the virus enters the body's cells. This means that these compounds are also suitable for use in medicines for infection prevention. These anti-infective properties, combined with additional antibacterial and immunomodulatory properties, make gold medications for inhalation applications unique for the topical treatment of spike protein-related infections, particularly SARS-CoV-2 infections. Due to their special properties, the medicines of the present invention are also particularly suitable for the prevention of viral infections.

[0014] The present invention therefore relates to inhalable medicaments with dual action against both infection and inflammation-immunomodulation, preferably medicaments comprising gold-containing pharmaceuticals such as gold thioglucose, gold thiomalate, auranofin, gold thiosulfate, gold thioprole and gold thiopolypeptide, or gold salts of sulfur-containing pharmaceuticals such as acetylcysteine, pyritinol, tiopronin and penicillamine.

[0015] The gold salt of N-acetylcysteine ​​is a particularly preferred compound among pharmaceutical gold salts, since N-acetylcysteine ​​is already used in the treatment of lung diseases as a pharmaceutical drug, acetylcysteine, and further positive therapeutic effects may be expected.

[0016] While the gold ion activity of the pharmaceuticals of the present invention is crucial, the counter ion is also crucial. Thus, the toxic phosphine moiety of auranofin significantly limits its dosage options. Furthermore, the release of gold ions from the compounds is largely determined by the counter ion.

[0017] The therapeutic relevance of anti-infective or anti-inflammatory immunomodulatory effects is time-dependent. While inhibiting infection and spreading during the early stages of disease is crucial, immunomodulation becomes particularly important during later stages and especially during severe infections. In the case of gold thioglucose and gold thiomalate, the binding of gold ions to the spike protein can be significantly improved by the addition of additional compounds containing sulfhydryl groups, allowing the activity profile of the drug to be controlled so that either a pre-absorption anti-infective profile (upon activation) or a post-absorption anti-inflammatory immunomodulatory profile (without activation) predominates. Thus, when these compounds are used without an activating additive, the anti-inflammatory immunomodulatory effect predominates. Therefore, gold thioglucose and gold thiomalate are preferred pharmaceuticals for severe infections, with gold thioglucose being particularly preferred.

[0018] For compounds containing a sulfhydryl group, the addition of N-acetylcysteine ​​has been shown to result in increased efficacy (see, e.g., Example 6). The combination of gold thioglucose and gold thiomalate with N-acetylcysteine ​​has been shown to be particularly advantageous. Thus, in a further aspect, the present invention provides a pharmaceutical combination in which a gold-containing compound is combined with a compound containing a sulfhydryl group, preferably N-acetylcysteine.

[0019] In antiviral therapy, the use of drug combinations has proven advantageous; they attack different targets, thus enhancing anti-infective activity and inhibiting the development of resistance through mutation. The anti-infective activity of gold compounds is based on different targets. Thus, during the research for this patent application, high affinity for the papain-like protease PL and the chymotrypsin-like protease 3CL was discovered. Both proteases are essential for viral proliferation and represent important target structures for the development of antiviral drugs against SARS-CoV-2 and other viruses. Further enhancement of the antiviral effect can be expected by adding antiviral drugs, preferably those that attack viral RNA synthesis.

[0020] In one aspect, the present invention relates to a medicament for inhalation comprising gold salts, in particular gold thioglucose, gold thiomalate, auranofin, gold thiosulfate, gold thioprole, gold thiopolypeptide and / or sulfur-containing pharmaceuticals (preferably N-acetylcysteine, pyritinol, tiopronin and / or penicillamine).

[0021] In a preferred embodiment, the medicament further comprises N-acetylcysteine.

[0022] More preferably, the medicament comprises an additional active substance, preferably the additional active substance has antiviral and / or antibacterial activity. In a preferred embodiment, the medicament comprises a viral inhibitor, preferably selected from remdesivir, molnupiravir, favipiravir, ribavirin, lopinavir, umifenovir, nelfinavir, and / or ritonavir, preferably favipiravir, molnupiravir, and / or ribavirin, in particular favipiravir. The combination of gold thioglucose and gold thiomalate with one of the preferred viral inhibitors has been shown to be particularly advantageous. In a preferred embodiment, the medicament comprising a viral inhibitor further comprises N-acetylcysteine ​​(e.g., a triple combination containing gold, in particular a combination of gold thioglucose, N-acetylcysteine, and a viral inhibitor, in particular a combination of gold thioglucose + N-acetylcysteine ​​+ favipiravir, or a combination of gold thioglucose + N-acetylcysteine ​​+ molnupiravir).

[0023] In a further preferred embodiment, the medicament comprises an active substance selected from hydroxychloroquine, chloroquine, and / or ivermectin. Preferably, the medicament further comprises N-acetylcysteine ​​(e.g., a triple combination containing gold, particularly gold thioglucose, N-acetylcysteine, and an active substance selected from hydroxychloroquine, chloroquine, and / or ivermectin). In a further preferred embodiment, the medicament (with or without N-acetylcysteine) further comprises a viral inhibitor as described herein.

[0024] In a further aspect, the present invention provides an inhaler, preferably a powder inhaler, a medicated inhaler or a nebulizer, comprising a medicament according to the present invention.

[0025] In a further aspect, the present invention provides a medicament according to the invention for use in the prevention or treatment of lung diseases, preferably in the prevention or treatment of inflammatory, infectious and mixed inflammatory and infectious lung diseases, in particular SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome) or Covid-19.

[0026] The present invention provides therapeutic gold-containing drugs and their use for the treatment of infectious lung diseases and mixed inflammatory and infectious lung diseases, in which the active substance can advantageously directly access and act at the site of action in the lungs by inhalation, and at the same time, this mode of application minimizes side effects as much as possible.

[0027] Bacterial infections are usually accompanied by inflammatory processes. This discovery is not coincidental, but rather a consequence of the synchronous interaction between pathogens and the host. Therefore, active substances with dual anti-infective and anti-inflammatory properties have been shown to be particularly suitable for treating bacterial infections. The dual action of gold compounds in this regard can offer particular advantages, particularly since their anti-inflammatory effect occurs through the inhibition of nuclear factor NFκB, which contributes to the development of interstitial pneumonia (Bodas M. and Vij N, 2010). The anti-inflammatory effect of the agents according to the present invention is comparable to that of inhaled steroids (see, for example, Example 3).

[0028] Gold-containing agents according to the present invention are particularly preferred for treating diseases caused by coronaviruses from the RNA virus group, such as SARS (Severe Acute Respiratory Syndrome), MERS-CoV (Middle East Respiratory Syndrome Coronavirus), and SARS-CoV-2. Gold-containing agents according to the present invention bind with high affinity to the cysteine ​​sulfhydryl-rich domains of the binding proteins of these viruses, particularly coronaviruses, which are functionally essential for binding and fusion with host cells (Chang et al., 2000, Broer et al., 2006). These viral diseases are often accompanied by superinfection with biofilm-forming bacteria, against which the agents according to the present invention are also active. Auranofin and other gold complexes inhibit the interaction of the spike protein of SARS-CoV-2 with the ACE2 receptor (ACE2: angiotensin-converting enzyme 2). Furthermore, gold complexes inhibit the activity of the viral protease PLpro (: papain-like protease) of SARS-CoV-1 and SARS-CoV-2. The IC of auranofin 50The values ​​are 22.2 mM for the spike / ACE2 interaction and 0.75 mM for PLpro from SARS-CoV-2 ( Gil-Moles et al., 2020 ).

[0029] The preferred administration form of the drug is inhalation as a liquid aerosol or by powder inhalation. The latter is distinguished from the former by the ease of handling of liquid inhalation, during which a significant amount of the active substance remains in the pharyngeal cavity, allowing for more accurate dosing. Although elemental gold can be used in the form of nanoparticles, the preferred gold is in ionic form, and the pharmaceuticals gold thioglucose, gold thiomalate, and auranofin, as well as gold acetylcysteine ​​salt, have proven effective in the treatment of antirheumatic diseases. Gold thioglucose has the advantage that the gold ions are particularly tightly bound to the molecule, allowing for more controlled release.

[0030] Commercially available devices can be used for inhalation purposes. In intensive care, an aqueous solution of the agent according to the present invention can be added to ventilation air using a spray nozzle. In the case of powder inhalation, micronized active substances (particle size preferably less than 5 μm) are the preferred administration form, since this method allows them to reach deeper regions of the lungs. It is also preferred to use them mixed with a support material. In this regard, it is particularly preferred to mix micronized active substances with a support material having a larger particle size, since this first ensures that the support material accumulates in the upper region of the pharyngeal cavity, allowing more active substance to penetrate into the lower region of the lungs. Lactose, mannose, and other carbohydrates are suitable support materials.

[0031] For combination medicines, the active substances are preferably placed in separate compartments of powder inhaler.Placing active substances in separate compartments makes it particularly easy to manufacture.Therefore, in a preferred embodiment of powder inhaler, gold or gold thioglucose and N-acetylcysteine ​​are in separate compartments of powder inhaler.In a particularly preferred embodiment of powder inhaler, gold or gold thioglucose and virus inhibitor are in separate compartments of powder inhaler.In the case of the triple combination described herein, all three active substances can be in separate compartments of powder inhaler.

[0032] In the context of the present invention, the medicament for use according to the invention preferably comprises a gold-containing antirheumatic drug. Particularly preferred antirheumatic drugs are gold thioglucose, gold thiomalate, auranofin, gold thiosulfate, gold thioprole and / or gold thiopolypeptide. Gold thioglucose in particular has been shown to be particularly advantageous in the present invention.

[0033] Preferably, the medicament comprises auxiliary substances. Particularly preferred auxiliary substances are those that are commonly used in inhalation formulations, particularly in inhalation powder and liquid formulations. In a preferred embodiment, the medicament comprises a support substance, preferably a carbohydrate, particularly preferably lactose and / or mannose.

[0034] In a preferred embodiment, the medicament comprises a further active substance for use; preferably, the further active substance has antiviral and / or antibacterial action. Virostatic agents, in particular favipiravir, molnupiravir, remdesivir or ribavirin, are particularly preferred.

[0035] In the context of the present invention, the pulmonary disease is preferably a pulmonary infection, preferably a viral pulmonary infection or a mixed viral and bacterial pulmonary infection, more preferably a disease caused by a coronavirus belonging to the RNA virus group, in particular SARS-CoV-1, SARS-CoV-2 or MERS-CoV. In this regard, it is preferably a coronavirus infection, in particular SARS-CoV-1 infection, SARS-CoV-2 infection or MERS-CoV infection. Particularly preferably, the pulmonary disease is SARS (caused by SARS-CoV-1 infection), Covid-19 (caused by SARS-CoV-2 infection) or MERS (caused by MERS-CoV infection).

[0036] For all aspects of the invention, the medicament is preferably administered by inhalation. Liquid inhalation or powder inhalation is particularly preferred. Especially preferably, administration is carried out by means of an inhaler according to the invention.

[0037] In a preferred embodiment, the dual action medicament of the present invention comprises gold (preferably in the form of gold thioglucose, gold thiomalate, auranofin, gold thiosulfate, gold thioprole, and / or gold thiopolypeptide) and no other active substances.

[0038] In a further preferred embodiment, the medicament according to the invention comprises gold (preferably in the form of gold thioglucose, gold thiomalate, auranofin, gold thiosulfate, gold thioprole, and / or gold thiopolypeptide, especially gold thioglucose) and N-acetylcysteine ​​in a molar ratio of 1:40 to 10:1, preferably 1:20 to 5:1, more preferably 1:10 to 2.5:1, even more preferably 1:5 to 1:1, even more preferably 1:2.5 to 1:1.5, and most preferably 1:2 (gold:N-acetylcysteine).

[0039] For all of the medicaments according to the present invention, the medicament is preferably present as an inhalation formulation.Particularly preferably, the formulation is a powder formulation.Preferably, the medicament is present as a dry powder for aerosol formulation.Powder formulation means that particularly simple administration is possible, for example, by powder inhaler.As an example, powder inhaler such as that already used for treating asthma or COPD can be used.For this application, the medicament is preferably micronized.

[0040] In another preferred embodiment, the medicament is provided as a powder or solution for aerosol formulation.This formulation is particularly suitable for administration by inhaler or nebulizer.For example, this formulation can also be used for patients who need artificial ventilation, for example, for coronavirus infection, particularly in severe cases of SARS, Covid-19 or MERS.

[0041] In a preferred embodiment, the inhaler according to the invention is a powder inhaler, wherein the medicament according to the invention is present as a powder formulation. In a further preferred embodiment, the inhaler is a medication inhaler (e.g. a pressurized gas medication inhaler or an atmospheric medication inhaler) or a nebulizer, wherein the medicament is present as a solution or aerosol.

[0042] Furthermore, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: - providing a medicament or pharmaceutical combination described herein; and - administering an effective amount of a medicament or combination of medicaments to an individual in need thereof; Disclosed is a method for the prevention or treatment of a pulmonary disease, preferably an infectious pulmonary disease or a mixed inflammatory and infectious pulmonary disease, comprising: Preferably, the method is for the treatment of a pulmonary disease when an individual is suffering from the pulmonary disease.

[0043] All preferred embodiments of the medicament for application according to the invention are also preferred for the method of treatment described herein. In particular, all preferred embodiments are also preferred for this method. Preferably, administration of the medicament is carried out by means of an inhaler according to the invention.

[0044] As used herein, the term "prevention" means to completely, or nearly completely, or at least to some extent (preferably to a significant extent) prevent the occurrence of a disease in an individual. However, this term should not be interpreted as a complete success in the sense that the individual will never develop such a disease, but rather as a reduction in the risk of the disease.

[0045] In the context of the present invention, the terms "agent", "pharmaceutical" or "pharmaceutical composition" should be understood to mean a composition comprising at least one active substance and preferably one or more pharmaceutically acceptable auxiliary substances. In particular, these compositions are intended for administration to animals, preferably mammals, most preferably humans.

[0046] Preferably, a dose of the pharmaceutical is administered to the individual, preferably a dose of the pharmaceutical is administered at least once a week, preferably at least once every two days, more preferably at least once a day, even more preferably at least twice a day, especially at least three times a day.

[0047] Preferably, the treatment is carried out with an effective amount of the medicament for a specific period of time, in particular, the medicament is administered for 1 to 30 days, preferably 2 to 21 days, more preferably 3 to 14 days, and most preferably 5 to 10 days.

[0048] In the context of the present invention, the individual to be treated is preferably an animal, preferably a mammal, in particular a human. Preferably, the individual has one of the pulmonary diseases described herein.

[0049] In a preferred embodiment, the concentration of gold in one dose of the medicament is 0.001 μmol to 450 μmol, preferably 0.01 μmol to 250 μmol, even more preferably 0.1 μmol to 50 μmol, and most preferably 0.5 μmol to 30 μmol. In a particularly preferred embodiment, the dose contains 0.1 μg to 1000 μg of gold per kg of patient body weight, preferably 0.2 μg / kg to 200 μg / kg, more preferably 0.5 μg / kg to 40 μg / kg, and most preferably 1 μg / kg to 10 μg / kg of body weight.

[0050] In particular, the present invention discloses the following preferred embodiments:

[0051] Embodiment A1. A medicament for inhalation comprising gold, preferably gold thioglucose, gold thiomalate, auranofin, gold thiosulfate, gold thioprole, gold thiopolypeptide, and / or gold salts of sulfur-containing pharmaceuticals (preferably N-acetylcysteine, pyritinol, tiopronin and / or penicillamine), in particular gold thioglucose.

[0052] Embodiment A2. A medicament according to embodiment A1, wherein the medicament comprises a gold-containing antirheumatic medicament, preferably gold thioglucose, gold thiomalate, auranofin, gold thiosulfate, gold thioprole, and / or gold thiopolypeptide, in particular gold thioglucose.

[0053] Embodiment A3. An inhaled medication comprising gold thioglucose.

[0054] Embodiment A4. The pharmaceutical agent according to any one of embodiments A1 to A3, further comprising N-acetylcysteine.

[0055] Embodiment A5. A medicament according to any one of embodiments A1 to A4, wherein the medicament comprises a further active substance, preferably wherein the further active substance has antiviral and / or antibacterial activity.

[0056] Embodiment A6. A medicament according to any one of embodiments A1 to A5, further comprising a viral inhibitor, preferably selected from remdesivir, molnupiravir, favipiravir, ribavirin, lopinavir, umifenovir, nelfinavir and / or ritonavir, preferably favipiravir, molnupiravir and / or ribavirin, in particular favipiravir.

[0057] Embodiment A7. A medicament according to any one of Embodiments A1 to A6, further comprising an active substance selected from hydroxychloroquine, chloroquine and / or ivermectin.

[0058] Embodiment A8. The following: gold, preferably gold salts of gold thioglucose, gold thiomalate, auranofin, gold thiosulfate, gold thioprole, gold thiopolypeptide, and / or sulfur-containing medicinal products (preferably N-acetylcysteine, pyritinol, tiopronin and / or penicillamine), in particular gold thioglucose; - a viral inhibitor, preferably selected from remdesivir, molnupiravir, favipiravir, ribavirin, lopinavir, umifenovir, nelfinavir and / or ritonavir, preferably favipiravir, molnupiravir and / or ribavirin, in particular favipiravir; and - N-acetylcysteine 10. A pharmaceutical composition for inhalation comprising:

[0059] Embodiment A9. The medicament according to any one of Embodiments A1 to A8, wherein the medicament comprises gold and N-acetylcysteine ​​in a molar ratio of 1:40 to 10:1, preferably 1:20 to 5:1, more preferably 1:10 to 2.5:1, even more preferably 1:5 to 1:1, even more preferably 1:2.5 to 1:1.5, and most preferably 1:2 (gold:N-acetylcysteine).

[0060] Embodiment A10. The medicament according to any one of Embodiments A1 to A9, wherein the medicament comprises gold thioglucose and N-acetylcysteine ​​in a molar ratio of 1:40 to 10:1, preferably 1:20 to 5:1, more preferably 1:10 to 2.5:1, even more preferably 1:5 to 1:1, even more preferably 1:2.5 to 1:1.5, and most preferably 1:2 (gold thioglucose:N-acetylcysteine).

[0061] Embodiment A11. A medicament according to any one of embodiments A1 to A10, wherein the medicament comprises a support substance, preferably a carbohydrate, particularly preferably lactose and / or mannose.

[0062] Embodiment A12. The medicament of any one of Embodiments A1 to A11, wherein the medicament is present as a powder formulation, preferably a micronized powder formulation.

[0063] Embodiment A13. The medicament of any one of Embodiments A1 to A11, wherein the medicament is present as a solution or an aerosol.

[0064] Embodiment A14. An inhaler, preferably a powder inhaler, a medicated inhaler or a nebulizer, comprising a medicament according to any one of Embodiments A1 to A13.

[0065] Embodiment A15. An inhaler, preferably a powder inhaler, containing a medicament according to embodiment A12.

[0066] Embodiment A16. An inhaler, preferably a medicated inhaler or nebulizer, containing a medicament according to embodiment A13.

[0067] Embodiment A17. A powder inhaler comprising a medicament according to any one of Embodiments A4 to A12, wherein the gold or gold thioglucose and N-acetylcysteine ​​are present in separate compartments of the powder inhaler.

[0068] Embodiment A18. A powder inhaler comprising a medicament according to any one of Embodiments A5 to A12, wherein the gold or gold thioglucose and the further active substance are present in separate compartments of the powder inhaler.

[0069] Embodiment A19. A powder inhaler comprising a medicament according to any one of Embodiments A6-A12, wherein the gold or gold thioglucose and the viral inhibitor are present in separate compartments of the powder inhaler.

[0070] Embodiment A20. A medicament according to any one of Embodiments A1 to A13 for application in the prevention or treatment of pulmonary diseases, preferably in the prevention or treatment of inflammatory pulmonary diseases, infectious pulmonary diseases and mixed inflammatory and infectious pulmonary diseases.

[0071] Embodiment A21. A medicament for use according to embodiment A20, wherein the pulmonary disease is an infectious pulmonary disease or a mixed inflammatory and infectious pulmonary disease.

[0072] Embodiment A22. A medicament for use according to any one of embodiments A20 or A21, wherein the pulmonary disease is caused by a pulmonary infection, preferably a viral infection or a mixed viral and bacterial pulmonary infection, more preferably a disease caused by the coronavirus family belonging to the RNA virus group, in particular SARS-CoV-1, SARS-CoV-2 or MERS-CoV.

[0073] Embodiment A23. A pharmaceutical for use according to any one of embodiments A20 to A22, wherein the pulmonary disease is SARS, MERS or Covid-19.

[0074] Embodiment A24. A medicament for use according to embodiment A20, wherein the pulmonary disease is an inflammatory pulmonary disease, preferably a chronic inflammatory pulmonary disease, in particular COPD, cystic fibrosis or interstitial pneumonia.

[0075] Embodiment A25. A medicament for use according to any one of Embodiments A20 to A24, wherein the medicament is administered in a dose comprising from 0.001 μmol to 450 μmol, preferably from 0.01 μmol to 250 μmol, more preferably from 0.1 μmol to 50 μmol, and most preferably from 0.5 μmol to 30 μmol of gold.

[0076] Embodiment A26. The medicament for use according to any one of Embodiments A20 to A25, wherein the medicament is administered at a dose comprising 0.1 μg to 1000 μg of gold per kg of patient body weight, preferably 0.2 μg / kg to 200 μg / kg, more preferably 0.5 μg / kg to 40 μg / kg, and most preferably 1 μg / kg to 10 μg / kg of gold per kg of body weight.

[0077] Embodiment A27. A medicament for use according to any one of Embodiments A20 to A26, wherein the use is by inhalation, preferably by liquid inhalation or powder inhalation.

[0078] Embodiment A28. A medicament for use according to any one of embodiments A20 to A27, wherein the use is by inhalation according to any one of embodiments A14 to A19.

[0079] Embodiment A27. The process of: - providing a medicament as defined in any one of embodiments A1 to A13; and - administering an effective amount of a medicament to an individual in need thereof; A method for the prevention or treatment of a pulmonary disease, preferably a pulmonary disease, as defined in any one of embodiments A20 to A26, comprising:

[0080] Embodiment A28. The method of embodiment 27, wherein the method is as defined in any one of embodiments A20 to A26.

[0081] Embodiment A29. The method of Embodiment A27 or A28, wherein the medicament is administered by an inhaler, preferably an inhaler according to any one of Embodiments A14 to A19.

[0082] Embodiment B1. A medicament for the treatment of inflammatory lung diseases, infectious lung diseases and mixed inflammatory and infectious lung diseases comprising gold.

[0083] Embodiment B2. A medicament according to embodiment B1, used for the inhalation treatment of pulmonary infections.

[0084] Embodiment B3. A medicament according to embodiment B1, used for the inhalation treatment of viral infections and mixed viral and bacterial pulmonary infections.

[0085] Embodiment B4. The agent of any one of Embodiments B1-B3, wherein the gold-containing material is either a pharmaceutical agent for the treatment of a rheumatic disease, or a gold salt of a pharmaceutical agent, or nanoparticulate gold.

[0086] Embodiment B5. The agent of any one of Embodiments B1-B4, wherein the antirheumatic drug is gold thioglucose.

[0087] Embodiment B6. The agent of any one of Embodiments B1-B4, wherein the antirheumatic drug is gold thiomalate.

[0088] Embodiment B7. The agent of any one of embodiments B1 to B4, wherein the antirheumatic drug is auranofin.

[0089] Embodiment B8. The agent of any one of Embodiments B1-B4, wherein the active agent is an acidic pharmaceutical agent, preferably a gold salt of N-acetylcysteine.

[0090] Embodiment B9. The agent according to any one of embodiments B1 to B8, wherein application is carried out by liquid inhalation.

[0091] Embodiment B10. The medicament of any one of Embodiments B1-B8, wherein application is by powder inhalation.

[0092] Embodiment B11. The agent of Embodiment B10, wherein the pharmaceutical agent is diluted with a support substance.

[0093] Embodiment B12. The agent of Embodiments B10 and B11, wherein the support substance is a carbohydrate, preferably lactose or mannose.

[0094] Embodiment B13. The agent of embodiment B10, wherein the pharmaceutical agent is used in micronized form.

[0095] Embodiment B14. A medicament according to any one of embodiments B1 to B13, comprising at least one further active substance.

[0096] Embodiment B15. An agent according to embodiment B14, wherein the further active substance has antiviral activity.

[0097] Embodiment B16. An agent according to Embodiments B14 and B15, wherein the further active substance has antibacterial activity.

[0098] Embodiment B17. Use of an agent according to any of embodiments B1 to B16 for the treatment of infectious and mixed inflammatory infectious diseases of the respiratory tract.

[0099] Embodiment B18. Use of an agent according to embodiment B17 for the treatment of diseases caused by coronaviruses belonging to the RNA virus group, such as SARS (Severe Acute Respiratory Syndrome), MERS-CoV (Middle East Respiratory Syndrome coronavirus), SARS-CoV-2 and Covid-19.

[0100] Embodiment B19. Use of an agent according to any of Embodiments B1 to B16 for the treatment of inflammatory lung diseases, preferably chronic inflammatory lung diseases, such as COPD, cystic fibrosis and interstitial pneumonia.

[0101] Embodiment B20. Use of gold acetylcysteine ​​in a medicament according to any one of Embodiments B17 to B19. [Brief explanation of the drawings]

[0102] The present invention will now be illustrated by the following examples and figures, without the present invention being obviously limited thereto. [Figure 1] Anti-inflammatory effects of gold acetylcysteine ​​in a mouse model of acute allergic asthma: experimental setting. [Figure 2] Anti-inflammatory effect of gold acetylcysteine ​​in a mouse model of acute allergic asthma: cell counts in bronchoalveolar lavage fluid for the study of airway inflammation. Graph: Mean ± SD, n = 5 (excluding AAC group, n = 4 due to one death), *P < 0.05 compared with placebo (supporting substance), Kruskal-Wallis test, Dunn's multiple comparison test. [Figure 3] Anti-inflammatory effects of gold acetylcysteine ​​in a mouse model of acute allergic asthma: a histological study of lung tissue. [Figure 4] Anti-inflammatory effects of gold acetylcysteine ​​in a mouse model of acute allergic asthma: A lung tissue study with HE and LUNA staining. [Figure 5] Anti-inflammatory effects of gold acetylcysteine ​​in a mouse model of acute allergic asthma: a cell population study. Graph: Mean ± SD, n = 5 (excluding AAC group, n = 4 due to one death), *P < 0.05 compared with placebo (supporting substance), Kruskal-Wallis test, Dunn's multiple comparison test. [Figure 6] Dose-effect curves of gold thioglucose (6A), gold thioglucose / N-acetylcysteine ​​at a ratio of 1 / 2 (6B), and gold thiomalate (6C) as inhibitors of SARS-CoV-2 PLpro. [Figure 7] Effect of added N-acetylcysteine ​​on the inhibition of SARS-CoV-2 PL by 1.0 μM gold thioglucose (n = 2–3). AG = gold thioglucose; N = N-acetylcysteine. The given ratios are molar ratios. [Figure 8] Activation of the effect of added N-acetylcysteine ​​on the inhibition of spike / ACE2 interaction by 20 μM gold thioglucose. N-acetylcysteine ​​alone did not result in inhibition of spike / ACE2 interaction (97% of control at 100 μM). AG = gold thioglucose; N = N-acetylcysteine. The given ratios are molar ratios. [Figure 9]Cytotoxicity of auranofin (AF), gold thiomalate (AM), gold thioglucose (AG), a 1 / 2 molar ratio combination of AM or AG with N-acetylcysteine ​​(N) (concentrations relative to AM-N, AG-N, AM, or AG), and gold acetylcysteine ​​after 24 hours in CaLu-3 cells (n=3). [Figure 10] Removal of zinc from PLpro by disulfiram, gold thioglucose (AG), and a mixture of gold thioglucose and N-acetylcysteine ​​in a 1:2 molar ratio (AG-N) (values ​​obtained compared to the untreated enzyme (PLpro)). [Example]

[0103] Example 1. Preparation of a single dose for inhalation 1.a. Liquid ampoules: A solution of 1.5 mg of auranofin in 2.5 mL of sodium chloride-containing water was placed in a single-dose container and placed in a nebulizer. 1.b. Dry ampoules: 1.5 mg of gold thioglucose was loaded into the ampoules. Before use, 2.5 mL of water was added and the solution was placed in an inhaler. The prepared product had to be consumed within 3 hours.

[0104] Example 2. Preparation of a multi-dose formulation for inhalation 2.a. Powder spray: 30 mg of micronized gold thioglucose was suspended in 300 μL of ethanol. 30 mg of sorbitan trioleate was added, and then, while cooling, added to a spray bottle containing 15 g of propellant. The product was sprayed 300 times. 2.b. Dry Inhaler: 0.2 mg of micronized gold thioglucose was mixed with 12 mg of lactose and prepared for powder inhalation by rigorously excluding moisture. This depends on the type of inhaler and may involve compression into a disk, if desired.

[0105] Example 3. Assay of the anti-inflammatory effects of inhaled gold acetylcysteine ​​in a preclinical pilot study in a mouse model of acute allergic rhinitis by intranasal application The anti-inflammatory effects of gold acetylcysteine ​​(AAC) were tested in a mouse model of acute allergic asthma at two doses (10 mg / kg and 100 mg / kg) compared with dexamethasone (1 mg / kg), using five mice per dose. Three repeat doses per group were administered intranasally in an aerosol chamber. Five mice were administered in each of four groups: AAC, dexamethasone, placebo (vehicle), or untreated (Figure 1). The evaluation was performed as follows: airway inflammation was determined by bronchoalveolar lavage (BAL). For this purpose, the cell count in the BAL was determined (Figure 2). Significant differences were observed compared with placebo. The reduction in total cell count was comparable to that observed with dexamethasone. Lung tissue inflammation was determined by histological study (Figure 3), HE and LUNA staining (Figure 4), and mucus production by PAS staining. However, different cell populations were affected compared with dexamethasone. Granulocytes, primarily eosinophils and neutrophils, as well as lymphocytes, were reduced by AAC. Macrophages were increased compared with dexamethasone (Figure 5). Additionally, serum specific Ag-IgG1 was measured (ELISA). The following results were obtained: gold acetylcysteine ​​at a concentration of 10 mg / kg reduced inflammatory parameters in both the peribronchial and parenchymal regions. The anti-inflammatory effect in tissues was comparable to that of dexamethasone. Treatment of mice with acute exacerbation of allergic asthma with 10 mg / kg gold acetylcysteine ​​for 5 days reduced the total number of anti-inflammatory cells in bronchial secretions, the degree of airway inflammation, the number of eosinophils and neutrophils in the airways, and the infiltration of inflammatory cells in the lung parenchyma.

[0106] Example 4. Preparation of gold acetylcysteine Five grams of tetrachloroauric acid was mixed with 5 mL of water and cooled on ice. 3.18 g of 2,2'-thiodiethanol was added dropwise over 45 minutes with vigorous stirring. The addition was complete when the solution became colorless and no precipitate remained. 1.75 g of N-acetylcysteine ​​in 27 mL of water was slowly added to the solution, resulting in the formation of a white precipitate. The suspension was stirred for 1 hour and filtered through a vacuum filter. The precipitate was washed with 30 mL of water, one drop of 2N hydrochloric acid was added, and then dried overnight. Gold acetylcysteine ​​was obtained in quantitative yield.

[0107] Example 5. Inhibition of SARS-CoV-protease PL by gold compounds Inhibition of SARS-CoV-2 protease papain-like protease (PLpro) was determined as follows: Test substances were dissolved in water as stock solutions and diluted 100-fold with HEPES buffer (50 mM HEPES, pH 7.5, 0.1 mg / mL fetal bovine serum, 0.1% Triton-X-100) to micromolar concentrations. A volume of 50 μL of a 200 nM solution of SARS-CoV-2 PLpro in HEPES buffer or pure HEPES buffer (negative control) was pipetted into wells of a black 96-well microtiter plate. 50 μL of test substance solution or pure HEPES buffer was added to each well (positive control), and the resulting solution was mixed and incubated for 1 hour at 37°C. Next, 100 μL of a 100 μM solution of the substrate Z-Arg-Leu-Arg-Gly-Gly-AMC was added to all of the samples, mixed thoroughly, and fluorescence emission was recorded every 30 seconds for 10 minutes (λ ex = 355 nm, λ em= 460nm, 37℃, Victor TM X4 Perkin Elmer 2030 microplate reader). The increase in fluorescence emission followed a linear trend (r 2 The enzyme activity in each sample was determined as its slope according to the IC (>0.97). The percentage calculation of enzyme activity was obtained relative to the untreated control (positive control). The negative control results were used to ensure that there were no false positive results due to, for example, reaction of the test substance with the substrate. 50 The value was taken as the concentration at which the test substance inhibited enzyme activity by 50% compared to the positive control.

[0108] Result: IC as below 50 Values ​​were determined from the dose-effect curve (Figure 6): Gold thioglucose: 7.03 μM (+ / - 2.31 μM) Authioglucose / N-acetylcysteine ​​molar ratio of 1 / 2: 9.55 μM (+ / - 1.61 μM) (relative to the amount of authioglucose) Gold thiomalate: 0.60 μM (+ / - 0.25 μM)

[0109] Addition of an equivalent amount of N-acetylcysteine ​​to gold thioglucose did not substantially alter the inhibition of PLpro (Fig. 7).

[0110] Example 6. Inhibition of SARS-CoV-2 spike protein interaction with the ACE2 receptor For this purpose, 96-well plates were coated with the receptor-binding domain of the spike protein and stored overnight at 4°C. The wells of the microtiter plate were emptied, replaced with blocking solution for 2 hours, washed, and emptied. Test substances and controls were added, mixed with the ACE2 receptor, and incubated for 1 hour at 37°C. The wells were washed. Streptavidin-horseradish peroxidase conjugate was added, and incubation was carried out for 1 hour at room temperature. After washing again, 3,3',5,5'-tetramethylbenzidine was added to the solution. After 5 minutes at room temperature, absorbance was determined at 450 nm (Perkin Elmer Victor X4 microplate reader). The activity remaining after inhibitor addition was calculated as a percentage of the untreated control.

[0111] Results: 20 μM gold thioglucose inhibited spike / ACE2 interaction (Figure 8). Inhibition could be significantly increased by the addition of N-acetylcysteine. A 1:2 molar ratio of gold thioglucose to N-acetylcysteine ​​proved to be particularly effective.

[0112] Example 7. Cytotoxicity in CaLu-3 cells To determine cytotoxicity, CaLu-3 cells were cultured in 96-well microtiter plates. The cell culture medium was replaced with fresh medium containing 25, 50, or 100 μM concentrations of gold compounds and incubated for 24 hours at 37°C / 5% CO2. The remaining cells were then determined photometrically using crystal violet staining (Victor X4 microplate reader). The amount of cells in the treated samples was calculated as a percentage of the untreated control.

[0113] The results are shown in Figure 9. In the experiment, auranofin was toxic to CaLu-3 cells (less than 20% of untreated controls at 25 μM). Gold thiomalate, gold thioglucose, a 1:2 molar ratio of gold thiomalate, or a combination of gold thioglucose and N-acetylcysteine ​​showed no relevant cytotoxicity at concentrations up to 100 μM.

[0114] Example 8. Removal of zinc from PLpro In addition to the cysteine ​​in the catalytic center of the enzyme, the protease Pl contains an additional cysteine ​​in the zinc-binding domain that stabilizes the structure and function of the enzyme. Removal of bound zinc constitutes an interesting mechanism of action for inhibitors of Pl.

[0115] To determine whether the inhibitor is a Zn scavenger, measure the Zn in the solution. 2+ The presence of cations was determined as follows: Inhibitor compounds were prepared as stock solutions in DMSO, water, or DMSO and diluted 100-fold to a concentration of 100 μM in HEPES buffer (50 μM HEPES, pH 7.5). A volume of 50 μL of SARS-CoV-2 PLpro (Elabscience) in HEPES buffer or blank HEPES buffer (control for false-positive results) was placed in wells of a black 96-well microtiter plate (Nunclon, Nunc). A volume of 50 μL of inhibitor solution or 1% DMSO in HEPES buffer (control) was added. The resulting solutions (500 nM SARS-CoV-2 PLpro, 0.5% DMSO, 50 μM test compound, or blank HEPES buffer) were mixed. 100 μL of 2.0 μM zinc-specific fluorophore FluoZin was added. TM -3 (Invitrogen / LifeTechnologies) was added to all wells. The resulting solution was mixed and fluorescence was determined after 10 minutes and then every 10 minutes for 90 minutes at 37°C (λ exc = 485 nm, λ em= 535 nm; Victor X4 microtiter plate reader). Relative fluorescence was calculated by dividing the absolute fluorescence emission of wells containing inhibitor by the corresponding wells containing enzyme but no inhibitor (control). Wells containing enzyme but no inhibitor were used to confirm false-positive results. Test compounds did not give false-positive results.

[0116] As can be seen in Figure 10, gold thioglucose and a mixture of gold thioglucose and acetylcysteine ​​resulted in zinc removal from PLpro comparable to the reference compound disulfiram. These results are consistent with inhibition of enzyme activity by gold thioglucose, further confirming its relevance.

[0117] Example 9. Inhibition of SARS-CoV-2 protease 3CL by gold compounds Inhibition of SARS-CoV-2 protease 3CL was determined as follows: Test substances were dissolved in water as stock solutions and diluted 100-fold with HEPES buffer (50 mM HEPES, pH 7.5, 0.1 mg / mL fetal bovine serum, 0.1% Triton-X-100) to micromolar concentrations. A 50 μL volume of a 300 nM solution of SARS-CoV-2 3CL protease (Mpro) MBP-tag in HEPES buffer or pure HEPES buffer (negative control) was pipetted into wells of a black 96-well microtiter plate. 50 μL of test substance solution or pure HEPES buffer (positive control) was added, respectively, and the resulting solutions were mixed and incubated at 37°C for 1 hour. Next, 100 μL of a 50 μM solution of the substrate DABCYL-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu-EDANS trifluoroacetate was added to all samples, mixed thoroughly, and fluorescence emission was recorded every 3 min for 75 min (λ ex = 60 nm, λ em =460nm, 37℃, Victor TMX4 Perkin Elmer 2030 microtiter plate reader). Evaluation was performed in a similar manner as with PLpro.

[0118] Results: The gold compounds are excellent inhibitors of SARS-CoV-2 3CL. The IC values ​​are as follows: 50 Values ​​were determined: auranofin: 11.69 μM (±0.40 μM); gold thioglucose: 8.25 μM (±0.04 μM); gold thiomalate: 22.89 μM (±0.72 μM).

[0119] Example 10. Inhibition of bovine coronavirus (BCoV) infectivity in cellular structures As a surrogate for SARS-CoV-2, which can only be tested in biosafety level 3 (BSL3) laboratories, we used bovine coronavirus (BCoV), a virus related to SARS-CoV-2 that is also classified in the Betacoronavirus genus, because experiments can be performed at BSL2, the lower biosafety level 2. The recipient cell culture used was Madin Darby Bovine Kidney (MDBK) cells.

[0120] After incubating various concentrations of gold thioglucose with 100 Tissue Culture Infectious Dose 50 (TCID50) of bovine coronavirus for 1 hour at 37°C, the gold thioglucose-bovine coronavirus suspension was inoculated onto MDBK cells receiving the virus, and incubation continued for an additional 12–28 hours at 37°C in a 5% CO2 atmosphere. A 10-fold reduction in viral load was observed at a gold thioglucose concentration of 256 μM.

[0121] The addition of 64 μM favipiravir when seeding the gold thioglucose-bovine coronavirus suspension into cell cultures also reduced the resulting viral load.

[0122] Example 11. Therapeutic Treatment To make Formulation A, 3 mg of micronized gold thioglucose is mixed with 9 mg of lactose and placed in a multi-dose powder inhaler. Four Covid-19 patients who developed symptoms within 48 hours before the start of treatment are treated with two spray applications of 200 μg each of the powder formulation twice daily for 10 days.

[0123] To prepare Combination Formulation B, liquid ampoules are prepared, each containing 0.1 mg of gold thioglucose and 0.4 mg of N-acetylcysteine ​​dissolved in 2.5 mL of water. Four mechanically ventilated Covid-19 patients are treated with one liquid ampoule per day via nebulizer for 10 days.

[0124] The present invention includes the following aspects and embodiments. [1] An inhaled medicine comprising gold thioglucose. [2] - gold thioglucose; and - N-acetylcysteine 10. A pharmaceutical composition for inhalation comprising: [3] - Gold thioglucose; - viral inhibitors, preferably selected from remdesivir, molnupiravir, favipiravir, ribavirin, lopinavir, umifenovir, nelfinavir and / or ritonavir, preferably favipiravir, molnupiravir and / or ribavirin, in particular favipiravir; and preferably - N-acetylcysteine 10. A pharmaceutical composition for inhalation comprising: [4] The pharmaceutical according to [2] or [3], wherein the pharmaceutical comprises gold thioglucose and N-acetylcysteine ​​in a molar ratio of 1:40 to 10:1, preferably 1:20 to 5:1, more preferably 1:10 to 2.5:1, even more preferably 1:5 to 1:1, even more preferably 1:2.5 to 1:1.5, and most preferably 1:2 (gold thioglucose:N-acetylcysteine). [5] - Gold thioglucose; - an active substance selected from hydroxychloroquine, chloroquine and / or ivermectin; and preferably - N-acetylcysteine An inhalation medicament, preferably the medicament according to any one of [1] to [4], comprising: [6] The pharmaceutical according to any one of [1] to [5], wherein the pharmaceutical comprises a support substance, preferably a carbohydrate, particularly preferably lactose and / or mannose. [7] The pharmaceutical composition according to any one of [1] to [6], wherein the pharmaceutical composition is present as a powder formulation, preferably a finely divided powder formulation. [8] The medicament according to any one of [1] to [6], wherein the medicament is present as a solution or an aerosol. [9] An inhaler, preferably a powder inhaler, a medicated inhaler or a nebulizer, comprising the medicament according to any one of [1] to [8].

[10] The pharmaceutical agent according to any one of [1] to [8], for use in the prevention or treatment of a pulmonary disease.

[11] The pharmaceutical for use according to

[10] , wherein the pulmonary disease is an infectious pulmonary disease or a mixed inflammatory and infectious pulmonary disease.

[12] The pharmaceutical for use according to

[10] or

[11] , wherein the pulmonary disease is a pulmonary infection, preferably a viral infection or a mixed viral and bacterial pulmonary infection.

[13] The pharmaceutical for use according to any one of

[10] to

[12] , wherein the pulmonary disease is a disease caused by the Coronaviridae family, which is included in the RNA virus group, in particular SARS-CoV-1, SARS-CoV-2 or MERS-CoV, preferably SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome) or Covid-19.

[14] The medicament for use according to any one of

[10] to

[13] , wherein the medicament is administered in a dose containing 0.001 μmol to 450 μmol, preferably 0.01 μmol to 250 μmol, even more preferably 0.1 μmol to 50 μmol, and most preferably 0.5 μmol to 30 μmol of gold.

[15] The medicament for use according to any one of

[10] to

[14] , wherein the medicament is administered at a dose comprising 0.1 μg to 1000 μg of gold per kg of patient body weight, preferably 0.2 μg / kg to 200 μg / kg, more preferably 0.5 μg / kg to 40 μg / kg, and most preferably 1 μg / kg to 10 μg / kg of body weight.

[16] The pharmaceutical for use according to any one of

[10] to

[15] , wherein the use is by inhalation, preferably liquid inhalation or powder inhalation.

[17] <00​​​​​​​​Rene Broer, Bertrand Boson, Willy Spaan, Francois-Loic Cosset, and Jeroen Corver; Important Role for the Transmembrane Domain of Severe Acute Respiratory Syndrome Coronavirus Spike Protein during Entry. J. Virol., Feb. 2006, p. 1302-1310 Vol. 80, No. 3 0022-538X / 06 / $08 .000 doi:10.1128 / JVI.80.3.1302-1310.2006 Kevin W. Chang, Yi Wei Sheng, and James L. Gombold, Coronavirus-Induced Membrane Fusion Requires the Cysteine-Rich Domain in the Spike Protein. Virology 269, 212-224 (2000) doi:10.1006 / viro.2000.0219 Ahmed Elkashif and Mohamed N. Seleem, Investigation of auranofin and gold-containing analogues antibacterial activity against multidrug-resistant Neisseria gonorrhoeae. Sei. Rep. 2020 March; 10; 5602 Maria Gil-Moles, Uttara Basu, Rolf Bussing, Henrik Hoffmeister, Sebastian Turck, Agnieszka Varchmin, Ingo Ott, Gold Metallodrugs to Target Coronavirus Proteins: Inhibitory Effects on the Spike-ACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics. Chem. Eur. J. 2020 September; https: / / doi.org / 10.1002 / chem. 202004112 Rodriguez-Izquierdo I, Serramia MJ, Gomez R, De La Mata FJ, Bullido MJ, and Munoz-Fernandez MA , Gold Nanoparticles Crossing Blood-Brain Barrier Prevent HSV-1 Infection and Reduce Herpes-Associated Amyloid-β secretion. J. Clin. Med. 2020, 9, 155; doi:10.3390 / jcm9010155

Claims

1. - gold thioglucose; and - N-acetylcysteine 1. A combination medicine for inhalation comprising:

2. - A viral inhibitor selected from the group consisting of remdesivir, molnupiravir, favipiravir, ribavirin, lopinavir, umifenovir, nelfinavir and / or ritonavir. The pharmaceutical composition of claim 1, further comprising:

3. 3. The medicament according to claim 1, wherein the medicament comprises gold thioglucose and N-acetylcysteine ​​in a molar ratio of 1:40 to 10:1 (gold thioglucose:N-acetylcysteine).

4. - an active substance selected from hydroxychloroquine, chloroquine and / or ivermectin The pharmaceutical composition according to any one of claims 1 to 3, comprising:

5. The medicament according to any one of claims 1 to 4, wherein the medicament comprises a support substance comprising lactose and / or mannose.

6. The medicament according to any one of claims 1 to 5, wherein the medicament is present as a powder formulation.

7. The medicament according to any one of claims 1 to 5, wherein the medicament is present as a solution or an aerosol.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pulmonary disease is a pulmonary infection.

9. A pharmaceutical described in any one of claims 1 to 8, wherein the pulmonary disease is a viral infection or a mixed viral and bacterial pulmonary infection.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pulmonary disease is a disease caused by a coronavirus, which belongs to the RNA virus group.

11. A pharmaceutical described in any one of claims 1 to 10, wherein the pulmonary disease is a disease caused by SARS-CoV-1, SARS-CoV-2 or MERS-CoV.

12. A pharmaceutical described in any one of claims 1 to 11, wherein the pulmonary disease is SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome) or Covid-19.

13. 13. The medicament of any one of claims 1 to 12, wherein the medicament is administered in a dose comprising 0.001 μmol to 450 μmol of gold.

14. 14. The method of claim 1, wherein the medicament is administered in a dose comprising 0.1 μg to 1000 μg of gold per kg of patient body weight.

15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered by liquid inhalation or powder inhalation.

16. An inhaler comprising a medicament according to any one of claims 1 to 15.

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