EP4121066A1

EP4121066A1 - Gold-containing agents for the treatment of lung infections

Info

Publication number: EP4121066A1
Application number: EP21712492.4A
Authority: EP
Inventors: Christian R. Noe; Marion Noe-Letschnig
Original assignee: Produkem Molekulares Design GmbH
Current assignee: AUROVIR PHARMA GMBH
Priority date: 2020-03-16
Filing date: 2021-03-15
Publication date: 2023-01-25
Also published as: AT523662A1; MX2022011434A; JP2023528127A; AU2021238580A1; CN115484965B; WO2021185773A1; CN115484965A; KR20220154220A; AT523662B1; US20230128434A1; CA3171788A1

Abstract

The present invention relates to pharmaceuticals for inhalation, containing aurothioglucose, and to an inhaler, preferably a powder inhaler, dosing inhaler or atomizer containing such pharmaceuticals. The invention provides these pharmaceuticals for use in the prevention and therapy of pulmonary diseases, in particular infectious and inflammatory-infectious pulmonary diseases.

Description

Gold-containing preparations used to treat lung infections

The field of the present invention are medicaments for the treatment of lung diseases, preferably infectious and mixed inflammatory-infectious lung diseases.

Infectious lung diseases are widespread and represent a major social problem. On the one hand, as seasonal infections such as flu, they are among the most common diseases, on the other hand, they are very often the direct cause of death in the elderly. The therapeutic options for viral and / or bacterial infections of the respiratory tract have so far been inadequate.

Among the infectious lung diseases, diseases caused by Coronaviridae have gained in importance in recent years. SARS (Severe Acute Respiratory Syndrome) was first observed in November 2002 in the southern Chinese province of Guangdong. The causative agent of SARS was a previously unknown coronavirus, which is now known as "SARS-Coronavirus" (SARS-CoV-1). In 2019, the SARS-CoV-2 virus was discovered for the first time, which causes the disease Covid- 19 and led to a global pandemic in 2020. MERS (Middle East respiratory syndrome) is also a lung disease caused by a coronavirus (MERS-CoV) with sometimes severe courses Like other viral infections, the cellular attack is initiated via the spike protein of the virus. The target of the spike protein is the membrane protein ACE2 (angiotensin-2 converting enzyme), which plays an important role in renin-angiotensin The system plays by enzymatically splitting the angiotensin-2, which increases blood pressure, and thus becoming its direct opponent in the physiological process. ACE inhibitors and AT2 antagonists are particularly important in life Extending drug classes for treating high blood pressure and preventing strokes and heart attacks. They work in the same direction as the physiological ACE2. Thus, every infection with SARS-CoV-2 also means a disruption of the function of one of the most important physiological systems.

In severe cases of COVID (or SARS-CoV-2 infection), the immune system reacts excessively, which becomes the actual cause of death. Therefore it is enough with these Infections are hardly sufficient to limit themselves to the therapy of the viral infection alone, rather the disturbances of the physiological system, especially the immune system, should be treated at the same time.

So far there are no sufficiently effective treatment methods against infections with coronaviruses, in particular SARS-CoV-1, SARS-CoV-2 and MERS. The nucleoside analogue remdesivir is sometimes used as an antiviral therapy for SARS-CoV-2. Other therapeutic approaches are aimed at the excessive reaction of the immune system, for example with the steroid dexamethasone.

There is therefore a great need for new therapies for lung diseases, in particular infectious and mixed inflammatory-infectious lung diseases. It is an object of the invention to make such therapies available.

The present invention therefore provides medicaments for inhalation containing gold, preferably aurothioglucose, available.

Medicinal substances containing gold are traditionally used in basic anti-rheumatic therapy. The use of the most frequently used drugs auranofin, aurothiomalate and aurothioglucose has been suppressed more and more in recent years despite their good efficacy due to the development of biologics and the frequent occurrence of undesirable side effects in long-term therapy. It is known that gold compounds have a strong anti-inflammatory effect, this being attributed to the inhibition of the nuclear factor NFkappa B. This factor also plays a central role in cystic fibrosis and interstitial pneumonia, which are feared as a consequence of viral lung infections, among other things.

At the same time, it is generally known that auranofin has a considerable antibacterial and antibiofilm effect (AbelKhaleka et al, 2019). Aurothioglucose also has antimicrobial activity (Elkashif and Seleem, 2020). An antiviral effect has been described for gold nanoparticles (Rodriguez-Isqierdo et al., 2020). The antibacterial effectiveness has not yet become the subject of approved drugs.

WO 2017/093544 A1 describes alkynylphosphine-gold complexes for the treatment of bacterial infections. WO 2017/058012 A1 discloses gold (III) compounds for the treatment of COPD and asthma. WO 2012/142615 A2 describes Auranofin and Auranofin analogs for the treatment of proliferative diseases. WO 2021011466 A1 describes metal-nanoparticle compositions for the treatment of respiratory infections associated with cystic fibrosis. KR 2015/0144679 A discloses compositions for the prevention and treatment of immune diseases containing mesenchymal stem cells treated with a STAT3 inhibitor. WO 2016/201524 A1 discloses a method for producing metal ion complexes, in which the metal in particle form is brought into contact with a chelating agent and a metal complex is formed with the aid of an oxidizing agent.

The antimicrobial effect of gold and gold compounds is directly attributable to the effects of gold ions on the microorganisms. Both the precious metal gold and gold ions are very little reactive. One exception to this - apart from the ionic effects of gold ions - is the high affinity of gold ions for sulfur atoms. From a structural and functional point of view, cysteine is a particularly important amino acid, as it makes a significant contribution to the tertiary structure of proteins due to the ability to form disulfide bridges. Cysteine-rich domains are therefore often found in reactive centers of proteins.

Although the importance of pharmacokinetics has long been known, particularly in the case of diseases of the lungs, it is often not taken into account that the direct topical application of a drug at the site of the disease offers a number of important advantages, such as the possibility of a lower dosage, less physiological stress and fewer side effects. Medicines containing gold, which are administered systemically, stick to sulfur atoms in amino acids and proteins on the way to the site of action. This can lead to accumulation in the body with parenteral or oral administration. Because of the side effects resulting from the strong interaction of the gold ions with sulfur compounds, the unfavorable pharmacokinetics in the case of conventional oral and parenteral use is a particularly great disadvantage of gold drugs. The oral and parenteral application forms customary up to now are therefore hardly suitable for the treatment of lung infections with gold compounds. Injected or oral gold compounds would have to be administered over a long period of time until the gold reaches the site of action in the lungs in the appropriate concentration. As direct a path as possible from the drug's entry into the body to the site of action, If possible, look for topical application. The lung tissue is also very capable of absorbing drugs.

In our investigations, we were able to show that aurothioglucose has a high affinity for the spike protein of the SARS-CoV-2 virus. This also has a cysteine-rich domain to which the virus binds so strongly that ACE2, the virus’s natural point of attack, is efficiently displaced from the binding. Since the spike protein-ACE2 interaction is crucial for the virus to attack the body's cells, this finding shows that the antiviral effect of gold compounds is also based on a specific prevention of infection before the virus enters the body's cells. As a result, these compounds are also suitable for use in medicaments for the prevention of infection. The anti-infective property is added to the other antimicrobial and immunomodulatory properties and makes gold medication for inhalational use unique drugs for topical therapy of spike protein-associated infections, especially SARS-CoV-2 infections. Because of their special properties, the medicaments according to the invention are also particularly suitable for the prevention of viral infections.

The present invention therefore relates to a medicament for inhalation which has a dual effect - at the same time anti-infective and anti-inflammatory-immunomodulatory - preferably a medicament which contains a medicinal substance containing gold, such as aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurotioprol and aurothiopolypeptide , or contains the gold salt of a sulfur-containing drug, such as acetylcysteine, pyritinol, tiopronin and penicillamine.

Among the gold salts before drugs, the gold salt of N-acetylcysteine is a particularly preferred compound because N-acetylcysteine is already the drug acetylcysteine used for the treatment of lung diseases and a positive therapeutic additional effect can be expected.

Even if the focus of the action of the pharmaceuticals in question is on the gold ion, the counterion is also of great importance. For example, the toxic phosphine part of Auranofin limits its possibilities for dosing considerably. The gold ion is also released from the connection the counterion co-determined to a large extent.

The respective therapeutic relevance of the anti-infective or anti-inflammatory immunomodulatory effect is dependent on time. While the inhibition and spread of infection are of particular importance in the early phase of the disease, immune modulation is of particular importance in the later phases and especially in the case of severe courses. In the case of aurothioglucose and aurothiomalate, the binding of the gold ion to the spike protein can be significantly improved by a further compound that contains a mercapto group, which makes it possible to control the activity profile of the drug so that either the anti- Infective profile before resorption (when activated) or the anti-inflammatory-immunodulatory profile after resorption (without activation) is in the foreground. Thus, when using these compounds without activating additives, the focus is on the anti-inflammatory-immunomodulatory effect. Preferred drugs in the case of severe disease are therefore aurothioglucose and aurothiomalate, aurothioglucose is particularly preferred.

With regard to the compounds containing mercapto groups, it has been found that the addition of N-acetylcysteine leads to an increase in the effectiveness (see e.g. Example 6). The combination of aurothioglucose and aurothiomalate with N-acetylcysteine has proven to be particularly advantageous. Another object of the invention is therefore a combination medicinal product in which the gold-containing compound is combined with a mercapto group-containing compound, preferably with N-acetylcysteine.

In antiviral therapies, the use of drug combinations has proven effective, which attack various targets and in this way both heighten the anti-infective effect and prevent the development of resistance through mutation. The anti-infective effect of gold compounds is based on various targets. Thus, in the course of the investigations into the present patent application, a high affinity for the papain-like protease PLpro and for the chymotrypsin-like protease 3CLpro was found. Both proteases are essential for virus replication and represent important target structures for the development of antiviral drugs against SARS-CoV-2 and other viruses. A further increase in the antiviral effect can be expected by adding antiviral drugs, preferably of those which intervene in virus RNA synthesis. In one aspect, the invention relates to a medicament for inhalation containing gold, preferably aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurotioprol, aurothiopolypeptide, and / or the gold salt of a sulfur-containing medicinal substance (preferably N-acetylcysteine, pyritinol, tiopronin and / or penicillamine), especially aurothioglucose.

In a preferred embodiment, the medicament also contains N-acetylcysteine.

It is further preferred that the medicament contains a further active ingredient, preferably wherein the further active ingredient has an antiviral and / or antibacterial effect. In a preferred embodiment, the drug contains a virostatic agent, preferably selected from the group consisting of remdesivir, molnupiravir, favipiravir, ribavirin, lopinavir, umifenovir, nelfinavir and / or ritonavir, preferably favipiravir, molnupiravir and / or ribavirin, especially favipiravir. The combination of aurothioglucose and aurothiomalate with one of the preferred antivirals has proven to be particularly advantageous. In a preferred embodiment, the medicament containing the antiviral additionally contains N-acetylcysteine (for example as a triple combination containing gold, in particular aurothioglucose, N-acetylcysteine and a virostatic, in particular the combination aurothioglucose + N-acetylcysteine + favipiravir or the combination aurothioglucose + N-acetylcysteine + Molnupi ravir).

In a further preferred embodiment, the drug contains an active ingredient selected from hydroxychloroquine, chloroquine and / or ivermectin. The medicament preferably also contains N-acetylcysteine (e.g. as a triple combination containing gold, in particular aurothioglucose, N-acetylcysteine and an active ingredient selected from hydroxychloroquine, chloroquine and / or ivermectin). In a further preferred embodiment, the medicament (with or without N-acetylcysteine) additionally contains a virostat as described herein.

In a further aspect, the invention provides an inhaler, preferably a powder inhaler, metered dose inhaler or nebuliser, containing a medicament according to the invention.

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

The present invention provides gold-containing agents for therapy and their use for the treatment of infectious and mixed inflammatory-infectious lung diseases in which the active ingredient is preferably inhaled directly to the site of action in the lungs and can develop its effect there. This application also reduces side effects to the lowest possible level.

Microbial infections are usually accompanied by inflammatory processes. This finding is not a coincidental coincidence, but rather is due to synchronous germ-host interactions. It has therefore been shown that active ingredients with dual anti-infective and anti-inflammatory effects are particularly suitable for the treatment of microbial infections. The dual effect of the gold compounds can offer a particular advantage because the anti-inflammatory effect is achieved by inhibiting the nuclear factor NFkappa B (Bodas M. and Vij N, 2010), which is involved in the development of interstitial pneumonia, among other things. The anti-inflammatory effect of the agents according to the invention is comparable to that of inhaled steroids (see e.g. Example 3).

Gold-containing agents according to the invention are particularly preferred for the treatment of diseases caused by Coronaviridae belonging to the group of RNA viruses, such as SARS (Severe Acute Respiratory Syndrome) MERS-CoV (Middle East Respiratory Syndrome Corona Virus) and SARS-CoV-2. The gold-containing agents according to the invention namely bind with high affinity to mercapto groups of cysteine-rich domains of binding proteins of these viruses, in particular of corona viruses, which is functionally essential for their binding to the host cells and the fusion (Chang et al, 2000 , Broer et al., 2006). In addition, these viral diseases are often accompanied by bacterial superinfections with biofilm formation, against which the agents according to the invention also act. 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). Further inhibit Gold complexes the activity of the viral protease PLpro (PLpro: Pa-pain-Like Protease) of SARS-CoV-1 and SARS-CoV-2. Auranofin showed IC 50 values of 22.2 mM against the Spike / ACE2 interaction and 0.75 mM against PLpro of SARS-CoV-2. (Gil-Moles et al., 2020)

The preferred form of application of the agents is inhalation as a liquid aerosol or by powder inhalation. The latter is distinguished from the easier-to-use liquid inhalation, in which considerable amounts of the active ingredient get stuck in the throat, through a more precise option for dosing. Elemental gold can be used in the form of nanoparticles, but the drugs aurothioglucose, aurothiomalate and auranofin, which have been tried and tested in anti-rheumatic practice, and the auroacetylcysteine salt, in which the gold is in ionic form, are preferred. Aurothioglucose has the advantage that the gold ion is particularly strongly bound to the molecule and is therefore released in a controlled manner.

Commercially available devices can be used for inhalation. In the case of intensive care treatments, aqueous solutions of the agents according to the invention can be added to the breathing air by means of spray nozzles. In the case of powder inhalation, micronization of the active ingredient (particle size preferably less than 5 micrometers) is a preferred form of application, because deeper lung areas are reached. Use in a mixture with a carrier is also preferred. Mixing the micronized active ingredient with a carrier with a larger grain size is particularly preferred because it ensures that the carrier is initially deposited in the higher areas of the pharynx and the active ingredient increasingly penetrates deeper lung areas. Lactose, mannose and other carbohydrates are particularly suitable as carrier substances.

In connection with combination drugs, it is preferred if the active ingredients are present in separate compartments of a powder inhaler. Bringing the active ingredients into separate compartments facilitates production, among other things. In a preferred embodiment of the powder inhaler, gold or aurothioglucose and N-acetylcysteine are therefore present in separate compartments of the powder inhaler. In a particularly preferred embodiment of the powder inhaler, gold or aurothioglucose and the antiviral are in separate compartments of the powder inhaler. The triple- All three active ingredients can be combined in separate compartments of the powder inhaler.

In connection with the invention it is preferred if the medicament for use according to the invention contains a gold-containing antirheumatic medicament. Particularly preferred anti-rheumatic drugs are aurothioglucose, aurothiomalat, auranofin, aurothiosulfate, aurotioprol, and / or aurothiopolypeptide. In particular, aurothioglucose has proven to be particularly advantageous in connection with the invention.

The medicament preferably contains auxiliary substances. Particularly preferred are auxiliaries such as are usually used in formulations for inhalation, in particular powder and liquid formulations for inhalation. In a preferred embodiment, the medicament contains a carrier, preferably a carbohydrate, particularly preferably lactose and / or mannose.

In a preferred embodiment, the medicament contains a further active ingredient for use, preferably wherein the further active ingredient has an antiviral and / or antibacterial effect. Antivirals are particularly preferred, in particular favipiravir, molnupiravir, remdesivir or ribavirin.

In connection with the invention, the lung disease is preferably a lung infection, preferably a viral or mixed viral-bacterial lung infection, even more preferably a disease caused by coronaviruses belonging to the group of RNA viruses, in particular SARS-CoV-1, SARS- CoV-2 or MERS-CoV. It is therefore preferably a corona virus infection, in particular a SARS-CoV-1 infection, a SARS-CoV-2 infection or a MERS-CoV infection. The lung disease is particularly preferably SARS (triggered by a SARS-CoV-1 infection), Covid-19 (triggered by a SARS-CoV-2 infection), or MERS (triggered by a MERS-CoV infection) .

In connection with all aspects of the invention, the medicament is preferably used by inhalation. Liquid inhalation or powder inhalation is particularly preferred. In particular, it is preferred if the administration takes place through an inhaler according to the invention.

In a preferred embodiment, the dual-acting drug according to the invention contains gold (preferably in the form of aurothioglucose, aurothiomalat, auranofin, aurothiosulfate, aurotioprol, and / or aurothiopolypeptide and no other active substances.

In a further preferred embodiment, the medicament according to the invention contains gold (preferably in the form of aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurotioprol, and / or aurothiopolypeptide, in particular aurothioglucose) and N-acetylcysteine in a molar ratio of between 1: 40 and 10: 1, preferably between 1:20 and 5: 1, more preferably between 1:10 and 2.5: 1, even more preferably between 1: 5 and 1: 1, even more preferably between 1: 2, 5 and 1: 1.5, most preferably 1: 2 (gold: N-acetylcysteine).

In connection with all medicaments according to the invention, it is preferred that the medicament is present as a formulation for inhalation. It is particularly preferred if the formulation is a powder formulation. The medicament is preferably in the form of a dry powder for aerosol preparation. A powder formulation enables particularly simple administration, e.g. through a powder inhaler. For example, powder inhalers can be used, as they are already used for the treatment of asthma or COPD. For this application, the medicament is preferably in micronized form.

In a further preferred embodiment, the medicament is in the form of a powder or solution for aerosol preparation. This formulation is particularly suitable for administration by metered dose inhalers or nebulizers. For example, such formulations can also be used for patients who are artificially ventilated, for example in the case of severe courses of coronavirus infections, in particular SARS, Covid-19 or MERS.

In a preferred embodiment, the inhaler according to the invention is a powder inhaler, the medicament according to the invention being in the form of a powder formulation. In a further preferred embodiment, the inhaler is a metered dose inhaler (e.g. a pressurized metered dose inhaler or a normal pressure metered dose inhaler) or nebulizer, the medicament according to the invention being present as a solution or as an aerosol.

The invention further discloses a method for the prevention or treatment of a lung disease, preferably an infectious or mixed inflammatory-infectious lung disease, comprising the steps: - providing a medicament or a combination medicament as described herein; and

- Administering an effective amount of the drug or the combination drug to an individual who needs this. Preferably the method is for treating the pulmonary disease in which the individual suffers from the pulmonary disease.

All preferred embodiments for the medicament for use according to the invention are also considered to be preferred for the method of treatment disclosed here. In particular, all preferred embodiments of the lung disease are also considered to be preferred for this method. The medicament is preferably administered through an inhaler according to the invention.

The term "prevention" as used herein means to prevent the occurrence of a disease in an individual completely or almost completely or at least to a (preferably significant) extent. However, this term should not be interpreted as an absolute success in the sense that the individual can never develop such a disease, but rather as a reduction in the risk of the disease.

In connection with the present invention, the terms “agent”, “medicament” or “pharmaceutical composition” are understood to mean a composition containing at least one active ingredient and preferably containing one or more pharmaceutically acceptable auxiliaries Animal, preferably a mammal, most preferably a human.

Preferably, a dose of the drug is administered to an indi viduum, it being preferred that a dose of the drug is administered at least once a week, preferably at least every two days, more preferably at least once a day, even more preferably at least twice a day , in particular at least three times a day.

The therapy is preferably carried out over a period of time and with an effective amount of drug. It is particularly preferred if the medicament is administered over a period of 1 to 30 days, preferably from 2 to 21 days, even more preferably from 3 to 14 days, most preferably from 5 to 10 days.

In connection with the present invention this is true treating individual preferably an animal, preferably a mammal, in particular a human. Preferably the individual has one of the lung diseases described herein.

In a preferred embodiment, the concentration of gold in a dose of the drug is between 0.001 mpioΐ and 450 mpioΐ, preferably between 0.01 mpioΐ and 250 mpioΐ, even more preferably between 0.1 mpioΐ and 50 mpioΐ, most preferably between 0, 5 mpioΐ and 30 mpioΐ. In a particularly preferred embodiment, a dose contains between 0.1 pg and 1000 pg gold per kg of body weight of the patient, preferably between 0.2 pg / kg and 200 pg / kg, more preferably between 0.5 pg / kg and 40 pg / kg, most preferably between 1 pg / kg and 10 pg / kg body weight.

The present invention particularly discloses the following preferred embodiments:

Embodiment Al. Medicines for inhalation containing gold, preferably aurothioglucose, aurothiomalate, auranofin, aurothiosulphate, aurotioprol, aurothiopolypeptide, and / or the gold salt of a sulfur-containing drug (preferably N-acetylcysteine, pyritinol, tiopronin and / or auricillamine), in particular auricillamine .

Embodiment A2. Medicament according to embodiment A1, characterized in that the medicament contains a gold-containing antirheumatic medicament, preferably aurothioglucose, aurothioglucose, aurothio malate, auranofin, aurothiosulfate, aurotioprol, and / or aurothio polypeptide, in particular aurothioglucose.

Embodiment A3. Medicines for inhalation containing aurothioglucose.

Embodiment A4. Medicament according to one of the embodiments A1 to A3, furthermore containing N-acetylcysteine.

Embodiment A5. Medicament according to one of the embodiments A1 to A4, characterized in that the medicament contains a further active substance, preferably wherein the further active substance has an antiviral and / or antibacterial effect. Embodiment A6. Medicament according to one of the embodiments A1 to A5, furthermore containing a virostat, preferably selected from the group consisting of remdesivir, molnupiravir, favipiravir, ribavirin, lopinavir, umifenovir, nelfinavir and / or ritonavir, preferably favipiravir, molnupiravir and / or ribavirin, in particular Favipiravir. Embodiment A7. Medicament according to one of the embodiments A1 to A6, furthermore containing an active ingredient selected from hydroxychloroquine, chloroquine and / or ivermectin.

Embodiment A8. Containing medicaments for inhalation

Gold, preferably aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurotioprol, aurothiopolypeptide, and / or the gold salt of a sulfur-containing drug (preferably N-acetylcysteine, pyritinol, tiopronine and / or penicillamine), in particular aurothioglucose;

- A virostat, preferably selected from the group consisting of remdesivir, molnupiravir, favipiravir, ribavirin, lopinavir, umifenovir, nelfinavir and / or ritonavir, preferably favipiravir, molnupiravir and / or ribavirin, in particular Favi piravir; and

- N-acetylcysteine.

Embodiment A9. Medicament according to one of the embodiments A1 to A8, characterized in that the medicament gold and N-acetylcysteine in a molar ratio of between 1:40 and 10: 1, preferably between 1:20 and 5: 1, more preferably between 1:10 and 2.5: 1, even more preferably between 1: 5 and 1: 1, even more preferably between 1: 2.5 and 1: 1.5, most preferably 1: 2 (gold: N-acetylcysteine).

Embodiment A10. Medicament according to one of the embodiments A1 to A9, characterized in that the medicament aurothioglucose and N-acetylcysteine in a molar ratio of between 1:40 and 10: 1, preferably between 1:20 and 5: 1, more preferably between 1: 10 and 2.5: 1, even more preferably between 1: 5 and 1: 1, even more preferably between 1: 2.5 and 1: 1.5, most preferably 1: 2 (aurothioglucose: N-acetylcysteine) . Embodiment All. Medicament according to one of the embodiments A1 to A10, characterized in that the medicament contains a carrier, preferably a carbohydrate, particularly preferably lactose and / or mannose.

Embodiment A12. Medicament according to one of the embodiments A1 to All, characterized in that the medicament is in the form of a powder formulation, preferably micronized.

Embodiment A13. Medicament according to one of the Ausführungsfor men Al to All, characterized in that the medicament is present as a solution or as an aerosol. Embodiment A14. Inhaler, preferably powder inhaler, metered dose inhaler or nebuliser, containing a medicament according to one of the embodiments A1 to A13.

Embodiment Al5. Inhaler, preferably powder inhaler, containing a medicament according to embodiment A12.

Embodiment A16. Inhaler, preferably metered dose inhaler or nebulizer, containing a medicament according to embodiment A13. Embodiment A17. Powder inhaler containing a medicament according to one of the embodiments A4 to A12, characterized in that gold or aurothioglucose and N-acetylcysteine are present in separate compartments of the powder inhaler.

Embodiment A18. Powder inhaler containing a medicament according to one of the embodiments A5 to A12, characterized in that gold or aurothioglucose and the further active ingredient are present in separate compartments of the powder inhaler.

Embodiment A19. Powder inhaler containing a medicament according to one of the embodiments A6 to A12, characterized in that gold or aurothioglucose and the antiviral are present in separate compartments of the powder inhaler.

Embodiment A20. Medicaments according to one of the Ausführungsfor men A1 to A13 for use in the prevention or therapy of lung diseases, preferably in the prevention or therapy of inflammatory, infectious and mixed inflammatory-infectious lung diseases.

Embodiment A21. Medicament for use according to embodiment A20, characterized in that the lung disease is an infectious or a mixed inflammatory-infectious lung disease.

Embodiment A22. Medicament for use according to one of the embodiments A20 or A21, characterized in that the lung disease is a lung infection, preferably a viral or mixed viral-bacterial lung infection, even more preferably a disease caused by Coronaviridae belonging to the group of RNA viruses, in particular SARS -CoV-1, SARS-CoV-2 or MERS-CoV.

Embodiment A23. Medicament for use according to one of the embodiments A20 to A22, characterized in that the lung disease is SARS, MERS, or Covid-19.

Embodiment A24. Medicines for use according to embodiment A20, characterized in that the lung disease is a inflammatory lung disease, preferably a chronic inflammatory lung disease, especially COPD, cystic fibrosis or interstitial pneumonia.

Embodiment A25. Medicament for use according to one of the embodiments A20 to A24, characterized in that the medicament in a dose containing between 0.001 mpioΐ and 450 mpioΐ, preferably between 0.01 mpioΐ and 250 mpioΐ, even more preferably between 0.1 mpioΐ and 50 mpioΐ , most preferably between 0.5 mpioΐ and 30 mpioΐ gold is administered.

Embodiment A26. Medicament for use according to one of the embodiments A20 to A25, characterized in that the medicament in a dose containing between 0.1 pg and 1000 pg gold per kg body weight of the patient, preferably between 0.2 pg / kg and 200 pg / kg, more preferably between 0.5 pg / kg and 40 pg / kg, most preferably between 1 pg / kg and 10 pg / kg body weight gold is administered.

Embodiment A27. Medicament for use according to one of the embodiments A20 to A26, characterized in that the use takes place by inhalation, preferably liquid inhalation or powder inhalation.

Embodiment A28. Medicament for use according to one of the embodiments A20 to A27, characterized in that the application takes place through an inhaler according to one of the embodiments A14 to A19.

Embodiment A27. A method for the prevention or treatment of a lung disease, preferably a lung disease as defined in one of the embodiments A20 to A26, comprising the steps:

Provision of a medicament as defined in one of the embodiments A1 to A13; and

- Administering an effective amount of the drug to an individual in need of it.

Embodiment A28. Method according to embodiment A27, wherein the method is defined as in one of embodiments A20 to A26.

Embodiment A29. Method according to embodiment A27 or A28, characterized in that the medicament is administered by an inhaler, preferably by an inhaler according to one of the embodiments A14 to A19.

Embodiment Bl. Means for the therapy of inflammatory, infectious and mixed inflammatory-infectious lung diseases, characterized in that they contain gold.

Embodiment B2. Agents according to embodiment B1 characterized in that they are used for inhalative therapy of lung infections.

Embodiment B3. Agents according to embodiment B1 characterized in that they are used for inhalative therapy of viral and mixed viral-bacterial lung infections. Embodiment B4. Agent according to embodiment B1-B3, characterized in that the gold-containing substance is either a medicament for the treatment of rheumatic diseases or the gold salt of a medicament or nanoparticulate gold.

Embodiment B5. Agent according to embodiments B1-B4, characterized in that the anti-rheumatic drug is aurothioglucose.

Embodiment B6. Agent according to embodiments B1-B4, characterized in that the anti-rheumatic drug is aurothio malate.

Embodiment B7. Agent according to embodiments B1-B4, characterized in that the anti-rheumatic drug is auranofin

Embodiment B8. Agent according to embodiments B1-B4, characterized in that the active ingredient is the gold salt of an acidic medicinal substance, preferably N-acetylcysteine.

Embodiment B9. Agent according to embodiment B1-B8, characterized in that it is used by liquid inhalation.

Embodiment BIO. Agent according to embodiment B1-B8, characterized in that it is used by powder inhalation. Embodiment Bll. Agent according to the embodiment BIO characterized in that the medicinal substance is diluted with a carrier.

Embodiment B12. Agent according to embodiment BIO and BIl, characterized in that the carrier is a carbohydrate, preferably lactose or mannose.

Embodiment B13. Agent according to the embodiment BIO characterized in that the medicinal substance is used in micronized form.

Embodiment B14. Medicament according to embodiments B1-B13, characterized in that at least one further Active ingredient is included.

Embodiment B15. Agent according to embodiment B14 characterized in that the additional active ingredient has an antiviral effect.

Embodiment B16. Agent according to embodiments B14 and B15, characterized in that the additional active ingredient has an anti-bacterial effect.

Embodiment B17. The use of agents according to execution forms B1-B16 for the treatment of infectious and mixed inflammatory infectious diseases of the respiratory tract.

Embodiment B18. The use of agents according to embodiment B17 for the treatment of diseases caused by Coronaviridae belonging to the group of RNA viruses, such as SARS (Severe Acute Respiratory Syndrome), MERS-CoV (Middle East Respiratory Syndrome Corona Virus), SARS-CoV- 2 and Covid-19.

Embodiment B19. The use of agents according to embodiment B1-B16 for the treatment of inflammatory lung diseases, preferably chronic inflammations, such as COPD, cystic fibrosis and interstitial pneumonia.

Embodiment B20. The use of auroacetylcysteine in medicaments according to embodiments B17-B19.

The present invention is illustrated by the following examples and the figures, to which it is of course not restricted.

Fig. 1 . Anti-inflammatory efficacy of auroacetylcysteine in a mouse model for acute allergic asthma: experimental set-up. Fig. 2. Anti-inflammatory efficacy of auroacetylcysteine in a mouse model for acute allergic asthma: cell count in the bronchoalveolar lavage to investigate the inflammation of the airways. Representation: mean values ± SD, n = 5 except in the AAC group (n = 4 (due to one death) * P <0.05 compared to placebo (carrier substance), Kruskal-Wallis test, Dünn's multiple comparison test.

Fig. 3. Anti-inflammatory efficacy of auroacetylcysteine in a mouse model for acute allergic asthma: histological examination of the lung tissue.

Fig. 4th Anti-inflammatory efficacy of auroacetylcysteine in a mouse model for acute allergic asthma: Examination of the lung tissue with HE and LUNA stains. Fig. 5. Anti-inflammatory efficacy of auroacetylcysteine in a mouse model for acute allergic asthma: study of cell populations. Representation: mean values ± SD, n = 5 except in the AAC group (n = 4 (due to one death) * P <0.05 compared to placebo (carrier substance), Kruskal-Wallis test, Dünn's multiple comparison test.

6. Dose-effect curves for aurothioglucose (6A), aurothioglucose / N-acetylcysteine in the ratio 1/2 (6B) and aurothiomalate (6C) as inhibitors of SARS-CoV-2 PLpro.

FIG. 7. Influence of added N-acetylcysteine on the inhibition of SARS-CoV-2 PLpro by 1.0 mM aurothioglucose (n = 2-3). AG = aurothioglucose; N = N-acetylcysteine. The specified ratios relate to the molar ratios.

Fig. 8. Activating influence of added N-acetylcysteine on the inhibition of the spike / ACE2 interaction by 20 mM aurothioglucose. N-acetylcysteine alone does not inhibit the spike / ACE2 interaction (97% of the control at 100 mM). AG = Au rothioglucose; N = N-acetylcysteine. The specified ratios relate to the molar ratios.

Fig. 9. Cytotoxicity of auranofin (AF), aurothiomalate (AM), aurothioglucose (AG), and the combinations of AM or AG with N-acetylcysteine (N) in the molar ratio 1/2 (AM-N, AG- N, concentrations refer to AM or AG), as well as auroacetylcysteine after 24 hours in CaLu-3 cells (n = 3).

Fig. 10. Removal of zinc from the PLpro by disulfiram, aurothioglucose (AG) and the mixture of aurothioglucose with N-acetylcysteine in a molar ratio of 1: 2 (AG-N). (Values given in comparison to untreated enzyme (PLpro)).

EXAMPLES:

Example 1. Preparation of single doses for inhalation. l.a. Liquid ampoule: A solution of 1.5 mg Auranofin in 2.5 ml water containing sodium chloride is placed in a single-dose container and placed in a nebuliser for use.

1.b. Dry ampoule: One ampoule is filled with 1.5 mg aurothioglucose. Before use, 2.5 ml of water is injected and the solution is placed in an inhaler. The finished product must be used within 3 hours.

Example 2. Preparation of multiple doses for inhalation.

2.a. Powder spray: 30 mg of micronized aurothioglucose will be suspended in 300 microliters of ethanol. 30 mg of sorbitan trioleate are added and, while cooling, 15 g of propellant are added in a spray can, which sprays the product in 300 strokes.

2 B. Dry inhaler: 0.2 mg micronized aurothioglucose is mixed with 12 mg lactose and prepared for powder inhalation with strict exclusion of moisture. This depends on the type of inhaler and, if necessary, can be pressed into a disc.

Example 3. Proof of the anti-inflammatory effect of inhaled auroacetylcysteine in a preclinical pilot study in a mouse model for acute allergic asthma by means of application via the nose.

The anti-inflammatory efficacy of auroacetylcysteine (AAC) was tested in 2 doses (10 mg / kg and 100 mg / kg) in a mouse model for acute allergic asthma with 5 mice each compared to dexamethasone (1 mg / kg). There were 5 mice each in four groups: AAC / dexamethasone / placebo (vehicle) / untreated in 3 repetitions / group in an arrangement for intranasal application in an aerosol chamber (Fig. 1). The evaluation was carried out as follows: The inflammation of the airways was determined with bronchoalveolar lavage (BAL). For this purpose, the number of cells in the bronchoalveolar lavage was determined (FIG. 2). There was a significant difference to placebo. The reduction in the total number of cells was comparable to that of dexamethasone. The inflammation of the lung tissue was determined by means of histological examination (FIG. 3), HE and LUNA staining (FIG. 4), the mucus production by means of PAS staining. However, different cell populations were affected compared to dexamethasone. AAC mainly reduces eosinophils and neutrophils, as well as lymphocytes. Macrophages are increased compared to dexamethasone. (Fig. 5) The serum-specific Ag - IgGl (ELISA) was also measured. The results were as follows: Auroacetylcysteine at a concentration of 10 mg / kg reduces the inflammation parameters both peribronchiolar and in the parenchyma. The anti-inflammatory effect in the tissue is comparable to that of dexamethasone. Treating mice with acute exacerbations of allergic asthma with 10 mg / kg auroacetylcysteine for 5 days reduces the total number of inflammatory cells in bronchial secretions, the extent of inflammation in the airways, the number of eosinophils and neutrophils in the airways, the infiltrates of inflammatory cells in the lung parenchyma.

Example 4. Preparation of auroacetylcysteine.

5 g of tetrachloroauric acid are mixed with 5 ml of water and cooled with ice. 3.18 g of 2,2'-thiodiethanol are added dropwise to this solution over 45 minutes with vigorous stirring. The addition is ended when the solution is colorless and free from precipitate. 1.75 g of N-acetylcysteine in 27 ml of water are slowly added to this solution with the formation of a white precipitate. This suspension is stirred for 1 hour and filtered with a vacuum suction filter. The precipitate is washed with 30 ml of water to which 1 drop of 2N hydrochloric acid has been added and dried overnight. Auroacetylcysteine is obtained in quantitative yield.

Example 5. Inhibition of the SARS-CoV-2 protease PLpro by gold compounds.

The inhibition of the SARS-CoV-2 protease Papain-Like Protease (PLpro) was determined as follows: The test substances were dissolved as stock solutions in water and 100 times with HEPES buffer (50 mM HEPES, pH 7.5, 0.1 mg / mL bovine serum albumin, 0.1% Triton-X-100) diluted so that micromolar concentrations were achieved. Volumes of 50 pL of a 200 nM solution of SARS-CoV-2 PLpro in HEPES buffer or pure HEPES buffer (negative control) were pipetted into the wells of a black 96-well microtiter plate. To this end, 50 pL of the solutions of the test substances or pure HEPES buffer (positive control) were added and the resulting solutions were mixed and incubated at 37 ° C. for one hour. Then a volume of 100 pL of a 100 pM solution of the substrate Z-Arg-Leu-Arg-Gly-Gly-AMC was added to all samples, mixed well, and the fluorescence emission recorded every 30 seconds for 10 minutes (Ä _ex = 355 nm, A _em = 460 nm, 37 ° C, Victor ™ X4 Perkin Elmer 2030 microplate reader). The increase in fluorescence emission followed a linear trend (r ² > 0.97) and the enzyme activities in the individual samples were recorded as its slope. The percentage calculation of the enzyme activity was made in relation to the untreated control (positive control). The results of the negative controls were used to determine the absence of false positive results, such as by Confirm the reaction of the test substance with the substrate. The IC 50 values were calculated as the concentration at which the test substance inhibits the enzyme activity by 50% compared to the positive control.

Results: The following IC 50 values were determined from the dose-effect curves (FIG. 6):

Aurothioglucose: 7.03 mM (+/- 2.31 mM)

Aurothioglucose / N-acetylcysteine in the molar ratio 1/2: 9.55 mM (+/- 1.61 mM) (based on the molar amount of aurothioglucose)

Aurothiomalate: 0.60 mM (+/- 0.25 mM)

The addition of several equivalents of N-acetylcysteine to aurothioglucose did not significantly change the inhibition of PLpro (FIG. 7).

Example 6. Inhibition of the interaction of the SARS-CoV-2 spike protein with the ACE2 receptor.

The influence of the test substances on the spike / ACE2 interaction can be determined by ELISA. For this purpose, a 96-well plate was coated with the receptor binding domain of the spike protein and stored at 4 ° C. overnight. The wells of the microtiter plate were emptied, a blocking solution was added for 2 hours, washed and emptied. The test substances and controls were added as a mixture with the ACE2 receptor and incubated at 37 ° C. for one hour. The wells were washed. Horseradish peroxidase conjugated with streptavidin was added and incubated for one hour at room temperature. After a further wash, a solution containing 3,3 ', 5,5'-tetramethylbenzidine was added. After 5 minutes at room temperature, the absorption at 450 nm was determined (Perkin Elmer Victor X4 microplate reader). The activity remaining after the addition of inhibitor was calculated as a percentage in relation to the untreated control.

Result :

20 mM aurothioglucose led to an inhibition of the spike / ACE2 interaction (FIG. 8). The inhibition could be increased significantly by adding N-acetylcysteine. A molar ratio of aurothioglucose to N-acetylcysteine of 1: 2 proved to be particularly effective. Example 7. Cytotoxicity in CaLu-3 cells.

To determine the cytotoxicity, CaLu-3 cells were grown in 96-well microtiter plates. The cell culture medium was replaced by fresh medium which contained the gold compounds in concentrations of 25, 50 or 100 mM and incubated for 24 hours at 37 ° C / 5% CO2. The remaining amount of cells was then determined photometrically by means of crystal violet staining (Victor X4 microplate reader). The amount of cells in the treated samples was calculated as a percentage in relation to an untreated control.

The results are shown in FIG. In the experiment, Auranofin showed toxicity in CaLu-3 cells (<20% of the untreated control at 25 mM). Aurothiomalate, aurothioglucose, the combinations of aurothiomalate or aurothioglucose with N-acetylcysteine in a molar ratio of 1: 2, as well as auroacetylcysteine in concentrations up to 100 mM showed no relevant cytotoxicity.

Example 8. Removal of zinc from the PLpro.

In addition to a cysteine in the catalytic center of the enzyme, the protease PLpro contains other cysteines in a zinc binding domain, which stabilize the structure and function of the enzyme. The removal of the bound zinc represents an interesting mechanism of action for inhibitors of PLpro.

To determine whether the inhibitors are Zn-removing agents, the presence of the Zn ²⁺ cation in solution was determined as follows. The inhibitor compounds were prepared as stock solutions in DMSO as stock solutions in water or DMSO and diluted a hundredfold with HEPES buffer (50 mm HEPES, pH 7.5) to 100 mM concentrations. Volumes of 50 pL of SARSCoV-2 PLpro (Elabscience) in HEPES buffer or empty HEPES buffer (control for false positive results) were added to the wells of a black 96-well microtiter plate (Nunclon, Nunc). Volumes of 50 pL of the inhibitor solutions or 1% DMSO in HEPES buffer (control) were added. The resulting solutions (500 nM PLpro SARS-CoV-2, 0.5% DMSO, 50 pM test compound or empty HEPES buffer) were mixed. A volume of 100 pL with 2.0 mM of the zinc-specific fluorophore FluoZin ™ - 3 (Invitrogen / Life Technologies) was added to all wells. The resulting solutions were mixed and the fluorescence emission was after 10 min every 10 min over a period of 90 _Determined minutes at 37 ° C (A ^{exc =} 485 nm, Ä _em ⁼ 535 nm; Victor X4 micro disk reader). The relative fluorescence was calculated by dividing the absolute fluorescence emission of the well which contained the inhibitor by the absolute fluorescence of the corresponding well which contained the enzyme but no inhibitor (control). Wells that contained the inhibitor but no enzyme were used to check for false positive results. None of the compounds tested showed false positive results.

As shown in FIG. 10, just like the mixture of aurothioglucose with acetylcysteine, aurothioglucose resulted in a removal of zinc from the PLpro comparable to that of the reference compound disulfiram. These results are consistent with the inhibition of the enzyme activity of PLpro by aurothioglucose and further confirm its relevance.

Example 9. Inhibition of the SARS-CoV-2 protease 3CLpro by gold compounds.

The inhibition of the SARS-CoV-2 protease 3CLpro was determined as follows: The test substances were dissolved as stock solutions in water and 100 times with HEPES buffer (50 mM HEPES, pH 7.5,

0.1 mg / mL bovine serum albumin, 0.1% Triton-X-100) diluted so that micromolar concentrations were achieved. Volumes of 50 pL of a 300 nM solution of SARS-CoV-23CL protease (Mpro) MBP-tag in HEPES buffer or pure HEPES buffer (negative control) were pipetted into the wells of a black 96-well microtiter plate. For this purpose, 50 pL of the solutions of the test substances or pure HEPES buffer (positive control) were added and the resulting solutions were mixed and incubated at 37 ° C. for one hour. Then a volume of 100 pL of a 50 pM 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, well mixed, and the fluorescence emission registered every 3 minutes for 75 minutes (Äex = 60 nm, Äem = 460 nm, 37 ° C, Victor ™ X4 Perkin Elmer 2030 microplate reader). The evaluation was carried out analogously to the procedure with PLpro.

Results: The gold compounds are good inhibitors of SARS-CoV-2 3CLpro. The following IC50 values were determined: Auranofin: 11.69 pM (± 0.40 pM); Aurothioglucose: 8.25 pM (± 0.04 pM); Aurothiomalate: 22.89 mM (± 0.72 mM).

Example 10. Inhibition of Bovine Coronavirus (BCoV) Infectivity in Cell Culture

Bovine coronavirus (BCoV), a virus related to SARS-CoV-2, which is also classified in the genus Betacoronavirus is used, since experiments with these sem can be carried out in the lower biological protection level BSL2. Madin Darby Bovine Kidney (MDBK) cells were used as susceptible cell cultures.

After incubation of various concentrations of aurothioglucose with 100 Tissue Culture Infectious Dose 50 (TCID50) of bovine coronavirus at 37 ° C for one hour, the aurothioglucose-bovine coronavirus suspension was inoculated onto the MDBK cells susceptible to this virus and used for Incubated for 12 - 48 hours at 37 ° C and 5% CO2 atmosphere. At an aurothioglucose concentration of 256 mM, a 10-fold reduction in the amount of virus was found.

The addition of 64 mM favipiravir at the time of inoculation of the aurothioglucose-bovine coronavirus suspension on the cell cultures also led to a reduction in the amount of virus formed.

Example 11. Therapeutic treatment.

To produce a preparation A, 3 mg of micronized aurothioglucose are mixed with 9 mg of lactose and made available in a multi-dose powder inhaler. Four Covid-19 patients with onset of symptoms within 48 hours before the start of treatment are administered 2 puffs of 200 pg of the powder formulation twice a day over a period of 10 days.

To provide a combination preparation B, liquid ampoules with 0.1 mg each of aurothioglucose and 0.4 mg of N-acetylcysteine dissolved in 2.5 mL of water are produced. Four Covid-19 patients under artificial respiration are given a liquid ampoule per day via a nebuliser over a period of 10 days.

credentials Ahmed Abdel Khaleka, Nader S. Abutaleba, Haroon Mohammada, and Mohamed N. Seleema: Antibacterial and antivirulence activities of auranofin against Clostridium difficile. Int J Antimicrob Agents. 2019 January; 53 (1): 54-62. doi: 10.1016 / j.ijantimi- cag.2018.09.018.

Manish Bodas and Neeraj Vij; The NFkB Signaling in Cystic Fibrosis Lung Disease: Pathophysiology and Therapeutic Potential. Discov. Med. 2010 April; 9 (47); 346-356.

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 auranofn and gold containing analogues antibacterial activity against multidrug-resistant Neisseria gonorrhoeae. May be. Rep. 2020 March; 10; 5602.

Maria Gil-Moles, Uttara Basu, Rolf Büssing, Henrik Hoffmeis ter, Sebastian Türck, Agnieszka Varchmin, Ingo Ott, Gold Metal- lodrugs 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-Fernändez MA, Gold Nanoparticles Crossing Blood-Brain Barrier Prevent HSV-1 Infection and Reduce Herpes As sociated Amyloid-ß secretion. J. Clin. Med. 2020, 9, 155; doi: 10.3390 / jcm9010155

Claims

1. Medicines for inhalation containing aurothioglucose.

2. Containing drugs for inhalation

- aurothioglucose; and

- N-acetylcysteine.

3. Containing medicinal products for inhalation

- aurothioglucose;

- A virostat, preferably selected from the group consisting of remdesivir, molnupiravir, favipiravir, ribavirin, lopinavir, umifenovir, nelfinavir and / or ritonavir, preferably favipiravir, molnupiravir and / or ribavirin, in particular Favi piravir; and preferably

- N-acetylcysteine.

4. Medicament according to claim 2 or 3, characterized in that the medicament aurothioglucose and N-acetylcysteine in a molar ratio of between 1:40 and 10: 1, preferably between 1:20 and 5: 1, more preferably between 1:10 and 2.5: 1, even more preferably between 1: 5 and 1: 1, even more preferably between 1: 2.5 and 1: 1.5, most preferably 1: 2 (aurothioglucose: N-acetylcysteine) .

5. Medicaments for inhalation, preferably medicaments according to one of claims 1 to 4, containing

- aurothioglucose;

- an active ingredient selected from hydroxychloroquine, chloroquine and / or ivermectin; and preferably

- N-acetylcysteine.

6. Medicament according to one of claims 1 to 5, characterized in that the medicament contains a carrier, preferably a carbohydrate, particularly preferably lactose and / or man nose.

7. Medicament according to one of claims 1 to 6, characterized in that the medicament is present as a powder formulation, preferably micronized before.

8. Medicament according to one of claims 1 to 6, characterized in that the medicament is present as a solution or as an aerosol.

9. Inhaler, preferably powder inhaler, metered dose inhaler or nebuliser, containing a medicament according to any one of claims 1 to 8.

10. Medicament according to one of claims 1 to 8 for use in the prevention or therapy of lung diseases.

11. Medicament for use according to claim 10, characterized in that the lung disease is an infectious or mixed inflammatory-infectious lung disease.

12. Medicament for use according to claim 10 or 11, characterized in that the lung disease is a lung infection, preferably a viral or mixed viral-bacterial lung infection.

13. Medicament for use according to one of claims 10 to

12, characterized in that the lung disease is a disease caused by coronaviridae belonging to the group of RNA viruses, 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. Medicament for use according to one of claims 10 to

13, characterized in that the medicament in a dose containing between 0.001 pmol and 450 pmol, preferably between 0.01 pmol and 250 pmol, even more preferably between 0.1 pmol and 50 mpioΐ, most preferably between 0.5 pmol and 30 pmol gold is administered.

15. Medicament for use according to one of claims 10 to

14, characterized in that the drug in a dose containing between 0.1 pg and 1000 pg gold per kg of body weight of the patient, preferably between 0.2 pg / kg and 200 pg / kg, more preferably between 0.5 pg / kg and 40 pg / kg, most preferred between 1 mg / kg and 10 g / kg of body weight gold is administered.

16. Medicament for use according to one of claims 10 to

15, characterized in that the application takes place by inhalation, preferably liquid inhalation or powder inhalation.

17. Medicament for use according to one of claims 10 to

16, characterized in that the application takes place by an inhaler according to claim 9.