Medicament for the prevention or therapy of COPD

Abstract

The invention relates to a medicament containing gold for use in the prevention or therapy of chronic obstructive pulmonary disease (COPD), preferably with accompanying respiratory tract infection, wherein the medicament is administered by inhalation. The invention further relates to a process for preparing a ready-to-administer solution of a medicament containing gold.

Description

[0001] Medicines for the prevention or treatment of COPP

[0002] The present invention relates to pharmaceuticals for use in the prevention or therapy of chronic obstructive pulmonary disease (COPD).

[0003] According to the 2024 GOLD (Global Initiative for Chronic Obstructive Lung Disease) report, COPD is a heterogeneous lung disease characterized by chronic respiratory symptoms (dyspnea, cough, sputum production, and / or exacerbations). These symptoms result from abnormalities of the airways (bronchitis, bronchiolitis) and / or alveoli (emphysema), causing persistent, often progressive, airway obstruction. The main causes and risk factors are environmental pollutants (primarily tobacco smoking) and genetic predisposition. COPD is now one of the three leading causes of death worldwide, with 90% of these deaths occurring in low- and middle-income countries. In 2012, more than 3 million people died from COPD, accounting for 6% of all deaths worldwide.COPD is a leading cause of chronic morbidity and mortality worldwide; many people suffer from the disease for years and die prematurely from its complications. Globally, the burden of COPD is expected to increase in the coming decades due to continued exposure to COPD risk factors and the aging population.

[0004] Current treatment strategies for COPD include both pharmacological and non-pharmacological approaches. Commonly used pharmacological treatments include bronchodilators, inhaled corticosteroids, and combination therapies that combine these agents. Non-pharmacological treatment approaches include measures such as smoking cessation, pulmonary rehabilitation, and vaccination against respiratory pathogens. Despite these treatment options, COPD remains a disease with high morbidity and mortality, particularly due to frequent exacerbations that lead to a worsening of the disease and an increased risk of hospitalization and death. A significant challenge in the management of COPD is the occurrence of co-occurring respiratory infections. These infections can be both viral and bacterial and contribute substantially to the disease burden.Viral infections play a particularly significant role in this context, with respiratory syncytial virus (RSV) and influenza viruses being especially noteworthy. RSV is a widespread pathogen that leads to infections primarily during the winter months and can cause serious respiratory complications, particularly in older adults and individuals with weakened immune systems, such as COPD patients. Studies have shown that RSV infections in COPD patients frequently lead to a worsening of airway obstruction and an increased incidence of exacerbations. This problem is further exacerbated by the fact that no specific medication against RSV is currently available. Influenza viruses also pose a considerable threat, as they can lead to severe respiratory illnesses and increase the likelihood of exacerbations.Similarly, the COVID-19 pandemic has highlighted the vulnerability of COPD patients to severe illness from coronavirus infections. The interactions between COPD and SARS-CoV-2 can further impair lung function and increase the risk of hospitalization and mortality.

[0005] Bacterial infections, for example caused by Streptococcus pneumoniae, are also of great importance, as they can worsen COPD symptoms and lead to exacerbations. These infections also frequently occur as a consequence of viral infections, since the immune system weakened by viruses has an increased susceptibility to bacterial pathogens.

[0006] These accompanying respiratory infections are problematic because they not only worsen airway obstruction but also increase the risk of exacerbations. Exacerbated COPD is characterized by acute worsenings of respiratory symptoms that exceed normal daily variability and often require a change in medication. Exacerbations can be triggered by various factors, including respiratory infections, pollution, and other comorbidities. They are associated with a significant burden for patients and contribute substantially to a decline in quality of life, frequent hospitalizations, and increased mortality. Patients with frequent exacerbations also experience a more rapid decline in lung function and are at higher risk of developing serious complications.

[0007] Another problem with current COPD treatment, particularly for exacerbated COPD, is the widespread use of corticosteroids. While corticosteroids have anti-inflammatory properties and can help prevent or control acute exacerbations, they also suppress the immune system. Therefore, when treating COPD with accompanying respiratory infections, corticosteroids can worsen the course of these infections by weakening the body's defenses and facilitating the spread of pathogens. This leads to increased morbidity and can prolong the duration and severity of infections. Furthermore, repeated infections and exacerbations can lead to further deterioration of lung function and an overall poorer prognosis.

[0008] In light of these challenges, there is an urgent need for new and improved treatment options for COPD, particularly treatment options that can minimize the risk and impact of accompanying infections. It is an object of the present invention to provide such treatment options.

[0009] The present invention therefore relates to a medicament containing gold for use in the prevention or therapy of chronic obstructive pulmonary disease (COPD), preferably with accompanying respiratory tract infection, wherein the medicament is administered by inhalation.

[0010] In another aspect, the invention relates to a method for producing a ready-to-administer solution of a drug containing gold, comprising the following steps:

[0011] - Filling a powder formulation containing a gold-containing active ingredient into a container;

[0012] - Storing the powder formulation in the container; - Adding an aqueous liquid to the container, which dissolves the powder formulation and creates a ready-to-administer solution of the medicinal product.

[0013] In previous publications, the inventors developed inhalable drugs containing gold as a novel therapeutic concept for lung diseases. For example, WO 2021 / 185773 Al describes, among other things, the inhalational application of aurothioglucose for the treatment of SARS-CoV-2 infections. Chronic inflammatory lung diseases such as COPD, cystic fibrosis, and interstitial pneumonia are also mentioned. WO 2021 / 185773 Al contains experimental data generated by the inventors, which demonstrate both anti-inflammatory and antiviral effects against SARS-CoV-2. Applications of various gold compounds are also described in WO 2017 / 058012 Al and WO 2017 / 093544 Al.

[0014] Within the scope of the present invention, it has surprisingly been found that the inhalational administration of gold represents a particularly effective treatment option for COPD, especially when accompanied by respiratory infection. COPD with accompanying respiratory infection is notoriously difficult to treat. Previous therapeutic approaches have mostly failed due to the complex interplay between COPD and infection. However, studies conducted in connection with the invention have shown that gold-containing drugs exhibit unexpectedly high efficacy against this complex pathology, as demonstrated by extensive experimental studies (see Example 1).

[0015] According to the inventors—without being bound to any specific theory—the unexpected treatment success is due to the unique combination of therapeutic effects associated with the inhalational administration of gold-containing medications. Gold has both anti-inflammatory and anti-infective properties, and can therefore treat both aspects of the pathology simultaneously. Unlike corticosteroids, which only address the anti-inflammatory aspect while negatively impacting infection, the therapeutic effects of gold work synergistically in the treatment of COPD with concomitant respiratory infections. The potent anti-inflammatory effect of gold is primarily attributed to the inhibition of the nuclear factor NF-κB, which acts as a central mediator of inflammatory responses (Liu et al., Signal Transduction and Targeted Therapy (2017) 2, el 7023).It has been shown that gold suppresses both NF-κB binding activity and the activation of I-κB kinase. This mechanism subsequently leads to a reduced production of pro-inflammatory cytokines, particularly TNF-α, interleukin-1, and interleukin-6.

[0016] The NF-κB signaling pathway is typically continuously activated in the macrophages and airway epithelium of COPD patients, particularly during bacterial or viral infections, and is involved in a complex signaling cascade. Upon pathogen stimulation, the pathway is primarily triggered by Toll-like receptors (TLRs) and pro-inflammatory cytokines such as TNF-α and IL-1. Sustained or prolonged activation of NF-κB may contribute to the pathogenesis of COPD by activating the transcriptional response of pro-inflammatory cytokines, chemokines, cell adhesion molecules (CAMs), proteases, and apoptosis inhibitors to enhance inflammation. According to the inventors, the inhibition of NF-κB by gold compounds is therefore a particularly important reason for the unexpected treatment success.

[0017] The second pillar responsible for the surprising therapeutic efficacy is the anti-infective properties of gold. Gold compounds have been shown to be effective against a broad spectrum of microorganisms, as demonstrated by the experimental data included herein for the viral pathogens RSV (Examples 1 and 4), influenza virus (Example 3), and coronavirus (Example 2), as well as for the bacterial pathogen Streptococcus pneumoniae (Example 3).

[0018] The antimicrobial effect of gold and gold compounds is directly attributable to the effects of gold ions on microorganisms. Both the precious metal gold and gold ions are very unreactive. An exception to this—apart from the ionic effects of gold ions—is the high affinity of gold ions for sulfur atoms. Cysteine ​​is a particularly important amino acid from a structural and functional perspective, as its ability to form disulfide bridges contributes significantly to the tertiary structure of proteins. Cysteine-rich domains are therefore frequently found in the reactive centers of proteins.

[0019] Another crucial factor for the effectiveness of the therapies described herein is the method of administration. Inhalation allows the gold-containing medication to reach its target site in the lungs directly, where it can exert its effect. This method of administration also minimizes side effects.

[0020] Although the importance of pharmacokinetics has long been recognized, it is often overlooked, particularly in the case of lung diseases, that the direct topical application of a drug at the site of the disease offers a number of significant advantages, such as the possibility of lower dosages, reduced physiological stress, and fewer side effects. For example, gold-containing drugs administered systemically bind to sulfur atoms in amino acids and proteins on their way to the site of action. This can lead to accumulation in the body when administered parenterally or orally. Due to the side effects resulting from the strong interaction of gold ions with sulfur compounds, the unfavorable pharmacokinetics associated with conventional oral and parenteral administration are a particularly significant disadvantage of gold-based medications.Therefore, the currently used oral and parenteral routes of administration are hardly suitable for treating lung infections with gold compounds. Injected or oral gold compounds would have to be administered over a long period until the gold reaches the site of action in the lungs in a sufficient concentration. The most direct route possible from the point of entry of the drug into the body to the site of action should, if possible, be sought through topical application. Furthermore, lung tissue is very well equipped to absorb drugs.

[0021] The medicament according to the invention contains gold. Preferably, the medicament comprises a gold-containing active ingredient, preferably selected from the group consisting of aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurothioprole, aurothiopolypeptide, elemental gold and / or a gold salt.

[0022] The drugs aurothioglucose and aurothiomalate, which have proven effective in antirheumatic practice, are particularly preferred. Aurothioglucose is especially preferred because the gold ion is complexly bound to the molecular component and is therefore released in a more controlled manner.

[0023] Elemental gold can be used in the form of nanoparticles. In a preferred formulation, the drug therefore contains gold nanoparticles.

[0024] Preferably, the pharmaceutical preparation contains gold(I). "Gold(I)" refers to gold in the +1 oxidation state. Unlike gold(III) ions, gold(I) ions are non-toxic and therefore particularly preferred for the purposes of the present invention. Preferably, the pharmaceutical preparation comprises a gold-containing active ingredient, wherein the gold-containing active ingredient is a gold(I) compound, preferably selected from the group consisting of aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurothioprole, and aurothiopolypeptide.

[0025] It has been shown that the addition of mercapto-containing compounds, particularly N-acetylcysteine, to a gold-containing active ingredient can lead to additional benefits. In particular, such compounds can act as enhancers and accelerate cellular uptake. The combination of aurothioglucose with N-acetylcysteine ​​has proven to be especially advantageous.

[0026] In a preferred formulation, the medicinal product therefore further contains a mercapto-containing compound, preferably N-acetylcysteine. The term "N-acetylcysteine" also includes possible salts of N-acetylcysteine; that is, in this formulation, the medicinal product preferably contains N-acetylcysteine ​​or a salt thereof. Since N-acetylcysteine ​​is a drug already used to treat lung diseases, a positive additional therapeutic effect can be achieved.

[0027] In a further preferred embodiment, the medicinal product according to the invention contains gold (preferably in the form of aurothioglucose, auranofin, 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).

[0028] COPD treatment usually involves combination therapies. These primarily consist of combinations of short-acting (SANA) or long-acting muscarinic antagonists (LAMA) with short- and long-acting beta-2 agonists (SABA and LABA). These drug classes combat airway constriction. A newer class, phosphodiesterase-4 inhibitors (PDE-4 inhibitors), has recently been added, which have both bronchodilatory and anti-inflammatory effects. Corticosteroids (ICS) are used, especially in more severe cases such as exacerbated COPD. These reduce inflammation and tissue swelling. The three drug classes mentioned above are most often administered in combinations of two or three drugs.

[0029] Since the combination with drugs from the groups of muscarinic antagonists, beta-2 agonists and PDE-4 inhibitors provides a complementary therapeutic effect, in another preferred formulation the gold-containing drug contains one or more additional active ingredients from these drug groups.

[0030] Preferred compounds from the SAMA / LAMA group are ipratropium, aclidinium, glycopyrronium, R, R-glycopyrrolate, umeclidinium, and tiotropium. Preferred compounds from the SABA / LABA group are salbutamol, fenoterol, orciprenaline, pirbuterol, procaterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, indacaterol, olodaterol, and vilanterol. Preferred drugs from the PDE-4 inhibitor group are roflumilast and cilomilast.

[0031] Since corticosteroids (inhaled corticosteroids; ICS), while having a fundamentally similar anti-inflammatory effect, exhibit an infection-promoting effect in contrast to the compounds according to the invention, replacing ICS with the gold compounds enables considerable therapeutic progress. Therefore, replacing the corticosteroid in combination agents for the treatment of COPD, preferably combinations containing beclomethasone, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate, or mometasone furoate, is a further object of the invention. In a preferred embodiment, the medicament according to the invention therefore replaces a glucocorticoid in an existing COPD treatment, preferably beclomethasone, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate, or mometasone furoate.

[0032] In another preferred formulation, the drug also contains an antibiotic. The addition of an antibiotic can complement the effect of gold and thus additionally combat accompanying respiratory infections or prevent further superinfections.

[0033] In connection with the invention, the drug is administered by inhalation. Liquid or powder inhalation is particularly preferred. Through inhalation, the gold-containing drug reaches the site of action in the lungs directly and can exert its effect there.

[0034] The preferred method of administration is inhalation as a liquid aerosol or by dry powder inhalation. The latter, compared to the easier-to-use liquid inhalation where considerable amounts of the active ingredient remain in the throat, offers a more precise method of dosage.

[0035] For inhalation, commercially available devices can be used. In the case of intensive care treatments, aqueous solutions of the agents according to the invention can be added to the ventilation air via spray nozzles. In the case of powder inhalation, micronization of the active ingredient (particle size preferably less than 5 micrometers) is a preferred method of application because it allows deeper lung areas to be reached. Application in a mixture with a carrier substance is also preferred. Mixing the micronized active ingredient with a carrier substance with a larger particle size is particularly preferred because this ensures that the carrier substance is initially deposited more readily in the upper regions of the pharynx, while the active ingredient penetrates deeper into the lungs. Lactose, mannose, and other carbohydrates are particularly suitable as carrier substances.

[0036] Preferably, the pharmaceutical product is in powder form, preferably enthroned. In an alternative, also preferred, formulation, the pharmaceutical product is in solution or aerosol form.

[0037] In connection with all medicaments for use according to the invention, it is preferred that the medicament be in the form of an inhalation formulation. It is particularly preferred if the formulation is a powder formulation. Preferably, the medicament is in the form of a dry powder for aerosol preparation. A powder formulation allows for particularly easy administration, e.g., by means of a powder inhaler. For example, powder inhalers such as those already used for the treatment of asthma or COPD can be used. For this application, the medicament is preferably in micronized form.

[0038] In another preferred formulation, the drug is available as a powder or solution for aerosol preparation. This formulation is particularly suitable for administration via metered-dose inhalers or nebulizers. For example, such formulations can also be used for patients who are mechanically ventilated.

[0039] Preferably, the medicinal product contains excipients. Excipients commonly used in inhalation formulations, especially powder and liquid formulations for inhalation, are particularly preferred. In a preferred embodiment, the medicinal product contains a carrier substance, preferably a carbohydrate, particularly preferably lactose and / or mannose.

[0040] Preferably, the medicinal product is administered using an inhaler, preferably a dry powder inhaler, metered-dose inhaler, or nebulizer. In a preferred embodiment, the inhaler is a dry powder inhaler, wherein the medicinal product is in powder form. In another 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, wherein the medicinal product is in solution or aerosol form. In the context of combination medicinal products, it is preferred if the active ingredients are contained in separate compartments of a dry powder inhaler. Containing the active ingredients in separate compartments facilitates, among other things, the manufacturing process. In a preferred embodiment of the dry powder inhaler, gold or the gold-containing active ingredient and N-acetylcysteine ​​are therefore contained in separate compartments of the dry powder inhaler.In a particularly preferred embodiment of the powder inhaler, gold or the gold-containing active ingredient and the antiviral and / or the antibiotic are located in separate compartments of the powder inhaler.

[0041] Preferably, a dose of the drug is administered to an individual, preferably at least once a week, more preferably at least every two days, more preferably at least once a day, and even more preferably at least twice a day. Administration once or twice a day, particularly twice a day, is especially preferred.

[0042] Preferably, the therapy is carried out over a certain period of time and with an effective amount of drug. In particular, it is preferred if the drug is administered over a period of 1 to 30 days, preferably 2 to 21 days, even more preferably 3 to 14 days, and most preferably 5 to 10 days.

[0043] In connection with the present invention, the individual to be treated is preferably an animal, preferably a mammal, in particular a human. Preferably, the individual has COPD with accompanying respiratory infection, as described herein.

[0044] In a preferred embodiment, one dose of the drug contains between 1 pg and 10 mg of gold, preferably between 2.5 pg and 7.5 mg, more preferably between 25 pg and 5 mg, most preferably between 50 mg and 1 mg.

[0045] In a particularly preferred embodiment, a dose contains between 2 pg and 20 mg aurothioglucose, preferably between 5 pg and 15 mg, more preferably between 50 pg and 10 mg, most preferably between 100 pg and 2 mg.

[0046] In connection with the invention, the medicinal product is used for the prevention or treatment of COPD, preferably COPD with concomitant respiratory infection. Preferably, the COPD is exacerbated COPD. "Exacerbated COPD" here preferably refers to COPD with an acute exacerbation, preferably according to code CA22.0 of the ICD-11. "ICD-11" refers to the 11th version of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO).

[0047] The accompanying respiratory infection is preferably a pulmonary infection. Pulmonary infections are particularly problematic in the context of COPD, but can be treated effectively using the specific treatment approach described here.

[0048] Preferably, the accompanying respiratory infection is a viral and / or bacterial infection. It is particularly preferred if it is a viral infection, especially caused by a virus selected from the group consisting of respiratory syncytial virus (RSV), coronavirus (especially SARS-CoV-2), rhinovirus, influenza virus, parainfluenza virus, metapneumovirus, and / or adenovirus. It is particularly preferred if the virus is RSV.

[0049] In another preferred form of implementation, the accompanying respiratory infection is an infection caused by Streptococcus pneumoniae.

[0050] The invention of fenbart further comprises a method for the prevention or therapy of COPD, preferably with accompanying respiratory infection, comprising the steps of:

[0051] - Providing a medicinal product as described herein; and

[0052] - Administering an effective amount of the drug to an individual who needs it.

[0053] Preferably, the method is for the treatment of COPD, preferably with concomitant respiratory infection, wherein the individual suffers from COPD, preferably with concomitant respiratory infection. In a further aspect, the invention relates to a method for producing a ready-to-administer solution of a medicament containing gold, comprising the following steps:

[0054] - Filling a powder formulation containing a gold-containing active ingredient into a container;

[0055] - Storing the powder formulation in the container;

[0056] - Addition of an aqueous liquid to the container, which dissolves the powder formulation and creates a ready-to-administer solution of the drug.

[0057] All preferred formulations described herein for use in the medicinal product are also preferred for the manufacturing process, in particular all formulations and features described in connection with the powder formulation and the gold-containing active ingredient.

[0058] Within the scope of the invention, it has proven advantageous to provide the gold-containing pharmaceutical product by means of dry powder filling and to store it in solid form until administration. It has been shown that gold-containing active ingredients, in particular aurothioglucose, are more stable in dry form than in aqueous solution, thus enabling advantageous quality assurance. It is particularly advantageous if small quantities of the pharmaceutical product, preferably a single dose, are filled and stored as a powder and only dissolved immediately before administration by adding an aqueous solution.

[0059] Preferably, the powder formulation is a dry-filled powder formulation. Preferably, the powder formulation is a dry powder formulation. Preferably, the powder formulation has a water content of less than 5 wt.%, more preferably less than 1 wt.%. The water content can preferably be determined by coulometric Karl Fischer titration, preferably according to ISO 760:1978.

[0060] In a preferred embodiment, filling takes place under a protective gas atmosphere, preferably a nitrogen atmosphere. It is particularly preferred if filling takes place under a substantially anhydrous atmosphere. This can further improve the stability of the drug product. In a preferred embodiment, a single dose of the powder formulation is filled into the container. This makes it possible to dissolve a single dose before administration without having to dissolve a larger quantity of the stored drug product.

[0061] It is particularly preferred if between 0.1 mg and 40 mg, preferably between 0.5 mg and 10 mg, more preferably between 1 mg and 4 mg of the powder formulation is filled into the container.

[0062] Preferably, the powder formulation filled into the container contains between 1 pg and 10 mg of gold, more preferably between 2.5 g and 7.5 mg, more preferably between 25 g and 5 mg, and most preferably between 50 mg and 1 mg. It is particularly preferred if the powder formulation filled into the container contains between 2 g and 20 mg of aurothioglucose, more preferably between 5 g and 15 mg, more preferably between 50 g and 10 mg, and most preferably between 100 g and 2 mg.

[0063] Furthermore, it is preferred if the powder formulation filled into the container contains between 10 oz and 10 mg, preferably between 0.1 and 4.0 mg, more preferably between 0.3 mg and 2 mg, more preferably between 0.5 mg and 1 mg N-acetylcysteine.

[0064] Preferably, the container is a vial. A vial is preferably understood to be a bottle with a pierceable stopper.

[0065] In a preferred embodiment, the powder formulation is stored in the container for a period of at least one month, preferably at least six months, before the aqueous liquid is added. It is particularly preferred if the powder formulation is stored in the container for a period of one to 36 months, preferably two to twelve months, before the aqueous liquid is added.

[0066] In a preferred embodiment, the aqueous liquid is added to the container immediately before administration of the drug. This is particularly advantageous for quality assurance.

[0067] In another preferred embodiment, the aqueous liquid is a sterile aqueous liquid, preferably water for injection purposes.

[0068] The term "prevention," as used herein, means preventing the occurrence of a disease in an individual completely, almost completely, or at least to a (preferably significant) extent. However, this term should not be interpreted as absolute success in the sense that the individual can never develop such a disease, but rather as a reduction in the risk of developing the disease.

[0069] In connection with the present invention, the terms "agent", "medicinal product" or "pharmaceutical composition" are understood to mean a composition containing at least one active ingredient and preferably containing one or more pharmaceutically acceptable excipients. These compositions are particularly suitable for administration to an animal, preferably to a mammal, most preferably to a human.

[0070] The present invention relates in particular to the following preferred embodiments:

[0071] From führungs form 1. Medicinal products containing gold for use in the prevention or treatment of chronic obstructive pulmonary disease (COPD).

[0072] From embodiment 2. Medicinal product for use according to embodiment 1, wherein the medicinal product is administered by inhalation.

[0073] From implementation form 3. Medicinal product for use according to one of the preceding embodiments, wherein the use is in the prevention or therapy of COPD with accompanying respiratory tract infection.

[0074] From embodiment 4. Medicinal product for use according to one of the preceding embodiments, wherein the medicinal product contains gold(I).

[0075] From embodiment 5. Medicinal product for use according to one of the preceding embodiments, wherein the medicinal product contains a gold-containing active ingredient, preferably selected from the group consisting of aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurotioprol, aurothiopolypeptide, elemental gold and / or a gold salt.

[0076] From embodiment 6. Pharmaceutical for use according to the preceding embodiment, wherein the gold-containing active ingredient is a gold ( I ) compound, preferably selected from the group consisting of aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurotioprol and aurothiopolypeptide.

[0077] From embodiment 7. Medicinal product for use according to one of the preceding embodiments, wherein the medicinal product contains aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurotioprol, aurothiopolypeptide, elemental gold and / or a gold salt.

[0078] From implementation form 8. Medicinal product for use according to one of the preceding embodiments, wherein the medicinal product further contains N-acetylcysteine.

[0079] From embodiment 9. Pharmaceutical for use according to one of the preceding embodiments, wherein the pharmaceutical contains gold and N-acetylcysteine ​​in a stoichiometric 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).

[0080] From embodiment 10. Pharmaceutical for use according to one of the preceding embodiments, wherein the pharmaceutical contains aurothioglucose and N-acetylcysteine ​​in a stoichiometric 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).

[0081] From the execution form 11. Drug for use according to one of the preceding embodiments, wherein the drug contains one or more further active substances that have an effect against COPD, preferably a muscarinic antagonist and / or a beta-2 agonist.

[0082] From embodiment 12. Drug for use according to one of the preceding embodiments, wherein the drug further comprises at least one additional active ingredient selected from the groups of muscarinic antagonists, beta-2 agonists and PDE-4 inhibitors, preferably wherein the additional active ingredient is selected from the group consisting of ipratropium, aclidinium, glycopyrronium, R, R-glycopyrrolate, umeclidinium, tiotropium, salbutamol, fenoterol, orciprenaline, piributerol, procaterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, indacaterol, olodaterol, vilanterol, roflumilast and cilomilast.

[0083] From the formulation form 13. Drug for use according to one of the preceding embodiments, wherein the drug contains a muscarinic antagonist, preferably selected from the group consisting of ipratropium, aclidinium, glycopyrronium, R, R-glycopyrrolate, umeclidinium and tiotropium.

[0084] From embodiment 14. Drug for use according to one of the preceding embodiments, wherein the drug contains a beta-2 agonist, preferably selected from the group consisting of salbutamol, fenoterol, orciprenaline, piributerol, procaterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, indacaterol, olodaterol and vilanterol.

[0085] From embodiment 15. Drug for use according to one of the preceding embodiments, wherein the drug contains a PDE-4 inhibitor, preferably roflumilast and / or cilomilast.

[0086] From embodiment 16. Drug for use according to one of the preceding embodiments, wherein the drug replaces a glucocorticoid in an existing COPD treatment, preferably beclometasone, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate or mometasone furoate.

[0087] From execution form 17. Pharmaceutical for use according to one of the preceding embodiments, wherein the pharmaceutical contains a carrier substance, preferably a carbohydrate, particularly preferably lactose and / or mannose.

[0088] From execution form 18. Medicinal product for use according to one of the preceding embodiments, wherein the medicinal product is in the form of a powder formulation, preferably micronized, or as a solution or as an aerosol.

[0089] Form 19. Medicinal product for use according to one of the preceding forms, wherein the application is by inhalation, preferably liquid inhalation or powder inhalation.

[0090] Form 20. Medicinal product for use according to one of the preceding forms, wherein the medicinal product is administered using an inhaler, preferably a powder inhaler, metered-dose inhaler or nebulizer.

[0091] Execution form 21. Medicinal product for use according to one of the preceding execution forms, wherein a dose of the medicinal product is administered at least once per week, preferably at least every two days, more preferably at least once per day, and even more preferably at least twice per day.

[0092] Form 22. Medicinal product for use according to one of the preceding forms, wherein one dose of the medicinal product is administered once a day.

[0093] Form 23. Medicinal product for use according to one of the preceding forms, wherein one dose of the medicinal product is administered twice a day.

[0094] Execution form 24. Medicinal product for use according to one of the preceding execution forms, wherein the medicinal product is administered over a period of 1 to 30 days, preferably 2 to 21 days, more preferably 3 to 14 days, most preferably 5 to 10 days.

[0095] Execution form 25. Medicinal product for use according to one of the preceding execution forms, wherein the medicinal product is administered in a dose containing between 1 pg and 10 mg, preferably between 2.5 pg and 7.5 mg, more preferably between 25 pg and 5 mg, most preferably between 50 mg and 1 mg gold.

[0096] Execution form 26. Medicinal product for use according to one of the preceding execution forms, wherein the medicinal product is administered in a dose containing between 2 pg and 20 mg, preferably between 5 pg and 15 mg, more preferably between 50 pg and 10 mg, most preferably between 100 pg and 2 mg aurothioglucose.

[0097] Execution form 27. Medicinal products for use in accordance with one of the preceding execution forms, wherein the COPD is an exacerbated COPD.

[0098] Form 28. Medicinal products for use according to one of the preceding forms, wherein the accompanying respiratory infection is a pulmonary infection.

[0099] Execution form 29. Medicinal products for use in accordance with one of the preceding execution forms, wherein the accompanying respiratory infection is a viral and / or bacterial infection.

[0100] Form 30. Medicinal product for use according to one of the preceding forms, wherein the accompanying respiratory infection is an infection caused by a virus selected from the group consisting of Respiratory Syncytial Virus (RSV), Coronavirus, Rhinovirus, Influenza Virus, Parainfluenza Virus, Metapneumovirus and / or Adenovirus.

[0101] Execution form 31. Medicinal products for use according to one of the preceding execution forms, wherein the accompanying respiratory infection is an infection caused by RSV.

[0102] Form 32. Medicinal product for use according to one of the preceding forms, wherein the accompanying respiratory infection is an infection caused by Streptococcus pneumoniae.

[0103] From embodiment 33. Method for producing a ready-to-administer solution of a medicament containing gold, preferably as defined in one of the preceding embodiments, comprising the following steps:

[0104] - Filling a powder formulation containing a gold-containing active ingredient into a container;

[0105] - Storing the powder formulation in the container;

[0106] - Addition of an aqueous liquid to the container, which dissolves the powder formulation and creates a ready-to-administer solution of the drug.

[0107] From embodiment 34. Method according to the preceding embodiment, wherein the filling takes place under a protective gas atmosphere, preferably a nitrogen atmosphere.

[0108] From implementation form 35. Method according to one of the preceding implementation forms, wherein the filling takes place under an essentially anhydrous atmosphere.

[0109] From implementation form 36. Method according to one of the preceding implementation forms, wherein a single dose of the powder formulation is filled into the container.

[0110] From embodiment 37. Method according to one of the preceding embodiments, wherein between 0.1 mg and 40 mg, preferably between 0.5 mg and 10 mg, more preferably between 1 mg and 4 mg of the powder formulation is filled into the container.

[0111] From embodiment 38. Method according to one of the preceding embodiments, wherein the powder formulation filled into the container contains between 1 pg and 10 mg, preferably between 2.5 pg and 7.5 mg, more preferably between 25 pg and 5 mg, most preferably between 50 mg and 1 mg gold.

[0112] From embodiment 39. Method according to one of the preceding embodiments, wherein the powder formulation filled into the container contains between 2 pg and 20 mg, preferably between 5 pg and 15 mg, more preferably between 50 pg and 10 mg, most preferably between 100 pg and 2 mg aurothioglucose.

[0113] From embodiment 40. Method according to one of the preceding embodiments, wherein the powder formulation filled into the container contains between 10 pg and 10 mg, preferably between 0.1 and 4.0 mg, more preferably between 0.3 mg and 2 mg, more preferably between 0.5 mg and 1 mg N-acetylcysteine.

[0114] From embodiment 41. Method according to one of the preceding embodiments, wherein the container is a vial.

[0115] From embodiment 42. Method according to one of the preceding embodiments, wherein the powder formulation is stored in the container for a period of at least 1 month, preferably at least 6 months, before the aqueous liquid is added.

[0116] Embodiment 43. A method according to any of the preceding embodiments, wherein the powder formulation is stored in the container for a period of 1 month to 36 months, preferably 2 months to 12 months, before the aqueous liquid is added. Embodiment 44. A method according to any of the preceding embodiments, wherein the aqueous liquid is added to the container immediately before administration of the drug.

[0117] From embodiment 45. Method according to one of the preceding embodiments, wherein the aqueous liquid is a sterile aqueous liquid, preferably water for injection purposes.

[0118] Form 46. Method according to one of the preceding forms, wherein the powder formulation is as defined for use in one of the preceding forms of the medicinal product.

[0119] From formulation 47. Method according to one of the preceding formulations, wherein the gold-containing active substance is as defined for use in one of the preceding formulations of the medicinal product.

[0120] The present invention is illustrated by the following examples and figures, to which it is of course not limited.

[0121] Figure 1. TEER measurements and LDH determination for tissue integrity assessment (healthy vs. COPD). The graphs show changes in TEER values ​​(AC) and LDH concentration (EF) measured every 48 hours over a 10-day treatment period. Tissue integrity and cumulative LDH concentration of healthy and COPD donors were treated with ATG 2000 pM (A, D), NAC 4000 pM and ATG 2000 pM (B, E), and NAC 2000 pM and ATG 1000 pM (C, F). Tissue treated with D-PBS was used as a control. The values ​​shown were normalized to the corresponding control (set to 100%).

[0122] Figure 2. TEER measurements and LDH determination for tissue integrity assessment (concentration assessment). The graphs show the changes in TEER values ​​(A and B) and LDH concentration (C and D) examined every 48 hours over a 10-day treatment period. Tissue integrity and cumulative LDH concentration of healthy (A and C) and COPD donors (B and D) were assessed after treatment with ATG 2000 pM, NAC 4000 pM, ATG 2000 pM, NAC 2000 pM, and ATG 1000 pM. Tissue treated with D-PBS was used as a control. The values ​​shown were normalized to the corresponding control (set to 100%).

[0123] Figure 3. TEER measurements of RSV-A-infected COPD tissue cultures. The bar charts show tissue integrity after RSV-A infection and treatment with ATG 500 pM, NAC 1000 pM and ATG 500 pM, NAC 500 pM and ATG 250 pM, and NAC 200 pM and ATG 100 pM, respectively. Both uninfected (UI) and untreated but infected (viral control) tissue cultures were used as controls. The values ​​(left) 2 days post-infection and (right) 5 days post-infection are given as mean TEER ± SEM in ohms per square centimeter, measured at three different positions in each transwell. High values ​​indicate high resistance and thus high tissue integrity. The degree of tissue damage was divided into three groups, with tar > 1000 being classified as healthy, tar < 1000 but > 500 as compromised, and tar < 500 as severely damaged.For statistical analysis, a two-way ANOVA using the Dunnet multiple comparison test against virus control was performed (p < 0.0001) (****) .

[0124] Figure 4. Quantification of viral infection in the apical supernatant of DHBE tissue. The bar charts show the infection as the mean viral copy number per pl ± SEM detected in the apical supernatant of infected and / or treated DHBE tissue. High values ​​indicate a highly productive infection, while lower copy numbers indicate a protective effect. Measurements were taken 2 days (left) and 5 days (right) post-infection. Uninfected (UI) and RSV-A infected but untreated tissue (viral control) were used as controls. A two-way ANOVA with Dunnett multiple comparisons against the viral control was used for statistical analysis. p < 0.0001 (****)

[0125] Figure 5. Quantification of replication-competent virus particles in the DHBE supernatant. The graphs show the mean percentage of active virus particles relative to the viral control ± SEM, measured by immunofluorescence plaque assay. Measurements were performed two (left) and five days (right) after RSV infection and subsequent ATG or NAC / ATG treatment at different concentrations. High values ​​indicate strong relative inhibition and thus a low viral load. All values ​​were normalized to the respective viral control (set to 0%). A two-way ANOVA using the Dunnett multiple comparison test against the viral control was used for statistical analysis; p < 0.0002 (***), p < 0.0001 (****).

[0126] Figure 6. Immunofluorescence imaging of DHBE tissue 5 days after RSV infection. Shown are representative images of uninfected, RSV-A-infected (virus only), and RSV-A and NAC / ATG-treated DHBE tissue 5 days post-infection. The blue spots represent cell nuclei, the red signal shows phalloidin staining to highlight the cytoskeleton, and the green signal shows stained viral antigen in the form of virus particle aggregates (small, distinct spots) or heavily infected cells (larger stained areas).

[0127] Figure 7. Neutralization capacity of ATG / NAC against SARS-CoV-2 wild type, Delta and Omicron variants. Data are given as mean ± SEM; n=3. Shown is the mean neutralization capacity of ATG alone or in combination with NAC at various concentrations against SARS-CoV-2 wild type (A), Delta (B) or Omicron BA.1 (C). All values ​​were normalized to the respective viral control (set to 100%).

[0128] Figure 8. Neutralization capacity of auroacetylcysteine ​​(AuNAC), ATG alone or in combination with NAC against influenza A and influenza B. Data are given as mean ± SEM; n=3. Shown is the mean neutralization capacity of AuNAC, ATG or ATG / NAC at various concentrations against influenza A (A) or influenza B (B). All values ​​were normalized to the respective viral control (set to 100%).

[0129] Figure 9. Antimicrobial efficacy of AuNAC against S. pneumoniae. Data are presented as mean ± SEM; n=3. The graph shows CFU in percent relative to the D-PBS control and after treatment for 6–24 hours. All values ​​were normalized to the D-PBS-treated bacteria (D-PBS control) at the respective time point. Statistical analysis was performed using GraphPad Prism v.9. Statistical significance of the relative CFU for each incubation period was determined by ordinary one-sided ANOVA using Sidäk's multiple comparison test; p>0.1234 (not significant, ns), p<0.0332 (*), p<0.0002 (***), p<0.0001 (****)

[0130] Figure 10. Neutralizing capacity of ATG alone or in combination with NAC against RSV. Data are given as mean ± SEM; n=3: Shown is the mean neutralizing capacity of ATG, NAC, and ATG / NAC at various concentrations against RSV type A (A) and RSV type B (B). All values ​​were normalized to the respective antiviral control (set to 100%). For statistical analysis, a standard one-sided ANOVA with Sidäk's test for multiple comparisons was performed (p < 0.0021 (**)).

[0131] Example 1 - Investigations in a COPD model with RSV infection

[0132] The following investigations were carried out as part of Example 1:

[0133] 1. Evaluation of the cytotoxic effects of ATG and the combination of ATG and NAC using healthy and CORD-affected human 3D respiratory models by analyzing tissue integrity (TEER measurement) and cell stress (LDH measurement) after repeated (48h) treatment over 10 days.

[0134] 2. Analysis of the protective effects on tissue integrity (TEER measurements) after RSV infection and treatment with ATG or ATG / NAC at different concentrations in a human 3D airway model suffering from COPD.

[0135] 3. Detection of a productive RSV-A infection by measuring the viral copy number (RT-PCR) and infectious virus particles (virus plaque assay) in apical supernatants after treatment with

[0136] ATG or ATG / NAC at different concentrations using a human 3D airway model of COPD.

[0137] 4. Analysis of tissue morphology and tissue infection using immunofluorescence imaging of untreated and treated human 3D airway tissue from COPD following RSV-A infection. Methods:

[0138] Generation of human 3D airway tissue using healthy (NHBE) and COPP-affected human bronchial epithelial cells (DHBE)

[0139] Diseased human bronchial epithelial cells (epithelix, Switzerland) were cultured on an air-liquid interface (ALI). The cells were cultured as a monolayer for 2 to 4 days until they reached 80% confluency. The cells were then detached and seeded onto 0.33 cm² porous (0.4 mm) polyester membrane inserts coated with GrowDexT (UPM) at a seeding density of 1 x 10⁵ cells per Transwell (Costar, Corning, NY, USA). The cells were submerged for 3 days using a specific epithelial cell growth medium according to the manufacturer's instructions (Stemcell Technologies, BC, Canada) until near-complete confluency was achieved. The cultures were maintained in a humid environment with 5% CO2 at 37°C and then transferred to an ALI culture for a further four weeks until the cells were fully differentiated.The epithelium was expanded and differentiated using Airway media from Stemcell Technologies (Vancouver, BC, Canada).

[0140] LDH measurement

[0141] Cellular stress was measured by quantifying the cumulative lactate dehydrogenase (LDH) concentration in the subnatant using a colorimetric display. The test was performed according to the manufacturer's instructions, with all supernatant samples tested at a 1:2 dilution (Cytotoxicity Detection Kit, Roche, Switzerland). Infection and treatment

[0142] For these experiments, transwells containing DHBE tissue were either left uninfected (UI) or infected with RSV type A at a MOI of 0.01. After 24 hours, the DHBE cells were either left untreated (UI & virus control) or treated with ATG at a concentration of 500 pM or with a combination of NAC and ATG at 1000 pM / 500 pM, 500 pM / 250 pM, or 200 pM / 100 pM, respectively. The treatments were administered after 24 hours, and the cells were incubated for a total of 5 days. Prior to each TEER measurement, the supernatant of each condition was collected for copy number determination and viral plaque testing.

[0143] Tar measurement

[0144] TEER values ​​were measured using an EVOM volt-ohm meter with STX-2 rod electrodes (World Precision Instruments, UK). Prior to measurements, 100 pl of medium was added to the apical chambers and 700 pl to the basolateral chambers to allow the cells to reach equilibrium. TEER values ​​were measured at three different positions for each transwell and corrected for the resistance and surface area of ​​the transwell filters. Copy number analysis was performed using quantitative real-time PCR (RT-PCR).

[0145] RSV genomic RNA was extracted from the apical DHBE supernatant using the FavorPrep Viral RNA Mini Kit according to the manufacturer's instructions (Favorgen Biotech, Taiwan). Primers and probes were used against the RSV matrix protein gene. Single-target assays were performed using the Luna Universal Probe One-Step RT-qPCR Kit (New England Biolabs, MA, USA). For absolute quantification, an in-house standard of the viral matrix protein (RSV) gene was used at a 10-fold serial dilution to generate a standard curve. All assays were performed on a Bio-Rad CFX 96 instrument and analyzed using Bio-Rad CFX Maestro 2.3 software (Bio-Rad, CA, USA).

[0146] Immune fluorescence-based virus pathogen assay

[0147] HEp-2 cells (2 x 10⁴) were inoculated in a 96-well plate with culture medium (MEM medium containing 10% FCS, 1% L-glutamine, and 1% penicillin / streptomycin) and incubated overnight at 37°C until confluency was reached. The following day, 100 µl of the DHBE supernatant was transferred to the respective cells in a 10-fold serial dilution and incubated for 1–2 h. Subsequently, the supernatant was removed, the cells were washed with pre-warmed D-PBS, and incubated in culture medium at 37°C and 5% CO₂. After 72 hours, the cells were washed and fixed in 4% neutral-buffered formaldehyde solution before being permeabilized at room temperature for 20 minutes. To visualize the infected loci, the cells were stained for 1 hour at RT with a primary antibody against the RSV fusion glycoprotein F (Sino Biological, China), followed by a secondary antibody coupled with an Alexa 488 immunofluorescence tag.After incubation with the secondary antibody, the cells were washed several times, and the infected loci were scanned and analyzed using an ImmunoSpot® S6 ULTRA-V device (CTL Europe GmbH, Germany). The relative inhibition of viral replication was determined by counting the total number of infected loci and subsequently normalizing to the respective viral control.

[0148] Immunofluorescence staining and confocal microscopy of DHBE tissue

[0149] On day 5 post-RSV infection, 3D cell cultures were fixed with 4% paraformaldehyde. Intracellular staining was performed using lX Intracellular Staining Permeabilization Wash Buffer (lX BioLegend, CA, USA). Cells were stained with phalloidin conjugated with Alexa647 (Thermofisher Scientific, MA, USA), and nuclei with Hoechst (Cell Signaling Technologies, MA, USA). Viral antigens in infected cells were detected using Alexa488-labeled RSV antibodies against viral fusion glycoprotein F. After staining, the 3D cultures were mounted in Mowiol (Sigma-Aldrich, MO, USA). Imaging and analysis were performed using the Operetta CLS system and Harmony 4.9 software (PerkinElmer, MA, USA).

[0150] Results :

[0151] The cytotoxicity of repeated (every 48 hours) ATG and NAC treatments in combination with ATG was evaluated over a 10-day period by measuring tissue integrity (TEER) and cumulative LDH concentration every 48 hours during treatment. Differences in TEER values ​​between normal (healthy) and COPD-affected tissue, compared to a D-PBS control set to 100% each day, were analyzed (Figure 1A-C, Figure 2A and B). Tissue integrity varied between healthy and diseased tissue due to excessive mucus production by COPD-derived cells. This is evident in the initial differences in TEER values ​​when comparing healthy and diseased tissue. No significant differences were found between treatment with D-PBS and repeated ATG exposure at 2000 gM for either normal or COPD tissue (Figure 1A, Figure 2A and B).In the case of combination treatment with NAC at 4000 gM in combination with ATG at 2000 gM (Figure 1B, Figure 2A and B) as well as NAC 2000 gM and ATG 1000 gM (Figure IC, Figure 2) no statistical differences were found compared to the D-PBS control.

[0152] These results were confirmed by assessing the cumulative LDH concentration in the cell subnatants over 10 days. Repeated exposure to ATG at 2000 gM (Figure ID, Figure 2C and D) or the combination of NAC and ATG at 4000 gM / 2000 gM (Figure IE, Figure 2C and D) and 2000 gM / 1000 gM (Figure 1F, Figure 2C and D) did not result in cell damage or cytotoxicity in either healthy or diseased tissue, and no significant changes were observed compared to tissue treated with D-PBS (Figure 2C and D).

[0153] The next objective of this example was to analyze the antiviral and protective effects of ATG or the combination of ATG and NAC against RSV-A infection in 3D tissue models derived from cells of COPD patients. For this purpose, tissue integrity (TEER) was measured over a five-day period following RSV-A infection and treatment with ATG at a concentration of 500 gM, as well as with NAC in combination with ATG at the following concentrations: 1000 gM / 500 gM, 500 gM / 250 gM, and 200 gM / 100 gM.

[0154] Tissue integrity (TEER) was nearly identical under all conditions two days post-infection (Figure 3, left). After five days, however, viral infection led to a significant reduction in TEER in the infected tissue (Figure 3, right). Compared to the infected but untreated state (Figure 3, gray bars), treatment with ATG at a concentration of 500 gM significantly reduced tissue destruction, preventing severe tissue damage. The strongest protective effect was achieved with NAC in combination with ATG at the highest concentrations (1000 gM / 500 gM). Under these conditions, a slight decrease in TEER was observed compared to the uninfected control, but tissue integrity was significantly stabilized, allowing the 3D cultures to remain within a healthy range.At the lower concentrations of the combination treatment (NAC 500 gM / ATG 250 gM and NAC 200 gM / ATG 100 gM), a similar protective effect was observed in a dose-dependent manner. Here, tissue integrity was significantly higher than in the infected control culture (viral control).

[0155] To determine the viral copy number in the supernatant of the DHBE tissue, quantitative RT-PCR was performed. Two days post-infection, the viral copy number in the infected but untreated state was slightly higher, without significant differences compared to the other treatments and consistent with observations from the TEER measurements (Figure 4, left). After five days, a significant reduction in viral copies was observed for ATG at a concentration of 500 gM, as well as for all combination treatments, in a dose-dependent manner (Figure 4, right). The combination treatment at the highest concentration (NAC 1000 gM / ATG 500 gM) showed the greatest reduction in viral copies, followed by ATG alone (500 gM). The lowest concentration of the combined treatment showed the smallest reduction.

[0156] Viral copy number determination does not allow for differentiation between active and replication-incompetent virus particles. Therefore, a viral plaque assay was introduced as a complementary method for quantifying active virus particles produced on the apical side of RSV-A-infected DHBE tissue (Figure 5). As early as two days post-infection, a marked and dose-dependent decrease in the number of active virus particles was observed compared to the viral control (Figure 5, left). The most efficient reduction was achieved with ATG / NAC at the highest concentration of 45.5%, closely followed by ATG alone at 43.5% (Figure 5, left). After five days, the number of active virus particles was significantly reduced with a relative inhibition of 79.0% after treatment with NAC 1000 gM and ATG 500 gM (Figure 5, right).The results showed that ATG alone at a concentration of 500 gM exhibited similar efficacy with a relative inhibition of 63.0%. The combination treatment for the two lower concentrations (NAC 500 pM and ATG 250 pM, NAC 200 pM and ATG 100 pM) followed a dose-dependent trend, resulting in relative inhibition of 35.5% and 15.0%, respectively.

[0157] To visualize viral infection and the protective effect following ATG and ATG / NAC treatment, immunofluorescence staining followed by confocal microscopy of DHBE tissue was performed 5 days after RSV-A infection (Figure 6). To determine cell number, location, and overall viability, a Hoechst stain, which stains the nucleus and is shown in blue, was used. Fluorophore-conjugated phalloidin (red) was also employed, which binds to actin filaments as part of the cytoskeleton, thus highlighting the characteristic cell morphology and structural elements of DHBE tissue. RSV antigens were stained green and appear as small, distinct spots for viral aggregates or as larger, intense areas in the cytoplasm of heavily infected cells (Figure 6).

[0158] The highest ATG / NAC concentration (500 pM, 1000 pM) showed the strongest antiviral effect and the ability to preserve tissue integrity compared to untreated virus control (Figure 6, virus only vs. NAC 1000 pM, ATG 500 pM, green). ATG 500 pM also showed high antiviral capacity and tissue protection, followed by the two combination treatments with lower ATG / NAC concentrations (Figure 6).

[0159] Scientific interpretation of the results:

[0160] Based on the results of the cytotoxicity tests, no cytotoxic effects were observed following repeated exposure to ATG at a concentration of 2000 pM or the combination of NAC and ATG at concentrations of 4000 pM and 2000 pM, as well as 2000 pM and 1000 pM. Furthermore, no significant cytotoxic effects were observed in 3D airway tissue culture models derived from cells of healthy individuals and those with CORD over a 10-day period with repeated treatment every 48 hours. This was confirmed by the LDH tests, as ATG or ATG / NAC treatments did not induce cell damage or cytotoxicity in either healthy or diseased tissue, and no significant changes were observed compared to tissue treated with D-PBS.

[0161] Using a human 3D airway model with COPD, the antiviral and protective properties of ATG or an ATG / NAC combination therapy were investigated in the context of RSV-A infection. An antiviral effect of ATG and a dose-dependent antiviral effect of NAC in combination with ATG were confirmed. The strongest antiviral capacity, as well as the ability to maintain tissue integrity, was observed for the combination of NAC and ATG at the highest concentration. ATG alone, followed by the combination therapy of NAC and ATG at concentrations of 500 ppm / 250 ppm and 200 ppm / 100 ppm, also significantly reduced tissue damage.

[0162] Furthermore, the combination of ATG and ATG / NAC showed a significant reduction in the number of virus copies detected in the apical supernatant of DHBE tissue five days post-infection. The highest efficacy against RSV-A infection was observed with the combination treatment at the highest concentration, resulting in an approximately 44-fold reduction in viral copies. Consistent with the reduced number of viral copies, the combination of 1000 pM NAC and 500 pM ATG showed the greatest reduction in active viral particles, reaching 79.0%.

[0163] These results were further visualized by immunofluorescence images, which are consistent with the overall picture obtained by TEER and LDH measurements, quantitative RT-PCR and virus plaque assays.

[0164] Example 2 - Effectiveness in SARS-CoV-2 infections

[0165] This example concerns the investigation of the neutralizing effect of aurothioglucose against the SARS-CoV-2 wild type, Delta and Omicron BA variants at different concentrations using a neutralization plaque assay.

[0166] Methods:

[0167] Neutralisation plaque assay

[0168] VeroE 6 / TMPRSS2 cells ( 2.5 x 10 5 The samples were placed in a 24-well plate with culture medium (DMEM High Glucose Medium supplemented with 10% FCS, 1% L-glutamine, 1% penicillin / streptomycin) and incubated overnight at 37 °C. The following day, SARS-CoV-2 wild type, Delta, or Omicron BA.l (5xl0) was tested. 3 PFU / ml) incubated with ATG alone or in combination with NAC for 1h at 37 °C.

[0169] After incubation, the cells were inoculated with each mixture for 1 hour at 37 °C and washed with D-PBS. They were then covered with a liquid overlay matrix (3% carboxymethylcellulose mixed in equal parts with MEM medium, supplemented with 10% FCS, 2% L-Glut, 2% NEAA, 1.5% sodium bicarbonate) and incubated for 72 hours at 37 °C. To visualize the plaques, the liquid overlay matrix was removed, the cells were washed, and fixed in 100 ml neutral buffered formaldehyde solution before being stained with 0.5% crystal violet solution for 15 minutes. After several washing steps, the plaques were scanned and analyzed using an ImmunoSpot® S6 ULTRA-V instrument (CTL Europe GmbH, Bonn, Germany). Relative neutralization was determined by counting the total number of plaques and then normalizing to the respective viral control.

[0170] Results :

[0171] The results of the neutralization plaque assay of SARS-CoV-2 wild type, Delta and Omicron BA.1 variant with or without ATG / NAC treatment are shown in Figure 7.

[0172] ATG exposure to SARS-CoV-2 wild type showed a dose-dependent neutralizing effect, ranging from 33.2% at 100 pM to 55% at 500 pM. Compared to ATG alone, the addition of NAC led to a slightly increased neutralization (Fig. 7A). Neutralization against the SARS-CoV-2 delta variant was less efficient at the two lower concentrations than against the wild type variant, but achieved higher overall neutralization at higher concentrations of ATG or ATG / NAC (Fig. 7B). For SARS-CoV-2 Omicron, an increase in neutralization with increasing ATG concentration was also observed, from 4.1% to 37.1% and finally to 69.9%. The addition of NAC led to a further increase to up to 77.7% neutralization capacity (Fig. 7C).

[0173] Scientific interpretation of the results: In this example, the neutralizing capacity of aurothioglucose against SARS-CoV-2 wild type, Delta and Omicron BA.l was investigated.

[0174] This study demonstrated that aurothioglucose, alone or in combination with N-acetylcysteine, exerts a dose-dependent neutralizing effect against all tested variants of SARS-CoV-2. This effect was mediated by ATG, while an enhanced effect was observed with the addition of NAC.

[0175] Example 3 - Efficacy in infections with influenza virus and Streptococcus pneumoniae

[0176] This example concerns the investigation of the antimicrobial efficacy of auroacetylcysteine ​​(AuNAC), aurothioglucose (ATG) and N-acetylcysteine ​​(NAC) against influenza A (H1N1), influenza B (Victoria Lineage) and Streptococcus pneumoniae.

[0177] The neutralizing capacity against influenza A and B was investigated using an immunofluorescence-based neutralization assay after 24 hours of treatment. Efficacy against S. pneumoniae was investigated by evaluating growth inhibition kinetics after 6 and 24 hours of treatment.

[0178] Effective against influenza virus:

[0179] VeroE6 / TMPRSS2 cells (2 x 10 4 ) were prepared in a 96-well plate with culture medium (DMEM High Glucose Medium, supplemented with 10% FCS, 1% L-glutamine, 1% penicillin / streptomycin) and incubated overnight at 37 °C. The following day, 5x0 3PFU / ml of influenza A (H1N1) and influenza B (Victoria lineage) were incubated with an antiviral substance as a positive control, as well as with AuNAC (1000 pM / 500 pM), ATG (500 pM), or NAC in combination with ATG at the following concentrations: 1000 pM / 500 pM, 500 pM / 250 pM for 1 h at 37 °C and 5% CO2. After incubation, the cells were inoculated with each mixture for 1 h at 37 °C and washed with D-PBS, which was then replaced with cell culture medium, which was again incubated for 16 h at 37 °C and 5% CO2. After incubation, the cells were washed and fixed in 4% neutral buffered formaldehyde solution before being permeabilized for 20 min at room temperature. To visualize the infected loci, the cells were stained for 1 hour at room temperature with a primary antibody against the viral hemagglutinin, followed by a secondary antibody coupled with an immunofluorescence tag (Alexa 488).After incubation with the secondary antibody, the cells were washed several times and the infected sites were scanned and analyzed using an ImmunoSpot® S6 ULTRA-V device (CTL Europe GmbH, Bonn, Germany). Relative neutralization was determined by counting the total number of infected loci and subsequently normalizing to the respective viral control.

[0180] The results of neutralization plaque assays of human influenza A (H1N1) or influenza B (Victoria lineage) with or without AuNAC, ATG or NAC / ATG treatment are shown in Figure 8.

[0181] ATG exposure to influenza A (H1N1) showed a neutralizing effect compared to the D-PBS-treated control, with 58.0% relative infection at 500 pM. Incubation of the virus with AuNAC resulted in a dose-dependent antiviral effect, with a relative infection of 53.4% ​​at 1000 pM and 71.0% at 500 pM. A similar dose-dependent effect was observed with the combination of NAC and ATG, ranging from 38.8% infection at the highest concentration (NAC 1000 pM / ATG 500 pM) to 68.2% infection at the lowest concentration (NAC 500 pM / ATG 250 pM). The antiviral control showed complete neutralization of the virus after 1 h of incubation (Figure 8A).

[0182] A similar pattern was observed in influenza B (Victoria lineage), with a slight overall decrease in antiviral efficacy. ATG at a concentration of 500 pM showed a relative infection of 66.7%. Similar to H1N1, a dose-dependent reduction in relative infection was observed for AuNAC, with 64.5% at 1000 pM and 81.0% at 500 pM. Again, the combination of NAC and ATG resulted in a substantial reduction compared to the D-PBS-treated control, with 66.1% relative infection for NAC 1000 pM / ATG 500 pM, followed by 77.9% for NAC 500 pM / ATG 250 pM, and 100% neutralization for the antiviral control treatment (Figure 8B). Efficacy against S. pneumoniae:

[0183] To ensure an exponential growth phase of S. pneumoniae, the bacteria were cultured for 15 hours at 37°C on Columbia blood agar plates. After 15 hours, approximately 10 colonies were harvested and transferred to 15 ml of pre-warmed tryptose-sodium bicarbonate broth (TSB). The cells were then incubated for a further 6 hours at 37°C on a shaker at 100 rpm, after which the density was determined using the MacFarland test. The bacterial cells were then harvested and tested to a concentration of 2 x 0. 10 CFU / ml diluted. For the standard, IxlO were used. 9 KFU 2-fold serially to a minimum concentration of 9.77 x 0 5 Cells were thinned. IxlO was used for the treatment. 8Cells were either left untreated or treated with 1000 units of penicillin and 100 ng / ml streptomycin as a positive control, or with 1000 pM and 500 pM AuNAC. The cells were then cultured at 37 °C and 5% CO2 for up to 24 hours with shaking at 300 rpm. To calculate growth inhibition, the optical density (OD) at 600 nm was measured immediately (0 h), after 6 h, and after 24 h using a Varioskan Lux (Thermo Fisher), and the CFU count was calculated at each time point using the standard curve from the initial time point. The data were normalized to the respective D-PBS control at each time point and set to 100%.

[0184] The results are shown in Figure 9. The antimicrobial efficacy of NAC and ATG showed a significant inhibitory effect on bacterial growth. The strongest antimicrobial effect was observed with 1000 pM AuNAC, with 47% growth after 6 hours and 19% growth after 24 hours compared to the D-PBS-treated control. Less concentrated AuNAC at 500 pM had a similar, albeit weaker, effect, with 54% growth after 6 hours and 35% after 24 hours. A very strong reduction was observed in the positive control with 1000 units of penicillin and 100 ng / ml streptomycin, with a relative growth of 12% after 6 hours and 0% after 24 hours.

[0185] Scientific interpretation of the results:

[0186] In this example, the neutralizing capacity of AuNAC, ATG, and NAC against influenza A (H1N1) and influenza B (Victoria lineage), as well as Streptococcus pneumoniae, was tested. The antiviral agent was hydrochloric acid. It was demonstrated that aurothioglucose alone, and especially in combination with N-acetylcysteine, exerts a neutralizing effect against influenza A and influenza B. The antiviral activity of AuNAC showed a dose-dependent antiviral effect similar to ATG alone, but less efficient than the combination of ATG and NAC at the same concentrations. Overall, influenza A was more susceptible to treatment with AuNAC, ATG, or ATG / NAC compared to influenza B.

[0187] The evaluation of the antimicrobial efficacy of AuNAC against Streptococcus pneumoniae revealed a time-dependent inhibition of bacterial growth for AuNAC at 1000 pM and 500 pM, with the strongest antimicrobial effect being observed at the higher concentration after 24 hours.

[0188] Example 4 - Efficacy in infections with RSV type A and type B

[0189] This example concerns the testing of the neutralization capacity of N-acetylcysteine ​​(NAC) and aurothioglucose (ATG) against respiratory syncytial virus type A using an immunofluorescence-based neutralization test.

[0190] Methods:

[0191] Immune fluorescence-based neutralization test

[0192] HEp-2 cells (2 x 10 4) were placed in a 96-well plate with culture medium (MEM medium supplemented with 10% FCS, 1% L-glutamine, 1% penicillin / streptomycin) and incubated overnight at 37°C. The following day, 5xl 0 3PFU / ml RSV (type A or B) was incubated with ATG (500 pM / 250 pM), NAC (1000 pM / 500 pM), or NAC in combination with ATG at the following concentrations: 1000 pM / 500 pM, 500 pM / 250 pM for 1 h at 37 °C and 5% CO2. An antiviral substance was additionally incubated with the virus and served as a positive control for this test. After incubation, HEp-2 cells were inoculated with each mixture for 1 h at 37 °C and washed with D-PBS, which was then replaced with cell culture medium after a further incubation of 72 h at 37 °C and 5% CO2. After incubation, the cells were washed and fixed in 4% neutral-buffered formaldehyde solution before being permeabilized at room temperature for 20 minutes.To visualize the infected loci, cells were stained for 1 hour at room temperature with a primary antibody targeting the viral glycoprotein, followed by a secondary antibody coupled to an immunofluorescence tag (Alexa 488). After incubation with the secondary antibody, the cells were washed several times, and the infected sites were scanned and analyzed using an ImmunoSpot® S6 ULTRA-V instrument (CTL Europe GmbH, Bonn, Germany). Relative neutralization was determined by counting the total number of infected loci and subsequently normalizing to the respective viral control.

[0193] Results :

[0194] The results of the neutralization plaque assay with human respiratory syncytial virus with or without treatment with NAC, ATG or NAC / ATG are shown in Figure 10.

[0195] Both ATG and NAC showed dose-dependent antiviral activity against RSV(A), resulting in relative neutralization rates of 60.2% (500 pM) to 45.3% (250 pM) and 67.5% (1000 pM) to 47.4% (500 pM), respectively. For RSV type B, the neutralization efficiency of ATG and NAC followed a similar pattern, ranging from 59.5% (500 pM) to 46.8% (250 pM), with a slightly reduced efficiency for NAC treatment, ranging from 59.8% (1000 pM) to 32.3% (500 pM) (Figure 10B). The combined treatment with ATG and NAC also showed dose-dependent antiviral neutralization, ranging from 70.8% (NAC 100 pM / ATG 500 pM) to 56.6% (NAC 500 pM / ATG 250 pM) for RSV type A (Figure 10A) and from 57.5% (NAC 100 pM / ATG 500 pM) to 42.3% (NAC 500 pM / ATG 250 pM) for RSV type B (Figure 10B). The overall neutralization efficiency against RSV type A was approximately 20% higher than against RSV type B.

[0196] Scientific interpretation of the results:

[0197] In this example, the neutralizing properties of ATG and NAC, as well as the combination treatment of ATG / NAC against RSV types A and B, were tested. It was demonstrated that aurothioglucose (ATG) alone and in combination with N-acetylcysteine ​​(NAC) exerts a strong neutralizing effect against both variants of the human respiratory syncytial virus. Example 5 - Preparation of a powder formulation and a ready-to-administer solution

[0198] A mixture consisting of 0.9 g aurothioglucose, 0.75 g N-acetylcysteine ​​and 0.5 g sodium bicarbonate is carefully homogenized for 10 minutes in a porcelain container and filled in 100 x 2 ml glass vials in a single quantity of 2 mg using a filling device (Drum TT - Harro Höfliger) and these are sealed with an inert rubber stopper after nitrogen purging.

[0199] To prepare a ready-to-administer solution, 2.5 mL of sterile water are added to a glass vial using a syringe to dissolve the powder formulation contained therein. The resulting solution can then be withdrawn again with a syringe for administration.

[0200] Example 6 - Therapeutic Treatment

[0201] Four COPD patients with acute RSV respiratory infection on mechanical ventilation will be administered two single doses of the ready-to-use solution, as described in Example 5, via a nebulizer per day for a period of 10 days.

Claims

39 Patent claims:

1. Medicinal product containing gold for use in the prevention or treatment of chronic obstructive pulmonary disease (COPD) with accompanying respiratory tract infection, wherein the medicinal product is administered by inhalation.

2. A medicament for use according to claim 1, wherein the medicament contains gold(I).

3. A medicament for use according to claim 1 or 2, wherein the medicament contains a gold-containing active ingredient, preferably selected from the group consisting of aurothioglucose, aurothiomalate, auranofin, aurothiosulfate, aurotioprol, aurothiopolypeptide, elemental gold and / or a gold salt.

4. A pharmaceutical product for use according to any one of claims 1 to 3, wherein the pharmaceutical product further contains N-acetylcysteine.

5. A medicament for use according to claim 4, wherein the medicament contains gold, in particular in the form of 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).

6. A pharmaceutical product for use according to any one of claims 1 to 5, wherein the pharmaceutical product further comprises at least one further active ingredient selected from the groups of muscarinic antagonists, beta-2 agonists and PDE-4 inhibitors, preferably wherein the further active ingredient is selected from the group consisting of ipratropium, aclidinium, glycopyrronium, R, R-glycopyrrolate, umeclidinium, tiotropium, salbutamol, fenoterol, orciprenaline, pirbuterol, procaterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, indacaterol, olodaterol, vilanterol, roflumilast and cilomilast.

7. Pharmaceutical for use according to any one of claims 1 to 10 40 6, wherein the medicinal product contains a carrier substance, preferably a carbohydrate, particularly preferably lactose and / or mannose.

8. Medicinal product for use according to any one of claims 1 to 7 , wherein the medicinal product is in the form of a powder formulation, preferably micronized, or as a solution or as an aerosol .

9. Medicinal product for use according to any one of claims 1 to 8 , wherein the application is carried out by inhalation, preferably liquid inhalation or powder inhalation .

10. Medicinal product for use according to any one of claims 1 to 9 , wherein the medicinal product is administered using an inhaler, preferably a powder inhaler, metered-dose inhaler or nebulizer .

11. Medicinal product for use according to any one of claims 1 to 10, where the COPD is an exacerbated COPD.

12. Medicinal product for use according to any one of claims 1 to 11, the accompanying respiratory infection being a pulmonary infection.

13. Medicinal product for use according to any one of claims 1 to 12 , where the accompanying respiratory infection is a viral and / or bacterial infection .

14. Medicinal product for use according to any one of claims 1 to 13 , wherein the accompanying respiratory infection is an infection caused by a virus selected from the group consisting of Respiratory Syncytial Virus (RSV), Coronavirus, Rhinovirus, Influenza Virus, Parainfluenza Virus, Metapneumovirus and / or Adenovirus, in particular RSV.

15. A method for producing a ready-to-administer solution of a medicament containing gold, preferably as defined in any one of claims 1 to 14, comprising the following 41 Steps: - Filling a powder formulation containing a gold-containing active ingredient into a container, wherein the filling preferably takes place under a protective gas atmosphere; - Storing the powder formulation in the container; - Addition of an aqueous liquid to the container, thereby dissolving the powder formulation and producing a ready-to-administer solution of the medicinal product; preferably wherein a single dose of the powder formulation is filled into the container.

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