Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of rare chronic inflammatory lung diseases

Abstract

The present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the treatment of rare chronic inflammatory lung diseases. The present invention particularly relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purpose.

Description

[Technical Field]

[0001] The present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof in the treatment of rare chronic inflammatory lung diseases. The present invention particularly relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purpose. [Background technology]

[0002] Pulmonary diseases encompass a wide range of disorders of the lower respiratory tract of the respiratory system, particularly the lungs. While pharmaceutical treatments are available for common lung diseases such as pneumonia, asthma, and chronic obstructive pulmonary disease (COPD), a wide range of rare chronic lung diseases exist for which effective drugs have not yet been developed or for which drugs are not very effective. Due to economic prospects, these rare diseases are not the focus of the pharmaceutical industry. Therefore, there is a medical need to provide drugs for the treatment of these rare chronic lung diseases to patients in need. Most of these rare chronic lung diseases are classified under ICD-10 Chapter X: Diseases of the Respiratory System (J00-J99), Version 2016, as of January 10, 2020.

[0003] The terms rare disease and orphan disease are often used interchangeably. However, rare disease refers rather to the epidemiological prevalence of a disease in a population. Orphan disease refers to the regulatory classification of a disease by the respective medical organization. An orphan disease must be rare, and no effective medicines are available due to a lack of economic incentives for the pharmaceutical industry (see U.S. Orphan Drug Act; European Organization for Rare Disorders (EURORDIS)).

[0004] The term prevalence refers to the overall proportion of the population that is affected by this particular disease. The term prevalence refers to the number of new cases of this particular disorder over the course of a year.

[0005] The frequency of such classifications may vary between countries, regions, and ethnic groups. Frequency may also change over time. For example, the European Union requires a prevalence of 1:2000 or less, while the United States requires an incidence of 1:1500 or less, and Japan requires an incidence of 1:2500 or less. Therefore, within the scope of this application, the term rare disease(s) refers to a global prevalence of 1:1500 or less.

[0006] The term pulmonary disease(s) encompasses pathological conditions that impair gas exchange in the lungs or bronchi of mammals. Generally, they are distinguished into obstructive and restrictive pulmonary diseases. Obstructive pulmonary diseases are characterized by airway obstruction, which limits the amount of air that can enter the alveoli due to narrowing of the bronchial tree caused by inflammation. Restrictive pulmonary diseases are characterized by a loss of lung compliance, leading to incomplete lung expansion and increased lung stiffness.

[0007] They can also be classified as airway diseases, lung tissue diseases, lung infections, and lung proliferative diseases. Airway diseases affect the tubes that carry oxygen and other gases in and out of the lungs. They usually cause narrowing or obstruction of the airways. Typical airway diseases include asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis. Lung tissue diseases affect the structure of lung tissue. Tissue scarring or inflammation prevents the lungs from fully expanding, complicating gas exchange. As a result, these patients are unable to breathe deeply. Pulmonary fibrosis and sarcoidosis are typical examples. Lung infections refer to disorders caused by infection of the lower respiratory tract, such as pneumonia. Lung proliferative diseases include all tumors or neoplasms of the lower respiratory tract.

[0008] Most airway diseases are caused by underlying inflammation or at least include an inflammatory component. Lung tissue diseases often also have an inflammatory component, unless caused by direct physical obstruction of the airways. Infectious and proliferative diseases of the lung may also have an inflammatory component, often secondary to infection or underlying malignancy.

[0009] Therefore, these inflammatory lung diseases have in common that they can be pharmacologically treated with anti-inflammatory drugs. Although there are established medicines for the treatment of acute inflammatory lung diseases, such as bacterial and viral infections, and tumors, there remains a need for pharmaceutical treatments for chronic inflammatory lung diseases, especially for rare diseases in this group.

[0010] Therefore, there is a medical need to find highly effective pharmaceutical agents for the treatment of rare chronic inflammatory lung diseases.

[0011] Surprisingly, this problem is solved by the administration of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts or solvates, hydrates, crystalline polymorphs, tautomers or isotopically enriched forms. DETAILED DESCRIPTION OF THE INVENTION

[0012] 5-Amino-2,3-dihydro-1,4-phthalazinedione belongs to the pharmaceutical class of phthalazinedione. This class of compounds is known for its beneficial anti-inflammatory properties. 5-Amino-2,3-dihydro-1,4-phthalazinedione is also known as luminol. Luminol has excellent chemiluminescent properties. It is widely used in diagnostic assays and forensics as a detection tool, for example, for tracing blood spots. In medicine, 5-amino-2,3-dihydro-1,4-phthalazinedione has been developed in the form of its sodium salt. In several countries, 5-amino-2,3-dihydro-1,4-phthalazinedione, for example (ao), is approved for a wide range of acute and chronic inflammatory disorders, including acute infections of bacterial and viral origin, especially of the intestinal tract, hepatitis B and C, gastroenteritis, prostatitis, endometriosis, inflammation of the throat, bronchial asthma, pneumonia, periodontitis, pyelonephritis, and autoimmune diseases such as Crohn's disease, ulcerative colitis, lupus erythematosus, and scleroderma. Furthermore, the scientific and patent literature continues to contain a long list of therapeutic indications for which 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has allegedly been tested or has been suggested to be of beneficial use (see, e.g., (ao), WO 2004 / 041169; WO 2007 / 018546; WO 2012 / 127441; WO 2017 / 202496; WO 2018 / 082814).

[0013] While most conventional immunomodulatory drugs have serious adverse reactions or are at least problematic with long-term treatment, 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts are well tolerated and have a high margin of safety relative to the doses administered.

[0014] To ensure better solubility and bioavailability, pharmaceutically acceptable salts of 5-amino-2,3-dihydro-1,4-phthalazinedione are used. Sodium, potassium, and lithium salts have been described for therapeutic use (see WO 2010 / 082858). The crystal structures of lithium, sodium, potassium, rubidium, and cesium salts are described in Guzei et al. (2013) Journal of Coordination Chemistry 66, 3722-3739. Therefore, this patent application also refers to the use of all pharmaceutically acceptable salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0015] 5-amino-2,3-dihydro-1,4-phthalazinedione is often used as a hydrate, for example, the sodium salt dihydrate. Therefore, this patent application also refers to the use of all hydrates and other solvates of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts can form a complex with a suitable ligand. Therefore, this patent application also refers to such complexes.

[0016] Accordingly, the present application relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory lung diseases, the global prevalence of which is less than or equal to 1:1500. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.

[0017] In particular, the present disclosure also refers to a global prevalence of 1:1700 or less, or 1:2000 or less, or 1:2500 or less, or 1:3000 or less, or 1:4000 or less, or 1:5000 or less, or 1:6000 or less, or 1:7000 or less, or 1:8000 or less, or 1:9000 or less, or 1:10000 or less.

[0018] Alternatively, the present disclosure also refers to a global prevalence in the range of 1:1500 to 1:2,000,000, or 1:1700 to 1:2,000,000, or 1:2,000 to 1:2,000,000, or 1:2500 to 1:2,000,000, or 1:3,000 to 1:2,000,000, or 1:4,000 to 1:2,000,000, or 1:5,000 to 1:2,000,000, or 1:6,000 to 1:2,000,000, or 1:7,000 to 1:2,000,000, or 1:8,000 to 1:2,000,000, or 1:9,000 to 1:2,000,000, or 1:10,000 to 1:2,000,000.

[0019] Anhydrous formulations are often preferred to ensure reproducible, standardized API manufacturing and provide improved stability characteristics of the active agent. The anhydrous forms of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt are described as crystalline polymorphs in WO 2011 / 107295 (Form I, Form II) and WO 2016 / 096143 (Form III). These polymorphs are substantially free of phase impurities and have been characterized by X-ray powder diffraction. This method yields a set of characteristic d-values, which indicate the interplanar spacing (Å) at which Bragg reflections occur and the corresponding 2-theta (2θ) angles (°). This provides a unique and unambiguous fingerprint for each polymorph.

[0020] For Form I, the following values ​​were determined: d-value: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or 2θ values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3.

[0021] Form II is characterized by the following values: d-value: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or 2θ values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8.

[0022] Form III gave the following values: d values: 13.131; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283; 3.222; 3.215; 3.127; 2.889 and / or 2θ values: 6.73; 11.07; 12.31; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.93.

[0023] 5-amino-2,3-dihydro-1,4-phthalazinedione itself also exhibits polymorphism: Form I (Paradies (1992) Ber. Bunsen-Ges. Phys. Chem 96:1027-1031) and Form II (WO 2017 / 140430) have been disclosed.

[0024] Therefore, the present patent application also refers to the use according to the invention of all crystalline forms of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and of its polymorphs.

[0025] Similar therapeutic effects are known for various phthalazinediones and their pharmaceutically acceptable salts, which are derivatives of 5-amino-2,3-dihydro-1,4-phthalazinedione. One example is 6-amino-2,3-dihydrophthalazine-1,4-dione (isoluminol). A summary of suitable phthalazinediones is given in WO 2007 / 018546. It is reasonable to assume that these compounds will exhibit similar effects when used in therapeutic applications according to the present invention.

[0026] Tautomerism refers to the rapid internal transformation of organic compounds in which a hydrogen atom or proton formally migrates to the interior of the compound. This involves switching a single bond and an adjacent double bond. A single form is called a tautomer. For example, keto-enol tautomerism occurs in 5-amino-2,3-dihydro-1,4-phthalazinedione (Proescher and Moody (1939) J Lab Clin Med, 1183-1189). Therefore, this patent application also refers to the use of all tautomers of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts.

[0027] Isomers are a general term for molecules with the same chemical formula but different chemical structures. They can be distinguished into constitutional (structural) isomers (atom or functional group exchanges) and stereoisomers. Stereoisomers can be further divided into enantiomers (non-superimposable mirror images of the same molecule) and diastereomers (the same molecule with different configurations at one or more stereocenters). Diastereomers can be further divided into cis / trans isomers (referring to the relative orientation of functional groups within a molecule), as well as conformational isomers (formally rotations around a single bond) and rotamers (different rotational configurations around a single bond). An example of a constitutional isomer of 5-amino-2,3-dihydro-1,4-phthalazinedione is 6-amino-2,3-dihydrophthalazine-1,4-dione (isoluminol). Stereoisomers of phthalazinedione derivatives can exist. Therefore, this patent application also refers to the use of all isomers of 5-amino-2,3-dihydro-1,4-phthalazinedione, its derivatives, and pharmaceutically acceptable salts.

[0028] In some applications, it may be desirable to use isotopically enriched forms of the compounds of the invention, for example for diagnostic purposes, and therefore the present patent application also refers to such isotopically enriched forms of the compounds of the invention.

[0029] From a pharmacokinetic point of view or for manufacturing rationale, it may be preferable to use a prodrug as a dosage form. A prodrug is administered in a pharmacologically inactive form and is converted in the body into a metabolically active form. This conversion can occur systemically or locally. Therefore, this patent application also refers to prodrugs of the compounds of the present invention.

[0030] As used throughout this application, the term "5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts" is intended to encompass 5-amino-2,3-dihydro-1,4-phthalazinedione, i.e., all the aforementioned molecular variants of 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharmaceutically acceptable salts, or solvates, hydrates, crystalline polymorphs, tautomers or isotopically enriched forms.

[0031] Unless otherwise defined, technical or scientific terms used herein have the meanings ascribed to them by one of ordinary skill in the relevant art.

[0032] According to this application, the terms "drug substance," "active substance," "active agent," "pharmaceutically active agent," "active ingredient," or "active pharmaceutical ingredient" (API), when not otherwise specified or used in their generic sense, refer to 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof.

[0033] The term "composition" or "pharmaceutical composition" includes at least one active ingredient in any pharmacologically acceptable defined dosage and dosage form together with at least one pharmaceutically acceptable excipient, as well as any pharmaceutical agent produced directly or indirectly from the ingredients outlined below, as a combination, accumulation, complex or crystal, or as a result of other reaction or interaction, optionally together with at least one additional pharmaceutical agent listed below.

[0034] The term "excipient" is used herein to describe any component of a pharmaceutical composition other than the pharmaceutically active principle. The selection of an appropriate excipient depends on various factors, such as the dosage form, dosage, desired solubility and stability of the composition, etc.

[0035] The terms "effect," "therapeutic effect," "action," "therapeutic action," "efficacy," and "effectiveness," with respect to a substance of the invention or any other active substance referred to herein, refer to a beneficial result that occurs causally in an organism to which the substance has previously been administered.

[0036] According to the present invention, the terms "effective amount" and "therapeutically effective amount" refer to an amount of a substance of the present invention that is large enough to cause the desired beneficial effect in a subject in need of such treatment.

[0037] The terms "treatment" and "therapy" include the administration of at least a substance of the invention alone or in combination with at least one additional pharmaceutical agent, regardless of the chronological order of administration. Such administration is intended to substantially improve the disease course of chronic inflammatory lung diseases with a global prevalence of 1:1500 or less, either by completely curing the disease or by halting or slowing the progression of damage during the course of the disease.

[0038] The terms "prevention" or "prophylactic treatment" include the administration of at least a substance of the invention, alone or in combination with at least one further pharmaceutical agent, regardless of the chronological order of administration, in order to prevent or inhibit the onset of symptoms resulting from chronic inflammatory lung diseases having a worldwide prevalence of 1:1500 or less. It particularly refers to a condition in a patient in which such an onset of symptoms is expected with a reasonable probability to occur in the distant or near future.

[0039] The terms "subject" and "patient" include individuals suffering from a disease condition or disorder associated with chronic inflammatory lung disease with a global prevalence of 1:1500 or less, whether the diagnosis is confirmed or suspected. The individual is a mammal, particularly a human.

[0040] For the purposes of this application, the term "medicine" is intended to include human and veterinary medicine.

[0041] In the context of this patent application, the term "inflammatory disease" or "inflammatory lung disease" refers to a disease, disorder, or other physical condition that manifests itself primarily in pulmonary inflammation. Inflammation is the response of bodily tissues to a stimulus (exogenous or endogenous pathogen) or injury. It can be triggered by physical, chemical, and biological stimuli, including, inter alia, mechanical trauma, radiation damage, caustic chemicals, extreme heat or cold, and infectious agents such as bacteria, viruses, fungi, and other pathogenic microorganisms or parts thereof. Inflammation can have beneficial (e.g., within the scope of wound healing) and / or harmful effects in the affected tissue(s). In the first stage, inflammation is considered acute. If it does not resolve after a period of time, inflammation can become chronic. Typical signs of inflammation are redness, swelling, fever, pain, and decreased function. This can even lead to loss of function in the affected tissue.

[0042] Inflammation is one of the first responses of the immune system, for example, when activated by infected or degenerated endogenous cells. The innate immune system mediates nonspecific responses, particularly general inflammatory responses, while the adaptive immune system provides specific responses to each pathogen, which are then memorized by the immune system. An organism may be in an immunodeficient state, i.e., the immune response cannot satisfactorily cope with the aforementioned stimuli or damage. On the other hand, the immune system may become overactive, altering the defense against endogenous tissues, as in the case of autoimmune diseases.

[0043] In the context of this patent application, the term "degenerative disease" or "degenerative lung disease" refers to a disease, disorder, or other physical condition in which a continuous process leads to degenerative cellular changes. The affected tissue or organ continuously deteriorates over time. Such degeneration can be due to physical or physiological overexertion of certain vulnerable body structures, lifestyle, dietary habits, age, congenital diseases, or other endogenous causes. The degeneration can be caused by or accompanied by atrophy or dystrophy of the respective tissue or organ, especially the lung. In many cases, loss of function and / or irreversible damage to the affected tissue or organ occurs.

[0044] In the sense of this patent application, the terms "lesion," "microlesion," and "trauma" refer to damage of different sizes and extents in the affected lung tissue. They can be caused by spontaneous physical impacts, where impact or rotational forces result in tissue damage. However, they can also be the final result of a previous degenerative disease of the affected lung tissue, or conversely, a microlesion can be the starting point of such a degenerative disease that follows the microlesion. Also, inflammation of the affected lung tissue can be favorable to such microlesions or trauma, or can be their sequelae. Therefore, these terms are interrelated with inflammation and degenerative disease.

[0045] In the sense of this patent application, the term "primary" disease, as for example "primary inflammatory or degenerative disease", refers to a lung disease that is not autoimmune mediated.

[0046] If it is known that a healthy individual suffers from or is susceptible to an inflammatory or degenerative disease, or that tissue damage is expected due to a certain excessive strain on the respective tissue or organ, it may be indicated to administer a prophylactic agent to prevent or at least alleviate the expected injury or damage. Therefore, the present patent application also refers to the prophylactic use according to the present invention.

[0047] Inflammatory lung diseases may also lead to degenerative diseases. Therefore, further examples are provided below. Therefore, the present patent application refers to the use according to the present invention in the prevention or treatment of inflammatory and / or degenerative lung diseases, in particular in the treatment of primary inflammatory and / or degenerative lung diseases.

[0048] Within the scope of this application, the term "pulmonary" refers to organs and tissues of the lower respiratory tract. Examples of organs and tissues of the lower respiratory tract include, but are not limited to, the lungs, including the lobes, apex, ligules, and alveoli; the bronchi, including the respiratory bronchioles; the tracheal and bronchial rings (including the carina); the pulmonary and bronchial vessels, including the pulmonary and bronchial vessels; the bronchopulmonary lymph nodes; and the pulmonary autonomic nervous system.

[0049] Within the scope of this application, "pulmonary" also refers to adjacent organs and tissues that are functionally or structurally closely related to the lower respiratory tract and / or thorax and therefore have excellent pharmaceutical accessibility via inhalation. Examples include, but are not limited to, the pleura and diaphragm.

[0050] Within the scope of this application, the terms "alveoli" and "alveolar" refer to the tissue structures at the base of the pulmonary airways. Alveoli are hollow, cup-shaped cavities found in the lung parenchyma where gas exchange takes place. They are sparsely located on the respiratory bronchioles, line the walls of the alveolar ducts, and are more numerous in the blind-ended alveolar sacs. The alveolar membrane is the gas exchange surface surrounded by a network of capillaries. Oxygen diffuses across the membrane into the capillaries, and carbon dioxide is released from the capillaries into the alveoli to be exhaled. Alveoli consist of an epithelial layer of simple squamous epithelium and an extracellular matrix surrounded by capillaries. The epithelial lining is part of the alveolar membrane, also known as the respiratory membrane.

[0051] Type I and type II pneumocytes are found in the walls of the alveoli. Alveolar macrophages are immune cells that move within the alveolar lumen and the connective tissue between them. Type I cells are squamous epithelial cells, thin and flat, that form the structure of the alveoli. Type II cells (goblet cells) release pulmonary surfactant to reduce surface tension.

[0052] A typical paired human lung contains approximately 300 million alveoli and 70 m 2 Each alveolus is surrounded by a fine mesh of capillaries that cover approximately 70% of its area. The diameter of a typical healthy alveolus is 200-500 μm.

[0053] There is no generally accepted time limit for when a disease, respectively its symptoms, must be considered chronic. In the art, this time point varies, ranging from 4 weeks to 6 months. A good compromise is 3 months (see Bernell and Howard (2016) Frontiers in Public Health 4:159). Therefore, within the scope of this application, the term chronic refers to a disease, respectively symptoms, that persist for more than 3 months. The term chronic also encompasses chronic relapsing diseases, respectively recurrent diseases. It further encompasses chronic progressive diseases.

[0054] Furthermore, there are inflammatory lung diseases or conditions that begin with a strong acute phase but have the risk of becoming chronic, either idiopathic or due to the lack of effective treatment. At the start of pharmaceutical treatment, it is not possible to predict whether acute treatment will be sufficient or whether permanent treatment will be required. An example of such a disease is postoperative inflammatory lung disease according to the present invention, for example, after lung surgery. Within the scope of this application, this group of diseases is considered to be included in the class of chronic inflammatory lung diseases.

[0055] In Example 1, ex vivo mouse lungs were exposed to cigarette smoke for 5 minutes. Cigarette smoke is known to contain numerous cytotoxic agents, resulting in a dramatic intracellular increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS) in affected lung tissue (a.o.). ROS / RNS are known to cause multiple cell damages, such as radical formation of additional cellular molecules, peroxide formation, lipid peroxidation, damage to cell and intracellular membranes, DNA damage, undesirable protein modifications, and induction of apoptosis. On the other hand, they are important mediators for initiating immune responses that help cells, tissues, or entire organisms deal with xenobiotics (e.g., toxins derived from cigarette smoke) and infection. The problem is an overshoot of the immune response, which causes the aforementioned symptoms of acute or chronic inflammation. Therefore, reducing excessive intracellular ROS / RNS levels is generally recognized as a promising approach for anti-inflammatory therapy, particularly for inflammatory lung diseases. Therefore, the ex vivo lung model used in Example 1 not only demonstrates therapeutic efficacy in cigarette smoke-induced lung diseases such as COPD, but also in all inflammatory lung diseases.

[0056] Administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt to the cigarette smoke-stimulated mouse lungs showed a dose-dependent reduction in ROS / RNS levels to control levels before cigarette smoke exposure, demonstrating that 5-amino-2,3-dihydro-1,4-phthalazinedione, and particularly 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, has great potential for preventive and therapeutic efficacy in inflammatory lung diseases.

[0057] Chronic inflammatory lung diseases with a global prevalence of 1:1500 or less can be classified as follows:

[0058] a) Chronic lower respiratory tract disease These diseases include, but are not limited to, bronchiectasis; alveolar microlithiasis.

[0059] b) Pulmonary diseases caused by external agents These diseases include, but are not limited to, coal workers' pneumoconiosis; asbestosis; talc dust pneumoconiosis; silicosis; aluminum lung disease; bauxite pulmonary fibrosis; beryllium lung disease; graphite pulmonary fibrosis; iron deposition disease; tin deposition disease; other specified inorganic dust pneumoconiosis; unspecified pneumoconiosis; pneumoconiosis associated with tuberculosis; byssinosis; linen wear disease; hemp fibrosis; other specified organic dust respiratory tract disease; farmer's lung; sugarcane lung disease; poultry farmer's disease; cork lung; malt worker's lung; mushroom grower's lung; maple bark processor's lung; air-conditioning and humidifier lung; cheesemaker's lung; coffee worker's lung; fishmeal-worker's lung; furrier's lung Includes other organic dust hypersensitivity pneumonitis such as allergic alveolitis and hypersensitivity pneumonitis; unspecified organic dust hypersensitivity pneumonitis such as allergic alveolitis and hypersensitivity pneumonitis; respiratory conditions due to inhalation of chemicals, gases, smoke, and vapors; solid and liquid pneumonitis; radiation pneumonitis; post-irradiation pulmonary fibrosis; acute drug-induced interstitial lung disorder; chronic drug-induced interstitial lung disorder; drug-induced interstitial lung disorder (unspecified); respiratory conditions due to other specified external agents; and respiratory conditions due to unspecified external agents.

[0060] c) Respiratory diseases that primarily affect the interstitium These diseases include, but are not limited to, pulmonary permeability fluid; high altitude pulmonary edema; eosinophilic asthma; Löffler's pneumonia; tropical pulmonary eosinophilia; alveolar and alveolar surface conditions; Hamman-Rich syndrome; other specified interstitial lung diseases; and unspecified interstitial lung diseases.

[0061] d) Suppuration and / or necrosis of the lower respiratory tract These diseases include, but are not limited to, lung abscesses with pneumonia, pneumothorax.

[0062] e) Pleural disease These conditions include, but are not limited to, pleural plaques; pneumothorax; chylothorax; fibrothorax; hemothorax; hemopneumothorax; hydrothorax; and pleural conditions (unspecified).

[0063] f) Postoperative or related lower respiratory tract illness These conditions include, but are not limited to, chronic pulmonary dysfunction after surgery; host-versus-graft disease after lung transplantation; graft-versus-host disease after lung transplantation; chronic pulmonary allograft dysfunction (CLAD), chronic pulmonary allograft dysfunction-bronchiolitis obliterans syndrome (CLAD-BOS); pulmonary ischemia-reperfusion injury; primary graft dysfunction after lung transplantation; Mendelsohn's syndrome; other postoperative respiratory disorders; postoperative respiratory disorders (unspecified); respiratory failure (not elsewhere classified); bronchial disease (not elsewhere classified); lung collapse; atelectasis; interstitial emphysema; mediastinal emphysema; compensated emphysema; mediastinitis; and diaphragmatic disorders.

[0064] g) Perinatal-specific lung diseases These diseases include, but are not limited to, transient tachypnea of ​​the newborn; congenital pneumonia due to viral agents; congenital pneumonia due to Chlamydia; congenital pneumonia due to Staphylococcus; congenital pneumonia due to Streptococcus group B; congenital pneumonia due to Escherichia coli; congenital pneumonia due to Pseudomonas; congenital pneumonia due to Haemophilus influenzae, Klebsiella pneumoniae, and other pathogens. pneumoniae, Mycoplasma, non-group B streptococci; congenital pneumonia due to other organisms; unspecified congenital pneumonia; neonatal meconium aspiration; perinatal pulmonary interstitial emphysema; perinatal pneumothorax; perinatal emphysema mediastinum; other conditions associated with perinatal interstitial emphysema; perinatal pulmonary hemorrhage; Wilson-Mikity syndrome; and perinatal unspecified chronic respiratory disease.

[0065] In particular, the present application relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory lung diseases by inhalation administration, said chronic inflammatory lung diseases being selected from the group of chronic lower respiratory tract diseases, lung diseases due to external agents, respiratory diseases mainly affecting the interstitium, suppurative and / or necrotic conditions of the lower respiratory tract, pleural diseases, post-operative or related lower respiratory tract diseases, and perinatal-specific lung diseases.

[0066] In particular, the present application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory lung diseases, which are chronic lower respiratory tract diseases.

[0067] In particular, the present application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory pulmonary diseases, which are pulmonary diseases caused by external agents.

[0068] In particular, the present application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory lung diseases, which are respiratory diseases that primarily affect the interstitium.

[0069] In particular, the present application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory lung diseases, which are suppurative and / or necrotic conditions of the lower respiratory tract.

[0070] In particular, the present application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory lung diseases, wherein the chronic inflammatory lung diseases are pleural diseases.

[0071] In particular, the present application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory lung disease, which is post-operative or related lower respiratory tract disease.

[0072] In particular, the present application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory lung disease, which is a perinatal-specific lung disease.

[0073] In particular, the disclosure refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence of 1:1500 or less, including bronchiectasis, alveolar microlithiasis, coal workers' pneumoconiosis, asbestosis, talc dust pneumoconiosis, silicosis, aluminum lung disease, bauxite pulmonary fibrosis, beryllium lung disease, graphite pulmonary fibrosis, iron deposition disease, tin deposition disease, tuberculosis-associated pneumoconiosis, assassination, linen wear disease, hemp fibrosis, farmer's lung, sugarcane lung disease, bird farmer's disease, cork lung, malt worker's lung, mushroom grower's lung, maple bark processor's lung, air-conditioning lung disease, humidifier lung, cheesemaker's lung, coffee worker's lung, fishmeal-worker's lung, furrier's lung, and the like. lung, sequiosis, allergic alveolitis, hypersensitivity pneumonitis, respiratory conditions due to inhalation of chemicals, gases, smoke, and vapors, solid and liquid pneumonitis, radiation pneumonitis, post-irradiation pulmonary fibrosis, chronic drug-induced interstitial lung disease, pulmonary permeability fluid, high-altitude pulmonary edema, eosinophilic asthma, Loffler's pneumonia pneumonia, tropical pulmonary eosinophilia, alveolar and mural alveolar conditions, Hamman-Rich syndrome, pulmonary abscess with pneumonia, empyema, pleural plaque, pneumothorax, chylous exudate, fibrothorax, hemothorax, hemopneumothorax, hydrothorax, chronic pulmonary dysfunction after surgery, host-versus-graft disease after lung transplantation, graft-versus-host disease after lung transplantation, chronic pulmonary allograft dysfunction, chronic pulmonary allograft dysfunction-bronchiolitis obliterans syndrome, pulmonary ischemia-reperfusion injury, primary graft dysfunction after lung transplantation, Mendelsohn's syndrome, lung collapse, atelectasis, interstitial emphysema, mediastinal emphysema, compensated emphysema, mediastinitis, diaphragmatic disorders, transient tachypnea of ​​the newborn, congenital pneumonia caused by viral agents, congenital pneumonia caused by chlamydia, congenital pneumonia caused by Staphylococcus, group B streptococcus B) congenital pneumonia, Escherichia coli congenital pneumonia, Pseudomonas congenital pneumonia, Haemophilus influenzae congenital pneumonia, Klebsiella pneumoniapneumoniae, congenital pneumonia caused by Mycoplasma, neonatal meconium inhalation, perinatal pulmonary interstitial emphysema, perinatal pneumothorax, perinatal pneumomediastinum, perinatal pulmonary hemorrhage, and Wilson-Mikity syndrome.

[0074] Bronchiectasis is also of particular interest within the scope of this application. Bronchiectasis is considered an idiopathic disease. Morphologically, it is characterized by permanent enlargement of a segment of the lower respiratory tract. Pathological conditions considered include, for example, post-infectious, immunodeficiency, exaggerated immune response, congenital anomalies, inflammatory pneumonia, fibrosis, and mechanical obstruction. Symptoms include chronic cough with daily mucus production. Therefore, it resembles cystic fibrosis, but without the characteristic genetic mutation. Pulmonary function test results generally show airflow obstruction ranging from moderate to severe. Additional symptoms include dyspnea, coughing up blood, chest pain, hemoptysis, fatigue, and weight loss.

[0075] Treatment of bronchiectasis aims to control infection and bronchial secretions, relieve airway obstruction, and remove affected lung segments through surgery or arterial embolization. Antibiotics, particularly macrolide antibiotics, are administered as needed. Excessive mucus production can be addressed with mucolytics. Bronchodilators are used to facilitate breathing. Continuous inhaled corticosteroids reduce phlegm production, decrease airway narrowing, and provide some protection against disease progression.

[0076] Therefore, the present application also refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the prevention or treatment of bronchiectasis.

[0077] A typical chronic inflammatory disease caused by external agents, with a global prevalence of 1:1500 or less, is beryllium pulmonary disease (interchangeably referred to herein as chronic beryllium disease, CBD). There is no cure for this occupational disease; only symptomatic treatment is available.

[0078] Prolonged exposure via inhalation can sensitize the lungs to beryllium, leading to the development of small inflammatory nodules called granulomas. Typically, CBD granulomas are not characterized by necrosis and therefore do not have a caseous appearance. Ultimately, this process leads to a decrease in the lung's diffusing capacity. Typical symptoms are cough and difficulty breathing. Other symptoms include chest pain, joint pain, weight loss, and fever. The patient's T cells become sensitized to beryllium. A pathological immune response leads to the accumulation of CD4+ helper T lymphocytes and macrophages in the lungs, where they aggregate together to form granulomas. Ultimately, this leads to pulmonary fibrosis. Treatment options include oxygen administration and oral corticosteroids.

[0079] Therefore, the present application also refers to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the prevention or treatment of beryllium pulmonary disease.

[0080] Chronic lung allograft dysfunction is also of particular interest within the scope of this application. Chronic lung allograft dysfunction (CLAD), and respectively chronic lung allograft dysfunction-bronchiolitis obliterans syndrome (CLAD-BOS), are major problems in the long-term management of lung transplant recipients. Both alloimmune-dependent (rejection) and alloimmune-independent factors contribute to the development of CLAD. It encompasses all forms of chronic pulmonary function decline after exclusion of known causes (persistent acute rejection, infection, anastomotic stenosis or disease recurrence, pleural disease, diaphragmatic insufficiency, or native lung hyperinflation). Thus, it is a heterogeneous entity in which two major phenotypes have currently been identified: bronchiolitis obliterans syndrome (BOS) (defined by a persistent decline in FEV1) and an obstructive functional pattern.

[0081] There is currently no treatment available to reverse CLAD after diagnosis. Pharmacological treatment of symptoms involves azithromycin (first-line treatment) or montelukast. In treatment-resistant cases, photopheresis is indicated.

[0082] Therefore, the present application also refers to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the prevention or treatment of CLAD, respectively CLAD-BOS.

[0083] Pulmonary edema is also of particular interest within the scope of this application. Pulmonary edema can have different causes. Fluid accumulation occurs in the tissues and air spaces of the lungs, leading to impaired gas exchange and, in the worst cases, respiratory failure. Treatment of pulmonary edema is primarily focused on maintaining vital functions, for example, by tracheal intubation and mechanical ventilation. Hypoxic symptoms can be addressed by supplemental oxygen.

[0084] Pulmonary permeability water species include alveolar Na + It is characterized by reduced uptake capacity and impaired capillary barrier function and is a potentially fatal complication, for example, in listeriolysin-induced listeriosis. + Uptake is primarily mediated by the epithelial sodium channel (ENaC) and initiates alveolar fluid clearance.

[0085] High-altitude pulmonary edema (HAPE) typically occurs in otherwise healthy people at altitudes above 2,500 meters and can be life-threatening. After rapid elevation gain, symptoms may include shortness of breath at rest, cough, weakness or decreased exercise capacity, chest tightness or congestion, crackles or wheezing, central blue skin color, tachypnea, and tachycardia. Arterial oxygen tension decreases due to lower atmospheric pressure at high altitudes. Increased capillary pressure occurs due to hypoxemic pulmonary hypertension secondary to hypoxic pulmonary vasoconstriction. This leads to subsequent leakage of cells and proteins into the alveoli. Hypoxic pulmonary vasoconstriction occurs diffusely, resulting in arterial vasoconstriction in all regions of the lungs.

[0086] The first medical action is to descend to a lower altitude as quickly as possible. pO2 Supplemental oxygen can be administered to maintain a blood oxygen level above 90%.

[0087] Pharmacological prevention of HAPE includes calcium channel blockers such as nifedipine, PDE5 inhibitors such as sildenafil and tadalafil, and inhaled beta-2 agonists such as salmeterol.

[0088] A new pharmaceutical approach to enhancing ENaC function is, for example, the peptide drug solnatide.

[0089] Therefore, the present application also refers to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of pulmonary permeability water and high altitude pulmonary edema.

[0090] Pulmonary ischemia-reperfusion injury is also of particular interest within the scope of this application. In lung transplantation, organ ischemia and subsequent reperfusion are inevitable, resulting in acute post-transplant sterile inflammation commonly referred to as ischemia-reperfusion (IR) injury. Severe IR injury leads to primary graft dysfunction (PGD), which is a major cause of both short- and long-term morbidity and mortality after lung transplantation. Currently, no therapeutic agents are clinically available to specifically prevent IR injury, and treatment strategies are limited to supportive care. When feasible, donor lungs, respectively, can be prophylactically treated with 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts.

[0091] Endothelial dysfunction and disruption of the endothelial barrier are hallmarks of pulmonary IR injury. Endothelial membrane depolarization induces ROS production and subsequent inflammation and leukocyte emigration. Activation of NADPH oxidase (NOX2), induction of nitric oxide (NO) production, and activation of integrin αvβ5 promote vascular permeability through ROS / RNS production. Alveolar macrophages are activated. Increased chemokine concentrations and adhesion molecule expression on endothelial cells and neutrophils lead to neutrophil binding and infiltration, releasing cytokines, ROS, and forming neutrophil extracellular traps (NETs).

[0092] Recent preventive strategies before lung transplantation include administering antioxidants (free radical scavengers) or inhibitors of oxidant-generating enzymes (e.g., methylene blue or N-acetylcysteine) to the organ recipient, anti-inflammatory strategies using inhibitors of pro-inflammatory transcription factors or inflammatory mediators, ventilation with gas molecules such as carbon monoxide or the inhaled anesthetic sevoflurane, growth factors or nutritional supplements such as creatine, and cell-based therapies such as the application of mesenchymal stem cells.

[0093] Therefore, the present application also refers to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the prevention or treatment of pulmonary ischemia-reperfusion injury.

[0094] Of particular interest within the scope of this application is primary graft dysfunction after lung transplantation. Primary graft dysfunction (PGD) is a devastating form of acute lung injury that affects approximately 10% to 25% of patients in the first few hours to days after lung transplantation. Clinically and pathologically, it mimics adult respiratory distress syndrome (ARDS) and is associated with a mortality rate of up to 50%. PGD can have different causes, including the aforementioned ischemia-reperfusion injury, epithelial cell death, endothelial cell dysfunction, innate immune activation, oxidative stress, release of inflammatory cytokines and chemokines, and iatrogenic factors such as mechanical ventilation and transfusion of blood components. Activation of the innate immune system has been demonstrated during the development and progression of ischemia-reperfusion injury. Herein, PGD is associated with the innate immune pathway of Toll-like receptor-mediated injury.

[0095] Molecular markers of PGD include intercellular adhesion molecule-1, surfactant protein-1, plasminogen activator inhibitor, soluble receptor for advanced glycation end products, and protein C.

[0096] Approaches to avoid PGD include optimizing reperfusion, adjusting prostaglandin concentrations, hemodynamic control, hormone replacement, ventilator management, and donor lung preparation strategies. To reduce the incidence of PGD, strategies such as the use of prostaglandins, nitric oxide, surfactants, and adenosine, or inhibition of proinflammatory mediators and / or scavenging free oxygen radicals have been used. Furthermore, inhibitors of free oxygen radicals, cytokines, proteases, lipid mediators, adhesion molecules, and complement cascades have been investigated for the inhibition of neutrophils and neutrophil-mediated mediators. Inhaled nitric oxide can reduce pulmonary artery pressure without affecting systemic blood pressure. As a last-ditch lifesaving option, extracorporeal membrane oxygenation (ECMO) is used to correct PGD-induced hypoxemia and provide the necessary gas exchange.

[0097] Therefore, the present application also refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of primary graft dysfunction after lung transplantation.

[0098] This applies to each of the aforementioned subtypes of inflammatory lung diseases as well as each of the aforementioned single inflammatory lung diseases.

[0099] Preferentially, the present application relates to the prevention or treatment of chronic inflammatory lung diseases with a global prevalence of less than or equal to 1:1500, in which 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is used.

[0100] More preferably, the present application refers to the aforementioned embodiment in which crystalline polymorphic Form I, II or III of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is used, as defined above by the respective d and / or 2θ values ​​determined by X-ray powder diagram.

[0101] Most preferably, the present application refers to the aforementioned embodiment in which the crystalline polymorphic Form I of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is used, as defined above by the respective d and / or 2θ values ​​determined by X-ray powder diagram.

[0102] 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, the composition according to the present invention or the pharmaceutical combination according to the present invention can be applied for the prevention or treatment of chronic inflammatory lung diseases having a global prevalence of 1:1500 or less by any medically acceptable route of administration to a patient in need thereof. Such medically acceptable routes of administration can be, for example, by inhalation, by intubation, orally, parenterally, intraperitoneally, intravenously, intraarterially, intramuscularly, topically, transdermally, subcutaneously, intradermally, sublingually, intraconjunctivally, intravaginally, intrarectally, intrathecally, intrapharyngeally or intranasally.

[0103] In particular, the present disclosure also relates to one such route of application of 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof in the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence of 1:1700 or less, or 1:2000 or less, or 1:2500 or less, or 1:3000 or less, or 1:4000 or less, or 1:5000 or less, or 1:6000 or less, or 1:7000 or less, or 1:8000 or less, or 1:9000 or less, or 1:10000 or less.

[0104] Alternatively, the present disclosure also provides a method for administering a medicament containing ... Reference is also made to such a route of application of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence in the range of 7000 to 1:2,000,000, or 1:8,000 to 1:2,000,000, or 1:9,000 to 1:2,000,000, or 1:10,000 to 1:2,000,000.

[0105] A preferred oral formulation for use in the prevention or treatment of chronic inflammatory lung diseases with a worldwide prevalence of 1:1500 or less is a capsule or tablet containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in an amount of 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg, preferably 100 mg, 150 mg, 200 mg, 300 mg or 400 mg, most preferably 300 mg.

[0106] In another aspect of the present invention, a composition for use in the prevention or treatment of chronic inflammatory lung disease is disclosed, the composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier, and at least one pharmaceutically acceptable excipient.

[0107] In particular, the present disclosure refers to a composition for use in the prevention or treatment of a chronic inflammatory lung disease having a global prevalence of 1:1500 or less, the composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier, and at least one pharmaceutically acceptable excipient, the chronic inflammatory lung disease being one of the following: bronchiectasis, alveolar microlithiasis, coal workers' pneumoconiosis, asbestosis, talc pulmonary edema, ... Dust-induced pneumoconiosis, silicosis, aluminum lung disease, bauxite pulmonary fibrosis, beryllium lung disease, graphite pulmonary fibrosis, iron deposition disease, tin deposition disease, tuberculosis-related pneumoconiosis, byssinosis, linen wear disease, hemp fibrosis, farmer's lung, sugarcane lung disease, poultry farmer's disease, cork lung, malt worker's lung, mushroom grower's lung, maple bark processor's lung, air-conditioning lung disease, humidifier lung, cheesemaker's lung, coffee worker's lung, fishmeal worker's lung lung, furrier's lung, sequiosis, allergic alveolitis, hypersensitivity pneumonitis, respiratory conditions due to inhalation of chemicals, gases, smoke, and vapors, solid and liquid pneumonitis, radiation pneumonitis, post-irradiation pulmonary fibrosis, chronic drug-induced interstitial lung disease, pulmonary permeability fluid, high-altitude pulmonary edema, eosinophilic asthma, Loffler's pneumonia pneumonia, tropical pulmonary eosinophilia, alveolar and mural alveolar conditions, Hamman-Rich syndrome, pulmonary abscess with pneumonia, empyema, pleural plaque, pneumothorax, chylous exudate, fibrothorax, hemothorax, hemopneumothorax, hydrothorax, chronic pulmonary dysfunction after surgery, host-versus-graft disease after lung transplantation, graft-versus-host disease after lung transplantation, chronic pulmonary allograft dysfunction, chronic pulmonary allograft dysfunction-bronchiolitis obliterans syndrome, pulmonary ischemia-reperfusion injury, primary graft dysfunction after lung transplantation, Mendelsohn's syndrome, lung collapse, atelectasis, interstitial emphysema, mediastinal emphysema, compensated emphysema, mediastinitis, diaphragmatic disorders, transient tachypnea of ​​the newborn, congenital pneumonia caused by viral agents, congenital pneumonia caused by chlamydia, congenital pneumonia caused by Staphylococcus, group B streptococcus B) congenital pneumonia, Escherichia coli (Escherichia coli) congenital pneumonia, Pseudomonas (Pseudomonas) congenital pneumonia, Haemophilus influenzae (Haemophilusinfluenzae congenital pneumonia, Klebsiella pneumoniae congenital pneumonia, Mycoplasma congenital pneumonia, neonatal meconium inhalation, perinatal pulmonary interstitial emphysema, perinatal pneumothorax, perinatal emphysema mediastinum, perinatal pulmonary hemorrhage, and Wilson-Mikity syndrome.

[0108] In particular, the present disclosure also refers to such compositions comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier and at least one pharmaceutically acceptable excipient, for use in the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence of 1:1700 or less, or 1:2000 or less, or 1:2500 or less, or 1:3000 or less, or 1:4000 or less, or 1:5000 or less, or 1:6000 or less, or 1:7000 or less, or 1:8000 or less, or 1:9000 or less, or 1:10000 or less.

[0109] Alternatively, the present disclosure also provides a method for detecting a virulence factor of 1:1500 to 1:2,000,000, or 1:1700 to 1:2,000,000, or 1:2,000 to 1:2,000,000, or 1:2,500 to 1:2,000,000, or 1:3,000 to 1:2,000,000, or 1:4,000 to 1:2,000,000, or 1:5,000 to 1:2,000,000, or 1:6,000 to 1:2,000,000, or 1:7,000 to 1:200,000 The present invention also refers to a composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier, and at least one pharmaceutically acceptable excipient for use in the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence in the range of 1:0, or 1:8000 to 1:2000000, or 1:9000 to 1:2000000, or 1:10000 to 1:2000000.

[0110] The term "pharmaceutically acceptable excipient(s)" refers to natural or synthetic compounds that are added to a pharmaceutical formulation along with a pharmaceutically active agent. They serve to bulk the formulation, improve the formulation's desired pharmacokinetic properties or stability, and may be beneficial in the manufacturing process. Advantageous classes of excipients according to the present invention include carriers, binders, colorants, buffers, preservatives, antioxidants, coating agents, sweeteners, thickeners, pH adjusters, acidity regulators, acidifiers, solvents, tonicity agents, penetration enhancers, disintegrants, glidants, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-caking agents (anti-adherents), adsorbents, foaming agents, anti-foaming agents, opacifiers, fat-liquoring agents, consistency enhancers, hydrotropes, fragrances, and flavoring substances.

[0111] Generally, one or more pharmaceutically acceptable carriers are added to pharmaceutically active agents.The subject is all carriers known in the art and their combinations.For solid dosage forms, they can be, for example, vegetable and animal fats, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talcum, zinc oxide.For liquid dosage forms and emulsions, suitable carriers are, for example, solvents, solubilizers, emulsifiers such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, cottonseed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethylene glycol, fatty acid esters of sorbitan. Suspensions according to the present invention may use carriers known in the art, such as diluents (e.g., water, ethanol, or propylene glycol), ethoxylated isostearyl alcohol, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonite, agar, tragacanth, and the like.

[0112] The term binder refers to substances that bind or glue powders together, making them cohesive through granulation. They function as the "glue" of the formulation. Binders increase the cohesive strength of the diluent or filler provided.

[0113] Suitable binders are, for example, starch derived from wheat, corn, rice or potato, gelatin, naturally occurring sugars such as glucose, sucrose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth or calcium ammonium alginate, sodium alginate, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, magnesium aluminum silicate, waxes, etc. The percentage of binder in the composition may range from 1 to 30% by weight, preferably from 2 to 20% by weight, more preferably from 3 to 10% by weight, most preferably from 3 to 6% by weight.

[0114] Colorants are excipients that impart color to pharmaceutical formulations. These excipients can be food colorants. They can be adsorbed onto suitable adsorbents, such as clay or aluminum oxide. A further advantage of colorants is that they can make aqueous solutions spilled on the sprayer and / or mouthpiece visible for easier cleaning. The amount of colorant can vary from 0.01 to 10% by weight of the pharmaceutical composition, preferably from 0.05 to 6% by weight, more preferably from 0.1 to 4% by weight, and most preferably from 0.1 to 1% by weight.

[0115] Suitable pharmaceutical colorants are, for example, curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, alkanine, quinolion yellow WS, fast yellow AB, riboflavin-5'-sodium phosphate, yellow 2G, sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, ponceau 4R, ponceau SX, ponceau 6R, erythrosine, red 2G, allura red AC, indanthrene blue RS, patent blue V, indigo carmine, brilliant blue FCF, chlorophyll and chlorophyllin, copper complexes of chlorophyll and chlorophyllin, green S, fast green FCF, plain caramel, caustic sulfite caramel, ammonia caramel, AL, sulfite ammonia caramel, black PN, carbon black, vegetable carbon, brown FK, brown HT, alpha-carotene, beta-carotene, gamma-carotene, annatto, bixin, norbixin, paprika oleoleoresin, capsanthin, capsorubin, lycopene, beta-apo-8'-carotenal, ethyl ester of beta-apo-8'-carotenoic acid, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanin, saffron, calcium carbonate, titanium dioxide, iron oxide, iron hydroxide, aluminum, silver, gold, pigment rubin, tannin, orcein, iron gluconate, ferrous lactate.

[0116] Furthermore, buffers are preferred for liquid formulations, especially pharmaceutical liquid formulations. The terms buffer, buffer system, and buffer, especially for aqueous solutions, refer to the ability of the system to resist pH changes due to the addition of an acid or base or dilution with a solvent. Preferred buffer systems include formate, lactate, benzoate, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (2-(N-morpholino)ethanesulfonic acid), maleic acid, cacodylate (dimethyl arsenate), carbonic acid, ADA (N-(2-acetamido)iminodiacetic acid), PIPES (4-piperazine-bis-ethanesulfonic acid), BIS-TRIS propane (1, 3-bis[tris(hydroxymethyl)methylamino]propane), ethylenediamine, ACES (2-[(amino-2-oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morphino)-propanesulfonic acid), diethylmalonate, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), and pK values ​​between 3.8 and 7.7. a The buffer may be selected from the group including other buffers having the formula:

[0117] Carbonate buffers such as acetate buffers and dicarboxylic acid buffers such as fumarate, tartrate and phthalate, as well as tricarboxylic acid buffers such as citrate are preferred.

[0118] Another group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide, and phosphate buffers. Another group of preferred buffers are nitrogen-containing puffers such as imidazole, diethylenediamine, and piperazine. Further preferred are sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1,1-bis-(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid (EEPS), MOPS, and N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers are glycine, glycylglycine, glycylglycylglycine, N,N-bis-(2-hydroxyethyl)glycine, and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine). Also preferred are amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, N,N,N-trimethyllysine, 3-methylhistidine, 5-hydroxylysine, o-phosphoserine, gamma-carboxyglutamate, [epsilon]-N-acetyllysine, [omega]-N-methylarginine, citrulline, ornithine, and derivatives thereof.

[0119] Preservatives for liquid and / or solid dosage forms may be used as desired, including, but not limited to, sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methylparaben, ethylparaben, methylethylparaben, propylparaben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl p-hydroxybenzoate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohol, cresol, cetylpyridinium chloride, chlorobutanol, thiomer (sodium 2-(ethylmercurithio)benzoate), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite. The antioxidant may be selected from the group comprising ammonium, calcium bisulfite, potassium bisulfite, biphenyl, orthophenylphenol, sodium orthophenylphenol, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl bicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, ammonium acetate, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper-(II)-sulfate, chlorine, chlorine dioxide, and other suitable substances or compositions known to those skilled in the art.

[0120] The addition of a sufficient amount of antioxidant is particularly preferred for liquid and topical formulations. Suitable examples of antioxidants include sodium metabisulfite, alpha-tocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, or propyl gallate. The use of sodium metabisulfite, alpha-tocopherol, and ascorbyl palmitate is preferred.

[0121] Tablets or pills are usually coated, i.e., the coating constitutes the outer layer. This can be a film coating, a sugar coating containing sugar, and a compression coating. Pharmaceutically acceptable varnishes or waxes, such as HPMC (hydroxypropylmethylcellulose), MC (methylcellulose), or HPC (hydroxypropylcellulose), can be used. Such coatings can serve to disguise the taste and facilitate swallowing or identification. Plasticizers and pigments are often included in the coating. Capsules usually have a gelatinous envelope that encapsulates the active substance. The specific composition and thickness of this gelatinous layer determine how quickly absorption occurs after ingestion of the capsule. As is known in the art, sustained-release formulations are of particular interest.

[0122] Suitable sweeteners may be selected from the group comprising mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidin dihydrochalcone, steviol glycosides, neotame, aspartame-acesulfame salt, maltitol, maltitol syrup, lactitol, xylitol, erythritol.

[0123] Suitable thickening agents may be selected from the group including, but not limited to, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, dextrin, polydextrose, modified starch, alkali modified starch, bleached starch, oxidized starch, enzyme-treated starch, monostarch phosphate, phosphate distarch starch esterified with sodium trimetaphosphate or phosphorus oxychloride, phosphate distarch starch, acetylated phosphate distarch starch, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated adipate cross-linked starch, acetylated distarch glycerol, distarch glycerin, hydroxypropyl starch, hydroxypropylglycerin cross-linked starch, sodium starch octenyl succinate, acetylated oxidized starch, hydroxyethylcellulose.

[0124] Suitable pH adjusting agents for liquid dosage forms are, for example, buffer substances such as sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0125] Suitable acidity regulators include acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, carbon dioxide, malic acid, fumaric acid, sodium lactate, potassium lactate, calcium lactate, ammonium lactate, magnesium lactate, citric acid, mono-, di-, trisodium citrate, mono-, di-, tripotassium citrate, mono-, di-, tricalcium citrate, tartaric acid, mono-, disodium tartrate, mono-, dipotassium tartrate, sodium potassium tartrate, orthophosphoric acid, lecithin citrate, magnesium citrate, ammonium malate, sodium malate, sodium hydrogen malate, calcium malate, calcium hydrogen malate, adipic acid, adipic acid The surfactant may be selected from the group comprising sodium, potassium adipate, ammonium adipate, succinic acid, sodium fumarate, potassium fumarate, calcium fumarate, ammonium fumarate, 1,4-heptonolactone, triammonium citrate, ferrous ammonium citrate, calcium glycerophosphate, isopropyl citrate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, magnesium carbonate, magnesium bicarbonate, ferrous carbonate, ammonium sulfate, aluminum potassium sulfate, aluminum ammonium sulfate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium hydroxide, gluconic acid.

[0126] Acidifying agents are used which are inorganic chemicals that generate or become acids. Suitable examples are ammonium chloride, calcium chloride.

[0127] Suitable solvents may be selected from the group including, but not limited to, water, carbonated water, water for injection, water containing an isotonic agent, saline, isotonic saline, alcohols, particularly ethyl and n-butyl alcohol, and mixtures thereof.

[0128] Suitable isotonicity agents are, for example, pharmaceutically acceptable salts, in particular sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrates, phosphates, borates and mixtures thereof.

[0129] Penetration enhancers (permeation or penetration enhancers) are substances that temporarily reduce the skin barrier and promote or facilitate the absorption of cosmetic agents. Suitable penetration enhancers can be selected from the group including, but not limited to, dimethyl isosorbide (Arlasolve®), dimethyl sulfoxide (DMSO) and its analogs, dimethylformamide (DMF), azone (1-dodecylazacycloheptan-2-one), pyrrolidones such as 2-pyrrolidone, fatty acids such as oleic acid, lauric acid, myristic acid, and capric acid, nonionic surfactants such as polyoxyethylene-2-oleyl ether and polyoxyethylene-2-stearyl ether, terpenes, terpenoids, and sesquiterpenes such as those from eucalyptus, chenopodium, and ylang-ylang essential oils, oxazolidinones such as 4-decyloxazolidin-2-one, turpentine oil, pine oil, and menthol.

[0130] Suitable disintegrants can be selected from the group consisting of starch, cold-soluble starches such as carboxymethyl starch, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, cross-linked microcrystalline cellulose such as microcrystalline cellulose and croscarmellose sodium, natural and synthetic gums such as guar, agar, and Karaya (Indian tragacanth), clays such as locust bean gum, tragacanth, and bentonite, xanthan gum, alginates such as alginic acid and sodium alginate, and effervescent compositions. Hydration is supported by, for example, starch, cellulose derivatives, alginates, polysaccharides, dextran, and cross-linked polyvinylpyrrolidone. The amount of disintegrant in the composition can vary from 1 to 40% by weight, preferably from 3 to 20% by weight, and most preferably from 5 to 10% by weight.

[0131] A lubricant is a material that prevents the respective dietary supplement from sticking and improves the flow characteristics of the granulation so that the flow is smooth and consistent. Suitable glidants include silicon dioxide, magnesium stearate, sodium stearate, starch, and talc. The amount of glidant in the composition can vary from 0.01 to 10% by weight, preferably 0.1 to 7% by weight, more preferably 0.2 to 5% by weight, and most preferably 0.5 to 2% by weight.

[0132] The term lubricant refers to substances added to dosage forms to facilitate the release of tablets, granules, etc. from the compression die or exit nozzle. They reduce friction or wear. Lubricants are usually added just before compression, since they must be present on the surfaces of the granules and between the granules and the components of the compression die. The amount of lubricant in the composition can vary from 0.05 to 15% by weight, preferably 0.2 to 5% by weight, more preferably 0.3 to 3% by weight, and most preferably 0.3 to 1.5% by weight. Suitable lubricants include, for example, (ao), metal stearates such as sodium oleate, sodium stearate, calcium stearate, potassium stearate, and magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, high-melting waxes, and polyethylene glycol.

[0133] The emulsifier can be selected from, for example, the following anionic and nonionic emulsifiers: anionic emulsifier wax, cetyl alcohol, cetylstearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymers, addition products of 2 to 60 mol of ethylene oxide onto castor oil and / or hydrogenated castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethenso Polyoxyethene sorbitan monolaurate, Polyoxyethene sorbitan monooleate, Polyoxyethene sorbitan monopalmitate, Polyoxyethene sorbitan monostearate, Polyoxyethene sorbitan tristearate, Polyoxyethene stearate, Polyvinyl alcohol, Metatartaric acid, Calcium tartrate, Alginic acid, Sodium alginate, Potassium alginate, Ammonium alginate, Calcium alginate, Propane-1,2-diol alginate, Carrageenan, Processed Eucheuma seaweed seaweed), locust bean gum, tragacanth, acacia gum, karaya gum, gellan gum, ghatti gum, glucomannan, pectin, amidated pectin, ammonium phosphatide, brominated vegetable oil, sucrose acetate isobutyrate, glycerol ester of wood rosin, disodium phosphate, trisodium diphosphate, dicalcium diphosphate, dicalcium dihydrogen phosphate, sodium triphosphate, pentapotassium triphosphate, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, beta-cyclodextrin, powdered cellulose, Methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylhydroxyethylcellulose, croscarmellose, enzymatically hydrolyzed carboxymethylcellulose, mono- and diglycerides of fatty acids, glyceryl monostearate, glyceryl distearate, acetate esters of mono- and diglycerides of fatty acids, lactate esters of mono- and diglycerides of fatty acids, citrate esters of mono- and diglycerides of fatty acids,Tartaric acid esters of mono- and diglycerides of fatty acids, mono- and diacetyltartaric acid esters of mono- and diglycerides of fatty acids, mixed acetate and tartaric acid esters of mono- and diglycerides of fatty acids, succinylated monoglycerides, sucrose esters of fatty acids, sucroglycerides, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propane-1,2-diol esters of fatty acids, propylene glycol esters of fatty acids, lactylated fatty acid esters of glycerol and propane-1, thermally oxidized soybean oil interacting with mono- and diglycerides of fatty acids, sodium dioctyl sulfosuccinate, sodium stearoyl-2-lactylate, stearoyl The glycerin may be selected from calcium 2-lactate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, sodium lauryl sulfate, ethoxylated monoglycerides and diglycerides, methyl glucoside-coconut oil ester, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, cholate salts, glycerol cross-linked starch, starch sodium octenylsuccinate, and acetylated oxidized starch. Phospholipids such as glycerol monooleate, stearic acid, and lecithin are preferred.

[0134] Suitable surface-active solubilizers (solubilizers) are, for example, diethylene glycol monoethyl ester, polyethylpropylene glycol copolymers, cyclodextrins such as α- and β-cyclodextrin, glyceryl monostearate such as Solutol HS 15 (Macrogol-15-hydroxystearate, PEG 660-15 hydroxystearate from BASF), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitan acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, (anionic) glyceryl monooleate.

[0135] Stabilizers are substances that can be added to prevent undesired changes. Although stabilizers are not actual emulsifiers, they can also contribute to the stability of emulsions. Suitable examples of stabilizers include oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethene stearate, aspartame-acesulfame salt, amylase, protease, papain, bromelain, ficin, invertase, polydextrose, polyvinylpyrrolidone, polyvinylpolypyrrolidone, triethyl citrate, maltitol, and maltitol syrup.

[0136] Diluents or fillers are inert substances added to a drug to handle a minimal amount of active agent. Examples of suitable diluents are water, mannitol, pregelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, xanthan gum, gum arabic, or any combination thereof.

[0137] Anti-caking agents (anti-adherents) can be added to the dietary supplement or dietary supplement composition to prevent clumping and facilitate packaging, transport, release from at least one chamber of the dispensing cap, and consumption. Suitable examples include tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talc powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, and polydimethylsiloxane. Sorbents are materials that absorb oil from water. Suitable examples include natural sorbents such as peat moss, sawdust, feathers, and any natural sorbent containing carbon, as well as synthetic sorbents such as polyethylene and nylon. Sorbents are used to protect tablets / capsules from moisture by limited fluid adsorption (by taking up or absorbing liquids or gases by adsorption) in a dry state.

[0138] In some galenical formulations, it may be desirable for liquid oral dosage forms to produce some foam upon dissolution. Such an effect can be supported by the addition of foaming agents, which reduce the surface tension of the liquid and thus promote the formation of bubbles, or increase its colloidal stability by inhibiting bubble coalescence. Alternatively, the foam can be stabilized. Suitable examples include mineral oil, Quillaja extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, and ammonium lauryl sulfate.

[0139] Alternatively, some liquid oral dosage forms may appear slightly foamy upon preparation. While this does not interfere with the desired use, it may affect patient compliance in the case of pharmaceuticals or commercial success in the case of dietary supplements. Therefore, it may be desirable to add a pharmaceutically acceptable anti-foaming agent (defoamer). Examples are polydimethylsiloxane or silicone oil in dietary supplements, or simethicone in pharmaceuticals.

[0140] Opacifiers are substances that, if necessary, make a liquid dosage opaque. They must have a refractive index substantially different from that of the solvent, most often water. At the same time, they must be inert to the other components of the composition. Suitable examples include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.

[0141] Suitable fats are, for example, decyl oleate, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium lauryl sulfate.

[0142] Thickeners are, for example, cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline wax, nonionic emulsifier wax, beeswax, paraffin or stearyl alcohol.

[0143] Suitable hydrotropes are alcohols such as ethanol, isopropyl alcohol, or polyols such as glycerin.

[0144] Suitable aromatic and flavoring substances include all essential oils that can be used for this purpose. Generally, this term refers to volatile extracts from plants or plant parts that have their characteristic odor. They can be extracted from plants or plant parts by steam distillation.

[0145] Suitable examples are essential oils, respectively sage, clove, chamomile, anise, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineole, borneol, gingerol, eucalyptus oil, mango, fig, lavender oil, chamomile flowers, pine needles, cypress, orange, rosewood, plum, currant, cherry, birch leaves, cinnamon, lime, grapefruit, tangerine, juniper, valerian, lemon balm, lemongrass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy leaf extract, blueberry, persimmon, melon, etc., or mixtures thereof, as well as mixtures of menthol, peppermint and star anise oil or menthol and cherry flavor.

[0146] These aromatic or flavoring substances may be present in an amount ranging from 0.0001 to 10% by weight (particularly in the composition), preferably from 0.001 to 6% by weight, more preferably from 0.001 to 4% by weight, and most preferably from 0.01 to 1% by weight, relative to the total composition. Depending on the application or on a single occasion, it may be advantageous to use different amounts.

[0147] According to the present invention, all of the above-mentioned excipients and classes of excipients may be used without restriction, alone or in any conceivable combination thereof, as long as the use of the present invention is not hindered, toxic effects may occur, or the legislation of the respective country is violated.

[0148] 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its acceptable salts can be used as a monotherapy or can be further combined with at least one further active ingredient selected from the group comprising active ingredients used in the disease-modifying therapy of chronic inflammatory lung diseases with a global prevalence of 1:1500 or less, the symptomatic treatment of chronic inflammatory lung diseases with a global prevalence of 1:1500 or less and the treatment of comorbidities.

[0149] The comorbidity may be due to or independent of the impairment caused by chronic inflammatory lung disease, which has a global prevalence of up to 1:1500. Thus, 5-amino-2,3-dihydro-1,4-phthalazinediones or one of their pharmaceutically acceptable salts may be combined with at least one further active agent for use in the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence of 1:1500 or less, such as bronchiectasis, alveolar microlithiasis, coal workers' pneumoconiosis, asbestosis, talc dust pneumoconiosis, silicosis, aluminum lung disease, bauxite pulmonary fibrosis, beryllium lung disease, graphite pulmonary fibrosis, iron deposition disease, tin deposition disease, tuberculosis-associated pneumoconiosis, assassination, linen wear disease, hemp fibrosis, farmer's lung, sugarcane lung disease, bird farmer's disease, cork lung, malt worker's lung, mushroom grower's lung, maple bark processor's lung, air-conditioning lung disease, humidifier lung, cheesemaker's lung, coffee worker's lung, fishmeal worker's lung, lung, furrier's lung, sequiosis, allergic alveolitis, hypersensitivity pneumonitis, respiratory conditions due to inhalation of chemicals, gases, smoke, and vapors, solid and liquid pneumonitis, radiation pneumonitis, post-irradiation pulmonary fibrosis, chronic drug-induced interstitial lung disease, pulmonary permeability fluid, high-altitude pulmonary edema, eosinophilic asthma, Loffler's pneumonia pneumonia, tropical pulmonary eosinophilia, alveolar and mural alveolar conditions, Hamman-Rich syndrome, pulmonary abscess with pneumonia, empyema, pleural plaque, pneumothorax, chylous exudate, fibrothorax, hemothorax, hemopneumothorax, hydrothorax, chronic pulmonary dysfunction after surgery, host-versus-graft disease after lung transplantation, graft-versus-host disease after lung transplantation, chronic pulmonary allograft dysfunction, chronic pulmonary allograft dysfunction-bronchiolitis obliterans syndrome, pulmonary ischemia-reperfusion injury, primary graft dysfunction after lung transplantation, Mendelsohn's syndrome, lung collapse, atelectasis, interstitial emphysema, mediastinal emphysema, compensated emphysema, mediastinitis, diaphragmatic disorders, transient tachypnea of ​​the newborn, congenital pneumonia caused by viral agents, congenital pneumonia caused by chlamydia, congenital pneumonia caused by Staphylococcus, group B streptococcus B) congenital pneumonia caused by Escherichia coliCongenital pneumonia caused by Pseudomonas, congenital pneumonia caused by Haemophilus influenzae, and Klebsiella pneumonia pneumoniae, congenital pneumonia caused by Mycoplasma, neonatal meconium aspiration, perinatal pulmonary interstitial emphysema, perinatal pneumothorax, perinatal pneumomediastinum, perinatal pulmonary hemorrhage, and Wilson-Mikity syndrome, and the at least one further active agent is selected from the group comprising steroidal and non-steroidal anti-inflammatory drugs; immunomodulators; immunostimulants; immunosuppressants; antibiotics; antivirals; antifungals; antiprotozoal agents; analgesics; anticoagulants; antiplatelet agents; bronchodilators; pulmonary vasodilators; mucolytics; pulmonary surfactants; antioxidants; ENaC activators; HMG-CoA reductase inhibitors, calcium antagonists, or AT1 receptor antagonists.

[0150] In particular, the present disclosure also refers to such combinations of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts with at least one further active agent for use in the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence of 1:1700 or less, or 1:2000 or less, or 1:2500 or less, or 1:3000 or less, or 1:4000 or less, or 1:5000 or less, or 1:6000 or less, or 1:7000 or less, or 1:8000 or less, or 1:9000 or less, or 1:10000 or less.

[0151] Alternatively, the present disclosure also provides a method for detecting a virulence factor of 1:1500 to 1:2,000,000, or 1:1700 to 1:2,000,000, or 1:2,000 to 1:2,000,000, or 1:2,500 to 1:2,000,000, or 1:3,000 to 1:2,000,000, or 1:4,000 to 1:2,000,000, or 1:5,000 to 1:2,000,000, or 1:6,000 to 1:2,000,000, or 1:7,000 to 1:200,000 The present invention also refers to such combinations of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier and at least one further active agent for use in the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence in the range of 1:0, or 1:8000 to 1:2000000, or 1:9000 to 1:2000000, or 1:10000 to 1:2000000.

[0152] Suitable examples of such steroidal anti-inflammatory drugs are corticosteroids, glucocorticoids, cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, deltasone, triamcinolone, tixocortol pivalate, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone, halcinonide, flucortolone, hydrocortisone-17-valerate, halometazoline, flumethasone, flumethasone-17-valerate, halometazoline ... These include flucloxone, alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prenicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, flucortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, and beclomethasone dipropionate.

[0153] Suitable examples of such nonsteroidal anti-inflammatory drugs (NSAIDs) include acetylsalicylic acid, salicylic acid and salicylates, acetaminophen (paracetamol), salsalate, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, benzodiazepine, benzocaine ... These include phenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celexoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide, clonixin, licofelone, H-harpagide, flunixin, and tiaprofenic acid.

[0154] Suitable examples of such immunomodulatory agents include, inter alia, thalidomide, lenalidomide, pomalidomide and apremilast.

[0155] Suitable examples of such antiviral drugs include ancriviroc, aplaviroc, cenicriviroc, enfuvirtide, maraviroc, vicriviroc, amantadine, rimantadine, pleconaril, idoxuridine, acyclovir, brivudine, famciclovir, penciclovir, sorivudine, valacyclovir, cidofovir, ganciclovir, valganciclovir, sofosbusvir, foscarnet, ribavirin, taribavirin, These include filibusterin, nesbuvir, tegovvir, fosdevirin, favipiravir, merimepodib, asunaprevir, valapiravir, boceprivir, cilprevir, danoprevir, daclatasvir, naraprevir, telaprevir, simeprevir, vanipevir, rupintrivir, fomivirsen, amenamevir, alisporivir, bevirimate, letermovir, laninamivir, oseltamivir, peramivir, remdesivir, and zanamivir.

[0156] Suitable examples of such immunostimulants include interferons (α-, β-, γ-, and τ-interferons), interleukins, CSFs (colony-stimulating factors), PDGFs (platelet-derived growth factors), EGFs (epidermal growth factors), IGFs (insulin-like growth factors), THF (tetrahydrofolic acid), levamisole, dimepranol, and inosine.

[0157] Suitable examples of such immunosuppressants are the group of glucocorticoids listed above; cytostatics such as alkylating agents (cyclophosphamide, etc.), antimetabolites such as methotrexate, azathioprine, mercaptopurine, fluorouracil, leflunomide, etc., protein synthesis inhibitors, and certain antibiotics such as dactinomycin, anthracyclines, mitomycin C, bleomycin and mithramycin, intercalating agents such as mitoxantrone; muromonab-CD3, rituximab, usuamivir serotonin, vasodilators, etc. Antibodies such as tekinumab, alemtuzumab, natalizumab, basiliximab and daclizumab; immunophilin-acting drugs such as cyclosporine, tacrolimus and sirolimus, non-classified immunosuppressants such as beta-interferon and gamma-interferon, opioids, TNF-binding proteins such as infliximab, etanercept and adalimumab; or curcumin, catechin, mycophenolic acid, fingolimod, myriocin and fumaric acid dimethyl ester.

[0158] Suitable examples of such cognitive enhancers include eugeroics such as armodafinil and modafinil; amphetamines such as dextroamphetamine and lisdexamphetamine; methamphetamine; racetams such as oxiracetam, piracetam, aniracetam, pramiracetam and phenylpiracetam; herbs such as Bacopa monnieri, Panax ginseng and Ginkgo biloba; xanthines such as Noopept (N-phenylacetyl-L-prolylglycine ethyl ester); caffeine; vitamin B6; vitamin B12; methylphenidate; and acetylcholinesterase inhibitors such as donepezil.

[0159] Suitable examples of such antidepressants and other mood regulators include tricyclic antidepressants such as desipramine, imipramine, amitriptyline and doxepin; tetracyclic antidepressants such as maprotiline and mirtazapine; selective serotonin reuptake inhibitors such as sertraline, citalopram and fluoxetine; serotonin-norepinephrine reuptake inhibitors such as venlafaxine, milnacipran and duloxetine; serotonin modulators and stimulants such as nefazodone, trazodone and vilazodone; norepinephrine reuptake inhibitors such as atomoxetine, reboxetine and viloxazine; tetracyclic antidepressants such as maprotiline and mirtazapine; and monoamine oxidase inhibitors such as selegiline, isocarboxazid, tranylcypromine, selegiline and phenelzine.

[0160] Suitable examples of such agents for preventing bone mineral density loss include bisphosphonates such as alendronate, risedronate sodium, ibandronate, and zoledronate; selective estrogen receptor modulators such as raloxifene; parathyroid hormones such as teriparatide; and mineral supplements such as vitamin D and calcium citrate.

[0161] Suitable examples of such sleep regulators include benzodiazepines such as temazepam, diazepam, alprazolam, and oxazepam; baclofen; tizanidine; melatonin (e.g., Circadin®); and wake-promoting agents such as armodafinil and modafinil. Wake-promoting agents are also suitable examples of drugs that prevent sleep apnea.

[0162] Suitable examples of such agents for treating or preventing sexual dysfunction include phosphodiesterase type 5 inhibitors such as sildenafil, tadalafil, and vardenafil; yohimbine, L-arginine; and herbs such as Panax ginseng, Lepidium meyenii, and Crocus sativus.

[0163] Suitable examples of such agents for treating metabolic syndrome include biguanide drugs such as metformin; sulfonylureas such as glimepiride; insulin sensitizers such as pioglitazone; lipid-lowering agents such as statins, niacin, fenofibrate and gemfibrozil; ACE inhibitors such as captopril, lisinopril and enalapril; angiotensin II receptor blockers such as irbesartan, losartan and valsartan; omega-3 polyunsaturated fatty acids; and antiplatelet agents, which are outlined in detail below.

[0164] Suitable examples of such agents for treating skin lesions such as pressure scores or intertrigo include topical treatments such as greer's goo (nystatin powder, hydrocortisone powder and zinc oxide paste), triple paste (containing petrolatum, zinc oxide paste and aluminum acetate solution) and Desitin® paste (containing zinc oxide, petrolatum, cod liver oil and lanolin), and antibacterial creams containing, for example, silver sulfadiazine or bactroban as an active agent.

[0165] Suitable examples of such antibiotics include imipenem, meropenem, ertapenem, cephalosporins, aztreonam, penicillins such as penicillin G and penicillin V, piperacillin, mezlocillin, ampicillin, amoxicillin, flucloxacillin, methicillin, oxacillin, clavulanic acid, sulbactam, tazobactam, sultamicillin, fosfomycin, teicoplanin, vancomycin, bacitracin, colistin, gramicidin, polymyxin B, tyrothricin, teixobactin, fosmidomycin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, chloramphenicol, fusidic acid, benzodiazepines ... These include benzodiazepines, cethromycin, narbomycin, telithromycin, clindamycin, lincomycin, daptomycin, dalfopristin, quinupristin, azithromycin, clarithromycin, erythromycin, roxithromycin, linezolid, doxycycline, minocycline, tetracycline, oxytetracycline, tigecycline, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, metronidazole, tinidazole, aminocoumarin, sulfadiazine, sulfadoxine, sulfamethoxazole, sulfasalazine, pyrimethamine, trimethoprim, and rifampin.

[0166] Anti-infective agents are a general term for compounds useful in the treatment of bacterial, viral, fungal, and parasitic (e.g., protozoan or helminth) infections, and include antibiotics, antivirals, antifungals, antiprotozoal and anthelmintics, and insecticides.

[0167] Suitable examples of such antiplatelet agents include abciximab, acetylsalicylic acid, dipyridamole, clopidogrel, eptifibatide, ilomedin, prostacyclin, prasugrel, ticagrelor, ticlopidine and tirofiban.

[0168] Suitable examples of such muscle relaxants include tercuronium, 1-ethylcarbamoyl-3-(3-trifluoromethylphenyl)pyrrolidine, metaxalone, methocarbamol, meprobamate, baclofen, carisoprodol, chlorzoxanzone, cyclobenzaprine, dantrolene, diazepam, orphenadrine, quinine, rocuronium, succinylcholine, decamethonium, pancuronium, veruronium, rapacuronium, dacuronium, Duadol, maroetine, dipyranthium, pipercuronium, chandonium, HS-342, atracurium, mivacurium, doxacurium, d-tubocurarine, dimethyltubocurarine, gallamine, alcuronium, anatruxonium, diadonium, fazadinium, tropeinium, and cisatracurium.

[0169] Suitable examples of such antifungal agents are abafungin, amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxy Includes conazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, amorolfine, butenafine, naftifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet, and balsam of Peru.

[0170] Suitable examples of such antiprotozoal agents include metronidazole, tinidazole, ornidazole, atovaquone, clioquinol, chlorquinaldol, emetine, pentamidine isethionate, eflornithine, nitrofural, halofuginone, miltefosine, chloroquine, hydroxychloroquine, mepacrine, primaquine, amodiaquine, pamaquine, piperaquine, proguanil, cyclohexanone, quinine, mefloquine, pyrimethamine, artemether, artemisinin, artesunate, dihydroartemisinin, halofantrine, lumefantrine, sulfadoxine.

[0171] Suitable examples of such anthelmintics include mebendazole, praziquantel, albendazole, diethylcarbamazine, flubendazole, ivermectin, levamisole, metrifonate, niclosamide, oxyclozanide, oxamniquine, oxantel, piperazine, pyrantel, pyrantel pamoate, monopantel, delquantel, pelletierin sulfate, pyrvinium, thiabendazole, fenbendazole, triclabendazole, abamectin, suramin, emodepside, pyrvinium embonate, aminoacetonitrile.

[0172] Suitable examples of further antiparasitic agents include meglumine antimoniate, benznidazole, sodium stibogluconate, fumagillin, halofantrine, melarsoprol, nifurtimox, nitazoxanide, permethrin, lindane, malathion, carbaryl, pyrethram, fenothrin, bioallethrin, imidacloprid, moxidectin, nitenpyram, fipronil, pyriprol, selamectin, dimpyrate, spinosad, indoxacarb, methoprene, pyriproxyfen, lufenuron, neem oil, citronella oil, clove oil, peppermint oil, eucalyptus oil.

[0173] Suitable examples of such local anesthetics include lidocaine, lignocaine, menthol, articaine, bupivacaine, ropivacaine, benzocaine, chloroprocaine, cocaine, cyclomethicane, dimethocane, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, tetracaine, amethocaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, mepravacaine, prilocaine, trimecaine, saxitoxin, neosaxitoxin, tetrodotoxin, and eugenol.

[0174] Suitable examples of analgesics include the above-mentioned NSAIDs; opioid analgesics such as morphine, fentanyl, methadone, oxycodone, carfetanil, dihydroetorphine, omefentanil, etorphine, sufentanil, remifentanil, alfentanil, buprenorphine, hydromorphone, levomethadone, hydrocodone, pintramide, nalbuphine, tapentadol, pentazocine, dihydrocodeine, codeine, pethidine, tramadol, tilidine, meptazinol, naloxone, naltrexone, diprenorphine, loperamide, apomorphine; epibatidine; scopolamine; ziconotide; cannabinoids such as tetrahydrocannabinol, cannabidiol, Marinol; flupirtine; ketamine, and the local anesthetics listed above.

[0175] Suitable examples of such anticoagulants include heparin, coumarins such as phenprocoumon (Marcumar) and warfarin, apixaban, rivaroxaban, edoxaban, dabigatran, ximelagatran, hirudin, lepirudin, bivalirudin, citrate, EDTA, fondaparinux, argatroban, otamixaban.

[0176] Tonic agents are a general term that refers to substances that invigorate, regulate, or restore the body and its physiological functions. They can be of herbal or animal origin.

[0177] Suitable examples of such antiplatelet agents include abciximab, acetylsalicylic acid, dipyridamole, clopidogrel, eptifibatide, ilomedin, prostacyclin, prasugrel, ticagrelor, ticlopidine and tirofiban.

[0178] Suitable bronchodilators, such as beta-2 adrenergic receptor agonists, include short-acting beta-2 agonists (SABAs), such as salbutamol, albuterol, bitolterol, fenoterol, isoprenaline, levosalbutamol, levalbuterol, orciprenaline, pirbuterol, procaterol, ritodrine, and terbutaline; long-acting beta-2 agonists (LABAs), such as arformoterol, bambuterol, clenbuterol, formoterol, and salmeterol; ultra-long-acting beta-2 agonists, such as abesiterol, carmoterol, indacaterol, olodaterol, and vilanterol, alone or in combination with umeclidinium bromide and / or fluticasone furoate; and beta-2 agonists of unknown duration of action, such as isoxsuprine, mabuterol, or zilpaterol.

[0179] Suitable muscarinic anticholinergics (bronchodilatory M3 receptor antagonists) include ipratropium bromide, tiotropium bromide, oxitropium bromide, glycopyrronium bromide, aclidinium bromide, umeclidinium bromide, atropine, hyoscyamine, aclidinium bromide, 4-DAMP, darifenacin, DAU-5884, HL-031, HL-120, J-104, J-129, procyclidine, oxybutynin, tolterodine and zamifenacin.

[0180] Further bronchodilators include epinephrine, ephedrine, theophylline and TSG12.

[0181] A potent pulmonary vasodilator is nitric oxide. Further suitable pulmonary vasodilators are prostacyclin (prostaglandin PGI2) analogues, such as iloprost, epoprostenol and treprostinil.

[0182] Suitable mucolytic agents include N-acetylcysteine ​​(NAC), ambroxol, bromhexine, carbocysteine, erdocysteine, mecysteine, and dornase alfa.

[0183] Suitable pulmonary surfactants include synthetic compositions such as colfosceril palmitate, pumactant, KL-4, venticute, and lucinactant, as well as animal-derived surfactants such as beractant, calfactant, and poractant alfa.

[0184] A powerful antioxidant is inhaled carbon monoxide (CO).

[0185] Suitable ENaC (epithelial sodium channel) activating peptides include AP301 and S3969.

[0186] Suitable HMG-CoA reductase inhibitors (statins) include atorvastatin, alone or in combination with amlodipine and / or perindopril, cerivastatin, fluvastatin, lovastatin, alone or in combination with niacin, mevastatin, pitavastatin, pravastatin, rosuvastatin, alone or in combination with ezetimibe, simvastatin, alone or in combination with ezetimibe or niacin.

[0187] Suitable calcium antagonists include verapamil, gallopamil, fendiline, nimodipine, nifedipine, nitrendipine, amlodipine, felodipine, lercanidipine, nicardipine, lacidipine, isradipine, nisoldipine, nivaldipine, manidipine, clevidipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, pranidipine, diltiazem, mibefradil, bepridil, flunarizine and fluspirilene.

[0188] Suitable AT1 antagonists (angiotensin II receptor blockers; sartans) include losartan, valsartan, candesartan, telmisartan, irbesartan, olmesartan, eprosartan, fimasartan, azilsartan, mirfasartan, pomisartan, pratosartan, lipisartan, tasosartan, saprosartan and EXP3174.

[0189] 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and an additional active ingredient can be used simultaneously, separately, or sequentially to treat or prevent disease symptoms. The two active agents may be provided in a single dosage form or as separate formulations, each formulation containing at least one of the two active agents. One or both of the two active agents may be formulated as a bolus.

[0190] Pharmaceutical formulations suitable for an oral dosage form of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention, or a combination according to the invention may be administered as discrete units such as capsules, tablets, dragees or pills; powders or granules; liquids, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or oil-in-water or water-in-oil lotions.

[0191] Thus, in oral dosage forms such as tablets or capsules, the active agent can be combined with a non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerin, or water. Powders are prepared by grinding the compound to a suitable small particle size and mixing them in a similar manner with a pharmaceutical carrier, for example, an edible carbohydrate, such as starch or mannitol. Flavoring agents, preservatives, dispersing agents, or coloring agents can also be present.

[0192] Tablets are formulated by preparing a powder mixture with the addition of a lubricant and disintegrant, granulating or dry-pressing the mixture, and then compressing the mixture into tablets. The powder mixture is prepared by mixing the appropriately comminuted compound with a diluent or base as described above, and, if applicable, with a binder such as carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone, a solution retarder such as paraffin, an absorption accelerator such as a quaternary salt, and / or an absorbent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, acacia, or a solution of cellulose or polymeric materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet press, resulting in unevenly shaped lumps that are broken down to form granules. The granules can be lubricated with the addition of stearic acid, a stearate salt, talc, or mineral oil to prevent adhesion to the tablet die. The lubricated mixture is then compressed to form tablets. The compounds according to the invention can also be combined with a flowable inert excipient and then directly compressed to give tablets without carrying out the granulation or dry-pressing steps.

[0193] In another embodiment of the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is provided in a hard gelatin capsule. These are produced by preparing a powder mixture as described above and filling a formed gelatin capsule with it. Glazing agents and lubricants such as highly dispersed silica, talcum, magnesium stearate, calcium stearate, or polyethylene glycol can be added as solids to the powder mixture. Disintegrants or solubilizers such as agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the drug after ingestion of the capsule. Furthermore, suitable binders and / or coloring agents can be added to the mixture as desired or necessary.

[0194] In another embodiment of the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is contained in a soft gelatin capsule (SGC). SGCs dissolve as they pass through the digestive tract. They consist primarily of gelatin enriched with varying amounts of plasticizers, such as glycerol or sorbitan. The release rate depends on the specific formulation of the SGC carrier material. They are also suitable for sustained release of active agents. SGCs are particularly useful for administering poorly water-soluble active agents.

[0195] In another aspect of the invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is contained in a chewable tablet or hard caramel, wherein the substance is incorporated into the matrix of the tablet or caramel.

[0196] Liquid dosage forms include solutions, suspensions, and emulsions. Examples are water and water / propylene glycol solutions for parenteral injection or the addition of sweeteners or opacifiers for oral solutions, suspensions, and emulsions. Liquid dosage forms may also include solutions for intranasal administration.

[0197] In another aspect the invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prevention or treatment of chronic inflammatory lung diseases having a global prevalence of less than or equal to 1:1500, wherein the substance, composition or combination is applied in the form of a sublingual tablet or lozenge.

[0198] Sublingual dosage forms can bypass hepatic metabolism, so compared with oral drug delivery, sublingual drug delivery can be an alternative.Fast onset of pharmacological effect is often desired for some drugs, especially for drugs used to treat acute disorders.Sublingual tablets disintegrate quickly, and the small amount of saliva present is usually sufficient to achieve disintegration of the dosage form, which combines with better dissolution and increased bioavailability.

[0199] Drugs must be sufficiently lipophilic to be able to partition through the lipid bilayer, but not so lipophilic that they will not repartition once inside. According to the diffusion model of absorption, the flux across the lipid bilayer is directly proportional to the concentration gradient. Therefore, lower salivary solubility results in a lower absorption rate, and vice versa. In general, drugs formulated for sublingual use should ideally have a molecular weight below 500 to facilitate their diffusion. The oral cavity has a narrow pH range, lying between 5.0 and 7.0. The inclusion of an appropriate buffer in the formulation of ionizable drugs allows for control of the pH of aqueous saliva.

[0200] A lozenge (troche) is a small, disk-shaped or diamond-shaped body composed of a solidified paste containing an astringent, antiseptic, or demulcent used for the local treatment of the mouth or throat; the lozenge is held in the mouth until it dissolves. The vehicle or base of a lozenge is usually sugar, an adhesive made by mixing with acacia or tragacanth, a fruit paste made from black or red currants, rose confection, or tolu balsam.

[0201] In another embodiment of the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is contained in a suppository. In a typical manufacturing method, a mixture of a low-melting wax and a fatty acid glyceride, such as cocoa butter, is first melted. The active agent is then dispersed uniformly by stirring or other mixing methods. The molten homogeneous mixture is then transferred to suitable molds and cooled until solidified.

[0202] In yet another aspect of the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is provided in a topical application form such as a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, paint, film, liposome, skin patch, transdermal patch, transdermal spray or suspension.

[0203] In yet another aspect of the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is provided as an inhalation formulation. For effective prophylactic or therapeutic treatment of chronic inflammatory lung diseases with a global prevalence of 1:1500 or less, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts must reach the patient's alveoli. Therefore, the particle size must be small enough to reach the lowest part of the airways in the lung tissue. Metered-dose inhalers (MDIs) are widely used, for example, in the treatment of asthma. They have a container for the pharmaceutical formulation, a canister, a metering valve for metering the dispensed amount, and a mouthpiece for inhalation. Pharmaceutical dosage forms consist of a drug, a liquefied gas propellant such as a hydrofluoroalkane, and optionally additional pharmaceutically acceptable excipients.

[0204] A particular group of MDIs are dry powder inhalers (DPIs). They deliver medication to the lungs in the form of a dry powder. Most DPIs rely on the patient's inhalation force to draw the powder from the device and subsequently break it down into particles small enough to reach the lungs. Therefore, insufficient patient inhalation flow rates can result in reduced dose delivery, incomplete powder breakup, and poor device performance. Therefore, most DPIs require minimal inspiratory effort for proper use. Therefore, their use is limited to older children and adults.

[0205] Nebulizers are used to administer active ingredients in the form of a mist that is inhaled into the lungs. Physically, this mist is an aerosol. It is generated in a nebulizer by breaking down solutions and suspensions into small aerosol droplets that can be inhaled directly through the device's mouthpiece. In conventional nebulizers, the aerosol can be generated by mechanical force, such as spring force in soft mist nebulizers, or electrical force. In jet nebulizers, a compressor actively flows oxygen or compressed air through an aqueous solution at high velocity, thus generating the aerosol. A variant is the pressurized metered dose inhaler (pMDIs). Ultrasonic nebulizers actively use an electronic oscillator that vibrates a piezoelectric element at high frequency to generate ultrasonic waves in a liquid reservoir.

[0206] The most promising technology is the vibrating mesh nebulizer. They typically provide better drug delivery than jet or ultrasonic nebulizers, although the latter two may also work in some indications. Vibrating mesh nebulizers use a mesh polymer membrane with a large number of laser-drilled holes. This membrane is placed between a liquid reservoir and an aerosol chamber. A piezoelectric element placed on the membrane induces high-frequency vibrations of the membrane, forming droplets in an aqueous solution and pressurizing these droplets through the membrane's holes into the aerosol chamber. This technology can produce very small droplet sizes. Furthermore, it can significantly reduce patient inhalation time, a feature that significantly improves patient compliance. Only these vibrating mesh nebulizers are believed to be capable of producing droplets containing active ingredients in the desired size range and delivering them to the patient's alveoli in therapeutically effective amounts within a reasonable time.

[0207] Mesh nebulizers can be divided into two groups based on their interaction with the patient: continuous-mode devices and trigger-activated devices. Continuous-mode mesh nebulizers release nebulized aerosol continuously into the mouthpiece, requiring the patient to inhale the aerosol. Trigger-activated devices release a defined amount of aerosol only during active, deep inspiration. Thus, a much larger volume of active-agent-containing aerosol is inhaled and reaches the lowest airways than continuous-mode devices. The latter lose a larger volume of active-agent-containing aerosol to either the periphery or the upper airway, since aerosol release is not coupled to the respiratory cycle.

[0208] Therefore, trigger-activated mesh nebulizers are preferred.

[0209] Trigger-activated vibrating mesh nebulizers are particularly preferred.

[0210] Mesh nebulizer models PARI eFlow® rapid, Philips Respironics I-neb, Philips InnoSpire Go, M-neb® dose + Mesh nebulizer inhalation MN-300 / 8, Hcmed Deepro HCM-86C and HCM860, OMRON MicroAir U100, Aerogen® Solo, KTMED NePlus NE-SM1, Vectura Fox, Vectura Bayer Breelib™ are preferred.

[0211] The most preferred vibrating mesh nebulizer models are the PARI eFlow® rapid, PARI Velox, Philips Respironics I-neb, and M-neb® dose. + High-end models include mesh nebulizer inhalation MN-300 / 8, Aerogen® Solo, Vectura Fox, and Vectura Bayer Breelib®.

[0212] Thus, the present application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence of 1:1500 or less, wherein the substance, composition or combination is applied by inhalation by using a vibrating mesh nebulizer, a metered dose inhaler, a jet nebulizer, an ultrasonic nebulizer or a dry powder inhaler.

[0213] Yet another aspect of the present invention refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the present invention, or a combination according to the present invention for use in the prevention or treatment of chronic inflammatory lung diseases with a global prevalence of 1:1500 or less, wherein the substance, composition, or combination is provided as an additive to the ventilation air of a cardiopulmonary bypass machine. During and after thoracic surgery, patients often need to be ventilated indefinitely in such machines until their own breathing allows for sufficient oxygenation. In these cases, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts can be added to the intubation ventilation air in solid form (dry powder) or liquid form (in an aqueous solution or as a nebulized aerosol, as described above).

[0214] In yet another aspect the invention refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prevention or treatment of chronic inflammatory lung diseases having a global prevalence of 1:1500 or less, wherein said substance, composition or combination is formulated as a retard.

[0215] In yet another aspect the invention refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prevention or treatment of chronic inflammatory lung diseases having a global prevalence of less than or equal to 1:1500, wherein said substance, composition or combination is formulated as a lyophilizate.

[0216] In yet another aspect of the invention, there is referred to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prevention or treatment of chronic inflammatory lung diseases having a worldwide prevalence of less than or equal to 1:1500, wherein said substance, composition or combination is applied in the form of liposomes, micelles, multilamellar vesicles or cyclodextrin complexes.

[0217] Further disclosed is a method for treating a chronic inflammatory lung disease having a worldwide prevalence of 1:1500 or less, wherein a therapeutically effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention is administered to a patient in need thereof, the chronic inflammatory lung disease being selected from the group consisting of bronchiectasis, alveolar microlithiasis, coal workers' pneumoconiosis, asbestosis, talc dust pneumoconiosis, silicosis, aluminum lung disease, bauxite pulmonary fibrosis, beryllium lung disease, graphite pulmonary fibrosis, iron deposition disease, tin deposition disease, tuberculosis-associated pneumoconiosis, assassination, linen wear disease, hemp fibrosis, farmer's lung, sugarcane lung disease, bird farmer's disease, cork lung, malt worker's lung, mushroom grower's lung, maple bark processor's lung, air-conditioning lung disease, humidifier lung, cheesemaker's lung, coffee worker's lung, fishmeal worker's lung, and lung, furrier's lung, sequiosis, allergic alveolitis, hypersensitivity pneumonitis, respiratory conditions due to inhalation of chemicals, gases, smoke, and vapors, solid and liquid pneumonitis, radiation pneumonitis, post-irradiation pulmonary fibrosis, chronic drug-induced interstitial lung disease, pulmonary permeability fluid, high-altitude pulmonary edema, eosinophilic asthma, Loffler's pneumonia pneumonia, tropical pulmonary eosinophilia, alveolar and mural alveolar conditions, Hamman-Rich syndrome, pulmonary abscess with pneumonia, empyema, pleural plaque, pneumothorax, chylous exudate, fibrothorax, hemothorax, hemopneumothorax, hydrothorax, chronic pulmonary dysfunction after surgery, host-versus-graft disease after lung transplantation, graft-versus-host disease after lung transplantation, chronic pulmonary allograft dysfunction, chronic pulmonary allograft dysfunction-bronchiolitis obliterans syndrome, pulmonary ischemia-reperfusion injury, primary graft dysfunction after lung transplantation, Mendelsohn's syndrome, lung collapse, atelectasis, interstitial emphysema, mediastinal emphysema, compensated emphysema, mediastinitis, diaphragmatic disorders, transient tachypnea of ​​the newborn, congenital pneumonia caused by viral agents, congenital pneumonia caused by chlamydia, congenital pneumonia caused by Staphylococcus, group B streptococcus B) congenital pneumonia, Escherichia coli (Escherichia coli) congenital pneumonia, Pseudomonas (Pseudomonas) congenital pneumonia, Haemophilus influenzae (Haemophilusinfluenzae congenital pneumonia, Klebsiella pneumoniae congenital pneumonia, Mycoplasma congenital pneumonia, neonatal meconium inhalation, perinatal pulmonary interstitial emphysema, perinatal pneumothorax, perinatal emphysema mediastinum, perinatal pulmonary hemorrhage, and Wilson-Mikity syndrome.

[0218] In particular, the present disclosure also refers to such methods of treating chronic inflammatory lung diseases with a global prevalence of 1:1700 or less, or 1:2000 or less, or 1:2500 or less, or 1:3000 or less, or 1:4000 or less, or 1:5000 or less, or 1:6000 or less, or 1:7000 or less, or 1:8000 or less, or 1:9000 or less, or 1:10000 or less.

[0219] Alternatively, the present disclosure also refers to methods of treating chronic inflammatory lung diseases with a global prevalence in the range of 1:1500 to 1:2,000,000, or 1:1700 to 1:2,000,000, or 1:2,000 to 1:2,000,000, or 1:2,500 to 1:2,000,000, or 1:3,000 to 1:2,000,000, or 1:4,000 to 1:2,000,000, or 1:5,000 to 1:2,000,000, or 1:6,000 to 1:2,000,000, or 1:7,000 to 1:2,000,000, or 1:8,000 to 1:2,000,000, or 1:9,000 to 1:2,000,000, or 1:10,000 to 1:2,000,000. [Example]

[0220] Example 1: 5-Amino-2,3-dihydro-1,4-phthalazinedione sodium salt Form I was tested in an isolated, ventilated, perfused mouse lung system challenged with cigarette smoke.

[0221] The isolated, ventilated, perfused mouse lung system (ILU) is an established model for studying the acute effects of various conditions and drugs on the lung parenchyma and vasculature. It is primarily used to examine the effects of hypoxia and evaluate the efficacy of potential drugs on hypoxic pulmonary vascular responses (see Weissmann et al. (2006) Proc Natl Acad Sci USA 103:19093-19098). Results from this experimental setting are considered indicative not only of the treatment of COPD, but also of all inflammatory disorders of the lower airways.

[0222] C57BL / 6J mice (n = 25, 5 per group; male / female, 3-6 months, 20-30 g; Charles River GmbH, Sulzfeld, Germany) were anesthetized with an intraperitoneal injection of ketamine (100 mg / kg body weight) and xylazine (20 mg / kg body weight) containing heparin (50 IE heparin / g body weight; Ratiopharm GmbH, Ulm, Germany) (Ceva Tiergesundheit GmbH, Düsseldorf, Germany). The lungs and heart were removed from the thoracic cavity and placed in an ILU system (see Figure 1A and Figure 1B). Lungs were ventilated in an isolated chamber using normoxic gas (21% O, 5% CO, 74% N; 150 breaths per minute with a PEEP (positive end-expiratory pressure) of 3 cm H2O) and perfused with modified Krebs-Henseleit buffer (120.0 mM NaCl, 4.3 mM KCl, 1.1 mM KH2PO4, 2.4 mM CaCl2, 1.3 mM MgCl2, 13.14 mM glucose, 0.25 mM hydroxyethyl starch 200,000 / 0.5, 25.0 mM NaHCO3, 800 mM L-arginine, adjusted to a constant pH range of 7.37–7.40; Serag-Wissner GmbH & Co. KG, Naira, Germany) at 37 °C. Lung weight, right and left ventricular pressures, and ventilation pressures were monitored and recorded throughout the experimental procedure. After 5–10 min, once the lungs had been adequately flushed and all parameters had stabilized, 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was applied by adding 150 μl of the stock solution to 15 ml of perfusion buffer. This substance was applied 10 min before the first cigarette smoke application. While the lungs were perfused with buffer containing 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, cigarette smoke was applied via the trachea. Cigarette smoke was freshly prepared before each application by burning one cigarette (University of Kentucky Research Cigarette 3R4F) for 1 min using normoxic gas at a flow rate of 1 L / min. The cigarette smoke was collected in a 1 L glass bottle containing 5 g of silica gel to remove moisture from the cigarette smoke. 50 ml of cigarette smoke was collected via a syringe and applied to the lungs via the trachea (Figure 1A) with deep breathing (periodic inflations of 3–4 s) over a 5-min period.The application was performed manually, carefully monitoring the inspiratory pressure to avoid lung damage. The application of cigarette smoke was repeated three times with a 1-hour break between applications.

[0223] Five treatment groups (n=5 each) were investigated: A: Indoor air exposure B: Cigarette smoke + diluent (buffer solution) C: Cigarette smoke + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt D: Cigarette smoke + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt E: Cigarette smoke + 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt

[0224] 5-Amino-2,3-dihydro-1,4-phthalazinedione sodium salt Form I was dissolved in water for injection (vehicle) at the required concentration as above. A stock solution was prepared in water for injection. A further 1:100 dilution was made using modified Krebs-Henseleit buffer (see above). The stock solution was stored in appropriate aliquots at -70°C. The required amount of stock solution was thawed and the corresponding working solution was prepared for immediate use.

[0225] One hour after the third cigarette smoke application, the lungs were removed from the system and fixed for 2 hours at room temperature by inflating (through the trachea) with formalin solution at a pressure of 12-15 cm HO. Fixed lungs were then kept at +4°C in PBS (phosphate-buffered saline, see below) until further dehydration and paraffin embedding. Paraffin blocks were cut at 3 μm thickness, dried overnight at 37°C, and stained for 3-nitrotyrosine (3-NT).

[0226] Toxins and xenobiotics in tobacco smoke result in a dramatic increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS). Oxidative and nitrosative stress correlate with the severity of inflammatory lung diseases. They increase the inflammatory response, cause an imbalance between proteolytic and antiproteolytic activity, increase the number of apoptotic cells, and decrease proliferation. These oxidants can overwhelm antioxidant defenses and initiate inflammation by various mechanisms (Foronjy and D'Armiento (2006) Clinical and Applied Immunology Reviews 6:53-72). The most potent RNS, peroxynitrite (ONOO), - ) is a product of nitric oxide (NO) and superoxide anion radical (O2 - ) (Szabo et al. (2007) Nat Rev Drug Discov 6:662-680). -Preferably, 3-NT attacks tyrosine residues in proteins to form the stable adduct 3-nitrotyrosine (Ricciardolo et al. (2004) Physiol Rev 84:731-765; Seimetz et al. (2011) Cell 147:293-305; Tsoumakidou et al. (2005) Chest 127:1911-1918). 3-NT levels in sputum proteins have been shown to be negatively correlated with FEV1 in COPD patients (Ricciardolo et al. (2004) Physiol Rev 84:731-765; Tsoumakidou et al. (2005) Chest 127:1911-1918). Nitrated tyrosine residues alter cell signaling, suggesting that 3-NT may not only be a marker of nitrosative stress but also have a functional relationship to the pathophysiology of inflammatory airway diseases (Davis et al. (2002); J Virol 76:8347-8359; Murata and Kawanishi (2004) Biochem Biophys Res Comm 316:123-128; Sugiura et al. (2004) Free Radic Res 38:49-57). 3-NT contributes to airway hyperresponsiveness and epithelial damage (Tsoumakidou et al. (2005) Chest 127:1911-1918) and has been proposed to play a major role in the development of airway remodeling (Ichinose et al. (2000) Am J Respir Crit Care Med 162:701-706).

[0227] Immunohistochemical staining for 3-nitrotyrosine was performed according to the following protocol: [Table 1]

[0228] Xylol was purchased from Carl Roth GmbH & Co. KG (Karlsruhe, Germany). Ethanol (96% and 99.6%) was purchased from Otto Fischar GmbH & Co. KG (Saarbrücken, Germany). Ethanol (70%) was purchased from SAV Liquid Production GmbH, Flintsbach am Inn, Germany. Hydrogen peroxide was purchased from Merck KGaA, Darmstadt, Germany. Methanol, bovine serum albumin (BSA), DAPI (4',6-diamidino-2-phenylidone), and anti-nitrotyrosine antibody (N0409; batch: 120M4825) were purchased from Sigma-Aldrich Co., Darmstadt, Germany. Rodent Decloacre's buffer (10x) and Warp Red Chromogen Kit were purchased from Biocare Medical, Pacheco, CA, USA. Tris wash buffer (TBS), CAT hematoxylin staining solution, and AP Polymer System (mouse / rabbit) were purchased from Zytomed Systems GmbH, Berlin, Germany. Dako Fluorescent Mounting Medium was purchased from Dako North America Inc., Villa Real Carpinteria, CA, USA. TruStain fcX (anti-mouse CD16 / 32; DR Fc block) was purchased from BioLegend Inc., San Diego, CA, USA. PBS (phosphate-buffered saline) was prepared using 8 g / L sodium chloride (Carl Roth GmbH+Co. KG, Karlsruhe, Germany), 0.2 g / L potassium chloride (Carl Roth GmbH+Co. KG, Karlsruhe, Germany), 1.42 g / L disodium hydrogen phosphate (Merck KGaA, Darmstadt, Germany), and 0.27 g / L potassium dihydrogen phosphate (Merck KGaA, Darmstadt, Germany).

[0229] Stained histological samples were analyzed blindly by light microscopy. 3-nitrotyrosine levels in the lung parenchyma were quantified as a percentage of the stained surface area. Quantification was performed at 200x magnification in 5-10 randomly selected fields, excluding large bronchi and blood vessels. For comparisons between groups, a one-way ANOVA statistical test with Bonferroni correction was performed. Differences of p<0.05 were considered statistically significant.

[0230] Cigarette smoke applied via the trachea resulted in a significant increase in 3-nitrotyrosine in the septum of exposed lungs (Figure 2B) compared with room air (Figure 2A). 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was added to the perfusion buffer before cigarette smoke application and maintained throughout the experiment. Cigarette smoke-induced 3-nitrotyrosine formation could be almost completely abolished in lungs perfused with buffer containing 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (Figure 2D) or 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (Figure 2E), whereas the lowest 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt concentration (0.5 mM; Figure 2C) produced a moderate effect.

[0231] Quantification of staining: [Table 2]

[0232] The results are shown as a bar graph in Figure 3. Values ​​(mean ± SEM) indicate the percentage of stained surface in the histological samples evaluated (5 mice per group; 5–6 evaluated histological samples per mouse).

[0233] From this experiment, it can be concluded that pretreatment with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt prevents cigarette smoke-induced 3-nitrotyrosine formation in the lung parenchyma of the ILU model.

[0234] This suggests that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has a protective effect against acute cigarette smoke-induced lung injury. Therefore, these results can be considered to predict the beneficial effects of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts in the inhalation prophylaxis or treatment of all inflammatory lung diseases, especially chronic inflammatory lung diseases.

[0235] Surprisingly, it has been found that the demonstrated beneficial effects of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt on acute cigarette smoke-induced lung injury are much stronger than could be predicted from experimental data known in the art regarding antioxidant activity and reduction of cytokine release. [Brief explanation of the drawings]

[0236] [Figure 1] A: Schematic diagram of the experimental setup of Example 1. 1 - Cigarette smoke 2 - Ventilator 3 - Trachea 4 - Lungs 5 ​​- Heart 6 - Reservoir 7 - Aqueous solution of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 8 - Roller pump B: Photograph of the experimental setup of Example 1. [Figure 2] Immunohistochemical staining of a representative sample from Example 1. Left panel: 200x magnification. Right panel: 400x magnification, more detailed enlargement than the left panel. A: Room air. B: Cigarette smoke + diluent (buffer). C: Cigarette smoke + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. D: Cigarette smoke + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. E: Cigarette smoke + 2mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. In the right panel, the inflamed area is highlighted. [Figure 3]Statistical evaluation of immunohistochemical staining of samples from Example 1. The percentage of stained surface area corresponds to the inflammation grade (n=5; mean±SEM). Bars with asterisks indicate highly significant differences between both groups (p<0.001). A: Room air B: Cigarette smoke + diluent (buffer) C: Cigarette smoke + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt D: Cigarette smoke + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt E: Cigarette smoke + 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt

[0237] List of abbreviations: [Table 3] TIFF0007807378000004.tif131166

Claims

1. A preventive or therapeutic agent for chronic inflammatory lung disease, comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts as an active ingredient, The chronic inflammatory lung disease is selected from the group of postoperative or related lower respiratory tract diseases consisting of chronic pulmonary dysfunction after surgery, host-versus-graft disease after lung transplantation, graft-versus-host disease after lung transplantation, chronic pulmonary allograft dysfunction, chronic pulmonary allograft dysfunction-bronchiolitis obliterans syndrome, pulmonary ischemia-reperfusion injury, primary graft dysfunction after lung transplantation, Mendelsohn's syndrome, lung collapse, atelectasis, pulmonary interstitial emphysema, mediastinal emphysema, compensated emphysema, mediastinitis, and diaphragmatic disorders. A preventive or therapeutic agent for chronic inflammatory lung diseases.

2. The preventive or therapeutic agent for chronic inflammatory pulmonary diseases according to claim 1, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

3. and wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has the X-ray powder diagram: for Form I, d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or 2θ values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3; for Form II, d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or 2θ values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8; and 3. The agent for preventing or treating chronic inflammatory lung diseases according to claim 2, wherein the agent is provided as one of crystalline anhydrous polymorphic Forms I, II or III characterized by crystallographic values ​​determined by the following in the case of Form III: d values: 13.131; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283; 3.222; 3.215; 3.127; 2.889; and / or 2θ values: 6.73; 11.07; 12.31; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.

93.

4. A preventive or therapeutic agent for chronic inflammatory lung diseases, comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier, and at least one pharmaceutically acceptable excipient, The chronic inflammatory lung disease is selected from the group of postoperative or related lower respiratory tract diseases consisting of chronic pulmonary dysfunction after surgery, host-versus-graft disease after lung transplantation, graft-versus-host disease after lung transplantation, chronic pulmonary allograft dysfunction, chronic pulmonary allograft dysfunction-bronchiolitis obliterans syndrome, pulmonary ischemia-reperfusion injury, primary graft dysfunction after lung transplantation, Mendelsohn's syndrome, lung collapse, atelectasis, pulmonary interstitial emphysema, mediastinal emphysema, compensated emphysema, mediastinitis, and diaphragmatic disorders. A preventive or therapeutic agent for chronic inflammatory lung diseases.

5. the at least one pharmaceutically acceptable excipient is selected from the group comprising binders, colorants, buffers, preservatives, antioxidants, coating agents, sweeteners, thickeners, pH adjusters, acidity regulators, acidifiers, solvents, isotonicity agents, penetration enhancers, disintegrants, glidants, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-caking agents, adsorbents, foaming agents, anti-foaming agents, opacifiers, fat-liquoring agents, consistency improvers, hydrotropes, fragrances and flavoring substances; The preventive or therapeutic agent for chronic inflammatory pulmonary disease according to claim 4.

6. A preventive or therapeutic agent for chronic inflammatory lung diseases, comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one additional active agent, the chronic inflammatory lung disease is selected from the group of postoperative or related lower respiratory tract diseases consisting of chronic pulmonary dysfunction after surgery, host-versus-graft disease after lung transplantation, graft-versus-host disease after lung transplantation, chronic pulmonary allograft dysfunction, chronic pulmonary allograft dysfunction-bronchiolitis obliterans syndrome, pulmonary ischemia-reperfusion injury, primary graft dysfunction after lung transplantation, Mendelsohn's syndrome, lung collapse, atelectasis, pulmonary interstitial emphysema, mediastinal emphysema, compensated emphysema, mediastinitis, and diaphragmatic disorders, the at least one further active agent is selected from the group comprising steroidal and non-steroidal anti-inflammatory drugs; immunomodulators; immunostimulants; immunosuppressants; antibiotics; antivirals; antifungals; antiprotozoal drugs; analgesics; anticoagulants; antiplatelet drugs; bronchodilators; pulmonary vasodilators; mucolytics; pulmonary surfactants; antioxidants; ENaC activators; HMG-CoA reductase inhibitors, calcium antagonists or AT1 receptor antagonists, A preventive or therapeutic agent for chronic inflammatory lung diseases.

7. 7. The preventive or therapeutic agent for chronic inflammatory pulmonary disease according to any one of claims 1 and 4 to 6, wherein the preventive or therapeutic agent is applied by inhalation, intubation, orally, parenterally, intraperitoneally, intravenously, intraarterially, intramuscularly, topically, transdermally, subcutaneously, intradermally, sublingually, conjunctivally, intravaginally, rectally, intrathecally, pharynx, or nasally.

8. The prophylactic or therapeutic agent is orally administered in the form of a tablet, a soft gelatin capsule, a hard gelatin capsule, a dragee, a pill, a powder, a granule, a liquid, a syrup, a drop, a tea, a solution or suspension in an aqueous liquid or a non-aqueous liquid, an edible foam, a mousse, an oil-in-water lotion or a water-in-oil lotion, The preventive or therapeutic agent for chronic inflammatory pulmonary disease according to any one of claims 4 to 7.

9. The preventive or therapeutic agent for chronic inflammatory pulmonary disease according to any one of claims 4 to 7, wherein the preventive or therapeutic agent is administered in the form of a sublingual tablet or lozenge.

10. The prophylactic or therapeutic agent is administered by inhalation using a vibrating mesh nebulizer, a metered dose inhaler, a jet nebulizer, an ultrasonic nebulizer, or a dry powder inhaler. The preventive or therapeutic agent for chronic inflammatory pulmonary disease according to any one of claims 4 to 7.

11. The preventive or therapeutic agent according to any one of claims 4 to 7, wherein the preventive or therapeutic agent is added to ventilation air in a cardiopulmonary bypass machine.

12. The prophylactic or therapeutic agent is formulated as a retard. The preventive or therapeutic agent for chronic inflammatory pulmonary disease according to any one of claims 4 to 7.

13. The prophylactic or therapeutic agent is formulated as a lyophilized product. The preventive or therapeutic agent for chronic inflammatory pulmonary disease according to any one of claims 4 to 7.

14. The prophylactic or therapeutic agent is applied in the form of a liposome, a micelle, a multilamellar vesicle or a cyclodextrin complex. The preventive or therapeutic agent for chronic inflammatory pulmonary disease according to any one of claims 4 to 7.

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