5-amino-2,3-dihydro-1,4-phthalazinedione for the treatment of acute lung injury

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 prevention or treatment of acute lung injury. 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] This application relates 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 acute lung injury. The present invention relates, in particular, to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for this purpose. [Background technology]

[0002] In early 2020, a pandemic caused by the coronavirus SARS-CoV-2 spread worldwide. While most infections present with a relatively mild course, approximately 15% of diagnosed patients develop severe symptoms, mainly severe pneumonia. About 3% of diagnosed patients have a fatal outcome. The most vulnerable groups are the elderly and those with a history of serious illness, such as those who are immunocompromised. The final stage of the disease is acute lung injury.

[0003] Acute lung injury (ALI) is a clinical syndrome of acute respiratory failure with significant morbidity and mortality. It is characterized by the acute onset of bilateral pulmonary infiltration with hypoxemia without evidence of hydrostatic pulmonary edema. For diagnosis, the American-European Consensus Conference Committee has outlined a consensus definition of ALI. This definition requires the acute onset of diffuse bilateral pulmonary infiltration on chest radiograph, PaO2 / FiO2 (partial pressure of oxygen / inspired oxygen concentration) ≤ 300 mmHg and pulmonary artery wedge pressure (PAWP) ≤ 18 mmHg or the absence of clinical findings of left atrial hypertension (Bernard et al. (1994) J Crit Care 9:72-81). The incidence of ALI in the United States is estimated to be 64-86 / 100,000 person-years. A mortality risk of 29-42% is listed (see Erickson et al. (2009) Crit Care Med 37:1574-1579).

[0004] ALI is acute inflammation resulting from the destruction of the endothelial and epithelial barriers of the lung. Cellular characteristics of ALI include loss of alveolar-capillary membrane integrity, excessive transepithelial neutrophil migration, and the release of pro-inflammatory cytotoxic mediators (see Matthay and Zimmerman (2005) Am J Respir Cell Mol Biol 33:319-327). Persistently elevated plasma levels of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α strongly predict mortality (Meduri et al. (1995) Chest 108:1303-1314).

[0005] Microvascular endothelial damage leads to increased capillary permeability. This change in permeability allows protein-rich fluid to flow into the peribronchial interstitium, ultimately crossing the epithelial barrier to the distal air spaces of the lung (Pugin et al. (1999) Crit Care Med 27:304-312). Excess and / or prolonged activation of neutrophils contributes to basement membrane disruption and increased permeability of the alveolar-capillary barrier. Neutrophil migration leads to the mechanical expansion of the paracellular neutrophil migration pathway. Neutrophils also release destructive pro-inflammatory and pro-apoptotic mediators that act on adjacent cells to create ulcerative lesions (Zemans et al. (2009) Am J Respir Cell Mol Biol 40:519-535).

[0006] Alveolar epithelial type II cell injury also leads to a loss of surfactant production (Greene et al. (1999) Am J Respir Cell Mol Biol 160:1843-1850), reducing overall lung compliance. Type II epithelial cells normally drive the epithelial repair process. Loss of this function can lead to disordered fibrotic repair (Bitterman (1992) Am J Med 92:39S-343S).

[0007] The resolution of ALI primarily depends on the timely and orderly repair of the alveolar gas exchange apparatus. To improve gas exchange, alveolar fluid transport must be upregulated, protein-rich edema fluid must be removed from the air spaces, and normal secretion of surfactants from alveolar type II cells must be restored (Matthay and Zimmerman (2005) Am J Respir Cell Mol Biol 33:319-327).

[0008] Treatment options for ALI include both assisted ventilation and pharmacological therapy. The best outcomes still involve improved ventilator management.

[0009] Numerous potential pharmacological treatments have been studied. However, the use of exogenous surfactants, inhaled nitric oxide, intravenous prostaglandin E1, glucocorticoids, ketoconazole, isophylline, N-acetylcysteine, and activated protein C has yielded mostly disappointing results (see Johnson and Matthay (2010) J Aerosol Medicine and Pulmonary Drug Delivery 23:243-252 for a review). β-2 agonists accelerate the resolution of pulmonary edema by reducing inflammation and upregulating alveolar salt and water transport. However, a large-scale, multicenter, randomized clinical trial of aerosolized albuterol was discontinued due to futility (Matthay et al. (2009) Am J Respir Cell Mol Biol 179:A2166). Intravenous administration of salbutamol significantly reduced extravascular pulmonary water (Perkins et al. (2006) Am J Respir Cell Mol Biol 173:281-287).

[0010] Statins are typically used to prevent or treat cardiovascular disease, but they also possess significant anti-inflammatory, immunomodulatory, and antioxidant effects. Statin users have been shown to have reduced sepsis severity and mortality despite having higher baseline comorbidities (Thomsen et al. (2008) Arch Intern Med 168:2081-2087).

[0011] Mice pre-treated with mesenchymal stem cells (MSCs) derived from bone marrow containing E. coli endotoxin showed reduced extravascular lung water, alveolar-capillary permeability, and overall mortality (Gupta et al. (2007) J Immunol 179:1855-1863).

[0012] A further treatment option is extracorporeal membrane oxygenation (ECMO) (see Freed et al. (2010) Can J Anaesth 57:240-247).

[0013] Delivery of pharmacoactive agents to the distal air space of the lungs via aerosols remains a promising option for both small molecules and proteins. Such dosage forms can also be applied to mechanically ventilated patients.

[0014] Therefore, there is a medical need to find pharmacologically active drugs to address inflammation in acute lung injury. In fact, it must reduce mortality, accelerate recovery rates, and shorten the number of days patients need to spend in the intensive care unit. This is especially crucial in light of the ongoing SARS-CoV-2 pandemic, as available intensive care unit beds and ventilators are limited in number, the latter being an essential feature. These locations will soon be filled by an unprecedented number of patients with acute lung injury.

[0015] Surprisingly, this problem is solved by a single dose of 5-amino-2,3-dihydro-1,4-phthalazinedione or its pharmaceutically acceptable salts or solvates, hydrates, crystalline polymorphs, tautomers, or isotopically enriched forms.

[0016] Accordingly, this application discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of acute lung injury. [Modes for carrying out the invention]

[0017] 5-amino-2,3-dihydro-1,4-phthalazinedione belongs to the pharmaceutical class of phthalazinediones. Compounds in this class are known for their beneficial anti-inflammatory effects. 5-amino-2,3-dihydro-1,4-phthalazinedione is also known as luminol. Luminol has excellent chemiluminescent properties. It is widely applied as a means of detection in diagnostic assays and forensic medicine, such as tracking blood spots. In medicine, 5-amino-2,3-dihydro-1,4-phthalazinedione is developed in the form of a sodium salt. In several countries, it is approved, among other things, for acute infections of bacterial and viral origin, particularly intestinal, hepatitis B and C, gastroenteritis, inflammation, such as prostatitis, endometriosis, throat inflammation, bronchial asthma, pneumonia, periodontitis, pyelonephritis, and autoimmune diseases, such as Crohn's disease, ulcerative colitis, lupus erythematosus, and scleroderma. Furthermore, a long list of therapeutic indications in scientific and patent literature still exists where 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has been tested for allergies or where its beneficial use has been suggested (see, in particular, International Publication Nos. 2004 / 041169; International Publication Nos. 2007 / 018546; International Publication Nos. 2012 / 127441; International Publication Nos. 2017 / 202496; and International Publication Nos. 2018 / 082814).

[0018] While most conventional immunomodulatory drugs cause serious adverse reactions or at least pose problems in long-term treatment, 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts are well-tolerated and have a high safety margin regarding the administered dose.

[0019] 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 are described for therapeutic applications (see International Publication No. 2010 / 082858). The crystal structures of the lithium, sodium, potassium, rubidium, and cesium salts are described in Guzei et al. (2013) Journal of Coordination Chemistry 66, 3722-3739. Accordingly, this patent application also refers to the use of all pharmaceutically acceptable salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0020] In particular, this application discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of acute lung injury, 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.

[0021] 5-amino-2,3-dihydro-1,4-phthalazinedione is often used as a hydrate, such as a 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 complexes with suitable ligands. Therefore, this patent application also refers to such complexes.

[0022] Anhydrous formulations are often preferred to ensure reproducible and standardized API production and to provide improved stability characteristics of the active drug substance. The anhydrous forms of the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione are described as crystal polymorphs in WO 2011 / 107295 (Form I, Form II) and WO 2016 / 096143 (Form III). These crystal polymorphs are substantially free of phase impurities and are characterized by X-ray powder diffraction. This method provides a set of characteristic d values indicating the interplanar spacing [Å] at which Bragg reflections occur and the corresponding 2-theta (2θ) angle [°]. Thereby, a unique and distinct fingerprint of each polymorph is obtained.

[0023] For Form I, the following values were determined. 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.

[0024] <{ Form II is characterized by the following values. 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.

[0025] 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.

[0026] 5-amino-2,3-dihydro-1,4-phthalazinedione itself exhibits polymorphism. Form I (Paradies (1992) Ber. Bunsen-Ges. Phys. Chem 96:1027-1031) and Form II (International Publication No. 2017 / 140430) have been disclosed.

[0027] Accordingly, this patent application also refers to the use according to the present invention of all crystalline forms and polymorphs of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts.

[0028] Similar therapeutic effects are known for various phthalazinediones, including derivatives of 5-amino-2,3-dihydro-1,4-phthalazinedione and their pharmaceutically acceptable salts. One example is 6-amino-2,3-dihydrophthalazine-1,4-dione (isoluminol). A summary of suitable phthalazinediones is given in International Publication No. 2007 / 018546. It is reasonable to assume that these compounds will exhibit equivalent effects when used for therapeutic purposes according to the present invention.

[0029] Tautomerism relates to the rapid internal transformation of organic compounds in which a hydrogen atom or proton formally moves into the interior of the compound. This involves the switching of single bonds and adjacent double bonds. 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.

[0030] Isomers are a group of molecules that have the same chemical formula but different chemical structures. They can be distinguished into structural isomers (where an exchange of atoms or functional groups occurs) and stereoisomers. Stereoiomers can be further subdivided into enantiomers (mirror images of the same molecule that cannot be superimposed) and diastereomers (the same molecule with different configurations of one or more stereocenters). Diastereomers can be further subdivided into cis / trans isomers (referring to the relative orientation of functional groups within the molecule) and conformational isomers (formally rotations around a single bond) and rotational isomers (different rotational configurations around a single bond). An example of a structural isomer of 5-amino-2,3-dihydro-1,4-phthalazinedione is 6-amino-2,3-dihydrophthalazine-1,4-dione (isoluminol). Stereoiomers can exist for phthalazinedione derivatives. Therefore, this patent application also refers to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione, its derivatives, and all isomers of pharmaceutically acceptable salts.

[0031] In some applications, it may be desirable for the isotopically enriched form of the compound of the present invention to be used, for example, for diagnostic purposes. Therefore, this patent application also refers to such isotopically enriched forms of the compound of the present invention.

[0032] From a pharmacokinetic standpoint 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 converted to a metabolically active form in the body. This conversion can occur systemically or locally. Therefore, this patent application also refers to prodrugs of the compounds of the present invention.

[0033] As used throughout this application, the term "5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts" encompasses all of the aforementioned molecular variants of 5-amino-2,3-dihydro-1,4-phthalazinedione, i.e., 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharmaceutically acceptable salts or solvates, hydrates, crystalline polymorphs, tautomers, or isotopic enriched forms.

[0034] Unless otherwise specified, the technical or scientific terms used in this invention have the meanings that those skilled in the art in the relevant field would have.

[0035] According to this application, the terms “API,” “active substance,” “active agent,” “pharmaceutical agent,” “active ingredient,” or “pharmaceutical active ingredient” (API) refer to 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, unless otherwise specified or used in a general sense.

[0036] The term “composition” or “pharmaceutical composition” includes at least one pharmaceutically acceptable excipient, and all agents generated directly or indirectly from the components outlined below, either in combination, accumulation, complex or crystal, or as a result of other reactions or interactions, and optionally together with at least one further pharmaceutical agent listed below, at least one active ingredient in any pharmacologically acceptable defined dose and dosage form.

[0037] The term "excipient" is used in this application 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 of the composition, the dosage, and the desired solubility and stability.

[0038] The terms “effect,” “therapeutic effect,” “action,” “therapeutic action,” “effectiveness,” and “effectiveness” used herein in reference to the substances of the present invention or any other active substances refer to beneficial results that occur irregularly and causally in organisms to which the substance has been previously administered.

[0039] According to the present invention, the terms “effective amount” and “therapeutic effective amount” refer to an amount of the substance of the present invention that is sufficiently large to produce the desired beneficial effect in a subject requiring such treatment.

[0040] The terms “treatment” and “therapy” include administering at least the substance of the present invention alone or in combination with at least one further pharmaceutical product, regardless of the time sequence of administration. Such administration is intended to substantially improve the course of acute lung injury by completely curing the disease or by stopping or slowing the progression of impairment during the course of the disease.

[0041] The terms “prevention” or “preventive treatment” include administering at least one of the substances of the present invention alone or in combination with at least one further pharmaceutical product, regardless of the time sequence of administration, to prevent or suppress the onset of symptoms resulting from acute lung injury. In particular, it refers to the medical condition of a patient in which the onset of such symptoms is expected with reasonable probability to occur in the distant or near future.

[0042] The terms "subject" and "patient" include individuals suffering from disease symptoms or disorders associated with acute lung injury, whether the diagnosis is confirmed or suspected. Individuals are mammals, particularly humans.

[0043] Within the scope of this application, the term "pharmaceuticals" includes human and veterinary drugs.

[0044] In the sense of this patent application, the terms “inflammatory disease” or “inflammatory lung disease” refer to a disease, disorder, or other physical condition characterized in particular by inflammation of the lungs. Inflammation is a response of body tissue to irritation (exogenous or endogenous pathogenic toxins) or injury. It can be triggered by physical, chemical, and biological irritations, including, among others, mechanical trauma, radiation injury, corrosive chemicals, extreme heat or cold, and infectious agents such as bacteria, viruses, fungi, and other pathogenic microorganisms or some thereof. Inflammation can have beneficial (e.g., within the scope of wound healing) and / or harmful effects in the affected tissue(s). This can even lead to loss of function of the affected tissue.

[0045] Inflammation is one of the initial responses of the immune system activated, for example, by infected or degenerated endogenous cells. The innate immune system mediates nonspecific responses, particularly general inflammatory responses, while the adaptive immune system provides responses specific to each pathogen, which are subsequently remembered by the immune system. An organism may be in an immunocompromised state, meaning that the immune response cannot adequately cope with the aforementioned stimuli or damage. On the other hand, the immune system may become hyperactive and alter its defenses against endogenous tissues, as in the case of autoimmune diseases.

[0046] If a healthy individual is known or likely to develop acute lung injury before surgery, for example, because the risk of exposure to bacteria or viruses that may cause tissue damage or acute lung injury is unavoidable for the medical or scientific staff of the respective laboratory, it may be indicated that a prophylactic agent may be administered to prevent or at least mitigate the expected injury or damage. Accordingly, this patent application also refers to the prophylactic use of the present invention.

[0047] Within the scope of this application, the term “lung” refers to the organs and tissues of the lower respiratory tract. Examples of the organs and tissues of the lower respiratory tract include, but are not limited to, the lungs, including the lobes, apex, lingula and alveoli; the bronchi, including the respiratory bronchioles; the rings of the trachea and bronchial rings, including the tracheal bifurcation; the pulmonary and bronchial blood vessels, including the pulmonary and bronchial blood vessels; the bronchopulmonary lymph nodes; and the autonomic nervous system of the lungs.

[0048] Within the scope of this application, the term “lung” further refers to adjacent organs and tissues that are functionally or structurally closely related to the lower respiratory tract and / or thoracic cavity and are therefore pharmaceutically accessible by inhalation. Examples include, but are not limited to, the pleura and diaphragm.

[0049] Within the scope of this application, the terms “alveolar” and “of the alveolar” refer to the tissue structures at the bottom of the lung airways. Alveoli are hollow, cup-shaped cavities found in the lung parenchyma where gas exchange takes place. Furthermore, they are sparsely located on the respiratory bronchioles, lining the walls of the alveolar ducts, and more numerous in the blind-ended alveolar sacs. The alveolar membrane is a gas exchange surface surrounded by a network of capillaries. Across the membrane, oxygen diffuses into the capillaries, and carbon dioxide is released from the capillaries into the alveoli and drawn out. The alveoli consist of an epithelial layer of simple squamous epithelium and an extracellular matrix surrounded by capillaries. The inner epithelial layer is part of the alveolar membrane and is also known as the respiratory membrane.

[0050] Type I and Type II lung cells are found in the alveolar walls. 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 flattened, and form the structure of the alveoli. Type II cells (goblet cells) release pulmonary surfactant, which reduces surface tension.

[0051] A typical pair of human lungs contains approximately 300 million alveoli, and is 70 m 2 This results in a large surface area. Each alveolus is surrounded by a fine mesh of capillaries that covers approximately 70% of its surface area. The diameter of a typical healthy alveolus is 200–500 μm.

[0052] Administration of 5-amino-2,3-dihydro-1,4-phthalazinedione to patients with acute lung injury results in a dose-dependent decrease in ROS / RNS levels in neutrophils and macrophages, slowing their migration through the lung epithelium and suppressing or at least mitigating the development of pulmonary edema. This significantly improves the survival rate of ALI patients in intensive care, significantly shortens the recovery time of surviving patients, and therefore reduces the number of days patients require intensive care and / or assisted ventilation.

[0053] The use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred. The use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I is particularly preferred.

[0054] Severe infections are the most common cause of ALI, accounting for nearly 50% of cases. These infections can lead to systemic diseases such as pneumonia or sepsis, septic syndrome, and septic shock (Piantadosi and Schwartz (2004) Ann Intern Med 141:460-470). Viral lung infections that cause ALI can result from either respiratory viruses or hospital-acquired viral infections caused by herpesviruses such as herpes simplex virus (HSV) and cytomegalovirus (CMV) (Luyt et al. (2008) Curr Opin Crit Care 14:605-608).

[0055] Bacterial pneumonia that can worsen into ALI includes Gram-positive bacteria such as Streptococcus pneumoniae, Staphylococcus aureus, and Bacillus anthracis; Gram-negative bacteria such as Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Bordetella pertussis, and Moraxella catarrhalis; and Coxilla burnetii and Chlamydophila pneumoniae. It is caused by infection with atypical bacteria such as Mycoplasma pneumoniae, Legionella pneumophila, Serratia marcescens, and Yersinia pestis.

[0056] Sepsis, septic syndrome, and septic shock are caused by Streptococcus pneumoniae, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii, Yersinia ssp., Salmonella spp., Burkholderia pseudomallei, Francisella tularensis, Rickettsia sp., Neisseria gonorrhoeae (Gonococcus neisseri). It is caused by infection with Gram-negative bacteria such as Neisseria neisseri and Neisseria meningitidis (Meningococcus), Gram-positive bacteria such as Haemophilus influenzae, Pseudomonas aeruginosa, Bacillus anthracis, Listeria sp., Erysipelothrix ssp., Clostridium perfringens, Actinomyces ssp., and Escherichia coli, and atypical bacteria such as Legionella ssp..

[0057] In some cases, such septic conditions can also be caused by fungal infections, such as those caused by Candida sp., Aspergillus sp., Histoplasma sp., or Pneumocystis jirovecii.

[0058] This application also discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of acute lung injury when the acute lung injury is caused by a viral infection.

[0059] The most common classes of respiratory viruses that cause ALI are influenza viruses and rhinoviruses, followed by parainfluenza viruses, adenoviruses, respiratory syncytial viruses, coronaviruses, and human metapneumoviruses (see Luyt et al. (2008) Curr Opin Crit Care 14:605-608).

[0060] Examples of such influenza A viruses include Spanish influenza virus H1N1, influenza virus H1N8, influenza virus H2N1, Asian influenza virus H2N2, Hong Kong influenza virus H3N2, avian influenza virus H5N1, swine influenza virus H9N2, and influenza virus H10N8.

[0061] Examples of generally harmless rhinovirus infections that can worsen include those caused by enterovirus-human rhinovirus (EV-HRV) and human rhinoviruses A, B, and C. Children, in particular, are susceptible and may require hospitalization in a PICU (Pediatric Intensive Care Unit).

[0062] Human parainfluenza viruses primarily endanger children. Examples include human parainfluenza viruses types 1-4 (HPIV1-4).

[0063] Adenovirus infections can progress from a simple cold to acute bronchitis and then to pneumonia. People with weakened immune systems are particularly at risk of developing ALI (Adenovirus Infection). These severe symptoms following adenovirus infection are mainly caused by subgroup B (serotypes HAdV-3, -7, -11, -14, -16, -21, -34, -35, -50, -55) and subgroup C (serotypes HAdV-1, 2, 5, 6, 57).

[0064] Respiratory syncytial viruses (RSV, HRSV) with subtypes A and B primarily affect children and the elderly and can be severe. Two to three percent of all infected children require intensive care (see Hall et al. (2009) New England J Med 360:588-598).

[0065] Human metapneumovirus (HMPV) is genetically similar to RSV and causes similar clinical symptoms. Children, in particular, are susceptible.

[0066] Herpesvirus infections can also cause severe symptoms such as ALI. In humans, the following herpesviruses are known: herpes simplex virus 1 and 2 (HSV-1 and HSV-2, or HHV1 and HHV2), varicella-zoster virus (VZV or HHV-3), Epstein-Barr virus (EBV or HHV-4), human cytomegalovirus (HCMV or HHV-5), human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus 7 (HHV-7), and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) (see Carter and Saunders (2007) Virology, Principles and Applications. John Wiley & Sons). In particular, HSV-1, HSV-2, and HCMV can cause serious lung problems if infection becomes uncontrolled (see Luyt al. (2011) Presse Med 40:e561-e568).

[0067] Hantavirus infections include those that can cause hantavirus pulmonary syndrome (HPS), which may terminate in ALI. Examples include infections with orthohantavirus hantan (HTNV), pumara orthohantavirus (PUUV), Dobrava-Belgrade orthohantavirus (DOBV), Seoul orho hantavirus (SEOV), Sin Nombre orthohantavirus (SNV), Black Creek Canal orthohantavirus (BCCV), Mononhagela virus (MGLV), New York orthohantavirus (NYV), El Moro Canyon orthohantavirus, Bayou orthohantavirus (BAYV), Choclo orthohantavirus (CHOV), and Andes orthohantavirus (ANDV).

[0068] Coronaviruses that are pathogenic to humans include SARS-CoV, SARS-CoV-2, MERS-CoV, and HCoV-HKU1, HCoV-NL-63, HCoV-OC43, and HCoV-229E. The last four cause only relatively mild symptoms (Andersen et al.: The Proximal Origin of SARS-CoV-2, on virologica.org, as of February 17). th (See 2020) On the other hand, infection with SARS-CoV, SARS-CoV-2, or MERS-CoV carries a relatively high risk of causing ALI.

[0069] Accordingly, in particular, this application discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of acute lung injury in which the acute lung injury is caused by a viral infection, and the viral infection is a coronavirus infection such as SARS-CoV, SARS-CoV-2, or MERS.

[0070] ALI may be iatrogenic. Such adverse drug reactions have been described, for example, with the intravenous administration of busulfan, bleomycin, methotrexate, azathioprine, BCNU (bis-chloroethyl-nitrosourea; carmustine), cytoxane, melphalan, mitomycin C, amiodarone, gold, nitrofurantoin, hexamethonium, and, to a limited extent, penicillamine and contrast agents.

[0071] ALI can also be a serious complication of other diseases such as connective tissue disease, systemic lupus erythematosus, rheumatoid arthritis, polymyositis / dermatomyositis, scleroderma, mixed connective tissue disease, pulmonary hemorrhagic syndrome and vasculitis, Goodpasture syndrome, microscopic polyangiitis, polyarteritis nodosa, granulomatous disease with polyangiitis, vasculitis associated with collagen vascular disease, acute pancreatitis, molal pregnancy, uremia and leukemia cytolysis.

[0072] ALI can also be caused by ingestion of paraquat, kerosene, modified rapeseed oil, etc., or by acute, massive inhalation, as well as by inhalants such as oxygen, amitrol-containing herbicides, ammonia and bleach mixtures, hydrogen sulfide, mercury vapor, nitric acid fumes, nitrogen dioxide, paint removers, smoke, smoke cylinders, sulfur dioxide, and toxic gases.

[0073] ALI can be caused by shock, toxic shock syndrome, trauma, bleeding, radiation exposure including via radioactive embolus beads, cardiopulmonary bypass, blood transfusion, heat, burns, drowning, peritoneal-venous shunts, post-lymphatic angiography, venous air embolism, and high altitude. It can also be neurogenic or cardiogenic.

[0074] 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the present invention, or a drug combination according to the present invention may be applied to the prevention or treatment of acute lung injury by any medically acceptable route of administration to a patient in need. Such medically acceptable routes of administration may be, for example, inhalation, intubation, oral, parenteral, intraperitoneal, intravenous, intra-arterial, or sublingual.

[0075] Preferred oral formulations for use in the prevention or treatment of acute lung injury are capsules or tablets containing 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, of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts.

[0076] In another aspect of the present invention, a composition for use in the prevention or treatment of acute lung injury is disclosed, the composition comprising one of 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof, a carrier, and at least one pharmaceutically acceptable excipient.

[0077] The term “pharmaceutically acceptable excipients” refers to natural or synthetic compounds added to pharmaceutical formulations together with pharmaceutically active agents. They may help increase the bulk of the formulation, improve the desired pharmacokinetic properties or stability of the formulation, and be beneficial in the manufacturing process. Advantageous classes of excipients according to the present invention include carriers, binders, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickeners, pH adjusters, acid adjusters, solvents, isotonic agents, disintegrants, flow enhancers, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-caking agents (anti-adhesion agents), adsorbents, anti-foaming agents, defoaming agents, opacifiers, fatliquoring agents, consistency enhancers, hydrotropes, fragrances, and flavoring substances.

[0078] Generally, one or more pharmaceutically acceptable carriers are added to a pharmaceutically active agent. Suitable carriers are all carriers and combinations thereof known in the art. In solid dosage forms, these may be, for example, plant and animal fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonite, silica, talcum, and zinc oxide. For liquid dosage forms and emulsions, suitable carriers are, for example, solvents, solubilizers, and 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, and sorbitan fatty acid esters. The suspension according to the present invention can use a diluent (e.g., water, ethanol, or propylene glycol), ethoxylated isostearyl alcohol, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonite, agar, tragacanth, or other carriers known in the art.

[0079] The term "binder" refers to a substance that binds powders together or adheres them together, making them cohesive through granular formation. They function as the "glue" of a formulation. Binders increase the cohesive strength of the diluent or filler provided.

[0080] Suitable binders include, for example, starches from wheat, corn, rice, or potatoes; gelatin; naturally occurring sugars such as glucose, sucrose, or beta-lactose; sweeteners from corn; natural and synthetic rubbers, such as acacia, tragacanth, or calcium ammonium alginate, sodium alginate, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, magnesium aluminum silicate, wax, and others. The percentage of binder in the composition may be in the range of 1 to 30% by weight, preferably 2 to 20% by weight, more preferably 3 to 10% by weight, and most preferably 3 to 6% by weight.

[0081] Colorants are excipients that impart color to pharmaceutical formulations. These excipients may be food colorants. They can be adsorbed onto suitable adsorption means such as clay or aluminum oxide. A further advantage of colorants is that spilled aqueous solutions on the nebulizer and / or mouthpiece can be visualized to facilitate cleaning. The amount of colorant may vary from 0.01 to 10% by weight of the pharmaceutical composition, preferably 0.05 to 6% by weight, more preferably 0.1 to 4% by weight, and most preferably 0.1 to 1% by weight.

[0082] Suitable pharmaceutical colorants include, for example, curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, alkannin, 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, ponseau 4R, ponseau SX, ponseau 6R, erythrosine, red 2G, allura red AC, induthrene blue RS, patent blue V, indigo carmine, brilliant blue FCF, chlorophyll and chlorophyllin, copper complex of chlorophyll and chlorophyllin, green S, fast green FCF, plain caramel, caustic sulfite caramel, ammonia caramel, sulfite ammonia caramel, black PN, carbon black, vegetable carbon, brown FK, brown These include HT, α-carotene, β-carotene, γ-carotene, anato, bixin, norbixin, paprika oleoresin, capsanthin, capsorbin, lycopene, β-apo-8'-carotenal, ethyl ester of β-apo-8'-carotenic 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, ferrous gluconate, and ferrous lactate.

[0083] Furthermore, buffers are preferred for liquid formulations, especially pharmaceutical liquid formulations. In particular, the terms buffer, buffer system, and buffer solution refer to the ability of a system to resist pH changes due to the addition of acids or bases, or dilution with solvents. Preferred buffer systems include formate, lactate, benzoic acid, 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-acetamide)iminodiacetic acid), PIPES (4-piperazine-bis-ethanesulfonic acid), BIS-TRIS pro The following can be selected from the group including pan(1,3-bis[tris(hydroxymethyl)methylaminool]propane), ethylenediamine, ACES(2-[(amino-2-oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS(3-(N-morphino)propanesulfonic acid), diethylmalonic acid, TES(2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), and HEPES(N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid).

[0084] Carbonate buffers such as acetate buffers, dicarboxylic acid buffers such as fumarate, tartrarate, and phthalate, and tricarboxylic acid buffers such as citrate are preferred.

[0085] Further groups of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide, and phosphate buffer. Another group of preferred buffers are nitrogen-containing buffers such as imidazole, diethylenediamine, and piperazine. Even more 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 includes glycine, glycyl-glycine, glycyl-glycyl-glycine, N,N-bis-(2-hydroxyethyl)glycine, and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine). Amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, N,N,N-trimethyllysine, 3-methylhistidine, 5-hydroxylysine, o-phosphoserine, γ-carboxyglutamate, [epsilon]-N-acetyllysine, [omega]-N-methylarginine, citrulline, ornithine, and their derivatives are also preferred. KH2PO4 buffer is particularly preferred.

[0086] Preservatives for liquid and / or solid dosage forms may be used as required. These include 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 para-hydroxybenzoate, sodium para-hydroxybenzoate, sodium para-hydroxybenzoate propyl para-hydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohol, cresol, cetylpyridinium chloride, chlorbutanol, thiomel (2-(ethyl mercurithiodesodium)benzoate), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, calcium bisulfite A selection may be made from the group including, but not limited to, sodium chlorine, potassium bisulfite, biphenyl, orthophenylphenol, sodium orthophenylphenol, thiabendazole, herring, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, 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.

[0087] The addition of a sufficient amount of antioxidant is particularly preferred for liquid formulations. Suitable examples of antioxidants include sodium metabisulfite, α-tocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, or propyl gallate. The use of sodium metabisulfite, α-tocopherol, and ascorbyl palmitate is preferred.

[0088] Tablets or pills are usually coated, meaning the coating constitutes the outer layer. This can be a film coating, a sugar coating containing sugars, or a compression coating. Pharmaceutically acceptable varnishes or waxes, HPMC (hydroxypropyl methylcellulose), MC (methylcellulose), or HPC (hydroxypropylcellulose) can be used. Such coatings can help mask the taste and facilitate swallowing or identification. Often, plasticizers and pigments are 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.

[0089] Suitable sweeteners can be selected from the group including mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidin dihydrochalcone, steviol glycoside, neotame, aspartame-acesulfame salt, maltitol, maltitol syrup, lactitol, xylitol, and erythritol.

[0090] Suitable thickeners can be selected from the group including, but not limited to, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, dextrin, polydextrose, modified starch, alkali-modified starch, bleached starch, oxidized starch, enzyme-treated starch, monostarch phosphate, distarch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, phosphate distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerin, hydroxypropyl starch, hydroxypropyl distarch glycerin, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerin, sodium octenyl succinate starch, acetylated oxidized starch, and hydroxyethylcellulose.

[0091] Suitable pH adjusting agents for liquid formulations include buffering substances such as sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate, or disodium hydrogen phosphate.

[0092] Appropriate acidity modifiers 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 tartarate, mono, dipotassium tartarate, sodium potassium tartrate, orthophosphate, lecithin citrate, magnesium citrate, ammonium malate, sodium malate, sodium hydrogen malate, calcium malate, calcium hydrogen malate, adipic acid, sodium adipic acid You can choose from the group including lium, potassium adipate, ammonium adipate, succinic acid, sodium fumarate, potassium fumarate, calcium fumarate, ammonium fumarate, 1,4-heptonolactone, triammonium citrate, ferric ammonium citrate, calcium glycerophosphate, isopropyl citrate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, magnesium carbonate, magnesium bicarbonate, ferrous carbonate, ammonium sulfate, potassium aluminum sulfate, ammonium aluminum sulfate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium hydroxide, and gluconic acid.

[0093] Acidifying agents are used as inorganic chemicals that produce or become acids. Suitable examples include ammonium chloride and calcium chloride.

[0094] Suitable solvents may be selected from, but are not limited to, water, carbonated water, water for injection, water containing an isotonic agent, physiological saline, isotonic physiological saline, alcohols, especially ethyl and n-butyl alcohols, and mixtures thereof.

[0095] Suitable isotonic agents include, for example, pharmaceutically acceptable salts, particularly sodium chloride and potassium chloride; sugars such as glucose or lactose; sugar alcohols such as mannitol and sorbitol; citrates, phosphates, borates, and mixtures thereof.

[0096] Suitable disintegrants can be selected from the group including, in particular, starch, cold water-soluble starches such as carboxymethyl starch, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, cross-linked microcrystalline cellulose such as microcrystalline cellulose and sodium croscarmellose, natural and synthetic rubbers such as guar, agar, karaya (Indian tragacanth), locust bean gum, tragacanth, clays such as bentonite, xanthan gum, alginates such as alginic acid and sodium alginate, and foaming compositions. Water expansion is supported, for example, by starch, cellulose derivatives, alginates, polysaccharides, dextran, and cross-linked polyvinylpyrrolidone. The amount of disintegrant in the composition can vary from 1 to 40% / weight, preferably 3 to 20% / weight, and most preferably 5 to 10% / weight.

[0097] Flow enhancers are materials that prevent sticking of each supplement and improve the flow characteristics of granules so that the flow is smooth and consistent. Suitable flow enhancers include silicon dioxide, magnesium stearate, sodium stearate, starch, and talc. The amount of flow enhancer in the composition may 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.

[0098] The term lubricant refers to a substance added to a dosage form, such as tablets or granules, to facilitate their discharge from a press die or exit nozzle. They reduce friction or wear. Since the lubricant must usually be present on the surface of the granules and between the granules and the parts of the press die, it is added immediately before pressing. 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, among others, metal stearate salts such as sodium oleate, sodium stearate, calcium stearate, potassium stearate and magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, waxes with high melting points, and polyethylene glycol.

[0099] Emulsifiers include, for example, the following anionic and nonionic emulsifiers, anionic emulsifier waxes, cetyl alcohol, cetyl stearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymer, addition products of 2 to 60 mol of ethylene oxide to castor oil and / or hydrogenated castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethensorbitan monolaurate, polyoxyethensorbitan monooleate, polyoxyethensorbitan monopalmitate, polyoxyethensorbitan monostearate, polyoxyethensorbitan tristearate, polyoxyethenstearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1,2-Diol Arginate, Carrageenan, Processed Eukema Seaweed, Locust Bean Gum, Tragacanth, Acacia Gum, Karaya Gum, Gellan Gum, Gatti Gum, Glucomannan, Pectin, Amidated Pectin, Ammonium Phosphatide, Brominated Vegetable Oil, Sucrose Acetate Isobutyrate, Glycerol Ester of Wood Rosin, Disodium Phosphate, Trisodium Diphosphate, Tetrasodium Diphosphate, Dicalcium Diphosphate, Calcium Dihydrogen Diphosphate, Sodium Triphosphate, Pentapotassium Triphosphate, Sodium Polyphosphate, Sodium Polyphosphate Calcium, Calcium Polyphosphate, Ammonium Polyphosphate, β-Cyclodextrin, Powdered Cellulose, Methylcellulose, Ethylcellulose, Hydroxypropylcellulose, Hydroxypropyl Methylcellulose, Ethyl Methylcellulose, Cal Boxymethylcellulose, sodium carboxymethylcellulose, ethyl hydroxyethylcellulose, croscarmellose, enzymatic 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 diacetyl tartaric acid esters of mono- and diglycerides of fatty acids, mixed acetate and tartaric acid esters of mono- and diglycerides of fatty acids, succinyl monoglycerides, sucrose esters of fatty acids, sucrose glycerides, polyglycerol esters of fatty acids, polyglycerol polyricinolate, propane-1 of fatty acids2-diol esters, propylene glycol esters of fatty acids, lactylated fatty acid esters of glycerol and propane-1, heat-oxidized soybean oil that interacts with monoglycerides and diglycerides of fatty acids, sodium dioctyl sulfosuccinate, sodium stearoyl-2-lactate, calcium stearoyl-2-lactate, stearyl tartrate, stearyl citrate, sodium stearyl fumarate, calcium stearoyl fumarate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate You can choose from 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, choline, choline salt, distem glycerol, sodium starch octenyl succinate, and acetylated oxidized starch. Phospholipids such as glycerin monooleate, stearic acid, and lecithin are preferred.

[0100] Suitable surface-active solubilizers (solubilizers) include, for example, diethylene glycol monoethyl ester, polyethylpropylene glycol copolymer, cyclodextrin, such as α- and β-cyclodextrin, glyceryl monostearate, such as Solutol HS 15 (Macrogol-15-hydroxystearate from BASF, PEG660-15 hydroxystearate), sorbitan ester, polyoxyethylene glycol, polyoxyethylene sorbitan acid ester, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearate triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, and (anionic) glyceryl monooleate.

[0101] Stabilizers are substances that can be added to prevent undesirable 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, aspartum acesulfame salt, amylase, protease, papain, bromelain, ficin, invertase, polydextrose, polyvinylpyrrolidone, polyvinylpolypyrrolidone, triethyl citrate, maltitol, and maltitol syrup.

[0102] Diluents or fillers are inert substances added to drugs to handle the minimum amount of activator. Examples of suitable diluents include 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.

[0103] To prevent clumping and facilitate packaging, transport, and dispensing from at least one chamber of a dispensing cap, an anti-caking agent (anti-adhesion agent) may be added to the supplement or supplement composition. 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.

[0104] Adsorbents are materials that absorb oil from water. Suitable examples include natural adsorbents, such as peat moss, sawdust, and feathers, as well as any natural adsorbents containing carbon and synthetic adsorbents, such as polyethylene and nylon. Adsorbents are used for moisture protection of tablets / capsules by limited fluid adsorption (adsorption or incorporation of liquids or gases by adsorption) in a dry state.

[0105] In some galenos formulations, it is desirable for the liquid oral dosage form to produce some foam upon dissolution. Such an effect can be supported by the addition of a foaming agent that reduces the surface tension of the liquid and thus promotes foam formation, or by increasing its colloidal stability by inhibiting the coalescence of the bubbles. Alternatively, the bubbles can be stabilized. Suitable examples include mineral oil, quillaja extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, and ammonium lauryl sulfate.

[0106] Alternatively, some liquid oral dosage forms may appear slightly foamy during preparation. While this does not hinder the intended use, in the case of pharmaceuticals, it may affect patient compliance. Therefore, it may be desirable to add a pharmaceutically acceptable antifoaming agent. Examples include polydimethylsiloxane, silicone oil, or simethicone.

[0107] Opacifiers are substances that, if necessary, make liquid dosages opaque. They must have a substantially different refractive index from the solvent, most often water as used herein. 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.

[0108] Suitable fats include, for example, decyl oleate, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, and sodium lauryl sulfate.

[0109] Consistency improvers include, for example, cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline wax, nonionic emulsifier wax, beeswax, paraffin, or stearyl alcohol.

[0110] Suitable hydrotropes are alcohols such as ethanol and isopropyl alcohol, or polyols such as glycerin.

[0111] 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 parts of plants that have their own characteristic scent. They can be extracted from plants or parts of plants by steam distillation.

[0112] Suitable examples include rapeseed, sage, cedar, clove, chamomile, anise, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineole, borneol, gingerol, eucalyptus, mango, fig, lavender oil, chamomile flowers, pine needles, cypress, orange, rose, rosewood, plum, quince, cherry, birch leaves, cinnamon, lime, grapefruit, tangerine. Juniper, valerian, lemon, lemon rose, lemongrass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy extract, blueberry, persimmon, melon, α- or beta-pinene, α-pinene oxide, α-camphorene aldehyde, α-citronellol, α-isoamyl cinnamic acid, α-terpinene cinnamate, α-terpineol, α-terpinene, aldehyde C 16α-Phellandrene, Amyl cinnamaldehyde, Amyl salicylate, Anisaldehyde, Basil, Anethole, Bay, Benzyl acetate, Benzyl alcohol, Bergamon, Bitter orange peel, Black pepper, Calamus, Camphor, Cananga oil, Cardamom, Carnation, Carvacrol, Carveol, Cassia, Castor, Cedarwood, Cinnamaldehyde, Cinnamyl alcohol, cis-Pinan, Citral, Citronella, Citronellal, Citronellol dextrose, Citronellol, Citronellyl acetate; Citronellyl nitrile, Citra Sunflower, clary sage, clove buds, coriander, corn, cotton seeds, d-dihydrocarbone, decyl aldehyde, diethyl phthalate, dihydroanethole, dihydrocarbeol, dihydrolinalool, dihydromyrcene, dihydromyrcenol, dihydromyrcenyl acetate; dihydroterpineol, dimethyl salicylate, dimethyloctanal, dimethyloctanol, dimethyloctanyl acetate, diphenyl oxide, dipropylene glycol, d-limonene, d-pulegone, estragole, ethyl vanillin, eucalyptol Eucalyptus citriodora, Eucalyptus globulus, Eugenol, Evening primrose, Fencol, Fennel, Ferniol, Fish, Florazone, Galaxolide, Geraniol, Geranium, Geranyl acetate, Geranyl nitrile, Guaiacol, Guaiac wood, Gourdung balsam, Heliotropin, Erbanate, Hiba, Hydroxynitroneral, i-Carvone, i-Methyl acetate, Ionone, Isobutylquinolein, Isobornyl acetate, Isobornyl methyl ether, Isoeugenol, Isolongifolene, Jasmine, Lavender, Limonene, Oxidation Linalool, linalool, linalool, linalyl acetate, flaxseed, dog hair, I-methyl acetate, longiphorene, mandarin, peppermint, menthane hydroperoxide, menthol crystals, menthol levo, menthone levo, methyl anthranilate, methyl cedryl ketone, methyl chavicol, methylhexyl ether, methyl ionone, methyl salicylate, minerals, mint, musk ambrette, musk ketone, muscoxylol, myrcene, nerol, neryl acetate, nonyl aldehyde, nutmeg, orris root, para-cymene, para-hydroxyphenyl butanone crystals,Patchouli, p-cymene, pentilloyl oil, pepper, perillaldehyde, petigren, phenylethyl alcohol, phenylethyl propionate, phenylethyl-2 methylbutyrate, pimento berry, pimento leaf, pinan hydroperoxide, pinanol, pinene ester, pine, pine, piperone, piperonyl acetate, piperonyl alcohol, prinol, prinyl acetate, pseudoionone, rhodinol, rhodinyl acetate, rosarine, lilac, white wood, sandenol, sassafras, sesame, soybean, spearmint, spices, spike lavender, spiranthol, starflower, tea seeds, terpenol These are essential oils of aromatic substances derived from citronella, terpineol, terpinolene, terpinyl acetate, tert-butylcyclohexyl acetate, tetrahydrolinalool, tetrahydrolinalyl acetate, tetrahydromyrcenolate, tulsi, thymol, tomato, trans-2-hexanol, trans-anethol, turmeric, terpentine, vanillin, vetiver, vitriol, white cedar, white grapefruit, wintergreen, etc., or mixtures thereof, as well as essential oils of aromatic substances derived from menthol, peppermint, and star anise oil, or a mixture of menthol and cherry flavor.

[0113] These aromatic or flavoring substances may be present in the composition at a concentration of 0.0001 to 10% by weight (particularly within the composition), preferably 0.001 to 6% by weight, more preferably 0.001 to 4% by weight, and most preferably 0.01 to 1% by weight. Different amounts may be advantageous in relation to the application or single case.

[0114] According to the present invention, all of the above-mentioned excipients and classes of excipients may be used without limitation, either alone or in any conceivable combination, unless they would prevent the use of the present invention, cause toxic effects, or are not permitted by the laws of their respective countries.

[0115] 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts may be used as monotherapy or in combination with at least one further active ingredient selected from the group containing active ingredients used for disease-modifying therapy for acute lung injury, symptomatic treatment of acute lung injury, and treatment of comorbidities.

[0116] Comorbidities may result from or be independent of impairment caused by acute lung injury. Therefore, for use in the prevention or treatment of acute lung injury, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts may be combined with at least one further active ingredient selected from the group including steroidal and nonsteroidal anti-inflammatory drugs, immunomodulators, immunosuppressants, antibiotics, antiretrovirals, antivirals, antifungals and antiprotozoa, analgesics, anticoagulants, antiplatelet agents, bronchodilators, pulmonary vasodilators, mucolytics, pulmonary surfactants, antioxidants, ENaC activators, HMG-CoA reductase inhibitors, calcium channel blockers or AT1 receptor antagonists.

[0117] Appropriate examples of such steroidal anti-inflammatory drugs include corticosteroids, glucocorticoids, cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, deltazone, triamcinolone, thixocortol pivalate, mometasone, amcinonide, budesonide, desonide, fluoconide, fluocinolone, halcinonide, flucortolone, hydrocortisone-17-valerate, halomethasone, and alkodium dipropionate. Examples include lometasone, betamethasone valerate, betamethasone dipropionate, plenicalvert, clobetazone-17-butyrate, clobetasol-17-propionate, flucortolone caproate, flucortolone pivalate, fluidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteplat, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, and beclomethasone dipropionate.

[0118] Suitable examples of such nonsteroidal anti-inflammatory drugs (NSAIDs) include acetylsalicylic acid, salicylic acid and salicylate, acetaminophen (paracetamol), sarsalate, diflunisal, ibuprofen, dexibprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketrolac, and diclo. Contains fenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, traminic acid, celexoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, flocoxib, nimeslid, clonixin, lycopherone, H-harpagid, flunixin, and tiaprofenic acid.

[0119] Suitable examples of such immunomodulatory drugs include, in particular, thalidomide, lenalidomide, pomalidomide, and apremilast.

[0120] Appropriate examples of such immunosuppressants include the glucocorticoid group listed above, cell proliferation inhibitors such as alkylating agents (cyclophosphamide, etc.), antimetabolites such as methotrexate, azathioprine, mercaptopurine, fluorouracil, and leflunomide, protein synthesis inhibitors, and certain antibiotics such as dactinomycin, anthracyclines, mitomycin C, bleomycin, and mitramycin, as well as interstitial agents such as mitoxantrone; muromonab-CD3, rituximab Antibodies such as ustekinumab, alemtuzumab, natalizumab, basiliximab, and daclizumab; immunophilin-acting drugs such as cyclosporine, tacrolimus, and sirolimus; unclassified immunosuppressants such as β-interferon and γ-interferon; opioids; TNF-binding proteins such as infliximab, etanercept, and adalimumab; or curcumin, catechin, mycophenolic acid, fingolimod, myriocin, and dimethyl fumarate.

[0121] Antiinfective agents are a general term for compounds useful in treating bacterial, viral, fungal, and parasitic infections (e.g., protozoa or parasites), and include antibiotics, antivirals, antifungals, and antiprotozoa.

[0122] Appropriate 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, tyrotricin, teixobactin, fosmidomycin, amikacin, gentamicin, kanamycin, neomycin, netylmycin, streptomycin, tobramycin, chloramphenicol, and fusidic acid. Contains cethromycin, nalbomycin, 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 rifampicin.

[0123] The following HIV-derived antiviral drugs, each used in antiretroviral therapy, may be suitable for combination therapy.

[0124] Reverse transcriptase inhibitors suitable for such combination therapy are nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Examples of NRTIs include, but are not limited to, abacavir, didanosine, emtricitabine, lamivudine, stabudine, tenofovir, zidovudine, zalcitabine, entecavir, adefovir, erbucitabine, fosalvudine (-tidoxil), fodivudine tidoxil, radiciclovir, aramihovir, klevudine, pradefovir, and terbivudine. Examples of NNRTIs include, but are not limited to, efavirenz, etravirine, nevirapine, rilpivirine, delavirudine, emivirine, and relcivirine.

[0125] Integrase inhibitors such as raltegravir, elvitegravir, dolutegravir, and MK-2048 are suitable for combination therapy according to the present invention.

[0126] Examples of HIV protease inhibitors suitable for combination therapy according to the present invention include saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosanprenavir, tipranavir, darunavir, brekanavir, mozenavir, and tipranavir.

[0127] Examples of entry inhibitors suitable for combination therapy according to the present invention are enfvirtide and maraviroc.

[0128] Suitable examples of common antiviral drugs include ancliviroc, apraviroc, senicliviroc, enfuvirtide, maraviroc, bicliviroc, amantadine, rimantadine, preconalil, idoxuridine, acyclovir, brivudine, famciclovir, penciclovir, sorivudine, valacyclovir, cidofovir, ganciclovir, valganciclovir, sofosbusvir, foscarnet, ribavirin, tarivirin, and fili. This includes buvir, nesbuvir, tegobuvir, fosdeviline, favipiravir, melimeepodib, asunaprevir, parapiravir, boceprivir, silprevir, danoprevir, daclatasvir, naraprevir, telaprevir, simeprevir, vanipevir, lupintorivir, hominivirsen, amenamevir, arisporivir, bevirimate, letermovir, laninamavir, oseltamivir, peramivir, zanamivir, and remdesivir.

[0129] Appropriate examples of such antifungal drugs include abafungin, amphotericin B, candicidine, philipin, hamycin, natamycin, nystatin, rimocidine, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, thioconazole, albaconazole, efinaconazole, and epoxy. Contains conazole, fluconazole, isabconazole, itraconazole, posaconazole, propiconazole, ravconazole, terconazole, voriconazole, amorolfine, butenafine, nafitifine, terbinafine, anidurafungin, caspafungin, micafungin, benzoic acid, cyclopirox, flucytosine, griseofulvin, haloprogin, tolnaphthate, undecylenic acid, crystal violet, and Peruvian balsam.

[0130] Appropriate examples of such antiparasitic drugs include metronidazole, tinidazole, ornidazole, atovaquone, clioquinol, chlorquinaldol, emetine, pentamidine isethionate, eflornithine, nitrofural, halofuginone, miltefosine, chloroquine, hydroxychloroquine, mepacrine, primaquine, amodiaquine, pamaquine, piperaquine, proguanil, cyclohanairenbonate, kinin, mefloquine, pyrimethamine, artemether, artemisinin, artesunate, dihydroartemisinin, halophanthrine, lumanthrine, and sulfadoxine.

[0131] Appropriate examples of further antiparasitic drugs include meglumine antimoniate, benznidazole, stivogluconate sodium, fumagiline, halophanthrin, melarsoprol, nifurtimox, nitazoxanide, permethrin, lindan, malathion, carbaryl, pyretrim, phenothrin, bioarethrin, imidacloprid, moxidectin, nitenpyram, fipronil, pyriprol, selamectin, dimpyrate, spinosad, indoxacarb, methoprene, pyriproxyfen, lufenuron, neem oil, citronella oil, clove oil, peppermint oil, and eucalyptus oil.

[0132] Appropriate examples of analgesics include opioid analgesics such as the NSAIDs listed above, morphine, fentanyl, methadone, oxycodone, carfentanil, dihydroethorphine, omefentanil, etorphine, sufentanil, remifentanil, alfentanil, buprenorphine, hydromorphone, levometadone, hydrocodone, pintramid, nalbufine, tapentadol, pentazocine, dihydrocodeine, codeine, pethidine, tramadol, tyrizine, meptazinol, naloxone, naltrexone, dyprenorphine, loperamide, and apomorphine; epibatidine; scopolamine; diconit; cannabinoids such as tetrahydrocannabinol, cannabidiol, and marinol; flupirtin; ketamine and the ketamines and local anesthetics listed above.

[0133] Suitable examples of such anticoagulants include heparin, coumarin, e.g., fenprocum (marcmar), and warfarin, apixaban, rivaroxaban, edoxaban, dabigatran, ximelagatran, hirudin, repirudine, bivalirudine, citrate, EDTA, fondaparinux, argatroban, and otamixaban.

[0134] Appropriate examples of such antiplatelet agents include absiximab, acetylsalicylic acid, dipyridamole, clopidogrel, eptifbatide, ilomezine, prostacyclin, prasugrel, ticagrelor, ticlopidine, and tyrofiban.

[0135] Appropriate bronchodilators, such as β-2 adrenergic receptor agonists, include short-acting β-2 agonists (SABAs) such as salbutamol, albuterol, bitorterol, fenoterol, isoprenaline, levosalbuterol, orciprenaline, pirbuterol, procaterol, ritodrine, and terbutaline; long-acting β-2 agonists (LABAs) such as alformoterol, bambuterol, clenbuterol, formoterol, and salmeterol; ultra-long-acting β-2 agonists such as avesiderol, carmoterol, indacaterol, orodaterol, and vilanterol (used alone or in combination with umeclidinium bromide and / or fluticasone furoate); and β-2 agonists with unknown durations of action such as isoxuprine, mabuterol, or zilpaterol.

[0136] Appropriate muscarinic anticholinergics (bronchodilator M3 receptor antagonists) include ipratropium bromide, tiotropium bromide, oxytropium bromide, glycopyrronium bromide, acridinium bromide, umeclidinium bromide, atropine, hyoscyamine, acridinium bromide, 4-DAMP, dalifenacin, DAU-5884, HL-031, HL-120, J-104, J-129, procyclidine, oxybutynin, tolterodine, and zamifenacin.

[0137] Further bronchodilators include epinephrine, ephedrine, theophylline, and TSG12.

[0138] A potent pulmonary vasodilator is nitric oxide. More suitable pulmonary vasodilators are prostacyclin (prostaglandin PGI2) analogs, such as iloprost, epoprostenol, and treprostinil.

[0139] Suitable mucolytic agents include N-acetylcysteine ​​(NAC), ambroxol, bromhexine, carbocysteine, erdocysteine, mecysteine, and dorunase α.

[0140] Suitable lung surfactants include synthetic compositions such as colfoseryl palmitate, pumactant, KL-4, venticute, and lucinactant, as well as animal-derived surfactants such as beractant, calfactant, and poractant alfa.

[0141] A powerful antioxidant is inhaled carbon monoxide (CO).

[0142] Suitable ENaC (epithelial sodium channel) activating peptides include AP301 and S3969.

[0143] Appropriate HMG-CoA reductase inhibitors (statins) include atorvastatin alone, or in combination with amlodipine and / or perindopril, cerivastatin, fluvastatin, or lovastatin, or in combination with niacin, mevastatin, pitavastatin, pravastatin, or rosuvastatin, or in combination with ezetimibe or simvastatin, or in combination with ezetimibe or niacin.

[0144] Appropriate calcium channel blockers include verapamil, garopamil, fendiline, nimodipine, nifedipine, nitrendipine, amlodipine, felodipine, relcanidipine, nicardipine, lasidipine, isradipine, nisoldipine, nivaldipine, manidipine, clibidipine, arnidipine, azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, pranidipine, diltiazem, mibeflazil, bepridil, flunarizine, and fluspiridine.

[0145] Suitable AT1 antagonists (angiotensin II receptor blockers; sartans) include losartan, valsartan, candesartan, telmisartan, irbesatan, olmesartan, eprosartan, fimasartan, azilsartan, milfasartan, pomisartan, platosartan, lipisartan, tasosartan, saprosartan, and EXP3174.

[0146] 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, and further active ingredients, may be used simultaneously, separately, or sequentially to treat or prevent disease symptoms. The two activators may be provided as a single dosage form or as separate formulations, each formulation comprising at least one of the two activators. One or both of the two activators may be formulated as a bolus.

[0147] In particular, this application discloses one of 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 treatment of acute lung injury that has been refractory to prior treatment with at least one other pharmaceutically active agent.

[0148] Pharmaceutical formulations suitable for oral dosage forms of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, compositions according to the present invention, or combinations according to the present invention may be administered as separate units such as soft gelatin capsules, hard gelatin capsules, tablets, sugar-coated tablets or pills; powders or granules; juices, syrups, drops; teas; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or emulsions in oil-in-water or water-in-oil form.

[0149] Therefore, in oral dosage forms such as tablets or capsules, the activator can be combined with a non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water. Powders are produced by grinding the compound to a suitable particle size and mixing them in a similar manner with a pharmaceutical carrier, such as starch or an edible carbohydrate such as mannitol. Flavoring agents, preservatives, dispersants, or colorants may also be present.

[0150] Tablets are formulated by manufacturing, granulating, or dry-pressing a powder mixture, adding lubricants and disintegrants, and pressing the mixture into tablets. Powder mixtures are manufactured by mixing a properly ground compound with a diluent or base as described above, and, if applicable, with a binder such as carboxymethylcellulose, arginate, gelatin, or polyvinylpyrrolidone, a dissolution retarder such as paraffin, an absorption enhancer 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 mucilage, or a solution of cellulose or polymer material, and pressing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet press to obtain irregularly shaped lumps, which are then broken down to form granules. The granules can be lubricated by adding stearic acid, stearphosphate, talc, or mineral oil to prevent them from adhering to the tablet mold. The lubricated mixture is then pressed to obtain tablets. The compound according to the present invention can also be combined with a fluid, inert excipient, and then directly pressed to obtain tablets without carrying out a granulation or dry pressing process.

[0151] In 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 rigid gelatin capsule. These are produced by preparing a powder mixture as described above and filling it into a molded gelatin cover. Brighteners and lubricants such as highly dispersed silica, talcum, magnesium stearate, calcium stearate, or polyethylene glycol can be added to the powder mixture as solids. 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 colorants can be added to the mixture as desired or as needed.

[0152] In another aspect 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). The SGC dissolves as it passes through the gastrointestinal tract. They are primarily made from gelatin concentrated 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 the sustained release of active drugs. SGCs are particularly useful for administering poorly water-soluble active drugs.

[0153] In another aspect of the present 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, where the substance is incorporated into the matrix of the tablet or caramel.

[0154] Sublingual drug delivery can be an alternative to oral drug delivery because it bypasses hepatic metabolism. Rapid onset of pharmacological effects is often desired for some drugs, particularly those used to treat acute injuries. Sublingual tablets disintegrate rapidly, and the small amount of saliva present is usually sufficient to achieve disintegration of the dosage form, coupled with better dissolution and increased bioavailability.

[0155] Drugs must be lipophilic enough to be distributed across the lipid bilayer, but once they enter the lipid bilayer, they are not lipophilic enough to be distributed again. According to the diffusion model of absorption, flow across the lipid bilayer is directly proportional to the concentration gradient. Therefore, lower salivary solubility results in a lower absorption rate, and vice versa. Generally, drugs formulated for sublingual administration should ideally have a molecular weight of less than 500 to facilitate their diffusion. The oral cavity has a narrow pH range of 5.0 to 7.0. By including an appropriate buffer in the formulation of ionizable drugs, it is possible to control the pH of aqueous saliva.

[0156] Taste masking is necessary to avoid the potential unpleasant taste or odor of the drug. Sweeteners, flavorings, and other taste masking agents (flavoring agents) are essential components. Sugar-based excipients dissolve rapidly in saliva, producing endothermic dissolution. They create a pleasant sensation in the mouth and, along with other flavors, are best suited for sublingual tablets.

[0157] Typical techniques for manufacturing sublingual tablets include direct compression, compression molding, freeze-drying, and hot-melt extrusion (Khan et al. (2017) J Pharmaceut Res 16:257-267).

[0158] If swallowing is to be avoided, the pharmaceutical active agent can also be administered sublingually, reaching the pharynx / throat locally. Absorption of the pharmaceutical active agent occurs through the pharyngeal mucosa in favorable areas.

[0159] A lozenge (troche) is a small, disc-shaped or rhomboid body made of a solidified paste containing an astringent, antiseptic, or thickener used for topical treatment of the mouth or throat, and is held in the mouth until it dissolves. The vehicle or base of the lozenge is usually a glue made by mixing with acacia or tragacanth, a fruit paste made from black or red currants, rose confectionery, or troux balsam.

[0160] This application also discloses parenteral administration of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, compositions, or combinations according to the present invention in the form of intravenous, intra-arterial, or intraperitoneal injection for the prevention or treatment of acute lung injury.

[0161] These liquid dosage forms include solutions, suspensions, and emulsions. Examples include water and water / propylene glycol solutions for parenteral injection, or the addition of sweeteners or emulsions to oral solutions, suspensions, and emulsions.

[0162] These liquid dosage forms can be stored in vials, IV bags, ampoules, cartridges, and pre-filled syringes. Suitable excipients include solubilizers, stabilizers, buffers, tonicity adjusters, volume extenders, thickeners / reducing agents, surfactants, chelating agents, and adjuvants.

[0163] In yet another aspect of the present invention, this application discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition, or a combination thereof for use in the prevention or treatment of acute lung injury, the substance, composition, or combination thereof being formulated as a lyophilized product. The lyophilized product can be reconstituted with water for injection, saline solution, or water / ethanol solution and then administered by injection.

[0164] Typical application forms for intravenous injection include infusion pumps, subcutaneous needles, infusion chambers, peripheral cannulas (peripheral venous catheters), and pressure bags.

[0165] In yet another aspect of the present invention, 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 is provided as an inhalation formulation.

[0166] For effective prophylactic or therapeutic treatment of acute lung injury, it is advantageous that 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 reaches the patient's lower respiratory tract, particularly the alveoli. Therefore, the particle size must be small enough to reach the lowest part of the airways in the lung tissue. The best class of inhalation device for the inhalation application of pharmaceutically active agents is the so-called mesh nebulizer described above. Within the scope of this application, substantially all mesh nebulizers known in the art can be used, from rather simple disposable mesh nebulizers for cough and cold or for malformed purposes, to sophisticated, high-end mesh nebulizers for the clinical or home treatment of serious diseases or conditions of the lower respiratory tract.

[0167] Suitable commercially available mesh nebulizers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers, and (pressurized) metered-dose inhalers include, but are not limited to, PARI eFlow® rapid, PARI LC STAR®, PARI Velox and PARI Velox Junior (PARI GmbH, Starnberg, Germany), Philips Respironics I-neb and Philips InnoSpire Go (Koninklijke Philips NV, Eindhoven, Netherlands), VENTA-NEB®-ir, OPTI-NEB®, and M-neb® dose. +Mesh nebulizer inhalation MN-300 / 8, M-Neb Flow+ and M-neb® mesh nebulizer MN-300 / X (NEBU-TEC, Eisenfeld, Germany), Hcmed Deepro HCM-86C and HCM860 (HCmed Innovations Co.,Ltd, Taipei, Taiwan), OMRON MicroAir U22 and U100 (OMRON, Kyoto, Japan), Aerogen® Solo, Aerogen® Ultra and Aerogen® PRO (Aerogen, Galway, Ireland), KTMED NePlus NE-SM1 (KTMED Inc., Seoul, South Korea), Vectura Bayer Breelib® (Bayer AG, Leverkusen, Germany), Vectura Fox, MPV Truma and MicroDrop® Smarty (MPV MEDICAL GmbH, Kirchheim, Germany), MOBI MESH (APEX Medical, New Taipei City, Taiwan), B.Well WN-114, TH-134 and TH-135 (B.Well Swiss AG, Widnau, Switzerland), Babybelle Asia BBU01 (Babybelle Asia Ltd., Hongkong), CA-MI Kiwi and others (CA-MI sri, Langhirano, Italy), Diagnosis PRO MESH (Diagnosis SA, Bialystok, Poland), DIGI O2 (DigiO2International Co., Ltd., New Taipei City, Taiwan), feellife AIR PLUS, AEROCENTRE+, AIR 360+, AIR GARDEN, AIRICU, AIR MASK, AIRGEL BOY, AIR ANGEL, AIRGEL GIRL and AIR PRO 4(Feellife Health Inc., Shenzhen, China), Hannox MA-02 (Hannox International Corp., Taipei, Taiwan), Health and Life HL100 and HL100A (HEALTH&LIFE Co., Ltd., New Taipei City, Taiwan), Honsun NB-810B (Honsun Co., Ltd., Nantong, China), K-jump (registered trademark) KN-9100 (K-jump Health Co., Ltd., New Taipei City, Taiwan), microlife NEB-800 (Microlife AG, Widnau, Switzerland), OK Biotech Docspray (OK Biotech Co., Ltd., Hsinchu City, Taiwan), Prodigy Mini-Mist (registered trademark) (Prodigy Diabetes Care, LLC, Charlotte, USA), Quatek NM211, NE203, NE320 and NE403 (Big Eagle Holding Ltd., Taipei, Taiwan), Simzo NBM-1 and NBM-2 (Simzo Electronic Technology Ltd., Dongguan, China), Mexus (registered trademark) BBU01 and BBU02 (Tai Yu International Manufactory Ltd., Dongguan, China), TaiDoc TD-7001 (TaiDoc Technology Co., New Taipei City, Taiwan), Vibralung (registered trademark) and HIFLO Miniheart Circulaire II (Westmed Medical Group, Purchase, USA), KEJIAN (Xuzhou Kejian Hi-Tech Co., Ltd., Xuzhou, China), YM-252, P&S-T45 and P&S-360 (TEKCELEO, Valbonne, France), Maxwell YS-31 (Maxwell India, Jaipur, India), Kernmed (registered trademark) JLN-MB001 (Kernmed, Durmersheim, Germany) are included.

[0168] A mesh nebulizer having piezoelectric activation in the spraying process, and a vibrating mesh nebulizer, are preferred.

[0169] Accordingly, in another aspect of the present invention, this application relates 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 acute lung injury in a formulation for inhalation administration, wherein the inhalation administration is performed by a vibrating mesh nebulizer.

[0170] Mesh nebulizers can be classified into two groups based on their interaction with the patient: continuous-mode devices and trigger-activated devices. In continuous-mode mesh nebulizers, the sprayed aerosol is continuously released into the mouthpiece, and the patient must inhale the provided aerosol. In trigger-activated devices, a predetermined amount of aerosol is released only during active, deep inspiratory breathing. In this way, a much larger amount of activator-containing aerosol is inhaled than in continuous-mode devices, reaching the lowest airways. The latter loses a large amount of activator-containing aerosol to either the surrounding airways or upper airway passages because the aerosol release is not coupled to the respiratory cycle.

[0171] Therefore, trigger-operated mesh nebulizers, particularly vibrating mesh nebulizers, are preferred.

[0172] A trigger-activated mesh nebulizer having piezoelectric activation of the spraying process is particularly preferred.

[0173] 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, and Vectura Bayer Breelib® are preferred.

[0174] The most preferred vibrating mesh nebulizer models are PARI eFlow® rapid, PARI Velox, Philips Respironics I-neb, and M-neb® dose. + These are high-end models such as the mesh nebulizer inhalation MN-300 / 8, Aerogen® Solo, Vectura Fox, and Vectura Bayer Breelib.

[0175] Accordingly, this application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, compositions, or combinations according to the present invention for use in the prevention or treatment of acute lung injury, the substance, composition, or combination being applied by inhalation using a vibrating mesh nebulizer, a metered-dose inhaler, or a dry powder inhaler.

[0176] The average droplet size is typically characterized as the MMAD (Aerodynamic Median Mass Diameter). The size of individual droplets is called the MAD (Mass Aerodynamic Diameter). This value indicates that 50% of the sprayed particles (droplets) have a smaller or larger diameter. Particles with an MMAD > 10 μm usually do not reach the lower respiratory tract and often become lodged in the throat. Particles with an MMAD greater than 5 μm but less than 10 μm usually reach the bronchi but not the alveoli. Particles with an MMAD between 100 nm and 1 μm do not deposit in the alveoli and are immediately exhaled. Therefore, the optimal range for MMAD is 1 μm to 5 μm. Recent publications further support a narrower range of 3.0 μm to 4.0 μm (see Amirav et al. (2010) J Allergy Clin Immunol 25:1206-1211; Haidl et al. (2012) Pneumologie 66:356-360).

[0177] A more commonly accepted quality parameter is the proportion of particles in the generated aerosol with a diameter in the range of 1 μm to 5 μm (FPM; particulate matter mass). FPM is a measure of particle distribution. It is calculated by subtracting the percentage of particles in the generated aerosol with a diameter in the range of less than 1 μm from the total percentage of particles in the generated aerosol with a diameter in the range of less than 5 μm (FPF; particulate matter fraction).

[0178] In another aspect of the present invention, this application also refers to a method for producing an aerosol according to the present invention for the prevention or treatment of acute lung injury, the following steps: a) Filling the spray chamber of a mesh nebulizer with 0.1 ml to 5 ml of an aqueous solution containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition or combination thereof according to the present invention, and optionally at least one pharmaceutically acceptable excipient; b) A step of initiating the vibration of the mesh of a mesh nebulizer at a frequency of 80kHz to 200kHz, c) A step of discharging the generated aerosol to the opposite side of the mesh spray chamber of the mesh nebulizer, Includes.

[0179] The vibration frequency of a vibrating mesh nebulizer is typically in the range of 80kHz to 200kHz, preferably 90kHz to 180kHz, more preferably 100kHz to 160kHz, and most preferably 105kHz to 130kHz (see Chen, The Aerosol Society: DDL2019; Gardenshire et al. (2017) A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th ed.).

[0180] Therefore, the aforementioned method is also disclosed along with the vibration frequency range.

[0181] Accordingly, the method according to the present invention is characterized in that at least 80% by weight, preferably at least 85% by weight, and most preferably at least 90% by weight of one of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, the composition according to the present invention, or a combination according to the present invention, is sprayed into the resulting aerosol.

[0182] The method of the present invention is particularly effective for spraying a high percentage of a pharmaceutically active agent(s) from a provided aqueous solution in a short period of time. This is a crucial feature for patient compliance. A significant proportion of the patient population finds the inhalation process unpleasant, tiring, and physically demanding. On the other hand, active patient cooperation is essential for effective and targeted inhalation applications. Therefore, it is desirable that a therapeutically sufficient amount be applied over the shortest possible period. Surprisingly, it has been shown that 95% of the substance provided in the aqueous solution can be sprayed within a 3-minute timeframe. This is an ideal period for high patient compliance.

[0183] Therefore, the method according to the present invention is characterized in that at least 80%, preferably at least 85%, and most preferably at least 90% of the generated aerosol is generated within 3 minutes after the start of spraying with a mesh nebulizer.

[0184] While the active pharmaceutical ingredient is typically supplied in a single dose container for each spraying procedure, the nebulizer and / or mouthpiece can be used over a period of time and should be replaced at regular intervals. Cleaning the nebulizer and mouthpiece is recommended by default after each spray. However, patient compliance cannot be reasonably guaranteed in this specification. Nevertheless, even after careful cleaning, some aerosol deposits will always be present in the spray chamber, outlet, and / or mouthpiece. Since aerosols are produced from aqueous solutions, these deposits pose a risk of generating a bioburden of bacteria that can contaminate inhaled aerosols. The deposits can also clog the pores of the mesh membrane in mesh nebulizers. In general, the nebulizer and / or mouthpiece should be replaced every one or two weeks. Therefore, it is convenient to supply the drug and nebulizer as a combined product.

[0185] Vibrating mesh nebulizers yielded better results than ultrasonic or jet nebulizers for antibiotic administration. When a constant-power vibrating mesh nebulizer was placed 10 cm into a Y-shaped section on the inspiratory limb and specific ventilation parameters were set (tidal volume of 8 ml / kg, respiratory rate of 12 c / min, duty cycle of 50%, constant and low inspiratory flow rate of less than 30 l / min, and end of inspiratory pause of 20%), 63% of the administered drug (ceftazidime, amikacin) reached the entrance of the endotracheal tube, with 37% extrapulmonary deposition (Lu et al. (2011) Am J Respir Crit Care Med 184:106-115). In most cases, the administered drug was uniformly distributed between both lungs. In pigs, it was found that using helium (He / O2) instead of nitrogen (N2 / O2) as the inhaled gas increased the concentration of ceftazidime in subpleural lung specimens (Tonnelier et al. (2005) Anesthesiology 102:995-1000).

[0186] In yet another aspect of the present invention, 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 is used for the prevention or treatment of acute lung injury, wherein the substance, composition, or combination is applied in the form of liposomes, micelles, multilayer vesicles, or cyclodextrin complexes. A method for producing multilayer vesicles of 5-amino-2,3-dihydro-1,4-phthalazinedione or its sodium salt is disclosed in International Publication No. 2019 / 137825.

[0187] In yet another aspect of the present invention, 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 is provided for use in the prevention or treatment of acute lung injury, the substance, composition, or combination being provided as an additive to the circulating air of a cardiopulmonary bypass device, which is a form of assisted ventilation. When a patient's condition deteriorates in an intensive care unit, the patient often needs to be ventilated indefinitely in such a device until their own respiration allows for sufficient oxygen supply. Good results have been achieved using an aerosol in a metered-dose inhaler combined with a Y-piece inhalation chamber. This allows for a 1.5 to 4-fold increase in the amount of bronchodilator administered (Fuller et al. (1994) Chest 105:214-218). 38% of the pharmaceutically active agent could be delivered (Marik et al. (1999) Chest 115:1653-1657). Alternatively, constant-power mesh nebulizers showed a 10-15% penetration rate in scintigraphy studies (Dugernier et al. (2016) Ann Intensive Care 6:73). Vibrating mesh nebulizers yielded better results than ultrasonic or jet nebulizers for antibiotic administration. When a constant-power vibrating mesh nebulizer was placed 10 cm into a Y-shaped area on the inspiratory limb and specific ventilation parameters were set (tidal volume 8 ml / kg, respiratory rate 12 c / min, duty cycle 50%, constant and low inspiratory flow rate less than 30 l / min, and inspiratory pause end 20%), 63% of the administered drug (ceftazidime, amikacin) reached the entrance of the endotracheal tube, with 37% extrapulmonary deposition (Lu et al. (2011) Am J Respir Crit Care Med 184:106-115). In most cases, the administered drug was uniformly distributed between both lungs. In pigs, it was found that using helium (He / O2) instead of nitrogen (N2 / O2) as the inhaled gas increased the concentration of ceftazidime in subpleural lung specimens (Tonnelier et al. (2005) Anesthesiology 102:995-1000).

[0188] In these cases, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts may be added to the intubation circulating air in solid form (dry powder) or liquid form (as previously described, in aqueous solution, or as a spray aerosol).

[0189] Accordingly, this application also discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, compositions, or combinations according to the present invention for use in the prevention or treatment of acute lung injury, the substance, composition, or combination being added to the circulating air of a cardiopulmonary bypass device.

[0190] Furthermore, a method for treating acute lung injury is disclosed, comprising administering 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 present invention, or a combination according to the present invention to a patient in need thereof. [Examples]

[0191] In all experiments and procedures, anhydrous form I of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is used (provided by MetrioPharm, synthesized at ChemCon, Freiburg, Germany). [Examples]

[0192] 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt reduces pro-inflammatory cytokine secretion in mouse peritoneal macrophages.

[0193] Female C57Bl / 6 mice (6-8 weeks old) were purchased from Envigo (San Petro al Natisone, Udine, Italy) and reared under standard laboratory conditions (free from specific pathogens). Food and water were provided freely. Animal handling and testing protocols followed international guidelines.

[0194] Four days after intravenous injection of 3% thioglycolate medium (w / v in distilled water; St. Louis, MO USA), mouse peritoneal macrophages (PMs) were isolated according to the protocol of Zhang et al. (Curr. Protoc. Immunol. 2008, Chapter 14, Unit 14.1).

[0195] In short, cells were collected by injecting 10 ml of complete culture medium (DMEM / F12 medium containing 10% fetal bovine serum) into the peritoneal cavity using a 30 cc syringe attached to a 19 G needle, followed by slowly withdrawing the lavage solution. The cells were washed twice in PBS (phosphate-buffered saline) and counted. A total of 3–4 × 10⁶ cells were obtained from each mouse. 6 We collected one macrophage.

[0196] Cell purity was confirmed by flow cytometry (using CD14 expression), and isolated PM cells were allowed to adhere overnight. One hour before LPS (lipopolysaccharide) stimulation (0.1 μg / ml; E. coli O55:B5, St. Louis, MO USA), cells (0.5 × 10⁶ in a 24-well plate containing 1 ml of culture medium) were placed. 6 Cells (per well) were pre-treated with scalar concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (ranging from 1 mM to 0.025 mM). Two independent experiments (each using pooled cells from three mice) were performed, and secreted cytokine levels were determined 24, 48, and 72 hours after LPS stimulation using ELISA techniques.

[0197] 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt did not affect cytokine secretion in unstimulated mouse PM (data not shown), however, LPS-induced pro-inflammatory cytokine concentrations were reduced by pretreatment with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (Figure 1). Specifically, 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt significantly reduced the levels of TNF-α, IL-6, IL-12, and IL-1-β by approximately 40%, 80%, 60%, and 50%, respectively. Interestingly, similar effects of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt were observed for all cytokines at 48 and 72 hours after culture. Furthermore, these effects were validated in PM of a second mouse strain (Balb / c), and a clear dose-dependent relationship was observed with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt at six different concentrations ranging from 1 mM to 0.25 mM (data not shown).

[0198] These experiments clearly demonstrate that treatment with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt significantly reduced the secretion of pro-inflammatory cytokines. [Examples]

[0199] 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I was tested in a PCI model for sepsis.

[0200] As mentioned above, severe infections are the most common cause of ALI. These can lead to systemic diseases such as pneumonia or sepsis, septic syndrome, and septic shock (Piantadosi and Schwartz (2004) Ann Intern Med 141:460-470). Therefore, a septic model of infection also demonstrates the efficacy of pharmacoactive agents in ALI.

[0201] In a PCI (peritoneal contamination and infection) model of sepsis, human fecal suspension was injected intraperitoneally into mice (3 μl / g body weight). All groups were administered the antibiotic meropenem (25 mg / kg body weight) 6 hours after PCI induction. At this point, all mice were also given a volumetric load of 5% glucose solution. This procedure was repeated at 24-hour intervals for two consecutive days after PCI induction. Group I: Control (no infection) Group II: PCI (infection, no treatment) Group III: PCI + 2 mg / kg body weight of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt Form I Group IV: PCI + 5 mg / kg body weight of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt Form I

[0202] a) Treatment mode Starting 8 hours after PCI induction, the treatment group mice were treated with intraperitoneal injections of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I at 2 mg / kg body weight, and separately at 5 mg / kg body weight, every 8 hours for 2 consecutive days. Subsequently, the mice were treated again for 8 days with intraperitoneal injections of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I at 2 mg / kg body weight, and separately at 5 mg / kg body weight (n=6).

[0203] Mouse mortality was assessed daily. As expected, all mice in the uninfected group (Group I) survived. In Group II, two mice died on day 3 and one mouse died on day 5. Therefore, the 10-day survival rate was 50%. In Group III, one mouse died on day 4 and two mice died on day 5. Therefore, the 10-day survival rate was also 50%. In Group IV, one mouse died on day 2, and all other mice survived. Therefore, the 10-day survival rate was 83%. Daily treatment with a dose of 5 mg / kg body weight of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I clearly reduces mouse mortality in the PCI model. A graphical evaluation is shown in Figure 2A.

[0204] b) Prevention mode Here, mice were treated with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I at a dose of 5 mg / kg body weight, but only twice: 3 hours before and 6 hours after PCI induction (n=8). All mice in group I survived. In group II, one mouse died on day 2, another on day 3, and yet another on day 5. Therefore, the survival rate was 63%. In group IV, no mice died. Therefore, the survival rate was 100%. This indicates that prophylactic administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can completely prevent mouse death in a PCI model of sepsis. A graphic evaluation is shown in Figure 2B.

[0205] c) Clinical severity score The clinical severity score (CSS) was assessed daily in mice in the prophylactic treatment group. CSS was assessed according to Gonnert et al. (2011) J Surg Res 170:e123-134. [Table 1]

[0206] Compared to the untreated group, the surviving animals in the prophylactically treated group (5 mg / kg body weight of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I) did not become as severely ill and recovered significantly more rapidly, especially from day 4 onwards. This is shown in Figure 2C. [Examples]

[0207] 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I was tested in isolated, ventilated, and perfused mouse lung systems stimulated with cigarette smoke.

[0208] The isolated, ventilated, and perfused mouse lung system (ILU) is an established model for studying the acute effects of various conditions and drugs on the lung parenchyma and vascular structure. It is primarily used to investigate the effects of hypoxia and to evaluate the potential efficacy of 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 to indicate not only the treatment of COPD but also all inflammatory disorders of the lower respiratory tract.

[0209] C57BL / 6J mice (n=25, 5 per group; male / female, 3-6 months, 20-30g; Charles River GmbH, Sulzfeld, Germany) were anesthetized by intraperitoneal injection of ketamine (100 mg / kg body weight) and xylazine (20 mg / kg body weight) containing heparin (50 I.E. heparin / g body weight; Ratiopharm GmbH, Ulm, Germany) (Ceva Tiergesundheit GmbH, Dusseldorf, Germany). The lungs and heart were removed from the thoracic cavity and placed on an ILU system (see Figures 1A and 1B). The lungs were ventilated in an isolated chamber using normoxic gas (21% O2, 5% CO2, 74% N2; 150 breaths per minute with 3 cm H2O PEEP (positive end-expiratory pressure)) and perfused with modified Krebs-Henselite buffer at 37°C (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 200000 / 0.5, 25.0 mM NaHCO3 adjusted to a constant pH range of 7.37-7.40, 800 mM L-arginine; Serag-Wissner GmbH&Co.KG, Naila, Germany). Lung weight, right and left ventricular pressure, and ventilation pressure were monitored and recorded throughout the entire experimental procedure. After 5–10 minutes, the lungs were adequately rinsed and, once all parameters had stabilized, 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was applied by adding 150 μl of stock solution to 15 ml of circulating perfusion buffer. This substance was applied 10 minutes before the first application of cigarette smoke. Cigarette smoke was applied via the trachea while the lungs were perfused with the buffer containing 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. Cigarette smoke was freshly prepared before each application by burning one cigarette (research cigarette 3R4F, University of Kentucky, USA) per minute using normal oxygen pressure gas at a flow rate of 1 l / min, and 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 syringe and applied to the lungs through the trachea with deep breathing (periodic expansion of 3-4 seconds) over a period of 5 minutes (Figure 4A). The application was performed manually, with careful monitoring of inspiratory pressure to avoid lung damage. The application of cigarette smoke was repeated three times with a 1-hour break in between.

[0210] Five treatment groups (n=5 each) were investigated. A: Indoor air exposure B: Tobacco smoke + diluent (buffer solution) C: Tobacco smoke + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt D: Tobacco smoke + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt E: Tobacco smoke + 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt

[0211] 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I was dissolved in sterile water for injection (vehicle) at the required concentration. The stock solution was prepared in sterile water for injection. Further dilution was performed at 1:100 using modified Krebs-Henselite buffer (see above). The stock solution was stored at -70°C in an appropriate fixed volume. The required amount of stock solution was thawed, and the corresponding working solution was prepared for immediate use.

[0212] One hour after the third application of tobacco smoke, the lungs were removed from the system and fixed at room temperature for 2 hours (through the trachea) by inflating them with formalin solution under a pressure of 12–15 cmH₂O. The fixed lungs were then maintained at +4°C in PBS (phosphate-buffered saline, see below) until further dehydration and paraffin embedding. The paraffin blocks were cut into 3 μm thick sections, dried overnight at 37°C, and stained for 3-nitrotyrosine (3-NT).

[0213] Toxins and foreign organisms in tobacco smoke lead to a dramatic increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS). Oxidative stress and nitrosative stress are correlated with the severity of inflammatory lung diseases. They increase the inflammatory response, cause an imbalance between proteolytic and anti-proteolytic activities, increase the number of apoptotic cells, and decrease proliferation. These oxidants overwhelm antioxidant defenses and can initiate inflammation through various mechanisms (Foronjy and D’Armiento (2006) Clinical and Applied Immunology Reviews 6:53-72). The most potent RNS, peroxynitrite (ONOO - ), is formed by the reaction between nitric oxide (NO) and the superoxide anion radical (O2 - ) (Szabo et al. (2007) Nat Rev Drug Discov 6:662-680). ONOO -Preferably, it attacks tyrosine residues in proteins to form a 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). Levels of 3-NT in salivary 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 cellular signaling, suggesting that 3-NT is not only a marker of nitrosation stress but may also have a functional relationship with 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).

[0214] Immunohistochemical staining for 3-nitrotyrosine was performed according to the following protocol. [Table 2]

[0215] Xylol was purchased from Carl Roth GmbH+Co.KG, Karlsruhe, Germany. Ethanol (96% and 99.6%) was purchased from Otto Fischar GmbH % Co.KG, Saarbrucken, 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. Decloaker buffer for rodents (10x dilution) 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., Via 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).

[0216] Stained histological specimens were analyzed blindly using a light microscope. 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 of view, excluding large bronchi and blood vessels. A one-way ANOVA test with Bonferroni correction was performed for comparisons between groups. A difference of p<0.05 was considered statistically significant.

[0217] Tobacco smoke applied via the trachea resulted in a significant increase in 3-nitrotyrosine in the exposed lung septum compared to room air as a control (Figure 5A) (Figure 5B). 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was added to the perfusion buffer before tobacco smoke application and maintained throughout the experiment. Tobacco smoke-induced 3-nitrotyrosine formation could be almost completely eliminated in lungs perfused with buffer containing 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (Figure 5D) or 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (Figure 5E), while the lowest 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt concentration (0.5 mM; Figure 5C) produced a moderate effect. Quantification of staining: [Table 3]

[0218] The results are shown as a bar graph in Figure 6. The values ​​(mean ± SEM) represent the percentage of stained surface in the evaluated histological samples (5 mice per group; 5-6 evaluated histological samples per mouse).

[0219] From this experiment, we can conclude that pretreatment with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt prevents tobacco smoke-induced 3-nitrotyrosine formation in the lung parenchyma of the ILU model.

[0220] This suggests that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has a protective effect against acute tobacco smoke-induced lung injury. Therefore, these results can be considered predictive of the beneficial effects of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts in the inhalation prophylaxis and / or treatment of all inflammatory lung diseases. [Examples]

[0221] 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt inhibits SARS-CoV-2 replication in infected Vero B4 cells.

[0222] Western blot (WB) analysis was performed to investigate whether 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt affects the spread of viral infection. Vero B4 cells (National Institute of Health, Bethesda, USA; Meyer et al. (2015) Emerg Infect Dis 21:181-182) were maintained in Dulbecco's Modified Eagle Medium (DMEM) containing 10% (v / v) inactivated fetal bovine serum (FCS), 2 mM L-glutamine, 100 U / mL penicillin, and 100 μg / mL streptomycin. 100-fold dilution of wild-type isolate SARS-CoV-2 was used. PR-1Confluent monolayers of Vero B4 cells were infected for 1 hour in FCS-free DMEM containing (isolated from a 61-year-old patient 6 days after the estimated date of infection and 2 days after the onset of mild COVID-19 symptoms). The cells were then washed with PBS (phosphate-buffered saline) and fresh medium containing non-cytotoxic concentrations (0.5 μM, 1 μM, 2 μM) of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. Treatment with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was performed throughout the experimental procedure. Virus-containing cell culture supernatant was collected 3 days after infection (dpi). Viions were purified from the cell culture supernatant via 20% (w / v) sucrose buffer (20,000 x g, 4°C, 90 min). Cells were washed with PBS, the pellet was dissolved in SDS (sodium dodecyl sulfate) sample buffer, separated by SDS-PAGE gel electrophoresis, transferred to a nitrocellulose membrane, blocked with 3% bovine serum albumin, and incubated with appropriate primary antibodies. SARS-CoV-2 proteins were visualized using convalescent SARS-CoV-2 patient serum. Anti-human secondary antibodies conjugated to horseradish peroxidase were obtained from Dianova (Hamburg, Germany). Visualization was performed by electrochemiluminescence.

[0223] Here, inhibition of SARS-CoV-2 replication was demonstrated in Vero B4 cells. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt showed a clear reduction in the SARS-CoV-2 nucleocapsid protein. The respective gel bands are shown in Figure 7A.

[0224] The concentration of SARS-CoV-2 nucleocapsid was evaluated using the AIDA® analysis program. This concentration evaluation allowed for the quantification of signal intensity in Western blotting, and therefore, the conclusion regarding the amount of specific proteins in the sample. The evaluation clearly showed that the production of SARS-CoV-2 protein was inhibited in a dose-dependent manner after the addition of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (Figure 7B). Statistical analysis was performed using Welch's corrected unpaired t-test. **p<0.01, *p<0.05. [Examples]

[0225] At effective concentrations, 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is not cytotoxic in Vero B4 cell cultures.

[0226] To address the question of whether 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt exhibits cytotoxic effects in the above system, uninfected Vero B4 cells were treated with increasing concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (0.25 mM, 0.5 mM, 1 mM, 2 mM, 4 mM) in parallel with Western blot studies. Toxicity was assessed by the WST (water-soluble tetrazolium salt 1) assay. Here, living cells with an intact mitochondrial succinate-tetrazolium dehydrogenase system result in the enzymatic conversion of the faintly red tetrazolium salt WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzenedisulfonate) to dark red formazan. This color change can be measured photometrically with a spectrophotometer. Therefore, the WST assay is a highly sensitive method for measuring the toxicity of substances to cellular metabolism. The values ​​for untreated cells were set to 100%.

[0227] 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can be shown to exhibit no significant toxic effects at antiviral effective concentrations in Vero B4 cells during a 3-day observation period.

[0228] Figure 8 shows the percentage of viable cells compared to untreated cells. The value for untreated cells was set to 100%. 1 μM staurosporine (an indolocarbazole compound derived from Streptomyces staurosporeus, an apoptosis inducer) was used as a positive control. Statistical analysis was performed using Welch's corrected unpaired t-test. **p<0.01, *p<0.05.

[0229] Therefore, it can be said that the antiviral effect of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is not due to a nonspecific cytotoxic effect. [Brief explanation of the drawing]

[0230] [Figure 1] The rate of reduction in the secretion of four pro-inflammatory cytokines after treatment with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. LPS induction only was set to 100%. Blocks from left to right: TNF-α, IL-6, IL-12, IL-1-β Each bar, from left to right: White: Untreated control Black: Treatment with LPS only Dark gray: LPS + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt Light gray: LPS + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt *: Significant; p<0.05 [Figure 2] Mouse survival rate in days after sepsis induction in PCI models A: Therapeutic treatment (daily intraperitoneal injection of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt) B: Prophylactic measures (intraperitoneal injection of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 3 hours before and 6 hours after sepsis induction) --- contrast ----- PCI ─ PCI+ 2 mg / kg of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt -- PCI+ 5 mg / kg of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt % Percent survival rate d. Number of days after sepsis induction [Figure 3] Clinical severity score in mice based on the number of days after sepsis induction in a PCI model. --- contrast ----- PCI ─ PCI+ 5 mg / kg of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt CSS Clinical Severity Score d. Number of days after sepsis induction [Figure 4] A: This is a schematic diagram of the experimental apparatus for Example 3. 1. Tobacco smoke 2. Ventilation system 3. Trachea 4-Lungs 5. Heart 6 Reservoirs Aqueous solution of 7-5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 8-Roller Pump B: Photograph of the experimental apparatus in Example 3 [Figure 5] Immunohistochemical staining of a representative sample from Example 3. Left panel: Magnification 200x Right panel: 400x magnification, magnified details from the left panel. A: Indoor air B: Tobacco smoke + diluent (buffer solution) C: Tobacco smoke + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt D: Tobacco smoke + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt E: Tobacco smoke + 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt The panel on the right highlights the inflamed areas. [Figure 6] Statistical evaluation of immunohistochemical staining of the samples from Example 3. The percentage of stained surface area corresponds to the grade of inflammation (n=5; mean ± SEM). Bars with asterisks indicate a high statistically significant difference between the two groups (p<0.001). A: Indoor air B: Tobacco smoke + diluent (buffer solution) C: Tobacco smoke + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt D: Tobacco smoke + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt E: Tobacco smoke + 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt [Figure 7] A: Western blot bands of SARS-CoV-2 nucleocapsid after treatment of vehicle and untreated cells with 0.5 mM, 1 mM, and 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for 3 days, respectively. B: Evaluation of SARS-CoV-2 nucleocapsid concentrations detected by Western blot bands after treatment of vehicle and untreated cells with 0.5 mM, 1 mM, and 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for 3 days, respectively. Percentage of detected viral protein is shown. Vehicle was set to 100%. (Mean ± SEM; n=3 / group; 2 pairs each; **p<0.01, *p<0.05) [Figure 8] Cell viability in WST assay after treatment with different concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for 3 days. Percentage of viable cells is shown. Untreated cells were set to 100%. Staurosporine (1 μM) was used as a positive control (mean ± SEM; n=3 / group; 2 rows each).

Claims

1. A pharmaceutical composition for use in the prevention or treatment of acute lung injury caused by coronavirus infection by SARS-CoV, SARS-CoV-2, or MERS, The composition contains one of 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof, a carrier, and at least one pharmaceutically acceptable excipient. A pharmaceutical composition for use in the prevention or treatment of acute lung injury.

2. The at least one pharmaceutically acceptable excipient is selected from the group comprising binders, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickeners, pH adjusters, acidity adjusters, acidifying agents, solvents, isotonic agents, disintegrants, flow enhancers, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-caking agents, adsorbents, foaming agents, defoaming agents, opacifiers, fatliquoring agents, viscosity enhancers, hydrotropes, aromatics, and flavoring substances. The composition according to claim 1.

3. For use in the prevention or treatment of acute lung injury caused by coronavirus infection by SARS-CoV, SARS-CoV-2, or MERS, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, and anti-infective agents such as steroidal and non-steroidal anti-inflammatory drugs, immunomodulators, immunosuppressants, antibiotics, antiretrovirals, antivirals, antifungals and antiprotozoa, analgesics, anticoagulants, antiplatelet agents, bronchodilators, pulmonary vasodilators, mucolytics, pulmonary surfactants, antioxidants, ENaC activators, HMG-CoA reductase inhibitors, calcium channel blockers, or AT １ A combination of at least one activator selected from the group including receptor antagonists.

4. The composition according to claim 1 or 2, or the combination according to claim 3, 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.

5. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is provided as one of crystalline anhydride polymorphs I, II, or III, characterized by crystallographic values ​​determined by X-ray powder mapping. For morphology I, the d values ​​were: 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 morphology II, the d values ​​were: 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 For morphology III, the d values ​​are: 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 The 2θ values ​​are: 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. The composition or combination according to claim 4.

6. A composition according to claim 1 or 2, or a combination according to claim 3, for use in the treatment of acute lung injury caused by coronavirus infection by SARS-CoV, SARS-CoV-2, or MERS, which has been refractory to prior treatment with at least one other pharmaceutically active agent.

7. It is administered orally in the form of tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets, pills, powders, granules, juices, syrups, drops, tea, solutions or suspensions in aqueous or non-aqueous liquids, edible foam, mousse, oil-in-water emulsions or water-in-oil emulsions. A composition according to claim 1 or 2, or a combination according to claim 3, for use in the prevention or treatment of acute lung injury caused by coronavirus infection by SARS-CoV, SARS-CoV-2, or MERS.

8. It is administered parenterally in the form of intravenous, intra-arterial, or intraperitoneal injection. A composition according to claim 1 or 2, or a combination according to claim 3, for use in the prevention or treatment of acute lung injury caused by coronavirus infection by SARS-CoV, SARS-CoV-2, or MERS.

9. This is applied by inhalation using a vibrating mesh nebulizer, a metered-dose inhaler, or a dry powder inhaler. A composition according to claim 1 or 2, or a combination according to claim 3, for use in the prevention or treatment of acute lung injury caused by coronavirus infection by SARS-CoV, SARS-CoV-2, or MERS.

10. It is added to the circulating air in the cardiopulmonary bypass device. A composition according to claim 1 or 2, or a combination according to claim 3, for use in the prevention or treatment of acute lung injury caused by coronavirus infection by SARS-CoV, SARS-CoV-2, or MERS.

11. It is applied in the form of liposomes, micelles, multilayer vesicles, or cyclodextrin complexes. A composition according to claim 1 or 2, or a combination according to claim 3, for use in the prevention or treatment of acute lung injury caused by coronavirus infection by SARS-CoV, SARS-CoV-2, or MERS.

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