Pharmaceutical composition containing PDE4 inhibitor compound a

Abstract

The present invention relates to a pharmaceutical composition containing a PDE4 inhibitor, in particular compound A. Further provided in the present invention are a method for preparing the pharmaceutical composition, and the use of the pharmaceutical composition in the treatment of a disease.

Description

Pharmaceutical composition containing PDE4 inhibitor compound A Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a pharmaceutical composition of compound A. Background Art

[0002] Compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one), Compound A is a new PDE4 inhibitor that can reduce the degradation of cAMP, thereby enhancing the activity of anti-fibrotic mediators (PGE2, prostaglandins and adenosine), which send signals through G protein-coupled receptors, thereby exerting anti-fibrotic effects. Among them, PGE2 exhibits multiple anti-fibrotic effects, including inhibiting fibroblast activation, enhancing the susceptibility of fibroblasts to apoptosis, and maintaining the integrity of alveolar epithelial cells. PGE2 can stimulate cAMP in lung fibroblasts through prostacyclin 2 receptors, disrupt calcium signaling and induce anti-fibrosis. PGE2 and treprostinil can also inhibit TGF-β-induced myofibroblast differentiation and promote the reversal of differentiated myofibroblasts into fibroblasts.

[0003] To facilitate the inhalation administration of Compound A, a suspension formulation was developed in the early stages. However, due to the long atomization and inhalation time of the suspension (greater than 5 minutes) and the need for a large nebulizer, it cannot meet the patient's need for outdoor inhalation. Therefore, it is necessary to develop an environmentally friendly, excellent atomization performance, and good stability pharmaceutical composition. Summary of the Invention

[0004] In one aspect, the present invention provides a pharmaceutical composition comprising: Compound A and / or its tautomers or pharmaceutically acceptable salts thereof, a metal chelating agent, a viscosity modifier, and a pharmaceutically acceptable carrier.

[0005] Another aspect of the present invention provides a method for preparing the pharmaceutical composition.

[0006] Another aspect of the present invention provides use of the pharmaceutical composition of the present invention in preparing a medicament for treating a disease.

[0007] In some embodiments, the pharmaceutical compositions of the present invention are used to treat diseases.

[0008] The pharmaceutical composition provided by the present invention has at least the following characteristics:

[0009] 1. The aerodynamic particle size is less than 4.5μm, the fine particle fraction is greater than 40%, and the atomization performance is excellent;

[0010] 2. Does not contain propellant, environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG1 shows the solubility of compound A in ethanol solutions of different concentrations. DETAILED DESCRIPTION

[0012] To make the purpose, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0013] The present invention may be implemented in other specific forms without departing from the essential attributes of the present invention. It should be understood that, without conflict, any and all embodiments of the present invention may be combined with the technical features of any other embodiment or multiple other embodiments to produce additional embodiments. The present invention includes additional embodiments resulting from such combinations.

[0014] All publications and patents mentioned in the present invention are hereby incorporated into the present invention in their entirety by reference. If the purposes or terms used in any publications and patents incorporated by reference conflict with the purposes or terms used in the present invention, then the purposes and terms of the present invention shall prevail.

[0015] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0016] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly used in the art to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0017] The following terms and symbols used in the present invention have the meanings described below unless otherwise indicated in the context.

[0018] Except in the working examples or otherwise indicated, all numbers stating quantitative properties such as dosages in the specification and claims should be understood to be modified by the term "about" in all cases. It should also be understood that any numerical range recited herein is intended to include all subranges within that range and any combination of the respective endpoints of that range or subrange. In the present invention, the term "about" should have the meaning of within 10%, preferably within 5%, of a specified value or range.

[0019] As used herein, words such as "include," "comprising," or "including" mean that the elements preceding the word include the elements listed after the word and their equivalents, without excluding unlisted elements. The terms "comprising" or "including" as used herein may be open, semi-closed, or closed. In other words, the terms also encompass "consisting essentially of" or "consisting of."

[0020] The terms "administer" or "administration" as they apply to an animal, human, experimental subject, cell, tissue, organ or biological fluid, refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent or composition with the subject, cell, tissue, organ or biological fluid.

[0021] As used herein, the term "treat" refers to the administration of one or more pharmaceutical substances to a subject having a disease or symptoms of a disease in order to cure, alleviate, relieve, alter, cure, ameliorate, improve or affect the disease or symptoms of the disease.

[0022] The term "pharmaceutically acceptable" indicates that the substance or composition in question is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the subject to be treated therewith.

[0023] As used herein, the term "subject" or "subject" refers to both mammals and non-mammals. Mammals refer to any member of the class mammalia, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds. The term "subject" does not limit the subject to a particular age or sex. In some embodiments, the subject is a human.

[0024] As used herein, the term "pharmaceutical composition" means a composition that is chemically and / or toxicologically compatible with the other ingredients comprising the formulation, and / or compatible with the subject being treated. As used herein, the term "therapeutically effective amount" refers to an amount that is generally sufficient to produce a beneficial therapeutic effect on the subject. The therapeutically effective amount of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., route of administration, pharmacokinetics of the compound, severity and course of the disease, medical history of the subject, health status of the subject, degree of response of the subject to the drug, etc.).

[0025] As used herein, the term "inhibit" refers to a decrease in the baseline activity of a biological activity or process.

[0026] The term "pharmaceutically acceptable carrier" (or therapeutically acceptable carrier) is well known to those skilled in the art and includes substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc. The specific carrier, diluent or excipient used depends on the manner and purpose for which the compound of the present invention will be applied. Solvents are generally selected based on solvents that are considered safe (GRAS) for administration to mammals by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc., and mixtures thereof.

[0027] "Radiation-induced lung injury" generally refers to damage to lung tissue caused by ionizing radiation (such as radiotherapy). Any radiotherapy used for thoracic tumors will cause radiation-induced lung injury. The radiotherapy includes external beam radiotherapy, internal beam radiotherapy, radionuclide therapy, whole body irradiation, intraoperative radiotherapy and 4D radiotherapy. More specifically, it includes three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), volumetric modulated radiotherapy (VMAT), image-guided radiotherapy (IGRT), stereotactic body radiation therapy (SBRT), proton therapy and brachytherapy.

[0028] "Radiation pneumonitis" is an early manifestation of radiation-induced lung injury. It differs from common inflammatory lung diseases. More specifically, common inflammatory lung diseases, such as pneumonia, have different causes. Pneumonia is a lung infection caused by bacteria, viruses, or other microorganisms that primarily invade the alveoli, with bacterial and viral pneumonia being the most common. Clinically, onset is relatively short, with symptoms primarily consisting of cough and high fever. Treatment primarily focuses on symptomatic treatment and antibiotics to combat bacterial or viral infections. Pneumonia generally resolves spontaneously after the cause is eliminated. However, the damage caused by radiation-induced lung injury continues to progress.

[0029] "Radiation-induced pulmonary fibrosis" is a late manifestation of radiation-induced lung injury. Radiation-induced pulmonary fibrosis is a type of pulmonary fibrosis with a relatively clear etiology, which is different from idiopathic pulmonary fibrosis (IPF). IPF is a chronic progressive fibrosing interstitial lung disease of unknown cause, with typical symptoms such as progressive dyspnea and dry cough, and patients eventually die of respiratory failure. IPF is a type of disease characterized by extracellular fibrosis deposition, which has a long and insidious onset time. In most cases, lung function has been severely reduced at the time of diagnosis. In contrast, patients with early-stage radiation-induced lung injury will show clinical symptoms, and most patients will not develop into the pulmonary fibrosis stage if they are intervened with early anti-inflammatory drugs. The PDE4 inhibitors of the present invention have significant effects in treating and / or preventing radiation-induced lung injury.

[0030] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0031] Pharmaceutical composition of compound A

[0032] In one aspect of the present invention, the present invention relates to a pharmaceutical composition comprising: Compound A and / or its tautomers or pharmaceutically acceptable salts thereof, a metal chelator, a viscosity modifier, and a pharmaceutically acceptable carrier.

[0033] In some embodiments, the viscosity modifier is selected from glycerol, Tween (e.g., Tween 80), povidone (e.g., povidone K30), polyvinyl alcohol, hypromellose, hydroxypropyl cellulose, sodium hyaluronate, or carbomer. In some specific embodiments, the viscosity modifier is glycerol. In other specific embodiments, the viscosity modifier is Tween (e.g., Tween 80). In other specific embodiments, the viscosity modifier is povidone (e.g., povidone K30). In other specific embodiments, the viscosity modifier is polyvinyl alcohol. In other specific embodiments, the viscosity modifier is hypromellose. In other specific embodiments, the viscosity modifier is hydroxypropyl cellulose. In other specific embodiments, the viscosity modifier is sodium hyaluronate. In other specific embodiments, the viscosity modifier is carbomer.

[0034] In some embodiments, the metal chelator is selected from disodium EDTA, sodium calcium EDTA, sodium thiosulfate, sodium hexametaphosphate, gluconic acid and its salts, citric acid and its salts, tartaric acid and its salts, glycine, or glutamic acid. In some specific embodiments, the metal chelator is disodium EDTA. In other specific embodiments, the metal chelator is sodium calcium EDTA. In other specific embodiments, the metal chelator is sodium thiosulfate. In other specific embodiments, the metal chelator is sodium hexametaphosphate. In other specific embodiments, the metal chelator is gluconic acid and its salts. In other specific embodiments, the metal chelator is citric acid and its salts. In other specific embodiments, the metal chelator is tartaric acid and its salts. In other specific embodiments, the metal chelator is glycine. In other specific embodiments, the metal chelator is glutamic acid. In some embodiments, for gluconate, citrate, tartrate, the salts may include alkali and alkaline earth metal based cations, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Salts of amino acids, such as arginine salts, gluconates, galacturonates, etc. are also contemplated.

[0035] In some embodiments, the concentration of the viscosity modifier is in the range of 0.1-5.0% (w / w). In some embodiments, the concentration of the viscosity modifier is in the range of 0.25-5.0% (w / w); in other embodiments, the concentration of the viscosity modifier is in the range of 0.25-2.0% (w / w); in other embodiments, the concentration of the viscosity modifier is in the range of 0.25-1.0% (w / w); in other embodiments, the concentration of the viscosity modifier is in the range of 0.25-0.5% (w / w); in other embodiments, the concentration of the viscosity modifier is in the range of 0.5-5.0% (w / w). ); in other specific embodiments, the concentration range of the viscosity modifier is 0.5-2.0% (w / w); in other specific embodiments, the concentration range of the viscosity modifier is 0.5-1.0% (w / w); in other specific embodiments, the concentration range of the viscosity modifier is 1.0-5.0% (w / w); in other specific embodiments, the concentration range of the viscosity modifier is 1.0-2.0% (w / w); in other specific embodiments, the concentration range of the viscosity modifier is 2.0-5.0% (w / w). In some preferred embodiments, the concentration range of the viscosity modifier is 0.5-1.0% (w / w).

[0036] In some embodiments, the concentration of the viscosity modifier is 0.1% (w / w), 0.25% (w / w), 0.5% (w / w), 1.0% (w / w), 2.0% (w / w), or 5.0% (w / w). In some preferred embodiments, the concentration of the viscosity modifier is 0.5% (w / w). In some preferred embodiments, the concentration of the viscosity modifier is 1.0% (w / w).

[0037] In some embodiments, the concentration of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof is in the range of 0.01-6.0% (w / w).

[0038] In some embodiments, the concentration of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof is 0.01% (w / w), 0.1% (w / w), 0.5% (w / w), 1.0% (w / w), 2.0% (w / w), 3.0% (w / w), 4.0% (w / w), 5.0% (w / w) or 6.0% (w / w).

[0039] In some embodiments, the concentration of the metal chelator ranges from 0.001% to 0.02% (w / w). In some specific embodiments, the concentration of the metal chelator ranges from 0.01% to 0.02% (w / w).

[0040] In some specific embodiments, the concentration of the metal chelator is 0.001% (w / w). In other specific embodiments, the concentration of the metal chelator is 0.002% (w / w). In other specific embodiments, the concentration of the metal chelator is 0.003% (w / w). In other specific embodiments, the concentration of the metal chelator is 0.004% (w / w). In other specific embodiments, the concentration of the metal chelator is 0.005% (w / w). In other specific embodiments, the concentration of the metal chelator is 0.006% (w / w). In other specific embodiments, the concentration of the metal chelator is 0.007% (w / w). In other specific embodiments, the concentration of the metal chelator is 0.008% (w / w). In other specific embodiments, the concentration of the metal chelator is 0.009% (w / w). In some other specific embodiments, the concentration of the metal chelator is 0.01% (w / w). In some other specific embodiments, the concentration of the metal chelator is 0.02% (w / w).

[0041] In some embodiments, the pharmaceutically acceptable carrier is an aqueous ethanol solution. In some specific embodiments, the ethanol concentration ranges from 30-90% (w / w).

[0042] In some specific embodiments, the ethanol concentration is 30% (w / w). In other specific embodiments, the ethanol concentration is 40% (w / w). In other specific embodiments, the ethanol concentration is 50% (w / w). In other specific embodiments, the ethanol concentration is 60% (w / w). In other specific embodiments, the ethanol concentration is 64% (w / w). In other specific embodiments, the ethanol concentration is 70% (w / w). In other specific embodiments, the ethanol concentration is 80% (w / w). In other specific embodiments, the ethanol concentration is 90% (w / w).

[0043] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0044] Compound A and / or its tautomer or a pharmaceutically acceptable salt thereof;

[0045] glycerin;

[0046] Disodium EDTA;

[0047] ethanol; and

[0048] Water for injection.

[0049] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0050] 0.01-6.0% (w / w) of Compound A and / or its tautomer or a pharmaceutically acceptable salt thereof;

[0051] 0.1-5.0% (w / w) glycerol;

[0052] 0.002-0.02% (w / w) disodium edetate;

[0053] 30-90% (w / w) ethanol; and

[0054] 10-70% (w / w) water for injection.

[0055] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0056] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0057] 0.5-1.0% (w / w) glycerol;

[0058] 0.01% (w / w) disodium edetate;

[0059] 64% (w / w) ethanol; and

[0060] Water for injection to 100% (w / w).

[0061] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0062] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0063] 0.5-1.0% (w / w) glycerol;

[0064] 0.01% (w / w) disodium edetate;

[0065] 64% (w / w) ethanol; and

[0066] Water for injection to 100% (w / w).

[0067] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0068] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0069] 0.5% (w / w) glycerol;

[0070] 0.01% (w / w) disodium edetate;

[0071] 64% (w / w) ethanol; and

[0072] Water for injection to 100% (w / w).

[0073] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0074] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0075] 0.6% (w / w) glycerol;

[0076] 0.01% (w / w) disodium edetate;

[0077] 64% (w / w) ethanol; and

[0078] Water for injection to 100% (w / w).

[0079] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0080] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0081] 0.7% (w / w) glycerol;

[0082] 0.01% (w / w) disodium edetate;

[0083] 64% (w / w) ethanol; and

[0084] Water for injection to 100% (w / w).

[0085] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0086] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0087] 0.8% (w / w) glycerol;

[0088] 0.01% (w / w) disodium edetate;

[0089] 64% (w / w) ethanol; and

[0090] Water for injection to 100% (w / w).

[0091] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0092] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0093] 0.9% (w / w) glycerol;

[0094] 0.01% (w / w) disodium edetate;

[0095] 64% (w / w) ethanol; and

[0096] Water for injection to 100% (w / w).

[0097] In some embodiments, the present invention relates to a pharmaceutical composition comprising:

[0098] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0099] 1.0% (w / w) glycerol;

[0100] 0.01% (w / w) disodium edetate;

[0101] 64% (w / w) ethanol; and

[0102] Water for injection to 100% (w / w).

[0103] In some embodiments, the viscosity of the pharmaceutical composition of the present invention is in the range of 0.8-1.5 mPa·s, preferably 1.1-1.5 mPa·s, and most preferably 1.3-1.4 mPa·s.

[0104] Preparation method of composition

[0105] In one aspect of the present invention, the present invention relates to a method for preparing the pharmaceutical composition of the present invention.

[0106] In some embodiments, the method comprises the following steps:

[0107] (1) adding a metal chelating agent and a viscosity modifier to water for injection, stirring and dissolving, and obtaining an excipient aqueous solution;

[0108] (2) dissolving Compound A in a pharmaceutically acceptable carrier to obtain a pharmaceutical carrier solution; and

[0109] (3) Mix the excipient aqueous solution and the drug carrier solution, stir evenly and filter.

[0110] In some embodiments, the method comprises the following steps:

[0111] (1) Add disodium edetate and glycerol to water for injection, stir and dissolve to obtain an excipient aqueous solution;

[0112] (2) dissolving compound A in anhydrous ethanol to obtain a drug ethanol solution; and

[0113] (3) Mix the excipient aqueous solution with the drug ethanol solution, stir evenly and filter.

[0114] In some embodiments, the filtration in the method is filtration through a 0.22 μm filter membrane.

[0115] Indications

[0116] In some embodiments, the pharmaceutical composition of the present invention is used to treat a disease, such as a lung disease. In some specific embodiments, the disease is a lung disease, preferably, the lung disease is selected from lung injury, lung inflammation, lung fibrosis, radiation lung injury (e.g., radiation lung injury caused by radiotherapy for a thoracic tumor, radiation lung injury caused by a radiotherapy selected from the following: external beam radiotherapy, internal beam radiotherapy, radionuclide therapy, whole body irradiation, intraoperative radiotherapy and 4D radiotherapy, or radiation lung injury caused by a radiotherapy selected from the following: three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT), volumetric rotation intensity modulated radiotherapy (VMAT), image guided radiotherapy (IGRT), stereotactic body radiation therapy (SBRT), proton therapy and brachytherapy, or radiation pneumonitis and radiation pulmonary fibrosis) or chronic obstructive pulmonary disease (e.g., chronic bronchitis type chronic obstructive pulmonary disease, emphysema type chronic obstructive pulmonary disease, mixed chronic obstructive pulmonary disease, stable chronic obstructive pulmonary disease and acute exacerbation chronic obstructive pulmonary disease).

[0117] In a further embodiment, the lung disease is lung injury.

[0118] In a further embodiment, the lung disease is lung inflammation.

[0119] In a further embodiment, the pulmonary disease is pulmonary fibrosis.

[0120] In a further embodiment, the lung disease is radiation lung injury.

[0121] In a further embodiment, the radiation-induced lung injury is caused by radiation therapy for thoracic tumors.

[0122] In a further embodiment, the radiation lung injury is caused by radiation therapy selected from the group consisting of external beam radiotherapy, internal beam radiotherapy, radionuclide therapy, total body irradiation, intraoperative radiotherapy, and 4D radiotherapy.

[0123] In a further embodiment, the radiation lung injury is caused by radiation therapy selected from the group consisting of three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), volumetric modulated radiation therapy (VMAT), image-guided radiation therapy (IGRT), stereotactic body body therapy (SBRT), proton therapy, and brachytherapy.

[0124] In a further embodiment, wherein the radiation lung injury is selected from radiation pneumonitis and radiation pulmonary fibrosis.

[0125] In a further embodiment, wherein the chronic obstructive pulmonary disease is chronic bronchitis-type chronic obstructive pulmonary disease

[0126] In a further embodiment, wherein the chronic obstructive pulmonary disease is emphysema-type chronic obstructive pulmonary disease

[0127] In a further embodiment, the chronic obstructive pulmonary disease is mixed chronic obstructive pulmonary disease.

[0128] In a further embodiment, the chronic obstructive pulmonary disease is stable chronic obstructive pulmonary disease.

[0129] In a further embodiment, the chronic obstructive pulmonary disease is acute exacerbation of chronic obstructive pulmonary disease.

[0130] The present invention also includes the following embodiments.

[0131] 1. A pharmaceutical composition comprising: Compound A and / or its tautomers or pharmaceutically acceptable salts thereof, a metal chelating agent, a viscosity modifier, and a pharmaceutically acceptable carrier,

[0132] 2. The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition consists of Compound A and / or its tautomer or a pharmaceutically acceptable salt thereof, a metal chelator, a viscosity modifier, and a pharmaceutically acceptable carrier.

[0133] 3. The pharmaceutical composition of embodiment 1 or 2, wherein the viscosity modifier is selected from glycerol, Tween (e.g., Tween 80), povidone (e.g., povidone K30), polyvinyl alcohol, hypromellose, hydroxypropyl cellulose, sodium hyaluronate or carbomer.

[0134] 4. The pharmaceutical composition according to any one of embodiments 1-3, wherein the pharmaceutically acceptable carrier is an ethanol aqueous solution.

[0135] 5. The pharmaceutical composition according to any one of embodiments 1 to 4, wherein the metal chelator is selected from disodium edetate, calcium sodium edetate, sodium thiosulfate, sodium hexametaphosphate, gluconic acid and its salts, citric acid and its salts, tartaric acid and its salts, glycine or glutamic acid.

[0136] 6. The pharmaceutical composition of any one of embodiments 1-5, wherein the concentration range of the viscosity modifier is 0.1-5.0% (w / w), 0.25-5.0% (w / w), 0.25-2.0% (w / w), 0.25-1.0% (w / w), 0.25-0.5% (w / w), 0.5-5.0% (w / w), 0.5-2.0% (w / w), 0.5-1.0% (w / w), 1.0-5.0% (w / w), 1.0-2.0% (w / w) or 2.0-5.0% (w / w), preferably, the concentration range of the viscosity modifier is 0.5-1.0% (w / w).

[0137] 7. The pharmaceutical composition of any one of embodiments 1-6, wherein the concentration of the viscosity modifier is 0.1% (w / w), 0.25% (w / w), 0.5% (w / w), 1.0% (w / w), 2.0% (w / w) or 5.0% (w / w), preferably, the concentration of the viscosity modifier is 0.5% (w / w) or 1.0% (w / w).

[0138] 8. The pharmaceutical composition of any one of embodiments 1-7, wherein the concentration of Compound A and / or its tautomer or pharmaceutically acceptable salt thereof is in the range of 0.01-6.0% (w / w).

[0139] 9. The pharmaceutical composition of any one of embodiments 1-8, wherein the concentration of Compound A and / or its tautomer or pharmaceutically acceptable salt thereof is 0.1% (w / w), 0.5% (w / w), 1.0% (w / w), 2.0% (w / w), 3.0% (w / w), 4.0% (w / w), 5.0% (w / w) or 6.0% (w / w).

[0140] 10. The pharmaceutical composition of any one of embodiments 1-9, wherein the concentration of the metal chelator is in the range of 0.002-0.02% (w / w).

[0141] 11. The pharmaceutical composition of any one of embodiments 1-10, wherein the concentration of the metal chelator is 0.001% (w / w), 0.002% (w / w), 0.003% (w / w), 0.004% (w / w), 0.005% (w / w), 0.006% (w / w), 0.007% (w / w), 0.008% (w / w), 0.009% (w / w), 0.01% (w / w), or 0.02% (w / w).

[0142] 12. The pharmaceutical composition of any one of embodiments 4-11, wherein the ethanol concentration ranges from 30-90% (w / w).

[0143] 13. The pharmaceutical composition of any one of embodiments 4-12, wherein the ethanol concentration is 30% (w / w), 40% (w / w), 50% (w / w), 60% (w / w), 64% (w / w), 70% (w / w), 80% (w / w), or 90% (w / w).

[0144] 14. The pharmaceutical composition of embodiment 1, comprising:

[0145] Compound A and / or its tautomer or a pharmaceutically acceptable salt thereof;

[0146] glycerin;

[0147] A metal chelating agent, wherein the metal chelating agent is selected from disodium edetate, calcium sodium edetate, sodium thiosulfate, sodium hexametaphosphate, gluconic acid and its salts, citric acid and its salts, tartaric acid and its salts, glycine or glutamic acid;

[0148] ethanol; and

[0149] Water for injection.

[0150] 15. The pharmaceutical composition of embodiment 1, consisting of:

[0151] Compound A and / or its tautomer or a pharmaceutically acceptable salt thereof;

[0152] glycerin;

[0153] A metal chelating agent, wherein the metal chelating agent is selected from disodium edetate, calcium sodium edetate, sodium thiosulfate, sodium hexametaphosphate, gluconic acid and its salts, citric acid and its salts, tartaric acid and its salts, glycine or glutamic acid;

[0154] ethanol; and

[0155] Water for injection.

[0156] 16. The pharmaceutical composition of embodiment 1, comprising:

[0157] Compound A and / or its tautomer or a pharmaceutically acceptable salt thereof;

[0158] glycerin;

[0159] Disodium EDTA;

[0160] ethanol; and

[0161] Water for injection.

[0162] 17. The pharmaceutical composition of embodiment 1, consisting of:

[0163] Compound A and / or its tautomer or a pharmaceutically acceptable salt thereof;

[0164] glycerin;

[0165] Disodium EDTA;

[0166] ethanol; and

[0167] Water for injection.

[0168] 18. The pharmaceutical composition of embodiment 1, comprising:

[0169] 0.01-6.0% (w / w) of Compound A and / or its tautomer or a pharmaceutically acceptable salt thereof;

[0170] 0.1-5.0% (w / w) glycerol;

[0171] 0.002-0.02% (w / w) disodium edetate;

[0172] 30-90% (w / w) ethanol; and

[0173] 10-70% (w / w) water for injection.

[0174] 19. The pharmaceutical composition of embodiment 1, consisting of:

[0175] 0.01-6.0% (w / w) of Compound A and / or its tautomer or a pharmaceutically acceptable salt thereof;

[0176] 0.1-5.0% (w / w) glycerol;

[0177] 0.002-0.02% (w / w) disodium edetate;

[0178] 30-90% (w / w) ethanol; and

[0179] 10-70% (w / w) water for injection.

[0180] 20. The pharmaceutical composition of embodiment 1, comprising:

[0181] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0182] 0.5-1.0% (w / w) glycerol;

[0183] 0.01% (w / w) disodium edetate;

[0184] 64% (w / w) ethanol; and

[0185] Water for injection to 100% (w / w).

[0186] 21. The pharmaceutical composition of embodiment 1, consisting of:

[0187] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0188] 0.5-1.0% (w / w) glycerol;

[0189] 0.01% (w / w) disodium edetate;

[0190] 64% (w / w) ethanol; and

[0191] Water for injection to 100% (w / w).

[0192] 22. The pharmaceutical composition of embodiment 1, comprising:

[0193] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0194] 0.5% (w / w) glycerol;

[0195] 0.01% (w / w) disodium edetate;

[0196] 64% (w / w) ethanol; and

[0197] Water for injection to 100% (w / w).

[0198] 23. The pharmaceutical composition of embodiment 1, consisting of:

[0199] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0200] 0.5% (w / w) glycerol;

[0201] 0.01% (w / w) disodium edetate;

[0202] 64% (w / w) ethanol; and

[0203] Water for injection to 100% (w / w).

[0204] 24. The pharmaceutical composition of embodiment 1, comprising:

[0205] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0206] 1.0% (w / w) glycerol;

[0207] 0.01% (w / w) disodium edetate;

[0208] 64% (w / w) ethanol; and

[0209] Water for injection to 100% (w / w).

[0210] 25. The pharmaceutical composition of embodiment 1, consisting of:

[0211] 2.0% (w / w) of Compound A and / or its tautomers or pharmaceutically acceptable salts thereof;

[0212] 1.0% (w / w) glycerol;

[0213] 0.01% (w / w) disodium edetate;

[0214] 64% (w / w) ethanol; and

[0215] Water for injection to 100% (w / w).

[0216] 26. A method for preparing the pharmaceutical composition of any one of embodiments 1-25, comprising the steps of:

[0217] (1) adding a metal chelating agent and a viscosity modifier to water for injection, stirring and dissolving, and obtaining an excipient aqueous solution;

[0218] (2) dissolving Compound A in a pharmaceutically acceptable carrier to obtain a pharmaceutical carrier solution; and

[0219] (3) Mix the excipient aqueous solution and the drug carrier solution, stir evenly and filter.

[0220] 27. A method for preparing the pharmaceutical composition of any one of embodiments 1-25, comprising the steps of:

[0221] (1) Add disodium edetate and glycerol to water for injection, stir and dissolve to obtain an excipient aqueous solution;

[0222] (2) dissolving compound A in anhydrous ethanol to obtain a drug ethanol solution; and

[0223] (3) Mix the excipient aqueous solution with the drug ethanol solution, stir evenly and filter.

[0224] 28. Use of the pharmaceutical composition according to any one of embodiments 1-25 in the preparation of a medicament for treating a disease.

[0225] 29. The pharmaceutical composition of any one of embodiments 1-25, for use in treating a disease.

[0226] 30. The use according to embodiment 28 or the use of the pharmaceutical composition according to embodiment 29, wherein the disease is a lung disease, preferably, the lung disease is selected from lung injury, lung inflammation, lung fibrosis, radiation lung injury (e.g., radiation lung injury caused by radiotherapy for thoracic tumors, radiation lung injury caused by radiotherapy selected from the following: external beam radiotherapy, internal beam radiotherapy, radionuclide therapy, whole body irradiation, intraoperative radiotherapy and 4D radiotherapy, or radiation lung injury caused by radiotherapy selected from the following: three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT), volumetric modulated radiotherapy (VMAT), image-guided radiotherapy (IGRT), stereotactic body radiation therapy (SBRT), proton therapy and brachytherapy) or chronic obstructive pulmonary disease (e.g., chronic bronchitis-type chronic obstructive pulmonary disease, emphysema-type chronic obstructive pulmonary disease, mixed chronic obstructive pulmonary disease, stable chronic obstructive pulmonary disease and acute exacerbation of chronic obstructive pulmonary disease).

[0227] Example

[0228] The following examples are provided to further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0229] The experimental methods in the following examples without specifying specific conditions can be carried out according to conventional conditions of such reactions or according to conditions recommended by the manufacturers.

[0230] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0231] Example 1 Investigation of drug saturation solubility

[0232] Anhydrous ethanol and water for injection were mixed to prepare ethanol solutions of different concentrations. An excess of compound A was then added and stirred at 25°C for 48 hours. The mixture was then filtered and the drug concentration was analyzed. The results are shown in Figure 1.

[0233] As can be seen from Figure 1, as the ethanol concentration in the aqueous solution increases, especially when the ethanol concentration exceeds 30%, the saturated solubility of the drug increases significantly. If 100% ethanol is used as the solvent, the drug solubility decreases.

[0234] Example 2 Sample Preparation and Viscosity Measurement of Different Glycerol Contents

[0235] The design prescription is as follows:

[0236] The process is as follows:

[0237] (1) Weigh the prescribed amount of disodium edetate and glycerol, then add water for injection and stir to dissolve to obtain an excipient aqueous solution;

[0238] (2) dissolving the prescribed amount of compound A in anhydrous ethanol to obtain a drug ethanol solution;

[0239] (3) Mix the excipient aqueous solution and the drug ethanol solution, stir evenly, and filter through a 0.22 μm filter membrane to obtain the product.

[0240] Solutions with different formulations were subjected to viscosity tests using a rheometer (test conditions: 25°C, shear rate 50-100 1 / s). The results are as follows:

[0241] The present invention unexpectedly found that within the range of 0-5% glycerol, as its concentration increases, the solution viscosity first increases, then decreases, and then increases again, and does not show a trend of continuous increase. When the glycerol dosage is about 1%, the system viscosity is the highest.

[0242] The viscosity range is 0.8-1.5 mPa·s, preferably 1.1-1.5 mPa·s, and most preferably 1.3-1.4 mPa·s. According to test results, viscosity affects the atomization effect, and both low and high viscosities will have an adverse effect on the atomization effect.

[0243] Example 3 Characterization of spray atomization characteristics

[0244] The main indicators of atomization characteristics include fine particle dose (FPD), fine particle fraction (FPF), and mass median aerodynamic diameter (MMAD). MMAD reflects the overall particle size level of the particles. The size of the atomized particles determines the location of particle deposition. It is generally believed that particles of 1-5μm can be deposited in the lower respiratory tract and lungs, particles of 5-10μm can be deposited in the upper respiratory tract, particles larger than 10μm cannot be deposited in the lungs, and particles smaller than 1μm are exhaled. Particles of 1-3μm can be deposited in the small bronchi and alveoli of the lower lung tissues, while particles of 3-5μm can only be deposited in the large trachea and bronchi of the upper lung tissues. FPF represents the proportion of particles that can be deposited in the lungs.

[0245] The new generation pharmaceutical impactor (NGI) was used for the measurement, with a volume flow rate of 30L / min and a variation range of ±5%. The operation was performed after placing it in a cooling device at 5°C for 90 minutes, and the ambient humidity was controlled to be greater than 70% RH. After a single spray cycle, the soft mist generator was used to clean the adapter, artificial throat, and each collection plate of the NGI instrument with 50% ethanol. The wash solution was collected and placed in a 25 mL volumetric flask. The drug concentration in each wash solution was then analyzed by HPLC. The HPLC results were imported into the CITDA data analysis system to calculate the values ​​of various indicators.

[0246] The specific results are as follows:

[0247] The results show that at the same drug concentration (2%) and a glycerol concentration no higher than 5%, as glycerol concentration increases, the MMAD shows a trend of first decreasing and then increasing, while the FPD and FPF first increase and then decrease, approaching a steady state. When the glycerol content is between 0.5-1.0%, the solution viscosity is higher, ranging from 1.3-1.4 mPa·s, and the atomization performance is better, with MMAD of 3.1μm, FPD above 150μg, and FPF greater than 60%.

[0248] Example 4 Stability Test

[0249] Samples of Formula 5 were placed in 60°C, 40°C, and light stability test chambers, respectively. The humidity in the 40°C stability test chamber did not exceed 25% RH, and the illumination in the light chamber was 4500 lx ± 500 lx. Samples were taken out at different times and their content and related substances were measured. The content test conditions were as follows:

[0250] The testing conditions for relevant substances are as follows:

[0251] Here are the results:

[0252] The results show that the pharmaceutical composition of the present application has good stability, and the content and related substances do not change significantly under high temperature and light conditions.

[0253] Example 5 Screening of packaging materials

[0254] To investigate the effect of inner packaging material on the weight loss of the formulation, a solution was prepared according to Recipe 5 and dispensed into bottles with polypropylene (PP) as the outer shell and base, and low-density polyethylene (LDPE) as the inner bag and cap. Samples containing high-density polyethylene (HDPE) as the outer shell, base, and cap, and LDPE / aluminum / polyethylene as the inner bag, were placed in a 40°C test chamber with humidity controlled to no more than 25%. Each bottle contained 3.5g of the solution, which was removed and weighed at various times to assess weight loss.

[0255] The results showed that when the drug solution was filled in a PP+LDPE bottle, the weight loss was significant (greater than 5%), and the product quality could not be guaranteed during the stability period. However, when HDPE+polyethylene / aluminum / polyethylene was used for packaging, the weight loss was not significant and the long-term storage requirements of the product could be met.

[0256] Example 6 Investigation of other viscosity modifiers

[0257] Tween 80 and povidone K30 were selected as two other viscosity modifiers to examine their solution viscosities at different concentrations. Two solutions with similar concentrations were selected for comparison of atomization performance. The formulation was the same as in Example 2, and atomization performance was measured using the same method as in Example 3. The results are as follows:

[0258] When the Tween 80 concentration was 0.1% and the Povidone K30 concentration was 1.0%, the two solutions had similar viscosities, both approximately 1.5 mPa·s. Characterization of the atomization properties of these two solutions revealed significant differences between the two. The Tween-containing solution significantly outperformed the Povidone K30-containing solution, but both were inferior to the glycerol-containing solution. This indicates that the atomization properties of the soft mist system are not only related to viscosity but also to the properties of the viscosity modifier itself.

[0259] Example 7 Inhalation spray PK test

[0260] 7.1 Study Objectives

[0261] The aerosol characteristics and pharmacokinetic characteristics of soft mist solution in Sprague-Dawley rats were investigated after single inhalation.

[0262] 7.2 Sample preparation

[0263] Preparation of soft mist solution (0.5%, w / w): Weigh 0.10 g of disodium ethylenediaminetetraacetate and 10.0 g of glycerol, then add 344.9 g of water for injection and stir to dissolve to obtain an excipient aqueous solution; dissolve 5.0 g of compound A in 640.0 g of anhydrous ethanol to obtain a drug ethanol solution; mix the excipient aqueous solution and the drug ethanol solution, stir to mix, and filter through a 0.22 μm filter membrane to obtain.

[0264] 7.3 Aerosol Generation Conditions and Environmental Parameters

[0265] An exposure chamber of the inhalation exposure system was selected, and a 12-hole liquid aerosol generator was used to generate the soft mist solution. The aerosol generation flow rate was set to 10 L / min, the aerosol dilution flow rate was set to 10 L / min, and the exhaust flow rate was set to 18 L / min.

[0266] 7.4 Aerosol Sampling and Concentration Analysis

[0267] During the administration process, aerosol concentration was sampled at a randomly selected exposed mouth or nose using a hydrophobic filter membrane. The sample concentration was measured at a sampling rate of 1 L / min and a collection time of 3 minutes.

[0268] The filter membrane was weighed before and after sampling, and the drug concentration in the aerosol was calculated according to the formula: concentration = (membrane weight after sampling - membrane weight before sampling) / (sampling flow rate × sampling time).

[0269] 7.5 Aerosol Particle Size Distribution Sampling and Analysis

[0270] A randomized, exposed mouth and nose port was connected to the NGI throat tube (MOC plate) for sampling. The suction flow rate was set at 15 L / min, and the collection time was 2 minutes. After the collection, the eight samples in the impactor and the throat tube were analyzed for concentration. The nine sample concentrations were then entered into the system software (Copley Inhaler Testing Data Analysis Software, version 3.10WIBU) to calculate the MMAD and FPF of the aerosol particles.

[0271] 7.6 Experimental Animals

[0272] Species and strain: Sprague-Dawley rats

[0273] Animal age and weight: 6-9 weeks, 200-300g

[0274] Number and sex of animals: 6, half male and half female.

[0275] 7.7 Animal Grouping and Dosage

[0276] Qualified animals with similar body weight were selected and divided into two groups according to sex, with 3 animals in each group, and the inhalation time was 50 minutes.

[0277] Dosage calculation: Dose (mg / kg) = RMV × Concentration × Duration / BW / 1000. The animal's minute ventilation (RMV) is calculated using the following formula: RMV (L / min) = 0.608 × BW (kg) 0.852 In the formula, BW is the animal weight in kg; Concentration is the measured average aerosol concentration in μg / L; Duration is the duration of drug administration in min.

[0278] 7.8 Sample Collection and Processing

[0279] Blood sample collection: About 0.25 mL of whole blood was collected from the jugular vein of the animals at each time point for sample analysis.

[0280] Blood collection time points: before drug administration, 50 minutes, 1 hour, 1.33 hours, 2 hours, 3 hours, 5 hours, 9 hours and 24 hours for each group of animals.

[0281] Blood Sample Processing: Add the collected blood to a centrifuge tube and mix thoroughly by inverting the tube at least five times. Place the tube in an ice box filled with crushed ice for temporary storage and transportation. Centrifuge at 2000g for 10 minutes at 4°C. Complete the centrifugation within 2 hours of blood collection and store below -60°C.

[0282] 7.9 Data Collection and Statistical Analysis

[0283] The plasma concentration data were analyzed using the pharmacokinetic data analysis software WinNonlin. The non-compartmental model (NCA) method was used to calculate the t 1 / 2 、C max 、T max , AUC last , and calculate the mean. The results are as follows:

[0284] The results show that the FPF of soft mist aerosol particles is close to 100%, indicating that almost all aerosol particles are smaller than 5μm. Furthermore, the MMAD is much smaller than 5μm, theoretically allowing the drug to reach the deep lungs, namely the bronchioles and terminal bronchioles, after inhalation. There are minimal differences in systemic exposure between genders.

[0285] All references mentioned in this invention are incorporated herein by reference in their entirety, just as if each reference were listed separately. It should be understood that after reading the disclosure of this invention, those skilled in the art may make various changes or modifications to the invention, and these equivalent forms also fall within the scope of the claims appended hereto.

Claims

1. A pharmaceutical composition comprising: Compound A and / or its tautomer, or a pharmaceutically acceptable salt thereof, a metal chelator, a viscosity modifier, and a pharmaceutically acceptable carrier, 2. The pharmaceutical composition of claim 1, wherein the viscosity modifier is selected from glycerol, Tween (e.g., Tween 80), povidone (e.g., povidone K30), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium hyaluronate, or carbomer.

3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutically acceptable carrier is an aqueous ethanol solution.

4. The pharmaceutical composition of any one of claims 1 - 3, wherein the metal chelator is selected from disodium edetate, calcium disodium edetate, sodium thiosulfate, sodium hexametaphosphate, gluconic acid and its salts, citric acid and its salts, tartaric acid and its salts, glycine, or glutamic acid.

5. The pharmaceutical composition of any one of claims 1 - 4, wherein the concentration range of the viscosity modifier is 0.1 - 5.0% (w / w), 0.25 - 5.0% (w / w), 0.25 - 2.0% (w / w), 0.25 - 1.0% (w / w), 0.25 - 0.5% (w / w), 0.5 - 5.0% (w / w), 0.5 - 2.0% (w / w), 0.5 - 1.0% (w / w), 1.0 - 5.0% (w / w), 1.0 - 2.0% (w / w), or 2.0 - 5.0% (w / w); preferably, the concentration range of the viscosity modifier is 0.5 - 1.0% (w / w).

6. The pharmaceutical composition of any one of claims 1 - 5, wherein the concentration of the viscosity modifier is 0.1% (w / w), 0.25% (w / w), 0.5% (w / w), 1.0% (w / w), 2.0% (w / w), or 5.0% (w / w); preferably, the concentration of the viscosity modifier is 0.5% (w / w) or 1.0% (w / w).

7. The pharmaceutical composition of any one of claims 1 - 6, wherein the concentration range of compound A and / or its tautomer or its pharmaceutically acceptable salt is 0.01 - 6.0% (w / w).

8. The pharmaceutical composition of any one of claims 1 - 7, wherein the concentration of compound A and / or its tautomer or its pharmaceutically acceptable salt is 0.1% (w / w), 0.5% (w / w), 1.0% (w / w), 2.0% (w / w), 3.0% (w / w), 4.0% (w / w), 5.0% (w / w), or 6.0% (w / w).

9. The pharmaceutical composition of any one of claims 1 - 8, wherein the concentration range of the metal chelator is 0.002 - 0.02% (w / w).

10. The pharmaceutical composition of any one of claims 1 - 9, wherein the concentration of the metal chelator is 0.01% (w / w).

11. The pharmaceutical composition of any one of claims 3 - 10, wherein the ethanol concentration range is 30 - 90% (w / w).

12. The pharmaceutical composition according to any one of claims 3-11, wherein the ethanol concentration is 30% (w / w), 40% (w / w), 50% (w / w), 60% (w / w), 64% (w / w), 70% (w / w), 80% (w / w) or 90% (w / w).

13. The pharmaceutical composition according to claim 1, comprising: Compound A and / or its tautomer or its pharmaceutically acceptable salt; Glycerol; A metal chelating agent selected from disodium edetate, calcium disodium edetate, sodium thiosulfate, sodium hexametaphosphate, gluconic acid and its salts, citric acid and its salts, tartaric acid and its salts, glycine or glutamic acid; Ethanol; and Water for injection.

14. The pharmaceutical composition according to claim 1, comprising: Compound A and / or its tautomer or its pharmaceutically acceptable salt; Glycerol; Disodium edetate; Ethanol; and Water for injection.

15. The pharmaceutical composition according to claim 1, comprising: 0.01-6.0% (w / w) of Compound A and / or its tautomer or its pharmaceutically acceptable salt; 0.1-5.0% (w / w) of glycerol; 0.002-0.02% (w / w) of disodium edetate; 30-90% (w / w) of ethanol; and 10-70% (w / w) of water for injection.

16. The pharmaceutical composition according to claim 1, comprising: 2.0% (w / w) of Compound A and / or its tautomer or its pharmaceutically acceptable salt; 0.5-1.0% (w / w) of glycerol; 0.01% (w / w) of disodium edetate; 64% (w / w) of ethanol; and Water for injection to 100% (w / w).

17. The pharmaceutical composition according to claim 1, comprising: 2.0% (w / w) of Compound A and / or its tautomer or its pharmaceutically acceptable salt; 0.5% (w / w) of glycerol; 0.1% (w / w) of disodium edetate; 64% (w / w) of ethanol; and Water for injection to 100% (w / w).

18. The pharmaceutical composition according to claim 1, comprising: 2.0% (w / w) of Compound A and / or its tautomer or its pharmaceutically acceptable salt; 1.0% (w / w) of glycerol; 0.1% (w / w) of disodium edetate; 64% (w / w) of ethanol; and Water for injection to 100% (w / w).

19. A method for preparing the pharmaceutical composition according to any one of claims 1-18, the method comprising the following steps: (1) Adding a metal chelating agent and a viscosity modifier to water for injection, stirring and dissolving to obtain an aqueous solution of excipients; (2) Dissolving Compound A in a pharmaceutically acceptable carrier to obtain a drug carrier solution; and (3) Mixing the aqueous solution of excipients with the drug carrier solution, stirring evenly and then filtering.

20. A method for preparing the pharmaceutical composition according to any one of claims 1-18, the method comprising the following steps: (1) Adding disodium edetate and glycerol to water for injection, stirring and dissolving to obtain an aqueous solution of excipients; (2) Dissolve compound A in absolute ethanol to obtain a drug ethanol solution; and (3) Mix the aqueous solution of the excipient with the drug ethanol solution, stir evenly and then filter.

21. Use of the pharmaceutical composition according to any one of claims 1-18 in the preparation of a drug for the treatment and / or prevention of a disease.

22. The use according to claim 21, wherein the disease is a lung disease, preferably, the lung disease is selected from lung injury, pulmonary inflammation, pulmonary fibrosis, radiation-induced lung injury (for example, radiation-induced lung injury caused by radiotherapy for thoracic tumors, radiation-induced lung injury caused by radiotherapy selected from the following: external beam radiotherapy, internal radiotherapy, radionuclide therapy, total body irradiation, intraoperative radiotherapy and 4D radiotherapy, or radiation-induced lung injury caused by radiotherapy selected from the following: three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), image-guided radiotherapy (IGRT), stereotactic body radiotherapy (SBRT), proton therapy and brachytherapy), or chronic obstructive pulmonary disease (for example, chronic bronchitis type chronic obstructive pulmonary disease, emphysema type chronic obstructive pulmonary disease, mixed type chronic obstructive pulmonary disease, stable phase chronic obstructive pulmonary disease and acute exacerbation phase chronic obstructive pulmonary disease).

23. The pharmaceutical composition according to any one of claims 1-18, which is used for the treatment of a disease.

24. Use of the pharmaceutical composition according to claim 23, wherein the disease is a lung disease, preferably, the lung disease is selected from lung injury, pulmonary inflammation, pulmonary fibrosis, radiation-induced lung injury (for example, radiation-induced lung injury caused by radiotherapy for thoracic tumors, radiation-induced lung injury caused by radiotherapy selected from the following: external beam radiotherapy, internal radiotherapy, radionuclide therapy, total body irradiation, intraoperative radiotherapy and 4D radiotherapy, or radiation-induced lung injury caused by radiotherapy selected from the following: three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), image-guided radiotherapy (IGRT), stereotactic body radiotherapy (SBRT), proton therapy and brachytherapy) or chronic obstructive pulmonary disease (for example, chronic bronchitis type chronic obstructive pulmonary disease, emphysema type chronic obstructive pulmonary disease, mixed type chronic obstructive pulmonary disease, stable phase chronic obstructive pulmonary disease and acute exacerbation phase chronic obstructive pulmonary disease).

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