Pharmaceutical composition and method for treating organ fibrosis related diseases

Abstract

Disclosed are a pharmaceutical composition and a method for treating organ fibrosis related diseases, the pharmaceutical composition and the method of the present invention comprise a combination of mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof, and can effectively inhibit organ fibrosis lesions of patients so as to treat organ fibrosis related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to a pharmaceutical composition and method for treating diseases related to organ fibrosis, and particularly to a pharmaceutical composition and method for treating fibrotic interstitial lung disease. Background Art

[0002] Organ fibrosis is a pathological change in which the fibrous connective tissue increases and the number of parenchymal cells decreases in organ tissues. It is a common pathological feature of many chronic diseases. Fibrosis of parenchymal organs such as the heart, liver, lungs and kidneys is the main cause of organ failure and disability and death in patients, but there is still a lack of therapeutic drugs specifically for fibrosis (Han Min et al., Research progress and important scientific issues of organ fibrosis [J]. Chinese Journal of Pathophysiology, 2018, 34(08): 1518-1526). Pulmonary fibrosis (PF) is a chronic progressive interstitial lung disease and the most common respiratory disease in clinical practice. Its pathogenesis is still unclear, and there is still a lack of specific drugs and treatment methods in clinical practice (Zhou Shiqin et al., Related molecular mechanisms and treatment status of pulmonary fibrosis [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(10): 1133-1147). Fibrosing interstitial lung diseases (FILDs) are a group of heterogeneous diseases with different etiologies, treatments, and a range of disease manifestations, characterized by pathological findings of fibrosis or honeycombing and / or traction bronchiectasis on high-resolution computed tomography (HRCT) (Rajan SK, et al., Progressive pulmonary fibrosis: an expert group consensus statement. Eur Respir J. 2023 Mar 30; 61(3): 2103187). Fibrosing interstitial lung diseases include idiopathic pulmonary fibrosis (IPF) and progressive fibrosing interstitial lung diseases (PF-ILDs). Progressive fibrotic interstitial lung disease is a group of refractory diseases with a high mortality rate and a 5-year survival rate of less than 50%, and idiopathic pulmonary fibrosis (IPF) is a type of disease with pulmonary fibrosis as the main pathological form (Zhou Ping, A Brief Discussion on the Pathogenesis of Pulmonary Fibrosis [J]. Smart Health, 2022, 8(24): 110-113). So far, only two drugs have been approved for the treatment of idiopathic pulmonary fibrosis: pirfenidone and nintedanib. However, nintedanib and pirfenidone can cause side effects such as loss of appetite, stomach discomfort, photoallergy, and diarrhea.It is understood that more than 30% of patients will choose to reduce the dose, temporarily stop the medication or stop treatment (Levra S, et al., Long-Term Safety of Antifibrotic Drugs in IPF: A Real-World Experience. Biomedicines. 2022 Dec 12; 10(12): 3229).

[0003] Mirtazapine has been approved for the treatment of depression in many countries. It has been reported that mirtazapine has the effect of reducing pulmonary fibrosis in experimental animal models (Abdelhady R et al., Biomed Pharmacother. 2023 May; 161: 114553). However, mirtazapine has more and more serious side effects, including weight gain, fatigue (15.2%), drowsiness (50%), sedation, dizziness and fatigue, headache, constipation (12.7%), dry mouth (20.6%), increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT) (12.4%) and increased γ-GTP, increased appetite, etc. So far, no literature has been found reporting that mirtazapine combined with other drugs has an additive or even synergistic effect on reducing fibrosis or its related diseases.

[0004] Noscapine is a peripheral antitussive drug, and WO 2009 / 155611 studies the effect of preventive administration of Noscapine in experimental animal models. However, no literature has been found so far reporting that Noscapine combined with other drugs has an additive or even synergistic effect on alleviating fibrosis or its related diseases.

[0005] Therefore, there is an unmet medical need for new drugs and new methods that are safe and can be taken by patients for long-term treatment of their organ fibrosis-related diseases. Summary of the invention

[0006] The purpose of the present invention is to provide new drugs and methods that can be used to treat organ fibrosis-related diseases in subjects in need, preferably to provide new drugs and methods that are highly safe and can be taken by patients for a long time.

[0007] The inventors unexpectedly discovered in experiments that mirtazapine, when used alone or in combination with certain marketed drugs that do not show anti-fibrotic effects in the prior art, can significantly inhibit mammalian organ fibrosis. It is particularly surprising that mirtazapine, when used alone or in combination with narcotine at a lower dose (i.e., lower than its effective dose for treating depression, such as lower than 15 mg daily dose, such as 1 to 10 mg daily dose), can significantly inhibit mammalian organ fibrosis. Based on this discovery, the inventors have completed the present invention, and it is therefore expected that the present invention can achieve the above-mentioned purpose.

[0008] The present invention can be described from different aspects. The invention described in any aspect of these aspects and any implementation scheme thereof are independent of each other but related to each other, and together constitute the content of the present invention.

[0009] One aspect of the present invention provides a method for treating a disease related to organ fibrosis in a patient, the method comprising the step of administering a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof to the patient.

[0010] In some embodiments, the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0011] In some embodiments, a method of treating progressive fibrotic interstitial lung disease in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, a method of treating progressive pulmonary fibrosis in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, a method of treating idiopathic pulmonary fibrosis in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof by oral administration of a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0015] Another aspect of the present invention provides use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an organ fibrosis-related disease in a patient in need thereof.

[0016] In some embodiments, the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0017] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating progressive fibrotic interstitial lung disease in a patient in need thereof.

[0018] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating progressive pulmonary fibrosis in a patient in need thereof.

[0019] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating idiopathic pulmonary fibrosis in a patient in need thereof.

[0020] Another aspect of the present invention provides a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, which is used for treating organ fibrosis-related diseases in patients in need thereof.

[0021] In some embodiments, the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis, liver fibrosis and myocardial fibrosis.

[0022] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating progressive fibrotic interstitial lung disease in a patient in need thereof.

[0023] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating progressive pulmonary fibrosis in a patient in need thereof.

[0024] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating idiopathic pulmonary fibrosis in a patient in need thereof.

[0025] Another aspect of the present invention provides a method for treating an organ fibrosis-related disease in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0027] In some embodiments, a method of treating progressive fibrosing interstitial lung disease in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, a method of treating progressive pulmonary fibrosis in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, a method of treating idiopathic pulmonary fibrosis in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0030] Another aspect of the present invention provides the use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an organ fibrosis-related disease in a patient in need thereof.

[0031] In some embodiments, the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0032] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating progressive fibrosing interstitial lung disease in a patient in need thereof.

[0033] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating progressive pulmonary fibrosis in a patient in need thereof.

[0034] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating idiopathic pulmonary fibrosis in a patient in need thereof.

[0035] Another aspect of the present invention provides a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0036] Another aspect of the present invention provides a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is used for treating organ fibrosis-related diseases in patients in need thereof.

[0037] In some embodiments, the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0038] In some embodiments, a pharmaceutical composition is provided, comprising mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is used for treating progressive fibrotic interstitial lung disease in a patient in need thereof.

[0039] In some embodiments, a pharmaceutical composition is provided, comprising mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is used for treating progressive pulmonary fibrosis in a patient in need thereof.

[0040] In some embodiments, a pharmaceutical composition is provided, comprising mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for use in treating idiopathic pulmonary fibrosis in a patient in need thereof.

[0041] Another aspect of the present invention provides a pharmaceutical combination comprising a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof, wherein mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof can be formulated in the same pharmaceutical preparation or in separate pharmaceutical preparations.

[0042] Another aspect of the present invention provides a packaged pharmaceutical product, which comprises (1) a pharmaceutical composition containing mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition containing narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat organ fibrosis-related diseases in patients in need thereof.

[0043] In some embodiments, the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0044] In some embodiments, a kit drug product is provided, comprising (1) a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition comprising narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat progressive fibrosing interstitial lung disease in a patient in need thereof.

[0045] In some embodiments, a kit pharmaceutical product is provided, comprising (1) a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition comprising narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat progressive pulmonary fibrosis in a patient in need thereof.

[0046] In some embodiments, a kit pharmaceutical product is provided, comprising (1) a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition comprising narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat idiopathic pulmonary fibrosis in a patient in need thereof.

[0047] The inventors have experimentally confirmed that mirtazapine or a pharmaceutically acceptable salt thereof can effectively inhibit pulmonary fibrosis in mammals by administering it alone or in combination with narcotine or a pharmaceutically acceptable salt thereof. It is particularly surprising that a low dose of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof inhibits pulmonary fibrosis more significantly than existing marketed drugs.

[0048] The inventors have also found in experiments that the anti-fibrosis effect of mirtazapine combined with other drugs is unpredictable. For example, experiments have shown that when mirtazapine is used in combination with simvastatin, the anti-fibrosis effect of the combination is less than the sum of the anti-fibrosis effects of each of them when used alone. On the contrary, in the present invention, when mirtazapine is used in combination with narcotine, the anti-fibrosis effect of the combination is greater than the sum of the anti-fibrosis effects of each of them when used alone, that is, a synergistic effect is produced.

[0049] Therefore, it can be expected that the method, drug combination and pharmaceutical composition of the present invention can effectively inhibit the patient's organ fibrosis, thereby treating organ fibrosis-related diseases, such as treating the patient's fibrosing interstitial lung disease, such as progressive fibrosing interstitial lung disease, progressive pulmonary fibrosis and idiopathic pulmonary fibrosis, and reducing the mental stress, dyspnea, cough and other symptoms of these patients. Based on the experimental results obtained by the inventors, it can also be expected that the method, drug combination and pharmaceutical composition of the present invention can inhibit the fibrotic lesions of other organs, such as renal fibrosis, liver fibrosis and cardiac fibrosis. The dosage of mirtazapine used in the present invention is relatively low, and the combined administration of mirtazapine and noscapine is not only less and smaller than the side effects of single drug administration, but also has a stronger anti-fibrosis effect. Therefore, it can also be expected that the method, drug combination and pharmaceutical composition of the present invention can avoid or reduce the side effects of mirtazapine while producing an effective anti-fibrosis effect, and have a higher safety relative to the anti-fibrosis drugs that have been listed, so that the compliance of the patient can be improved. DETAILED DESCRIPTION

[0050] In order to make the present invention more easily understood, certain terms used in the present invention are defined herein. The definitions of these terms should be understood in conjunction with the understanding of the rest of this specification by a person of ordinary skill in the art. Unless otherwise specifically defined in this specification, all technical and scientific terms used in the present invention have the same meanings as those generally understood by those skilled in the art. If the meaning of a term specifically defined in this specification is inconsistent with the meaning generally understood by those skilled in the art, the meaning specifically defined in this specification shall prevail.

[0051] The term "organ fibrosis-related diseases" used in the present invention refers to fibrotic lesions and diseases associated with or caused by fibrosis in the internal organs of mammals, especially humans, including one or more clinical symptoms of the disease, including but not limited to diseases or symptoms caused by cardiac fibrosis, liver fibrosis, lung fibrosis and kidney fibrosis. Fibrosis refers to excessive deposition of extracellular matrix proteins, scarring and thickening of tissues.

[0052] The term "fibrotic interstitial lung disease" used in the present invention refers to fibrotic lesions occurring in the lungs of mammals, especially humans, and diseases or symptoms accompanying or caused by them. Examples of fibrotic interstitial lung diseases are fibrotic interstitial lung diseases or pulmonary fibrosis, including idiopathic pulmonary fibrosis and progressive fibrotic interstitial lung diseases.

[0053] The term "progressive fibrotic interstitial lung disease" used in the present invention refers to a group of interstitial lung diseases, and even if immunosuppressive therapy is used and factors that promote disease progression are eliminated, the patient's pulmonary fibrosis continues to progress. In some embodiments, "progressive fibrotic interstitial lung disease" is also referred to as "progressive pulmonary fibrosis (PPF)", which can be used interchangeably in the present invention. Progressive fibrotic interstitial lung diseases include idiopathic non-specific interstitial pneumonia (INSIP), connective tissue disease-associated ILD (CTD-ILD), hypersensitivity pneumonitis (HP), unclassifiable interstitial lung disease (UILD), pneumoconiosis and sarcoidosis, etc.

[0054] The term "idiopathic pulmonary fibrosis" used in the present invention refers to a group of diseases with pulmonary fibrosis as the main pathological form, which can cause the progressive loss of normal lung function, specifically manifested as progressive dyspnea, cough and sputum and other related respiratory symptoms, and with the aggravation of damage and the worsening of the disease, the respiratory function gradually fails, and the clinical incidence of such diseases increases year by year, and the average survival period after diagnosis is 2.5 to 3 years. The pathogenesis of pulmonary fibrosis is still unclear, and it is currently believed that damage to alveolar epithelial cells, inflammatory response, alveolar macrophages and apoptosis are all key target mechanisms for the onset of pulmonary fibrosis.

[0055] The term "treatment" used in the present invention refers to the prevention, improvement, alleviation or elimination of at least one identifiable symptom of the organ fibrosis-related disease, including the reduction of the degree of fibrosis of the organ or tissue. In particular, the term "treatment" used in the present invention refers to reducing the severity of fibrosis of the affected organ or tissue, improving the physiological function of the affected organ or tissue, and / or preventing the affected organ or tissue from developing varying degrees of fibrosis.

[0056] The terms "subject", "subject" and "patient" used in the present invention have the same meaning and can be used interchangeably in the present invention, referring to mammals, particularly humans, who have suffered from or are at risk of suffering from the fibrotic disease.

[0057] Unless otherwise specified, the phrase "therapeutically effective amount" used in the present invention refers to the amount of the drug or compound that provides the desired therapeutic effect when administered to a patient, wherein the desired therapeutic effect is to reduce the severity of fibrosis of the diseased organ or tissue, improve the physiological function of the affected organ or tissue, and / or prevent the affected organ or tissue from developing varying degrees of fibrosis. It is understood by those skilled in the art that the "therapeutically effective amount" of the drug used in the present invention can be determined and adjusted based on the patient's age, weight, sex, type and severity of the disease, route of administration, etc.

[0058] The term "mirtazapine" used in the present invention refers to an organic compound, the chemical structural formula of which is The chemical name is 1,2,3,4,10,14b-hexahydro-2-methylpyrazinyl[2,1-a]pyrido[2,3-c][2]benzazepine The molecular formula is C 17 H 19N3. For example, the compound is disclosed in U.S. Pat. No. 4,062,848, the entire contents of which are incorporated herein by reference. The compound contains a chiral center and can exist in the form of different enantiomers and enantiomeric mixtures. The term "mirtazapine" used in the present invention includes any specific enantiomer itself and a mixture (including a racemic mixture) formed in any ratio. The pharmaceutically acceptable salt of mirtazapine used in the present invention includes various pharmaceutically acceptable salts of mirtazapine, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, formates, acetates, lactates, citrates, tartrates, ascorbates, succinates, maleates, fumarates, gluconates, glucuronates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates and pamoates.

[0059] The mirtazapine described in the present invention also includes all metabolites and analogs known in the art that have the same pharmacological activity as mirtazapine. The mirtazapine or its pharmaceutically acceptable salt used in the present invention includes solvates (such as hydrates, etc.). Solvates can be coordinated with any number of solvent molecules (such as water molecules, etc.) to form mirtazapine or its pharmaceutically acceptable salt. Placing mirtazapine or its pharmaceutically acceptable salt in the atmosphere may cause it to absorb moisture, and the adsorbed water may adhere to it or form a hydrate. The preparation of mirtazapine and its pharmaceutically acceptable salts and solvates (such as hydrates, etc.) is known to those skilled in the art.

[0060] Mirtazapine used in the present invention also includes isotope-labeled mirtazapine thereof, which has the same structure as the compound shown in the above formula except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes include isotopes of hydrogen, carbon and nitrogen, such as but not limited to 2 H. 3 H. 13 C. 14 C and 15 N. In general, isotopically labeled mirtazapine can be prepared using procedures known in the art by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0061] The term "Narcotin" used in the present invention is a peripheral antitussive drug, and its chemical name is [S-(R*,S*)]-6,7-dimethoxy-3-(5,6,7,8-tetrahydro-6-methyl-4-methoxy-1,3-dioxol[4,5-g]-5-isoquinolyl)-1(3H)-isobenzofuranone, and its molecular formula is C 22 H 23 NO7, the structural formula is The Narcotine described in the present invention also includes all metabolites and analogs known in the art that have the same pharmacological activity as that of Narcotine. The pharmaceutically acceptable salts of Narcotine used in the present invention include various pharmaceutically acceptable salts of Narcotine, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, formate, acetate, lactate, citrate, tartrate, ascorbate, succinate, maleate, fumarate, gluconate, glucuronate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.

[0062] The narcotine or its pharmaceutically acceptable salt used in the present invention includes solvates (such as hydrates, etc.). Solvates can be coordinated with any number of solvent molecules (such as water molecules, etc.) to form narcotine or its pharmaceutically acceptable salt. Placing narcotine or its pharmaceutically acceptable salt in the atmosphere may cause it to absorb moisture, and the adsorbed water may adhere to it or form a hydrate. The preparation of narcotine and its pharmaceutically acceptable salts and solvates (such as hydrates, etc.) is known to those skilled in the art.

[0063] The Narcotine used in the present invention also includes isotope-labeled Narcotine, which has the same structure as the compound shown in the above formula except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of suitable isotopes include isotopes of hydrogen, carbon, nitrogen and oxygen, such as but not limited to 2 H. 3 H. 13 C. 14 C. 15 N. 17 O and 18 O. In general, isotopically labeled Noscapine can be prepared using procedures known in the art by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0064] The expression "administering mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof simultaneously" used in the present invention has the same meaning as "administering mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof", and can be used interchangeably in the present invention. The expression "administering mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof" used in the present invention means administering mirtazapine or a pharmaceutically acceptable salt thereof before, after or at about the same time as administering narcotine or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0065] According to one aspect of the present invention, a method for treating an organ fibrosis-related disease in a patient is provided, the method comprising the step of administering a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof to the patient, wherein the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0066] In some embodiments, a method of treating renal interstitial fibrosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, a method of inhibiting or reducing the extent of renal interstitial fibrosis in a patient is provided, the method comprising administering a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof to the patient.

[0068] In some embodiments, a method of treating a liver fibrosis disease in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, a method of inhibiting liver fibrosis or reducing the degree of liver fibrosis in a patient is provided, the method comprising administering a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof to the patient.

[0070] In some embodiments, a method of treating a myocardial fibrotic disease in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, a method of inhibiting myocardial fibrosis or reducing the degree of myocardial fibrosis in a patient is provided, the method comprising administering a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof to the patient.

[0072] In some embodiments, a method of treating progressive fibrotic interstitial lung disease in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, a method of treating progressive pulmonary fibrosis in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, a method of treating idiopathic pulmonary fibrosis in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, a method for improving a patient's pulmonary fibrosis lesions, inhibiting the progression of a patient's pulmonary fibrosis, or reducing the extent of a patient's pulmonary fibrosis is provided, the method comprising the step of administering a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0076] In some embodiments, a method of treating idiopathic nonspecific interstitial pneumonia in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, a method of treating connective tissue disease-associated interstitial lung disease in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, a method of treating, reducing the severity of, or preventing exacerbation of pneumoconiosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, a method of treating pulmonary sarcoidosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in the form of a pharmaceutical composition in the form of an oral solid dosage form, wherein the pharmaceutical composition comprises mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0081] In some embodiments, a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in the form of a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0082] In some embodiments, a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in the form of a pharmaceutical composition in the form of a capsule, wherein the pharmaceutical composition comprises mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0083] In some embodiments, mirtazapine or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof at any dose within the range of 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, and more preferably 1 mg to 10 mg as the therapeutically effective amount.

[0084] In some embodiments, the patient is administered a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable composition thereof once or more per day.

[0085] In some embodiments, the method comprises administering to the patient once daily a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof.

[0086] In some embodiments, the method comprises administering to the patient twice daily a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof.

[0087] In some embodiments, the pharmaceutical composition is administered to a patient in need thereof as a dosage unit, and each dosage unit comprises 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of mirtazapine or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the pharmaceutical composition is administered as two dosage units, and wherein each dosage unit comprises 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg or 20 mg of mirtazapine or a pharmaceutically acceptable salt thereof.

[0089] According to another aspect of the present invention, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an organ fibrosis-related disease in a patient in need thereof, wherein the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0090] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating renal interstitial fibrosis disease in a patient in need thereof.

[0091] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting renal interstitial fibrosis or reducing the degree of renal interstitial fibrosis.

[0092] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a liver fibrosis disease in a patient in need thereof.

[0093] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting liver fibrosis or reducing the degree of liver fibrosis.

[0094] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a myocardial fibrotic disease in a patient in need thereof.

[0095] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting myocardial fibrosis or reducing the degree of myocardial fibrosis.

[0096] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating idiopathic nonspecific interstitial pneumonia in a patient in need thereof.

[0097] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating connective tissue disease-associated interstitial lung disease in a patient in need thereof.

[0098] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, reducing the severity of, or preventing the exacerbation of pneumoconiosis in a patient in need thereof.

[0099] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pulmonary sarcoidosis in a patient in need thereof.

[0100] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving a patient's pulmonary fibrosis lesions, inhibiting the progression of a patient's pulmonary fibrosis, or reducing the degree of a patient's pulmonary fibrosis.

[0101] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating progressive fibrotic interstitial lung disease in a patient in need thereof.

[0102] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating progressive pulmonary fibrosis in a patient in need thereof.

[0103] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating idiopathic pulmonary fibrosis in a patient in need thereof.

[0104] In some embodiments, the prepared drug contains any amount of mirtazapine or a pharmaceutically acceptable salt thereof in the range of 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, more preferably 1 mg to 10 mg, and the drug is prepared in a dosage unit form, such as a tablet or capsule.

[0105] In some embodiments, the dosage unit forms each contain 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg of mirtazapine or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating progressive fibrosing interstitial lung disease, progressive pulmonary fibrosis or idiopathic pulmonary fibrosis in a patient in need thereof, wherein the content of mirtazapine or a pharmaceutically acceptable salt thereof in the medicament is in the range of 0.1 mg to 45 mg, preferably in the range of 1 mg to 15 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg.

[0107] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for treating an organ fibrosis-related disease in a patient in need thereof, wherein the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0108] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating renal interstitial fibrosis in a patient in need thereof.

[0109] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for inhibiting renal interstitial fibrosis or reducing the degree of renal interstitial fibrosis.

[0110] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating liver fibrosis in a patient in need thereof.

[0111] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for inhibiting liver fibrosis or reducing the degree of liver fibrosis.

[0112] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating myocardial fibrosis in a patient in need thereof.

[0113] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for inhibiting myocardial fibrosis or reducing the degree of myocardial fibrosis.

[0114] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating progressive fibrotic interstitial lung disease in a patient in need thereof.

[0115] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating progressive pulmonary fibrosis in a patient in need thereof.

[0116] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating idiopathic pulmonary fibrosis in a patient in need thereof.

[0117] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided, which is used to improve a patient's pulmonary fibrosis lesions, inhibit the progression of a patient's pulmonary fibrosis, or reduce the degree of pulmonary fibrosis.

[0118] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating idiopathic nonspecific interstitial pneumonia in a patient in need thereof.

[0119] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating connective tissue disease-associated interstitial lung disease in a patient in need thereof.

[0120] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for treating pneumoconiosis in a patient in need thereof, reducing its severity, or preventing its exacerbation.

[0121] In some embodiments, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in treating pulmonary sarcoidosis in a patient in need thereof.

[0122] In some embodiments, the pharmaceutical composition is in the form of an oral solid dosage form, such as a tablet or capsule.

[0123] In some embodiments, the pharmaceutical composition comprises any dose in the range of 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, more preferably 1 mg to 10 mg, for example 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of mirtazapine or a pharmaceutically acceptable salt thereof.

[0124] According to another aspect of the present invention, a method for treating a patient's organ fibrosis-related disease is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof, wherein the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease, and myocardial fibrosis disease. In some embodiments, a method for treating a patient's progressive fibrosing interstitial lung disease is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, a method of treating progressive pulmonary fibrosis in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, a method of treating idiopathic pulmonary fibrosis in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, a method of treating renal interstitial fibrosis in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, a method of inhibiting or reducing the extent of renal interstitial fibrosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, a method of treating a liver fibrosis disease in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, a method of inhibiting liver fibrosis or reducing the degree of liver fibrosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, a method of treating a myocardial fibrotic disease in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, a method of inhibiting myocardial fibrosis or reducing the degree of myocardial fibrosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, a method of treating progressive fibrosing interstitial lung disease in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, a method of treating progressive pulmonary fibrosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, a method of treating idiopathic pulmonary fibrosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, a method for improving a patient's pulmonary fibrosis lesions, inhibiting the progression of a patient's pulmonary fibrosis, or reducing the extent of a patient's pulmonary fibrosis is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, a method of treating idiopathic nonspecific interstitial pneumonia in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, a method of treating connective tissue disease-associated interstitial lung disease in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, a method of treating, reducing the severity of, or preventing exacerbation of pneumoconiosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, a method of treating pulmonary sarcoidosis in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, a pharmaceutical composition in the form of an oral solid dosage form is administered to a subject in need thereof a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition may be the same preparation comprising narcotine or a pharmaceutically acceptable salt thereof and mirtazapine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; or may be separate preparations, each comprising narcotine or a pharmaceutically acceptable salt thereof or mirtazapine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0142] In some embodiments, the oral solid dosage form is a tablet or a capsule.

[0143] In some embodiments, the therapeutically effective amount of Narcotine or a pharmaceutically acceptable salt thereof is 10-120 mg / person / day, 10 mg / person / day, 20 mg / person / day or 30 mg / person / day.

[0144] In some embodiments, the therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof is 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, more preferably any dose in the range of 1 mg to 10 mg, for example 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg.

[0145] In some embodiments, the patient is administered a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable composition thereof once or more per day.

[0146] In some embodiments, the patient is administered a drug comprising Narcotine or a pharmaceutically acceptable composition thereof once or more per day.

[0147] In some embodiments, the method comprises administering to the patient once daily a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof.

[0148] In some embodiments, the method comprises administering to the patient twice daily a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof.

[0149] In some embodiments, the method comprises administering to the patient once a day a drug comprising Narcotine or a pharmaceutically acceptable composition thereof.

[0150] In some embodiments, the method comprises administering to the patient twice daily a drug comprising Narcotine or a pharmaceutically acceptable composition thereof.

[0151] In some embodiments, the method comprises administering to the patient three times daily a drug comprising Narcotine or a pharmaceutically acceptable composition thereof.

[0152] In some embodiments, the ratio of the therapeutically effective amount of mirtazapine to narcotine is 1:1200-9:2, preferably 1:120-3:1, more preferably 1:120-3:2, for example 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-110, 1-120, 1.5-1, 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7 or 1-8.

[0153] According to another aspect of the present invention, there is provided a use of a combination of mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an organ fibrosis-related disease in a patient in need thereof, wherein the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0154] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating progressive fibrosing interstitial lung disease in a patient in need thereof.

[0155] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating progressive pulmonary fibrosis in a patient in need thereof.

[0156] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating idiopathic pulmonary fibrosis in a patient in need thereof.

[0157] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving a patient's pulmonary fibrosis lesions, inhibiting the progression of a patient's pulmonary fibrosis, or reducing the degree of a patient's pulmonary fibrosis.

[0158] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating renal interstitial fibrosis disease in a patient in need thereof.

[0159] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting renal interstitial fibrosis or reducing the degree of renal interstitial fibrosis.

[0160] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a liver fibrosis disease in a patient in need thereof.

[0161] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting liver fibrosis or reducing the degree of liver fibrosis.

[0162] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a myocardial fibrotic disease in a patient in need thereof.

[0163] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting myocardial fibrosis or reducing the degree of myocardial fibrosis.

[0164] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating idiopathic nonspecific interstitial pneumonia in a patient in need thereof.

[0165] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating connective tissue disease-associated interstitial lung disease in a patient in need thereof.

[0166] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, reducing the severity of, or preventing the exacerbation of pneumoconiosis in a patient in need thereof.

[0167] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pulmonary sarcoidosis in a patient in need thereof.

[0168] In some embodiments, the drug is prepared into the same preparation, which contains narcotine or a pharmaceutically acceptable salt thereof and mirtazapine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0169] In some embodiments, the drug is prepared as separate preparations, each of which contains narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, or contains mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0170] In some embodiments, the drug is prepared in dosage unit form, such as tablets or capsules, each dosage unit containing 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, more preferably any dose in the range of 1 mg to 10 mg, for example 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of mirtazapine or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the drug is prepared in dosage unit form, such as tablets or capsules, each dosage unit containing any dose in the range of 10 to 120 mg, such as 10 mg, 20 mg or 30 mg of Narcotine or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the drug is prepared in dosage unit form, such as tablets or capsules, each dosage unit containing any dose in the range of 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, more preferably 1 mg to 10 mg, for example 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of mirtazapine or a pharmaceutically acceptable salt thereof, and any dose in the range of 10 to 120 mg, for example 10 mg, 20 mg or 30 mg of narcotine or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the pharmaceutically acceptable salt of Noscapine is Noscapine hydrochloride.

[0174] In some embodiments, the content ratio of mirtazapine to narcotine in the prepared medicine is 1:1200-9:2, preferably 1:120-3:1, more preferably 1:120-3:2, for example 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-110, 1-120, 1.5-1, 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7 or 1-8.

[0175] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0176] In some embodiments, the pharmaceutical composition is in the form of a dosage unit, such as a tablet or a capsule, each dosage unit containing 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, more preferably any dose in the range of 1 mg to 10 mg, for example 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of mirtazapine or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the pharmaceutical composition is in the form of dosage units, such as tablets or capsules, each dosage unit containing any dose in the range of 10 to 120 mg, such as 10 mg, 20 mg or 30 mg of Narcotine or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the pharmaceutical composition is in the form of dosage units, such as tablets or capsules, each dosage unit containing any dose in the range of 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, more preferably 1 mg to 10 mg, for example 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of mirtazapine or a pharmaceutically acceptable salt thereof, and any dose in the range of 10 to 120 mg, for example 10 mg, 20 mg or 30 mg of narcotine or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the pharmaceutically acceptable salt of Noscapine is Noscapine hydrochloride.

[0180] In some embodiments, the ratio of mirtazapine to narcotine in the pharmaceutical composition is 1:1200-9:2, preferably 1:120-3:1, more preferably 1:120-3:2, for example 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-110, 1-120, 1.5-1, 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7 or 1-8.

[0181] According to another aspect of the present invention, a pharmaceutical composition is provided, comprising mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is used to treat an organ fibrosis-related disease in a patient in need thereof, wherein the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0182] In some embodiments, the pharmaceutical composition is used to treat progressive fibrotic interstitial lung disease in a patient.

[0183] In some embodiments, the pharmaceutical composition is used to treat progressive pulmonary fibrosis in a patient.

[0184] In some embodiments, the pharmaceutical composition is used to treat idiopathic pulmonary fibrosis in a patient in need thereof.

[0185] In some embodiments, the pharmaceutical composition is used to treat renal interstitial fibrosis in a patient in need thereof.

[0186] In some embodiments, the pharmaceutical composition is used to inhibit renal interstitial fibrosis or reduce the degree of renal interstitial fibrosis in a patient in need thereof.

[0187] In some embodiments, the pharmaceutical composition is used to treat liver fibrosis in a patient in need thereof.

[0188] In some embodiments, the pharmaceutical composition is used to inhibit liver fibrosis or reduce the degree of liver fibrosis in a patient in need thereof.

[0189] In some embodiments, the pharmaceutical composition is used to treat myocardial fibrosis in a patient in need thereof.

[0190] In some embodiments, the pharmaceutical composition is used to inhibit myocardial fibrosis or reduce the degree of myocardial fibrosis in a patient in need thereof.

[0191] In some embodiments, the pharmaceutical composition is used to treat idiopathic nonspecific interstitial pneumonia in a patient in need thereof.

[0192] In some embodiments, the pharmaceutical composition is used to treat connective tissue disease-associated interstitial lung disease in a patient in need thereof.

[0193] In some embodiments, the pharmaceutical composition is used to treat, reduce the severity of, or prevent the exacerbation of pneumoconiosis in a patient in need thereof.

[0194] In some embodiments, the pharmaceutical composition is used to treat pulmonary sarcoidosis in a patient in need thereof.

[0195] In some embodiments, the pharmaceutical composition is in the form of a dosage unit, such as a tablet or a capsule, each dosage unit containing 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, more preferably any dose in the range of 1 mg to 10 mg, for example 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of mirtazapine or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the pharmaceutical composition is in the form of dosage units, such as tablets or capsules, each dosage unit containing any dose in the range of 10 to 120 mg, such as 10 mg, 20 mg or 30 mg of Narcotine or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the pharmaceutical composition is in the form of dosage units, such as tablets or capsules, each dosage unit containing any dose in the range of 0.1 mg to 45 mg, preferably 0.5 mg to 15 mg, more preferably 0.5 mg to 10 mg, more preferably 1 mg to 10 mg, for example 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of mirtazapine or a pharmaceutically acceptable salt thereof, and any dose in the range of 10 to 120 mg, for example 10 mg, 20 mg or 30 mg of narcotine or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the pharmaceutically acceptable salt of Noscapine is Noscapine hydrochloride.

[0199] In some embodiments, the ratio of mirtazapine to narcotine in the pharmaceutical composition is 1:1200-9:2, preferably 1:120-3:1, more preferably 1:120-3:2, for example 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-110, 1-120, 1.5-1, 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7 or 1-8.

[0200] Another aspect of the present invention provides a drug combination, comprising a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of narcotine or a pharmaceutically acceptable salt thereof, wherein mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof are respectively formulated in separate pharmaceutical preparations, but are simultaneously administered to a patient in need thereof for treating an organ fibrosis-related disease of the patient, wherein the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

[0201] In some embodiments of the dough, the pharmaceutically acceptable salt of Noscapine is Noscapine hydrochloride.

[0202] In some embodiments, the ratio of the therapeutically effective amount of mirtazapine to narcotine is 1:1200-9:2, preferably 1:120-3:1, more preferably 1:120-3:2, for example 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-110, 1-120, 1.5-1, 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7 or 1-8.

[0203] According to another aspect of the present invention, a packaged drug product is provided, which comprises (1) a pharmaceutical composition containing mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition containing narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat an organ fibrosis-related disease in a patient in need thereof, wherein the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis, liver fibrosis and myocardial fibrosis.

[0204] In some embodiments, a kit drug product is provided, comprising (1) a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition comprising narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat progressive fibrosing interstitial lung disease in a patient in need thereof.

[0205] In some embodiments, a kit pharmaceutical product is provided, comprising (1) a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition comprising narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat progressive pulmonary fibrosis in a patient in need thereof.

[0206] In some embodiments, a kit pharmaceutical product is provided, comprising (1) a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition comprising narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat idiopathic pulmonary fibrosis in a patient in need thereof.

[0207] In some embodiments, a kit drug product is provided, which comprises (1) a pharmaceutical composition containing mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition containing narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat pneumoconiosis in a patient in need thereof, reduce its severity, or prevent its exacerbation.

[0208] In some embodiments of the kit drug product, the pharmaceutically acceptable salt of Noscapine is Noscapine hydrochloride.

[0209] The pharmaceutical composition of the present invention can be prepared for administration in a unit dosage form. The dosage form can be a liquid dosage form or a solid dosage form. The liquid dosage form can be a solution, a colloid, an emulsion dosage form or a suspension dosage form. The solid dosage form can be, for example, a tablet, a powder, a suppository, a granule or a capsule. Other dosage forms include aerosols, implants, patches or liniments.

[0210] The pharmaceutical composition of the present invention can be prepared into a dosage form suitable for use with a patient using methods known in the art using a suitable pharmaceutical excipient. The selection of a specific excipient will depend on the mode of administration or the type of disease and state used to treat a specific patient. For example, pharmaceutically acceptable excipients can include conventional diluents, carriers, fillers, adhesives, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers and lubricants in the pharmaceutical field, etc. If necessary, flavoring agents, preservatives and sweeteners, etc. can also be added to the pharmaceutical composition. The preparation method of a suitable pharmaceutical composition for a specific mode of administration is fully within the knowledge of the pharmaceutical field technician.

[0211] The pharmaceutical composition of the present invention can be administered in any manner and in any form commonly used in the art. For example, the pharmaceutical composition of the present invention can be administered in the following manners: oral administration, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection, wherein oral administration, intramuscular injection, intraperitoneal or intravenous injection is preferred. Preferably, the pharmaceutical composition of the present invention is administered to a patient in need thereof by oral administration.

[0212] For oral administration, any suitable pharmaceutical excipient commonly used in the preparation of solid preparations can be used, using formulation techniques known in the art, to prepare the pharmaceutical composition of the present invention into solid preparations, such as tablets, capsules and powders. Alternatively, any suitable pharmaceutical excipient commonly used in the preparation of liquid preparations can be used, using formulation techniques known in the art, to prepare the pharmaceutical composition of the present invention into liquid preparations such as solutions, syrups, suspensions and emulsions.

[0213] For administration via parenteral route, any appropriate pharmaceutical excipient commonly used for preparation of parenteral route can be used, and the pharmaceutical composition of the present invention can be formulated into a preparation suitable for parenteral route administration using formulation techniques known in the art, such as sterile injection, lyophilized powder, transdermal patch, aerosol, oral and nasal inhalation and suppository, etc. Parenteral administration routes include intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical routes.

[0214] By using formulation techniques known in the art, by appropriately changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention, the pharmaceutical composition can also be prepared into a pharmaceutical preparation suitable for children, the elderly, critically ill patients or surgical patients.

[0215] According to the blood drug concentration when the anti-fibrosis effect is observed in the animal experiment, the ratio of the dose when the anti-depressant effect is observed in the animal experiment to the dose when the anti-fibrosis effect is observed, the effective dose range of mirtazapine for anti-fibrosis can be deduced through the dose range in which the anti-depressant effect can be observed after administration to the human body. When the subject is a human, the therapeutic effective dose of mirtazapine applicable to the present invention is 0.1 to 45 mg / person / day, preferably 1 to 15 mg / person / day, 1 to 10 mg / person / day, 1 mg / person / day, 5 mg / person / day, 10 mg / person / day or 15 mg / person / day.

[0216] When the subject is a human, the therapeutically effective dose of Noscapine applicable to the present invention is any dose within the range of 10 to 120 mg / person / day, for example, 10 mg / person / day, 20 mg / person / day, 30 mg / person / day, 40 mg / person / day, 50 mg / person / day, 60 mg / person / day, 70 mg / person / day, 80 mg / person / day, 90 mg / person / day, 100 mg / person / day, 110 mg / person / day or 120 mg / person / day.

[0217] Unless otherwise specifically stated in the specification, the dosages, dosage ratios, contents or content ratios of mirtazapine and narcotine disclosed in the present application are all calculated based on their respective free forms rather than salt or hydrate forms.

[0218] Unless otherwise specifically stated in the specification, the expression "mg / person / day" used in the present invention refers to the number of milligrams of a daily dose for an adult with a body weight of about 70 kg.

[0219] Example

[0220] Exemplary methods and materials are described in this application, although methods and materials similar or equivalent to those described in this application can also be used to implement or test various aspects and embodiments. The materials, methods and examples specifically disclosed in this application are only for illustration and are not intended to limit the scope of the invention.

[0221] Example 1: Construction of bleomycin pulmonary fibrosis mouse model and evaluation of drug effects.

[0222] This model is a classic model for evaluating the effects of substances on pulmonary fibrosis, and its construction method is known to those skilled in the art.

[0223] Experimental animals: C57BL / 6J mice, 8 weeks old, male.

[0224] Preparation of bleomycin solution:

[0225] Weigh 6.26 mg of bleomycin sulfate into a clean test tube, then add 19.436 mg of saline and vortex until the solution becomes clear.

[0226] The method for constructing the bleomycin pulmonary fibrosis mouse model is as follows:

[0227] All mice were anesthetized with Zoletil / Xylazine (50 mpk / 10 mpk; IP). On the first day of the experiment, mice in the model group were injected intratracheally with bleomycin hydrochloride at a dose of 0.66 mg / kg (equivalent to 1 U / kg) in a volume of 50 μL. The sham group was injected intratracheally with normal saline in a volume of 50 μL. The dosing cycle started on the fifth day of the experiment and lasted until the twenty-first day of the experiment.

[0228] Lung tissue was collected and Masson's trichrome staining was performed to quantify the fibrosis area as follows:

[0229] At the end of the study (experimental day 21), all animals were euthanized 2 hours after the last administration. After all animals were perfused with saline, the left lungs of the animals were collected and fixed in a fixative containing 10% neutral formalin for histological analysis. The right lungs of the animals were placed in precooled EP tubes, quickly frozen in liquid nitrogen, and stored at -80°C. Collagen in lung tissue was quantified using Masson's trichrome staining as described below.

[0230] The lung sections were 4 μm thick, dried in an oven for 1 hour, and stained with a standardized Masson's trichrome stain according to our SOP. The steps were as follows: staining with Weigert's hematoxylin working solution for 10 minutes and then washed with water, staining with a mixture of Bibliopectin and fuchsin for 10 minutes and then washed with water. Staining was performed in a mixture of 5% phosphomolybdic acid and 5% tungstic acid for 5 minutes or until the collagen was no longer red. The slides were immersed in aniline blue solution for 1 minute and then degraded in 1% acetic acid solution. After gradient dehydration, the slides were mounted with coverslips. For the stained sections, Aperio GT450 was used to scan at 200 times and the images were opened with HALO. Using the pen tool, the entire left lobe of the lung was selected as the annotation layer, and the bronchi and blood vessels were removed. The blue collagen fiber positions were highlighted using the drawing tool, and the percentage of fibrosis (positive area) in the selected annotation was calculated using the HALO program. Fibrosis was expressed as a percentage for each lung section. The pathological sections stained with Masson's trichrome were then manually scored according to the table below.

[0231] Before the experiment, the mice were allowed to acclimate to the environment for 1 week and each mouse was given a health check, including an assessment of the coat, limbs, and mouthparts, and an examination of each mouse's posture and movements for signs of abnormality.

[0232] Example 2: Evaluation of the effects of mirtazapine and simvastatin alone and in combination in the bleomycin pulmonary fibrosis mouse model

[0233] Preparation of medium (0.5% methylcellulose, w / w): weigh 5.0 g of methylcellulose, add 995.0 ml of normal saline, stir vigorously, and store at 4°C.

[0234] Preparation of mirtazapine solution: weigh 10.20 mg of mirtazapine and add it to 20.00 ml of medium, then add 20.00 mg of normal saline, vortex and sonicate until the solution becomes clear. The concentration of the solution is 0.5 mg / ml. The dosage is 10 ml / kg.

[0235] Preparation of simvastatin solution: Weigh 4.13 mg of simvastatin and add it to 20.00 ml of medium, then add 20.00 mg of saline, vortex and sonicate until the solution becomes clear. The concentration of the solution is 0.2 mg / ml. The dosage is 10 ml / kg.

[0236] Preparation of mirtazapine + simvastatin combined solution: weigh 10.24 mg of mirtazapine and 4.14 mg of simvastatin and add them to 20.00 ml of medium, vortex and sonicate until the solution becomes clear. The concentration of the solution is 0.5 mg / ml for mirtazapine and 0.2 mg / ml for simvastatin. The dosage is 10 ml / kg.

[0237] Table 1. Composition of mirtazapine and simvastatin administered alone and in combination

[0238] Group Treatment (oral) Number of mice 1 medium 10 2 Mirtazapine 5 mg / kg 10 3 Simvastatin 2mg / kg + mirtazapine 5mg / kg 10 4 Simvastatin 2 mg / kg 10

[0239] Experimental Results

[0240] According to the dosage and route of administration shown in Table 1, the animals were administered according to the method described in Example 1. The results showed that mirtazapine alone reduced the fibrosis area by 10.8%, simvastatin alone reduced the fibrosis area by 8.3%, and the combination of mirtazapine and simvastatin only reduced the fibrosis area by 15.3%, which was less than the sum of the anti-fibrosis effects of each of them alone.

[0241] The results showed that mirtazapine and simvastatin each showed a trend of reducing the area of ​​fibrosis; however, when the combination of mirtazapine and simvastatin was compared with the results of either drug alone, it was found that the anti-fibrotic efficacy of the combination was not increased.

[0242] Example 3: Evaluation of the effects of mirtazapine and noscapine alone and in combination in the bleomycin pulmonary fibrosis mouse model

[0243] Preparation of medium (0.5% methylcellulose, w / w): weigh 5.0 g of methylcellulose, add 995.0 ml of normal saline, stir vigorously, and store at 4°C.

[0244] Preparation of mirtazapine solution: weigh 10.20 mg of mirtazapine and add it to 20.00 ml of medium, then add 20.00 mg of normal saline, vortex and sonicate until the solution becomes clear. The concentration of the solution is 0.5 mg / ml. The dosage is 10 ml / kg.

[0245] Preparation of Narcotine solution: Weigh 66.74 mg of Narcotine hydrochloride and add it to 20.00 ml of medium, then add 20.00 mg of normal saline, vortex and sonicate until the solution becomes clear. The concentration of the solution is 3 mg / ml. The dosage is 10 ml / kg.

[0246] Preparation of mirtazapine + narcotine combined solution: weigh 10.20 mg of mirtazapine and 66.80 mg of narcotine hydrochloride and add them to 20.00 ml of medium, vortex and sonicate until the solution becomes clear. The concentration of the solution is 0.5 mg / ml of mirtazapine and 3 mg / ml of narcotine. The dosage is 10 ml / kg.

[0247] Table 2. Composition of mirtazapine and noscapine administered alone and in combination

[0248] Group Treatment (oral) Number of mice 1 medium 8 2 Mirtazapine 5 mg / kg 8 3 Nascotine 30mg / kg + Mirtazapine 5mg / kg 8 4 Nascotine 30mg / kg 8

[0249] Experimental Results

[0250] According to the dosage and route of administration shown in Table 2, the animals were administered according to the method described in Example 1. The results showed that mirtazapine alone reduced the fibrosis area by 14.3%, narcotine alone reduced the fibrosis area by 3.3%, and the combination of mirtazapine and narcotine unexpectedly reduced the fibrosis area by 20.5%, which was greater than the sum of the anti-fibrosis effects of each of them alone. From a statistical point of view, the reduction was very significant.

[0251] The results showed that mirtazapine alone showed a tendency to reduce the area of ​​fibrosis, while narcotine alone failed to reduce the area of ​​fibrosis. However, when narcotine, which had no observed efficacy as a single drug, was used in combination with mirtazapine, it was observed that the anti-fibrosis effect of the combination was greater than the sum of the anti-fibrosis effects of each drug alone, indicating a synergistic effect.

[0252] Therefore, the inventors have experimentally confirmed that when certain compounds that show anti-fibrotic effects when used alone are used in combination, the combination does not show an increase in anti-fibrotic effects, which indicates that the anti-fibrotic effects of drug combinations are unpredictable. Surprisingly, when the inventors used noscapine, which did not show anti-fibrotic effects when used alone, in combination with mirtazapine, the combination showed a synergistic increase in anti-fibrotic effects. The combination of mirtazapine and noscapine has a synergistic anti-fibrotic effect that is unexpected by those skilled in the art.

Claims

1. A pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1, which is in the form of dosage units, wherein each dosage unit comprises mirtazapine or a pharmaceutically acceptable salt thereof in any dose within the range of 0.1 mg to 45 mg, 0.5 mg to 15 mg, 0.5 mg to 10 mg or 1 mg to 10 mg.

3. The pharmaceutical composition according to claim 1, which is in the form of dosage units, wherein each dosage unit contains any dose of Narcotine or a pharmaceutically acceptable salt thereof within the range of 10 to 120 mg.

4. The pharmaceutical composition according to claim 1, which is in the form of dosage units, wherein each dosage unit comprises mirtazapine or a pharmaceutically acceptable salt thereof at any dose in the range of 0.1 mg to 45 mg, 0.5 mg to 15 mg, 0.5 mg to 10 mg or 1 mg to 10 mg, and narcotine or a pharmaceutically acceptable salt thereof at any dose in the range of 10 to 120 mg.

5. Use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an organ fibrosis-related disease in a patient in need thereof, wherein the organ fibrosis-related disease is selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis disease, liver fibrosis disease and myocardial fibrosis disease.

6. The use according to claim 5, wherein the disease related to organ fibrosis is progressive fibrotic interstitial lung disease.

7. The use according to claim 5, wherein the organ fibrosis-related disease is progressive pulmonary fibrosis.

8. The use according to claim 5, wherein the disease related to organ fibrosis is idiopathic pulmonary fibrosis.

9. Use of mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving a patient's pulmonary fibrosis lesions, inhibiting the progression of a patient's pulmonary fibrosis, or alleviating the degree of a patient's pulmonary fibrosis.

10. A packaged pharmaceutical product comprising (1) a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a pharmaceutical composition comprising narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) instructions for using the pharmaceutical composition to treat an organ fibrosis-related disease in a patient in need thereof.

11. The packaged pharmaceutical product according to claim 10, wherein the pharmaceutical composition (1) comprises any dose of mirtazapine or a pharmaceutically acceptable salt thereof in the range of 0.1 mg to 45 mg, 0.5 mg to 15 mg, 0.5 mg to 10 mg or 1 mg to 10 mg.

12. The packaged pharmaceutical product according to claim 10 or 11, wherein the pharmaceutical composition (2) comprises any dose of Narcotine or a pharmaceutically acceptable salt thereof within the range of 10 to 120 mg.

13. The packaged pharmaceutical product according to any one of claims 10 to 12, wherein the disease associated with organ fibrosis is progressive fibrotic interstitial lung disease.

14. The packaged pharmaceutical product according to any one of claims 10 to 12, wherein the organ fibrosis-related disease is progressive pulmonary fibrosis.

15. The packaged pharmaceutical product according to any one of claims 10 to 12, wherein the disease associated with organ fibrosis is idiopathic pulmonary fibrosis.