Pharmaceutical composition and method for treating organ fibrosis-related diseases

Abstract

A pharmaceutical composition and method for treating organ fibrosis-related diseases. The pharmaceutical composition and method comprise mirtazapine or a pharmaceutically acceptable salt thereof, or a combination of mirtazapine or a pharmaceutically acceptable salt thereof and noscapine or a pharmaceutically acceptable salt thereof, and can effectively inhibit organ fibrosis lesions of a patient so as to treat organ fibrosis-related diseases.

Description

Pharmaceutical compositions and methods for treating organ fibrosis-related diseases 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 relates to a pharmaceutical composition and method for treating fibrotic interstitial lung disease. Background Art

[0002] Organ fibrosis is a pathological change characterized by an increase in fibrous connective tissue and a decrease in parenchymal cells within 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 targeting fibrosis (Han Min et al., Research progress and important scientific issues in 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 heterogeneous group of diseases with different etiologies, treatments, and a range of disease manifestations. They are characterized by pathological findings of fibrosis or honeycombing and / or traction-like 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). FILDs 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]. Wisdom Health, 2022, 8(24): 110-113). To date, 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 multiple countries. Mirtazapine has been reported to alleviate pulmonary fibrosis in experimental animal models (Abdelhady R et al., Biomed Pharmacother. 2023 May;161:114553). However, mirtazapine has numerous and severe side effects, including weight gain, fatigue (15.2%), drowsiness (50%), sedation, dizziness, and fatigue, headache, constipation (12.7%), dry mouth (20.6%), elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT) (12.4%), elevated γ-GTP, and increased appetite. To date, no literature has been found reporting that low-dose mirtazapine alone can be used to treat organ fibrosis or related diseases, or that mirtazapine combined with other drugs has an additive or even synergistic effect on organ fibrosis or related diseases.

[0004] Noscapine is a peripherally acting antitussive drug. WO 2009 / 155611 studied the preventive effects of noscapine on fibrosis in experimental animal models. However, no literature has been found to date reporting that noscapine combined with other drugs has additive or even synergistic effects on organ fibrosis or 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.

[0006] Summary of the Invention

[0007] 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 safe and can be taken by patients for a long time.

[0008] The inventors unexpectedly found in the experiment that mirtazapine, when used alone or in combination with some drugs already on the market, can very significantly suppress mammalian organ fibrosis. Particularly unexpectedly, it was found that of the two enantiomers of mirtazapine, only the R configuration mirtazapine had a statistically significant anti-fibrotic effect when used alone, while the S configuration mirtazapine, which is considered to be the main active body in the antidepressant effect, did not have a statistically significant anti-fibrotic effect. In addition, the anti-fibrotic effect of mirtazapine can be achieved at a lower dosage (that is, lower than its effective dose for treating depression, for example, lower than 15 milligrams of daily dose, for example, 1 to 10 milligrams of daily dose). Based on this discovery, the inventors have completed the present invention, and therefore the present invention can achieve the above-mentioned purpose.

[0009] The present invention can be described from different aspects. The invention described in any aspect and any embodiment of these aspects is independent of each other but related to each other, and together constitutes the content of the present invention.

[0010] One aspect of the present invention provides a method for treating an organ fibrosis-related disease in a patient, comprising the step of administering a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof to the patient.

[0011] 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.

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

[0015] 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.

[0016] In some embodiments, the therapeutically effective amount of mirtazapine is a single dose of 0.1 to 45 mg, such as 1 to 10 mg, preferably 3 to 5 mg, administered once or more daily.

[0017] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0018] 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.

[0019] 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.

[0020] In some embodiments, provided is the use of mirtazapine 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.

[0021] 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.

[0022] 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.

[0023] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0024] Another aspect of the present invention provides a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for treating organ fibrosis-related diseases in patients in need thereof.

[0025] In some embodiments, mirtazapine is administered in a therapeutically effective amount.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] In some embodiments, the therapeutically effective amount of mirtazapine is a single dose of 0.1 to 45 mg, such as 1 to 10 mg, preferably 3 to 5 mg, administered once or more daily.

[0031] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0032] Another aspect of the present invention provides substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof, which is used as a medicament for improving pulmonary fibrosis lesions, inhibiting the progression of pulmonary fibrosis in patients, or reducing the degree of pulmonary fibrosis in patients.

[0033] In some embodiments, mirtazapine is administered in a therapeutically effective amount for use as a medicament for improving pulmonary fibrosis lesions in a patient, inhibiting the progression of pulmonary fibrosis in a patient, or reducing the extent of pulmonary fibrosis in a patient.

[0034] In some embodiments, the therapeutically effective amount of mirtazapine is a single dose of 0.1 to 45 mg, such as 1 to 10 mg, preferably 3 to 5 mg, administered once or more daily.

[0035] Another aspect of the present invention provides substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof for use in treating a patient suffering from an organ fibrosis-related disease, wherein the organ fibrosis-related disease may be one or more selected from fibrosing interstitial lung disease, renal interstitial fibrosis, hepatic fibrosis, and myocardial fibrosis. In some embodiments, mirtazapine is administered in a therapeutically effective amount for treating an organ fibrosis-related disease.

[0036] In some embodiments, the therapeutically effective amount of mirtazapine is a single dose of 0.1 to 45 mg, such as 1 to 10 mg, preferably 3 to 5 mg, administered once or more daily.

[0037] Another aspect of the present invention provides a method for treating an organ fibrosis-related disease in a patient, 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.

[0038] 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.

[0039] In some embodiments, a method of treating progressive fibrosing interstitial lung disease in a patient is provided, 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.

[0040] In some embodiments, a method of treating progressive pulmonary fibrosis in a patient is provided, 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.

[0041] In some embodiments, a method of treating idiopathic pulmonary fibrosis in a patient is provided, 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.

[0042] In some embodiments, the therapeutically effective amount of mirtazapine is a single dose of 0.1 to 45 mg, such as 1 to 10 mg, preferably 3 to 5 mg, administered once or more daily.

[0043] In some embodiments, the therapeutically effective amount of Noscapine is a single dose of 1 to 3000 mg, preferably 10 to 120 mg, administered once or more daily.

[0044] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0045] Another aspect of the present invention provides 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 organ fibrosis-related diseases in patients in need thereof.

[0046] 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.

[0047] 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 fibrosing interstitial lung disease in a patient in need thereof.

[0048] 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.

[0049] 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.

[0050] In some embodiments, mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof are formulated in the same pharmaceutical formulation.

[0051] In some embodiments, mirtazapine, or a pharmaceutically acceptable salt thereof, and narcotine, or a pharmaceutically acceptable salt thereof, are each formulated in separate pharmaceutical formulations.

[0052] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0053] Another aspect of the present invention provides a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof, narcotine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0054] In some embodiments, mirtazapine and narcotine are each administered to a patient in need thereof in a therapeutically effective amount thereof.

[0055] In some embodiments, the therapeutically effective amount of mirtazapine is a single dose of 0.1 to 45 mg, such as 1 to 10 mg, preferably 3 to 5 mg, administered once or more daily.

[0056] In some practical embodiments, the therapeutically effective amount of Noscapine is 1 to 3000 mg, preferably 10 to 120 mg, administered once or more daily.

[0057] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0058] 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 to treat organ fibrosis-related diseases in patients in need thereof.

[0059] In some embodiments, mirtazapine and noscapine are each administered in a therapeutically effective amount for treating an organ fibrosis-related disease in a patient in need thereof.

[0060] 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.

[0061] 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 treating progressive fibrotic interstitial lung disease in a patient in need thereof.

[0062] 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 treating progressive pulmonary fibrosis in a patient in need thereof.

[0063] 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 treating idiopathic pulmonary fibrosis in a patient in need thereof.

[0064] In some embodiments, the therapeutically effective amount of mirtazapine is a single dose of 0.1 to 45 mg, such as 1 to 10 mg, preferably 3 to 5 mg, administered once or more daily.

[0065] In some practical embodiments, the therapeutically effective amount of Noscapine is a single dose of 1 to 3000 mg, preferably 10 to 120 mg, administered once or more per day.

[0066] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0067] 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.

[0068] In some embodiments, the therapeutically effective amount of mirtazapine is a single dose of 0.1 to 45 mg, such as 1 to 10 mg, preferably 3 to 5 mg, administered once or more daily.

[0069] In some practical embodiments, the therapeutically effective amount of Noscapine is a single dose of 1 to 3000 mg, preferably 10 to 120 mg, administered once or more per day.

[0070] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0071] Another aspect of the present invention provides a packaged pharmaceutical product comprising (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.

[0072] 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.

[0073] In some embodiments, a kit 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.

[0074] In some embodiments, a kit 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.

[0075] In some embodiments, a kit 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.

[0076] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0077] The present inventors have experimentally demonstrated that mirtazapine, or a pharmaceutically acceptable salt thereof, administered alone or in combination with narcotine, or a pharmaceutically acceptable salt thereof, can effectively inhibit pulmonary fibrosis in mammals. Particularly surprising is that a low-dose combination of mirtazapine, or a pharmaceutically acceptable salt thereof, and narcotine, or a pharmaceutically acceptable salt thereof, significantly inhibits pulmonary fibrosis compared to existing marketed drugs.

[0078] The inventors have also discovered through experiments that the anti-fibrotic effect of mirtazapine combined with other drugs is unpredictable. For example, experiments have shown that when mirtazapine and simvastatin are used together, the anti-fibrotic effect of the combination is less than the sum of the anti-fibrotic effects of each drug when used alone. In contrast, in the present invention, when mirtazapine and narcotine are used together, the anti-fibrotic effect of the combination is greater than the sum of the anti-fibrotic effects of each drug when used alone, indicating a synergistic effect.

[0079] Therefore, it can be expected that the method, drug combination and pharmaceutical composition of the present invention can effectively suppress 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, alleviate the symptoms such as the mental stress, dyspnea, cough 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 suppress the fibrotic lesions of other organs, such as renal fibrosis lesions, liver fibrosis lesions and cardiac fibrosis lesions. The dosage of mirtazapine used in the present invention is relatively low, and the combined administration of mirtazapine and noscapine not only has fewer and smaller side effects than single-drug administration, but also has stronger anti-fibrotic 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 effect of mirtazapine while producing an effective anti-fibrotic effect, have higher safety relative to listed anti-fibrosis drugs, thereby can improve the compliance of patients. DETAILED DESCRIPTION

[0080] To facilitate understanding of the present invention, certain terms used herein 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 this specification have the same meanings as those commonly understood by those skilled in the art. If the meaning of a term specifically defined in this specification is inconsistent with the meaning commonly understood by those skilled in the art, the meaning specifically defined in this specification shall prevail.

[0081] As used herein, the term "organ fibrosis-related diseases" refers to fibrotic lesions that occur in the internal organs of mammals, particularly humans, and the diseases associated with or caused by them, including one or more clinical symptoms of such diseases, including but not limited to diseases or symptoms caused by cardiac fibrosis, liver fibrosis, lung fibrosis, and kidney fibrosis. Fibrosis refers to the excessive deposition of extracellular matrix proteins, resulting in scarring and thickening of tissues.

[0082] As used herein, the term "fibrosing interstitial lung disease" refers to fibrotic lesions occurring in the lungs of mammals, particularly humans, and the diseases or symptoms associated with or caused by them. Examples of fibrosing interstitial lung diseases are fibrosing interstitial lung disease or pulmonary fibrosis, including idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung disease.

[0083] The term "progressive fibrosing interstitial lung disease" used in the present invention refers to a group of interstitial lung diseases in which the patient's pulmonary fibrosis continues to progress even after treatment with immunosuppressants and elimination of factors that promote disease progression. In some embodiments, "progressive fibrosing interstitial lung disease" is also referred to as "progressive pulmonary fibrosis (PPF)", which can be used interchangeably in the present invention. Progressive fibrosing 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.

[0084] The term "idiopathic pulmonary fibrosis" as used herein refers to a group of diseases characterized by pulmonary fibrosis as the primary pathological form. These diseases can lead to a progressive loss of normal lung function, manifested by progressive dyspnea, coughing, and expectoration, among other respiratory symptoms. As the damage and condition worsen, respiratory function gradually declines. The clinical incidence of these diseases is increasing annually, and the average survival after diagnosis is 2.5 to 3 years. The pathogenesis of pulmonary fibrosis remains unclear, but damage to alveolar epithelial cells, inflammation, and alveolar macrophage and cell apoptosis are currently believed to be key target mechanisms in the pathogenesis of pulmonary fibrosis.

[0085] As used herein, the term "treating" refers to the prevention, amelioration, alleviation, or elimination of at least one discernible symptom of a disease associated with organ fibrosis, including a reduction in the degree of fibrosis in an organ or tissue. Specifically, the term "treating" as used herein refers to reducing the severity of fibrosis in an affected organ or tissue, improving the physiological function of an affected organ or tissue, and / or preventing the development of varying degrees of fibrosis in an affected organ or tissue.

[0086] 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.

[0087] Unless otherwise specified, the phrase "therapeutically effective amount" as used herein refers to the amount of the drug or compound that, when administered to a patient, provides the desired therapeutic effect, namely, reducing the severity of fibrosis in the diseased organ or tissue, improving the physiological function of the affected organ or tissue, and / or preventing the development of varying degrees of fibrosis in the affected organ or tissue. Those skilled in the art will appreciate that the "therapeutically effective amount" of the drug used herein can be determined and adjusted based on the patient's age, weight, sex, type and severity of the disease, route of administration, and the like.

[0088] The term "mirtazapine" used in the present invention refers to a drug with the chemical formula The chemical name is 1,2,3,4,10,14b-hexahydro-2-methylpyrazinyl[2,1-a]pyrido[2,3-c][2]benzazepine An organic compound with the molecular formula C 17 H 19 N3. 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 (i.e., R-configuration mirtazapine and S-configuration mirtazapine) and a mixture of enantiomers. In the embodiment in which mirtazapine or a pharmaceutically acceptable salt thereof is used alone, mirtazapine refers to a mixture of R-configuration mirtazapine and S-configuration mirtazapine, such as racemic mirtazapine, preferably substantially pure (R)-mirtazapine; in the embodiment in which mirtazapine or a pharmaceutically acceptable salt thereof is used in combination with narcotine or a pharmaceutically acceptable salt thereof, mirtazapine refers to a mixture of any proportion of R-configuration mirtazapine, S-configuration mirtazapine, or R-configuration mirtazapine and S-configuration mirtazapine.

[0089] As used herein, the term "substantially pure (R)-mirtazapine" refers to a mixture of (R)-mirtazapine and (S)-mirtazapine, wherein the content of (R)-mirtazapine is greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

[0090] The pharmaceutically acceptable salts of mirtazapine used in the present invention include various pharmaceutically acceptable salts of mirtazapine, 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.

[0091] 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.). The solvate 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.

[0092] 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 an atom 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.

[0093] The term "Narcotin" used in the present invention is a peripheral antitussive drug, the chemical name of which 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 the 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.

[0094] The Narcotine or its pharmaceutically acceptable salt used in the present invention includes solvates (e.g., hydrates, etc.). Solvates can be coordinated with any number of solvent molecules (e.g., water molecules, etc.) to form Narcotine or its pharmaceutically acceptable salt. Exposing Narcotine or its pharmaceutically acceptable salt to the atmosphere may cause it to absorb water, and the adsorbed water may adhere to it or form a hydrate. The preparation of Narcotine and its pharmaceutically acceptable salts and solvates (e.g., hydrates, etc.) is known to those skilled in the art.

[0095] 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 weight or mass number different from the atomic weight or mass number usually 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.

[0096] As used herein, the expression "simultaneously administering mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof" and "administering mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof" have the same meaning and are used interchangeably herein. As used herein, the expression "administering mirtazapine or a pharmaceutically acceptable salt thereof in combination with narcotine or a pharmaceutically acceptable salt thereof" means administering mirtazapine or a pharmaceutically acceptable salt thereof before, after, or at approximately the same time as administering narcotine or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0097] 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 to the patient a therapeutically effective amount of mirtazapine 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, liver fibrosis, and myocardial fibrosis.

[0098] 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.

[0099] In some embodiments, a method of inhibiting or reducing the extent of renal interstitial fibrosis in a patient is provided, comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0100] 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.

[0101] In some embodiments, a method of inhibiting or reducing the degree of liver fibrosis in a patient is provided, comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0102] 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.

[0103] In some embodiments, a method of inhibiting or reducing the degree of myocardial fibrosis in a patient is provided, comprising administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, a method of treating progressive fibrotic interstitial lung disease in a patient is provided, comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, a method of treating progressive pulmonary fibrosis in a patient is provided, comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, a method of treating idiopathic pulmonary fibrosis in a patient is provided, comprising the step of administering to the patient a therapeutically effective amount of mirtazapine or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, a method for improving pulmonary fibrosis lesions in a patient, inhibiting the progression of pulmonary fibrosis in a patient, or reducing the extent of pulmonary fibrosis 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 a subject in need thereof.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] In some embodiments, the treatment comprises administering to a subject in need thereof once or more daily a dose of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine in any range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg.

[0116] In some embodiments, the patient is administered a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof once or more daily.

[0117] In some embodiments, the method comprises administering to the patient once daily a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof.

[0118] In some embodiments, the method comprises administering to the patient twice daily a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof.

[0119] In some embodiments, the pharmaceutical composition is administered to a patient in need thereof in the form of dosage units, and each dosage unit contains any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

[0120] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0121] 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, liver fibrosis, and myocardial fibrosis.

[0122] 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 in a patient in need thereof.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] In some embodiments, provided is 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.

[0130] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, lessening the severity of, or preventing the exacerbation of pneumoconiosis in a patient in need thereof.

[0131] In some embodiments, provided is the 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.

[0132] 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.

[0133] In some embodiments, provided is the use of mirtazapine 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.

[0134] 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.

[0135] In some embodiments, provided is the 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.

[0136] In some embodiments, the drug is prepared in dosage unit form, such as a tablet or capsule, containing any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

[0137] In some embodiments, there is provided a use of mirtazapine or a pharmaceutically acceptable salt thereof for 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 medicament comprises any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

[0138] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0139] According to another aspect of the present invention, a pharmaceutical composition comprising mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided, which is used to treat organ fibrosis-related diseases in patients in need thereof, wherein the organ fibrosis-related diseases are selected from one or more of fibrosing interstitial lung disease, renal interstitial fibrosis, liver fibrosis and myocardial fibrosis.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] In some embodiments, the treatment comprises administering to a subject in need thereof once or more daily any dose within the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

[0155] In some embodiments, the pharmaceutical composition is in the form of an oral solid dosage form, such as a tablet or capsule.

[0156] In some embodiments, the pharmaceutical composition comprises any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

[0157] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0158] According to another aspect of the present invention, a method for treating an organ fibrosis-related disease in a patient is provided, 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, hepatic fibrosis, and myocardial fibrosis. In some embodiments, a method for treating progressive fibrosing interstitial lung disease in a patient is provided, 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.

[0159] In some embodiments, a method of treating progressive pulmonary fibrosis in a patient is provided, 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.

[0160] In some embodiments, a method of treating idiopathic pulmonary fibrosis in a patient is provided, 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.

[0161] In some embodiments, a method of treating renal interstitial fibrosis in a patient is provided, 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.

[0162] 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.

[0163] 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.

[0164] In some embodiments, a method of inhibiting or reducing the degree of liver fibrosis in a patient is provided, 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.

[0165] In some embodiments, a method of treating a myocardial fibrotic disease in a patient is provided, 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.

[0166] In some embodiments, a method of inhibiting or reducing the degree of myocardial fibrosis in a patient is provided, 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.

[0167] In some embodiments, a method of treating progressive fibrosing interstitial lung disease in a patient is provided, 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.

[0168] In some embodiments, a method of treating progressive pulmonary fibrosis in a patient is provided, 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.

[0169] In some embodiments, a method of treating idiopathic pulmonary fibrosis in a patient is provided, 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.

[0170] In some embodiments, a method is provided for improving pulmonary fibrosis lesions in a patient, inhibiting the progression of pulmonary fibrosis in a patient, or reducing the extent of pulmonary fibrosis in a patient, 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.

[0171] 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.

[0172] In some embodiments, a method of treating connective tissue disease-associated interstitial lung disease in a patient is provided, 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.

[0173] 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.

[0174] In some embodiments, a method of treating pulmonary sarcoidosis in a patient is provided, 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.

[0175] In some embodiments, a pharmaceutical composition in the form of an oral solid dosage form is administered to a subject in need thereof with 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 can 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 it can be separate preparations, each of which comprises narcotine or a pharmaceutically acceptable salt thereof or mirtazapine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0176] In some embodiments, the oral solid dosage form is a tablet or a capsule.

[0177] In some embodiments, the therapeutically effective amount of Noscapine is a single dose of 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg, or 10 to 120 mg, preferably 10 to 120 mg, administered once or multiple times a day, preferably once a day. Based on the therapeutically effective amount of Noscapine, those skilled in the art can easily determine the therapeutically effective amount of a pharmaceutically acceptable salt of Noscapine.

[0178] In some embodiments, the therapeutically effective amount of mirtazapine is a single dose of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg. Based on the therapeutically effective amount of mirtazapine, those skilled in the art can easily determine the therapeutically effective amount of a pharmaceutically acceptable salt of mirtazapine.

[0179] In some embodiments, the patient is administered a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof once or more daily.

[0180] In some embodiments, the patient is administered a drug comprising Narcotine or a pharmaceutically acceptable composition thereof once or more daily.

[0181] In some embodiments, the method comprises administering to the patient once daily a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof.

[0182] In some embodiments, the method comprises administering to the patient twice daily a drug comprising mirtazapine or a pharmaceutically acceptable composition thereof.

[0183] In some embodiments, the method comprises administering to the patient once daily a drug comprising Narcotine or a pharmaceutically acceptable composition thereof.

[0184] In some embodiments, the method comprises administering to the patient twice daily a drug comprising Narcotine or a pharmaceutically acceptable composition thereof.

[0185] In some embodiments, the method comprises administering to the patient three times daily a drug comprising Narcotine or a pharmaceutically acceptable composition thereof.

[0186] In some embodiments, the ratio of the therapeutically effective amount of mirtazapine to narcotine is 1:30000 to 45:1, for example 1:120 to 10:1, preferably 1:120 to 3:1, more preferably 1:120 to 3:2, for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.

[0187] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0188] According to another aspect of the present invention, 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 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.

[0189] 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 fibrosing interstitial lung disease in a patient in need thereof.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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 in a patient in need thereof.

[0194] 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.

[0195] 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 a liver fibrosis disease in a patient in need thereof.

[0196] 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.

[0197] 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 a myocardial fibrotic disease in a patient in need thereof.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] In some embodiments, the drug is prepared into the same formulation, which comprises narcotine or a pharmaceutically acceptable salt thereof and mirtazapine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0204] 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.

[0205] In some embodiments, the drug is prepared in dosage unit form, such as tablets or capsules, each dosage unit containing 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg or 10 to 120 mg, preferably any dose in the range of 10 to 120 mg, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg of narcotine or a corresponding amount of a pharmaceutically acceptable salt of narcotine.

[0206] 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 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 45 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

[0207] In some embodiments, the drug is prepared in the form of a dosage unit, such as a tablet or capsule, each dosage unit containing 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg or 10 to 120 mg, preferably any dose in the range of 10 to 120 mg, such as 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg. 0 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine, and any dose within the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 45 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

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

[0209] In some embodiments, the ratio of mirtazapine to narcotine in the prepared medicament is 1:30000 to 45:1, for example 1:120 to 10:1, preferably 1:120 to 3:1, more preferably 1:120 to 3:2, for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.

[0210] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0211] According to another aspect of the present invention, a pharmaceutical composition is provided, comprising mirtazapine or a pharmaceutically acceptable salt thereof, narcotine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0212] In some embodiments, the pharmaceutical composition is in the form of dosage units, such as tablets or capsules, each dosage unit comprising any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

[0213] In some embodiments, the pharmaceutical composition is in the form of a dosage unit, each dosage unit containing 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg, or 10 to 120 mg, preferably 10 to 120 mg of Noscapine or a corresponding amount of a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition can be in the form of a tablet or capsule, each tablet or capsule containing any dose within the range of 10 to 120 mg, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, or 120 mg of Noscapine or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the pharmaceutical composition is in the form of a dosage unit, such as a tablet or capsule, each dosage unit comprising any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, such as 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg of mirtazapine or a corresponding amount. A pharmaceutically acceptable salt of mirtazapine, and any dose within the range of 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg or 10 to 120 mg, preferably 10 to 120 mg, for example 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg of narcotine or a corresponding amount of a pharmaceutically acceptable salt of narcotine.

[0215] In some embodiments, the pharmaceutically acceptable salt of Noscapine is Noscapine hydrochloride.

[0216] In some embodiments, the ratio of mirtazapine to narcotine in the pharmaceutical composition is 1:30000 to 45:1, such as 1:120 to 10:1, preferably 1:120 to 3:1, more preferably 1:120 to 3:2, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.

[0217] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0218] 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. 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, liver fibrosis, and myocardial fibrosis.

[0219] In some embodiments, the pharmaceutical composition is used to treat progressive fibrotic interstitial lung disease in a patient.

[0220] In some embodiments, the pharmaceutical composition is used to treat progressive pulmonary fibrosis in a patient.

[0221] In some embodiments, the pharmaceutical composition is used to treat idiopathic pulmonary fibrosis in a patient in need thereof.

[0222] In some embodiments, the pharmaceutical composition is used to treat renal interstitial fibrosis in a patient in need thereof.

[0223] 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.

[0224] In some embodiments, the pharmaceutical composition is used to treat liver fibrosis in a patient in need thereof.

[0225] 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.

[0226] In some embodiments, the pharmaceutical composition is used to treat myocardial fibrosis in a patient in need thereof.

[0227] 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.

[0228] In some embodiments, the pharmaceutical composition is used to treat idiopathic nonspecific interstitial pneumonia in a patient in need thereof.

[0229] In some embodiments, the pharmaceutical composition is used to treat connective tissue disease-associated interstitial lung disease in a patient in need thereof.

[0230] In some embodiments, the pharmaceutical composition is used to treat, reduce the severity of, or prevent exacerbation of pneumoconiosis in a patient in need thereof.

[0231] In some embodiments, the pharmaceutical composition is used to treat pulmonary sarcoidosis in a patient in need thereof.

[0232] In some embodiments, the pharmaceutical composition is in the form of dosage units, such as tablets or capsules, each dosage unit comprising any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

[0233] In some embodiments, the pharmaceutical composition is in the form of dosage units, such as tablets or capsules, each dosage unit containing 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg or 10 to 120 mg, preferably any dose in the range of 10 to 120 mg, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg of narcotine or a corresponding amount of a pharmaceutically acceptable salt of narcotine.

[0234] In some embodiments, the pharmaceutical composition is in the form of a dosage unit, such as a tablet or capsule, each dosage unit comprising any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg, such as 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg of mirtazapine or a corresponding amount. A pharmaceutically acceptable salt of mirtazapine, and any dose within the range of 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg or 10 to 120 mg, preferably 10 to 120 mg, for example 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg of narcotine or a corresponding amount of a pharmaceutically acceptable salt of narcotine.

[0235] In some embodiments, the pharmaceutically acceptable salt of Noscapine is Noscapine hydrochloride.

[0236] In some embodiments, the ratio of mirtazapine to narcotine in the pharmaceutical composition is 1:30000 to 45:1, such as 1:120 to 10:1, preferably 1:120 to 3:1, more preferably 1:120 to 3:2, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.

[0237] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0238] 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.

[0239] In some embodiments, mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof are formulated in separate pharmaceutical preparations, but are administered simultaneously or sequentially to a patient in need thereof for treating the patient's organ fibrosis-related disease, which may be one or more selected from fibrosing interstitial lung disease, renal interstitial fibrosis, liver fibrosis, and myocardial fibrosis.

[0240] In some embodiments, the pharmaceutically acceptable salt of Noscapine is Noscapine hydrochloride.

[0241] In some embodiments, the ratio of the therapeutically effective amount of mirtazapine to narcotine is 1:30000 to 45:1, such as 1:120 to 10:1, preferably 1:120 to 3:1, more preferably 1:120 to 3:2, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1. Wherein, the therapeutically effective amount of each of mirtazapine and narcotine is as described above.

[0242] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0243] According to another aspect of the present invention, a set of pharmaceutical products 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.

[0244] In some embodiments, a kit 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.

[0245] In some embodiments, a kit 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.

[0246] In some embodiments, a kit 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.

[0247] In some embodiments, a packaged 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, reduce the severity of, or prevent the exacerbation of pneumoconiosis in a patient in need thereof.

[0248] In some embodiments, the pharmaceutically acceptable salt of Noscapine is Noscapine hydrochloride.

[0249] In some embodiments, the mirtazapine is substantially pure R-configuration mirtazapine, ie, substantially pure (R)-mirtazapine.

[0250] Those skilled in the art will understand that the above technical features regarding the pharmaceutical composition containing mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, as well as the technical features regarding the pharmaceutical composition containing narcotine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, can be applied to the packaged pharmaceutical product of the present invention.

[0251] The pharmaceutical compositions of the present invention can be prepared and administered in unit dosage forms. The dosage form can be a liquid or solid dosage form. Liquid dosage forms can be solutions, colloids, emulsions, or suspensions. Solid dosage forms can be, for example, tablets, powders, suppositories, granules, or capsules. Other dosage forms include aerosols, implants, patches, or liniments.

[0252] The pharmaceutical composition of the present invention can be prepared into a dosage form suitable for use with a patient using suitable pharmaceutical excipients using methods known in the art. 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 enhancers, surfactants, adsorption carriers, and lubricants in the pharmaceutical field. If necessary, flavoring agents, preservatives, and sweeteners 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 those skilled in the art of pharmaceuticals.

[0253] The pharmaceutical composition of the present invention can be administered by any method and form commonly used in the art. For example, the pharmaceutical composition of the present invention can be administered by a method selected from the following: 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, with oral administration, intramuscular injection, intraperitoneal injection, or intravenous injection being preferred. Preferably, the pharmaceutical composition of the present invention is administered to a patient in need thereof by oral administration.

[0254] For oral administration, the pharmaceutical composition of the present invention can be formulated into solid preparations, such as tablets, capsules, and powders, using any suitable pharmaceutical excipient commonly used in the preparation of solid preparations, using formulation techniques known in the art. Alternatively, the pharmaceutical composition of the present invention can be formulated into liquid preparations, such as solutions, syrups, suspensions, and emulsions, using any suitable pharmaceutical excipient commonly used in the preparation of liquid preparations, using formulation techniques known in the art.

[0255] For parenteral administration, the pharmaceutical composition of the present invention can be formulated into a formulation suitable for parenteral administration using any appropriate pharmaceutical excipient commonly used in the preparation of parenteral drugs, using formulation techniques known in the art, such as sterile injections, lyophilized powders, transdermal patches, aerosols, oral and nasal inhalers, and suppositories. Parenteral administration routes include intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical routes.

[0256] By using formulation techniques known in the art and 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.

[0257] According to the blood drug concentration when the anti-fibrotic effect is observed in the animal experiment, the dosage when the antidepressant effect is observed in the reference animal experiment and the ratio of the dosage when the anti-fibrotic effect is observed, the dosage range of mirtazapine for anti-fibrosis can be calculated by observing the antidepressant effect after human medication. When the subject is a human, the therapeutically effective amount of mirtazapine applicable in the present invention is a single dose of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, 3 to 5 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 45 mg, once a day or multiple administration, preferably once a day administration. Based on this therapeutically effective amount of mirtazapine, those skilled in the art can easily determine the therapeutically effective amount of a pharmaceutically acceptable salt of mirtazapine.

[0258] When the subject is a human, the therapeutically effective amount of Noscapine applicable to the present invention is a single dose of 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg, or 10 to 120 mg, preferably 10 to 120 mg, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, or 120 mg, administered once or multiple times a day, preferably once a day. Based on the therapeutically effective amount of Noscapine, those skilled in the art can easily determine the therapeutically effective amount of a pharmaceutically acceptable salt of Noscapine.

[0259] 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 based on their respective free forms rather than their salt or hydrate forms.

[0260] Example

[0261] 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 for illustration only and are not intended to limit the scope of the invention.

[0262] Example 1: Construction of bleomycin-induced pulmonary fibrosis mouse model and evaluation of drug effects.

[0263] 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.

[0264] Experimental animals: C57BL / 6J mice, 8 weeks old, male.

[0265] Preparation of bleomycin solution:

[0266] Weigh bleomycin sulfate into a clean test tube, then add normal saline to make a 0.32 mg / mL solution, and vortex until the solution becomes clear.

[0267] The method for establishing the bleomycin pulmonary fibrosis mouse model is as follows:

[0268] All mice were anesthetized with Zoletil / Xylazine hydrochloride (50 mpk / 10 mpk; IP). On the first day of the experiment, mice in the model group received an intratracheal injection of bleomycin hydrochloride (50 μL). The sham-operated group received an intratracheal injection of normal saline (50 μL). Dosing began on the fifth day of the experiment and continued until the 21st day.

[0269] Lung tissue was collected and Masson's trichrome staining was performed to quantify the fibrosis area as follows:

[0270] At the study endpoint (experimental day 21), all animals were euthanized 2 hours after the last dose. After perfusion with normal saline, the left lungs of all animals were collected and fixed in a 10% neutral formalin fixative for histological analysis. Collagen in lung tissue was quantified using Masson's trichrome staining as described below.

[0271] The lung sections were 4 μm thick, dried in an oven for 1 hour, and stained with standardized Masson's trichrome. The steps were as follows: stain with Weigert's hematoxylin working solution for 10 minutes and then wash with water, and stain with a mixed solution of Biblical scarlet and fuchsin for 10 minutes and then wash with water. Stain in a mixture of 5% phosphomolybdate and 5% tungstic acid for 5 minutes or until the collagen is no longer red. Immerse the slides in aniline blue solution, stain for 1 minute, and then dedifferentiate in 1% acetic acid solution. After gradient dehydration, cover the slides with coverslips. For the stained sections, use Aperio GT450 to scan at 200 times, and then calculate the percentage of fibrosis (positive area) in the selected annotation using the HALO program. Fibrosis is expressed as a percentage for each lung section.

[0272] Before the experiment, the mice were allowed to acclimate to the environment for one week and each mouse was given a health check, including an assessment of its coat, limbs, and mouthparts, and an inspection of each mouse's posture and movements for any abnormal signs.

[0273] Example 2: Evaluation of the effects of mirtazapine and simvastatin alone and in combination in the bleomycin-induced pulmonary fibrosis mouse model.

[0274] Preparation of medium (0.5% methylcellulose, w / w): Weigh methylcellulose, add physiological saline, stir vigorously, and store at 4°C.

[0275] Preparation of mirtazapine solution: Weigh mirtazapine into the medium, then add normal saline to a 0.5 mg / mL solution. Vortex and sonicate until the solution becomes clear. Administer a 10 mL / kg dose.

[0276] Preparation of simvastatin solution: Weigh simvastatin into the medium, then add normal saline to a 0.2 mg / mL solution. Vortex and sonicate until the solution becomes clear. Administer a dose of 10 ml / kg.

[0277] Preparation of mirtazapine + simvastatin combination solution: Weigh mirtazapine and simvastatin into medium to prepare a solution of 0.5 mg / mL mirtazapine and 0.2 mg / mL simvastatin. Vortex and sonicate until the solution becomes clear. Administer a 10 mL / kg dose.

[0278] Table 1. Composition of mirtazapine and simvastatin administered alone and in combination

[0279] Experimental results

[0280] 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-fibrotic effects of each of them alone.

[0281] The results showed that mirtazapine and simvastatin each showed a trend to reduce 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.

[0282] Example 3: Evaluation of the effects of mirtazapine and noscapine alone and in combination in the bleomycin-induced pulmonary fibrosis mouse model.

[0283] Preparation of medium (0.5% methylcellulose, w / w): Weigh methylcellulose, add physiological saline, stir vigorously, and store at 4°C.

[0284] Preparation of mirtazapine solution: Weigh mirtazapine into the medium, then add normal saline to a 0.5 mg / mL solution. Vortex and sonicate until the solution becomes clear. Administer a 10 mL / kg dose.

[0285] To prepare the Narcotine solution: Weigh Narcotine hydrochloride into the medium, then add normal saline to a 3 mg / mL solution. Vortex and sonicate until the solution becomes clear. Administer a dose of 10 ml / kg.

[0286] Preparation of mirtazapine + narcotine combination solution: Weigh mirtazapine and narcotine hydrochloride into medium to prepare a solution of 0.5 mg / mL mirtazapine and 3 mg / mL narcotine. Vortex and sonicate until the solution becomes clear. Administer a dose of 10 ml / kg.

[0287] Table 2. Composition of mirtazapine and noscapine administered alone and in combination

[0288] Experimental results

[0289] 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-fibrotic effects of each drug alone. From a statistical point of view, the reduction was very significant.

[0290] 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 effect when used alone, was combined 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, that is, a synergistic effect was produced.

[0291] Therefore, the present inventors have experimentally confirmed that when certain compounds that exhibit anti-fibrotic effects when used alone are used in combination, the combination does not show an increase in anti-fibrotic effect, suggesting that the anti-fibrotic effect of drug combinations is unpredictable. Surprisingly, when the present inventors combined noscapine, which does not exhibit an anti-fibrotic effect when used alone, with mirtazapine, the combination showed a synergistic increase in anti-fibrotic effect. The synergistic anti-fibrotic effect of the combination of mirtazapine and noscapine was unexpected by those skilled in the art.

[0292] Example 4: Evaluation of the effect of R-mirtazapine in the bleomycin pulmonary fibrosis mouse model.

[0293] Preparation of bleomycin solution: Weigh bleomycin into a clean test tube, then add normal saline to make a 0.32 mg / mL solution, and vortex until the solution turns clear.

[0294] Preparation of medium (0.5% methylcellulose, w / w): Weigh methylcellulose, add physiological saline, stir vigorously, and store at 4°C.

[0295] Preparation of mirtazapine solution: Weigh S- or R-mirtazapine into the medium, then add normal saline to a 0.5 mg / mL solution. Vortex and sonicate until the solution becomes clear. Administer a dose of 10 mL / kg.

[0296] Table 3. Dosage composition of S-configuration mirtazapine and R-configuration mirtazapine

[0297] The method for establishing the bleomycin pulmonary fibrosis mouse model is as follows:

[0298] Before the experiment, the mice were allowed to acclimate to the environment for one week and each mouse was given a health check, including an assessment of its coat, limbs, and mouthparts, and an inspection of each mouse's posture and movements for any abnormal signs.

[0299] All mice were anesthetized with Zoletil / Xylazine hydrochloride (50 mpk / 10 mpk; IP). On the first day of the experiment, all three groups of mice received an intratracheal injection of bleomycin hydrochloride (50 μL). Dosing began on the fifth day of the experiment and continued orally until the 21st day, with daily dosing for 17 consecutive days.

[0300] Experimental results

[0301] According to the dosage and route of administration shown in Table 3, animals were administered according to the method described in Example 4. The results showed that the S-mirtazapine group reduced the fibrosis area by 18.2%, while the R-mirtazapine group reduced the fibrosis area by 25.1%. A statistically significant reduction in fibrosis area was observed only in the R-mirtazapine group. The more pronounced anti-fibrotic effect was not achieved with the S-mirtazapine, which is considered the primary active form in antidepressant effects, but with the R-mirtazapine group, a result that would not have been anticipated by those skilled in the art.

[0302] Example 5: Clinical evaluation of the effects of mirtazapine and narcotine alone and in combination in patients with idiopathic pulmonary fibrosis.

[0303] The following clinical study will be conducted to evaluate the efficacy of mirtazapine and narcotine alone and in combination in patients with idiopathic pulmonary fibrosis.

[0304] The efficacy of mirtazapine and narcotine, both alone and in combination, was evaluated through clinical and biological monitoring in approximately 100 patients diagnosed with idiopathic pulmonary fibrosis over a five-year period according to the ATS / ERS / JRS / ALAT international diagnostic guidelines and / or the 2022 updated guidelines. Patients were treated orally with a single dose of mirtazapine, a single dose of narcotine, or a combination of mirtazapine and narcotine, at doses of 3 to 5 mg of mirtazapine (e.g., one-quarter of a 15 mg mirtazapine tablet) once daily and 20 mg of narcotine once daily for 24 weeks. Symptoms of idiopathic pulmonary fibrosis were assessed objectively using methods such as forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO), or imaging assessment using high-resolution computed tomography (HRCT).

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 corresponding amount of a pharmaceutically acceptable salt of mirtazapine in any dose within the range of 0.1 to 45 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg or 3 to 5 mg.

3. The pharmaceutical composition according to claim 1 or 2, which is in the form of dosage units, wherein each dosage unit comprises any dose of Noscapine in the range of 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg or 10 to 120 mg, or a corresponding amount of a pharmaceutically acceptable salt of Noscapine.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein mirtazapine is substantially pure (R)-mirtazapine.

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 organ fibrosis-related diseases in patients in need thereof.

6. The use according to claim 5, 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.

7. The use according to claim 5, wherein the organ fibrosis-related disease is progressive fibrosing interstitial lung disease, progressive pulmonary fibrosis or idiopathic pulmonary fibrosis.

8. The use according to any one of claims 5 to 7, wherein the prepared medicament comprises any dose of mirtazapine in the range of 0.1 to 45 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg or 3 to 5 mg, or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

9. The use according to any one of claims 5 to 8, wherein the prepared medicine comprises any dose of Noscapine in the range of 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg or 10 to 120 mg, or a corresponding amount of a pharmaceutically acceptable salt of Noscapine.

10. 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.

11. The use according to any one of claims 5 to 10, characterized in that: The mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof may be formulated in a single pharmaceutical preparation.

12. The use according to any one of claims 5 to 10, characterized in that: The mirtazapine or a pharmaceutically acceptable salt thereof and narcotine or a pharmaceutically acceptable salt thereof may be formulated in separate pharmaceutical preparations for simultaneous or sequential use.

13. The use according to any one of claims 5 to 12, wherein mirtazapine is substantially pure (R)-mirtazapine.

14. 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.

15. The package pharmaceutical product according to claim 14, wherein the pharmaceutical composition (1) comprises mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine in a dose within the range of 0.1 to 45 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg or 3 to 5 mg.

16. The packaged pharmaceutical product according to claim 14 or 15, wherein the pharmaceutical composition (2) comprises any dose of Noscapine in the range of 1 to 3000 mg, 1 to 2000 mg, 1 to 1000 mg, 5 to 1000 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 200 mg or 10 to 120 mg, or a corresponding amount of a pharmaceutically acceptable salt of Noscapine.

17. The packaged pharmaceutical product according to any one of claims 14 to 16, wherein the organ fibrosis-related disease is progressive fibrosing interstitial lung disease, progressive pulmonary fibrosis or idiopathic pulmonary fibrosis.

18. A packaged pharmaceutical product according to any one of claims 14 to 17, wherein the mirtazapine is substantially pure (R)-mirtazapine.

19. A method for treating a patient's organ fibrosis-related disease, the method comprising the step of administering to the patient once or more daily any dose of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg or 3 to 5 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

20. The method according to claim 19, wherein the organ fibrosis-related disease is selected from one or more of fibrotic interstitial lung disease, renal interstitial fibrosis, liver fibrosis and myocardial fibrosis.

21. The method according to claim 19 or 20, which comprises administering to the patient a daily dose of less than 15 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

22. The method of any one of claims 19-21, wherein the mirtazapine is substantially pure (R)-mirtazapine.

23. A method for improving a patient's pulmonary fibrosis, inhibiting the progression of a patient's pulmonary fibrosis, or reducing the extent of a patient's pulmonary fibrosis, the method comprising the step of administering to the patient once or more daily any dose of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg of substantially pure mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

24. The method according to claim 23, comprising administering to the patient a daily dose of less than 15 mg of mirtazapine or a corresponding amount of a pharmaceutically acceptable salt of mirtazapine.

25. The method of claim 23 or 24, wherein the mirtazapine is substantially pure (R)-mirtazapine.

26. A method for treating a disease associated with organ fibrosis in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof.

27. The method according to claim 26, wherein the organ fibrosis-related disease is selected from one or more of fibrotic interstitial lung disease, renal interstitial fibrosis, liver fibrosis and myocardial fibrosis.

28. The method of claim 26 or 27, wherein the therapeutically effective amount of substantially pure (R)-mirtazapine is any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg.

29. Use of substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an organ fibrosis-related disease in a patient.

30. The use according to claim 29, 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.

31. Use of substantially pure (R)-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.

32. A method for improving pulmonary fibrosis in a patient, inhibiting the progression of pulmonary fibrosis in a patient, or reducing the extent of pulmonary fibrosis in a patient, the method comprising the step of administering to the patient an effective amount of substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the therapeutically effective amount of substantially pure (R)-mirtazapine is any dose in the range of 0.1 to 45 mg, 0.5 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 3 to 5 mg.

34. A pharmaceutical composition comprising substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for use in treating a disease associated with organ fibrosis in a patient.

35. The pharmaceutical composition for use according to claim 34, 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.

36. A pharmaceutical composition comprising substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is used to improve a patient's pulmonary fibrosis lesions, inhibit the progression of a patient's pulmonary fibrosis, or reduce the degree of a patient's pulmonary fibrosis.

37. Substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof, for use in improving pulmonary fibrosis lesions, inhibiting the progression of pulmonary fibrosis or reducing the degree of pulmonary fibrosis in a patient.

38. Substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof for use in treating a disease associated with organ fibrosis in a patient.

39. Substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof for use according to claim 38, 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.

40. A pharmaceutical composition comprising substantially pure (R)-mirtazapine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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